Non-Small Cell Lung Cancer Treatment (PDQ®) 3/3 —Health Professional Version - National Cancer Institute

Non-Small Cell Lung Cancer Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

1. Combined modality therapy, including chemotherapy, radiation therapy, and surgery in various combinations.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Darling GE, Allen MS, Decker PA, et al.: Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial. J Thorac Cardiovasc Surg 141 (3): 662-70, 2011. [PUBMED Abstract]
2. Albain KS, Swann RS, Rusch VW, et al.: Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 374 (9687): 379-86, 2009. [PUBMED Abstract]
3. Manser R, Wright G, Hart D, et al.: Surgery for early stage non-small cell lung cancer. Cochrane Database Syst Rev (1): CD004699, 2005. [PUBMED Abstract]
4. Allen MS, Darling GE, Pechet TT, et al.: Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg 81 (3): 1013-9; discussion 1019-20, 2006. [PUBMED Abstract]
5. Burdett SS, Stewart LA, Rydzewska L: Chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Cochrane Database Syst Rev (3): CD006157, 2007. [PUBMED Abstract]
6. Douillard JY, Rosell R, De Lena M, et al.: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 7 (9): 719-27, 2006. [PUBMED Abstract]
7. Gilligan D, Nicolson M, Smith I, et al.: Preoperative chemotherapy in patients with resectable non-small cell lung cancer: results of the MRC LU22/NVALT 2/EORTC 08012 multicentre randomised trial and update of systematic review. Lancet 369 (9577): 1929-37, 2007. [PUBMED Abstract]
8. Albain KS, Rusch VW, Crowley JJ, et al.: Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13 (8): 1880-92, 1995. [PUBMED Abstract]
9. Suntharalingam M, Paulus R, Edelman MJ, et al.: Radiation therapy oncology group protocol 02-29: a phase II trial of neoadjuvant therapy with concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally advanced non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys 84 (2): 456-63, 2012. [PUBMED Abstract]
10. Pignon JP, Tribodet H, Scagliotti GV, et al.: Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 26 (21): 3552-9, 2008. [PUBMED Abstract]
11. Winton T, Livingston R, Johnson D, et al.: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352 (25): 2589-97, 2005. [PUBMED Abstract]
12. Arriagada R, Bergman B, Dunant A, et al.: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350 (4): 351-60, 2004. [PUBMED Abstract]
13. Scagliotti GV, Fossati R, Torri V, et al.: Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst 95 (19): 1453-61, 2003. [PUBMED Abstract]
14. Hotta K, Matsuo K, Ueoka H, et al.: Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol 22 (19): 3860-7, 2004. [PUBMED Abstract]
15. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102 (5): 1319-22, 1992. [PUBMED Abstract]
16. Corti L, Toniolo L, Boso C, et al.: Long-term survival of patients treated with photodynamic therapy for carcinoma in situ and early non-small-cell lung carcinoma. Lasers Surg Med 39 (5): 394-402, 2007. [PUBMED Abstract]
17. Pepe C, Hasan B, Winton TL, et al.: Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR.10. J Clin Oncol 25 (12): 1553-61, 2007. [PUBMED Abstract]
18. PORT Meta-analysis Trialists Group: Postoperative radiotherapy for non-small cell lung cancer. Cochrane Database Syst Rev (2): CD002142, 2005. [PUBMED Abstract]
19. Lally BE, Zelterman D, Colasanto JM, et al.: Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 24 (19): 2998-3006, 2006. [PUBMED Abstract]
20. Johnstone DW, Byhardt RW, Ettinger D, et al.: Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG 89-01. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 54 (2): 365-9, 2002. [PUBMED Abstract]
21. Taylor NA, Liao ZX, Cox JD, et al.: Equivalent outcome of patients with clinical Stage IIIA non-small-cell lung cancer treated with concurrent chemoradiation compared with induction chemotherapy followed by surgical resection. Int J Radiat Oncol Biol Phys 58 (1): 204-12, 2004. [PUBMED Abstract]
22. van Meerbeeck JP, Kramer GW, Van Schil PE, et al.: Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 99 (6): 442-50, 2007. [PUBMED Abstract]
23. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985. [PUBMED Abstract]
24. Saunders M, Dische S, Barrett A, et al.: Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial. CHART Steering Committee. Lancet 350 (9072): 161-5, 1997. [PUBMED Abstract]
25. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990. [PUBMED Abstract]
26. Ung YC, Yu E, Falkson C, et al.: The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy 5 (3): 189-202, 2006 Jul-Sep. [PUBMED Abstract]
27. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004. [PUBMED Abstract]
28. Lester JF, Macbeth FR, Toy E, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002143, 2006. [PUBMED Abstract]
29. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002. [PUBMED Abstract]
30. Erridge SC, Gaze MN, Price A, et al.: Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol (R Coll Radiol) 17 (1): 61-7, 2005. [PUBMED Abstract]
31. Kramer GW, Wanders SL, Noordijk EM, et al.: Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol 23 (13): 2962-70, 2005. [PUBMED Abstract]
32. Senkus-Konefka E, Dziadziuszko R, Bednaruk-Młyński E, et al.: A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer 92 (6): 1038-45, 2005. [PUBMED Abstract]
33. Aupérin A, Le Péchoux C, Pignon JP, et al.: Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 17 (3): 473-83, 2006. [PUBMED Abstract]
34. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995. [PUBMED Abstract]
35. Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004. [PUBMED Abstract]
36. Furuse K, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17 (9): 2692-9, 1999. [PUBMED Abstract]
37. Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005. [PUBMED Abstract]
38. Curran WJ Jr, Paulus R, Langer CJ, et al.: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103 (19): 1452-60, 2011. [PUBMED Abstract]
39. Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004. [PUBMED Abstract]
40. Rosenman JG, Halle JS, Socinski MA, et al.: High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys 54 (2): 348-56, 2002. [PUBMED Abstract]
41. Socinski MA, Blackstock AW, Bogart JA, et al.: Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol 26 (15): 2457-63, 2008. [PUBMED Abstract]
42. Bradley JD, Bae K, Graham MV, et al.: Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117. J Clin Oncol 28 (14): 2475-80, 2010. [PUBMED Abstract]
43. Bradley JD, Paulus R, Komaki R, et al.: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 16 (2): 187-99, 2015. [PUBMED Abstract]
44. Senan S, Brade A, Wang LH, et al.: PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 34 (9): 953-62, 2016. [PUBMED Abstract]
45. Vokes EE, Herndon JE 2nd, Kelley MJ, et al.: Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 25 (13): 1698-704, 2007. [PUBMED Abstract]
46. Antonia SJ, Villegas A, Daniel D, et al.: Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377 (20): 1919-1929, 2017. [PUBMED Abstract]
47. Hanna N, Neubauer M, Yiannoutsos C, et al.: Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 26 (35): 5755-60, 2008. [PUBMED Abstract]
48. Kelly K, Chansky K, Gaspar LE, et al.: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 26 (15): 2450-6, 2008. [PUBMED Abstract]
49. Butts C, Socinski MA, Mitchell PL, et al.: Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 15 (1): 59-68, 2014. [PUBMED Abstract]
50. Rusch VW: Management of Pancoast tumours. Lancet Oncol 7 (12): 997-1005, 2006. [PUBMED Abstract]
51. Narayan S, Thomas CR Jr: Multimodality therapy for Pancoast tumor. Nat Clin Pract Oncol 3 (9): 484-91, 2006. [PUBMED Abstract]
52. Rusch VW, Parekh KR, Leon L, et al.: Factors determining outcome after surgical resection of T3 and T4 lung cancers of the superior sulcus. J Thorac Cardiovasc Surg 119 (6): 1147-53, 2000. [PUBMED Abstract]
53. Kunitoh H, Kato H, Tsuboi M, et al.: Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806. J Clin Oncol 26 (4): 644-9, 2008. [PUBMED Abstract]
54. Rusch VW, Giroux DJ, Kraut MJ, et al.: Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol 25 (3): 313-8, 2007. [PUBMED Abstract]
55. Matsuoka H, Nishio W, Okada M, et al.: Resection of chest wall invasion in patients with non-small cell lung cancer. Eur J Cardiothorac Surg 26 (6): 1200-4, 2004. [PUBMED Abstract]
56. Facciolo F, Cardillo G, Lopergolo M, et al.: Chest wall invasion in non-small cell lung carcinoma: a rationale for en bloc resection. J Thorac Cardiovasc Surg 121 (4): 649-56, 2001. [PUBMED Abstract]
57. Doddoli C, D'Journo B, Le Pimpec-Barthes F, et al.: Lung cancer invading the chest wall: a plea for en-bloc resection but the need for new treatment strategies. Ann Thorac Surg 80 (6): 2032-40, 2005. [PUBMED Abstract]

Stages IIIB and IIIC NSCLC Treatment

In This Section

• Standard Treatment Options for Stages IIIB and IIIC NSCLC
  • Sequential or concurrent chemotherapy and radiation therapy
  • Radiation therapy dose escalation for concurrent chemoradiation
  • Additional systemic therapy before or after concurrent chemotherapy and radiation therapy
  • Radiation therapy alone
• Treatment Options Under Clinical Evaluation
• Current Clinical Trials

On the basis of the Surveillance, Epidemiology, and End Results (SEER) program registry, the estimated incidence of stage IIIB non-small cell lung cancer (NSCLC) is 17.6%.[1] The anticipated 5-year survival for the vast majority of patients who present with clinical stage IIIB NSCLC is 3% to 7%.[2] In small case series, selected patients with T4, N0-1 disease, solely as the result of satellite tumor nodule(s) within the primary lobe, have been reported to have 5-year survival rates of 20%.[3,4][Level of evidence: 3iiiA]

Standard Treatment Options for Stages IIIB and IIIC NSCLC

Standard treatment options for stages IIIB NSCLC and IIIC NSCLC include the following:

1. Sequential or concurrent chemotherapy and radiation therapy.
2. Radiation therapy dose escalation for concurrent chemoradiation.
3. Additional systemic therapy before or after concurrent chemotherapy and radiation therapy.
4. Radiation therapy alone.
   • For treatment of locally advanced unresectable tumor in patients who are not candidates for chemotherapy.
   • For patients requiring palliative treatment.

In general, patients with stages IIIB and IIIC NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on the following:

• Sites of tumor involvement.
• The patient's performance status (PS).

Most patients with excellent PS are candidates for combined-modality chemotherapy and radiation therapy with the following exceptions:

• Selected patients with T4, N0 disease may be treated with combined-modality therapy and surgery similar to patients with superior sulcus tumors.

Sequential or concurrent chemotherapy and radiation therapy

Many randomized studies of patients with unresectable stage III NSCLC show that treatment with preoperative or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone. Although patients with unresectable stages IIIB or IIIC disease may benefit from radiation therapy, long-term outcomes have generally been poor, often the result of local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials.

Evidence (sequential or concurrent chemotherapy and radiation therapy):

1. A meta-analysis of patient data from 11 randomized clinical trials showed the following:[5]
   • Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[5][Level of evidence: 1iiA]
2. A meta-analysis of 13 trials (based on 2,214 evaluable patients) showed the following:[6]
   • The addition of concurrent chemotherapy to radical radiation therapy reduced the risk of death at 2 years (relative risk [RR], 0.93; 95% confidence interval [CI], 0.88–0.98; P = .01).
   • For the 11 trials with platinum-based chemotherapy, RR was 0.93 (95% CI, 0.87–0.99; P = .02).[6]
3. A meta-analysis of individual data from 1,764 patients evaluated nine trials.[7]
   • The hazard ratio (HR)death among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years.
   • The combination of platinum with etoposide appeared to be more effective than platinum alone. Concomitant platinum-based chemotherapy and radiation therapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.[7]
4. The results from two randomized trials (including RTOG-9410 [NCT01134861]) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[8-10][Level of evidence: 1iiA]
   1. In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared with chemotherapy followed by continuous daily radiation therapy to 56 Gy.[8]
      • Five-year overall survival (OS) favored concurrent therapy (27% vs. 9%).
      • Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[8]
   2. In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy, or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiation therapy.[9,10]
      • Median and 5-year survival were superior in the concurrent chemotherapy with daily radiation therapy arm (17 months vs. 14.6 months and 16% vs. 10% for sequential regimen [P = .046]).
   3. Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[10][Level of evidence: 1iiA]; [11]
5. A meta-analysis of three trials evaluated concurrent versus sequential treatment (711 patients).[6]
   • The analysis indicated a significant benefit of concurrent versus sequential treatment (RR, 0.86; 95% CI, 0.78–0.95; P = .003). All used cisplatin-based regimens and once-daily radiation therapy.[6]
   • More deaths (3% overall) were reported in the concurrent arm, but this did not reach statistical significance (RR, 1.60; CI, 0.75–3.44; P = .2).
   • There was more acute esophagitis (grade 3 or worse) with concurrent treatment (range, 17%–26%) compared with sequential treatment (range, 0%–4%; RR, 6.77; P = .001). Overall, the incidence of neutropenia (grade 3 or worse) was similar in both arms.

Radiation therapy dose escalation for concurrent chemoradiation

With improvement in radiation therapy–delivery technology in the 1990s, including tumor-motion management and image guidance, phase I/II trials demonstrated the feasibility of dose-escalation radiation therapy to 74 Gy with concurrent chemotherapy.[12-14] However, a phase III trial of a conventional dose of 60 Gy versus dose escalation to 74 Gy with concurrent weekly carboplatin/paclitaxel did not demonstrate improved local control or progression-free survival (PFS), and OS was worse with dose escalation (HR, 1.38 [1.09–1.76]; P = .004). There was a nonsignificant increase in grade 5 events with dose escalation (10% vs. 2%) and higher incidence of grade 3 esophagitis (21% vs. 7%; P = .0003).[15][Level of evidence: 1iiA]

Additional systemic therapy before or after concurrent chemotherapy and radiation therapy

The addition of induction chemotherapy before concurrent chemotherapy and radiation therapy has not been shown to improve survival.[16][Level of evidence: 1iiA]

Consolidation Immunotherapy

Durvalumab

Durvalumab is a selective human IgG1 monoclonal antibody that blocks programmed death ligand 1 (PD-L1) binding to programmed death 1 (PD-1) and CD80, allowing T cells to recognize and kill tumor cells.[17]

Evidence (durvalumab):

1. The phase III PACIFIC trial (NCT02125461) enrolled 713 patients with stage III NSCLC whose disease had not progressed after two or more cycles of platinum-based chemoradiation therapy. Patients were randomly assigned in a 2:1 ratio to receive durvalumab (10 mg/kg intravenously) or placebo (every 2 weeks for up to 12 months).[17] The coprimary endpoints were PFS assessed by blinded independent central review and OS (unplanned for the interim analysis).
   • At the interim analysis, the coprimary endpoint of PFS was met. The median PFS was 16.8 months with durvalumab versus 5.6 months with placebo (HR, 0.52; 95% CI, 0.42–0.65; P < .001).[17][Level of evidence:1iiDiii] The 18-month PFS rate was 44.2% with durvalumab versus 27% with placebo.
   • PFS benefit was seen across all prespecified subgroups and was irrespective of PD-L1 expression before chemoradiation therapy or smoking status. Epidermal growth factor receptor (EGFR) mutations were observed in 6% of patients (29 treated with durvalumab vs. 14 treated with placebo). The unstratified HR for the EGFR-mutated subgroup was 0.76 (95% CI, 0.35–1.64).
   • Grade 3 or 4 adverse events occurred in 29.9% of patients treated with durvalumab and in 26.1% of patients treated with placebo. The most common adverse event of grade 3 or 4 was pneumonia in 4.4% of patients treated with durvalumab and in 3.8% of patients treated with placebo.
   • OS was not assessed at the interim analysis.

Other systemic consolidation therapies

Randomized trials of other consolidation systemic therapies, including docetaxel,[18] gefitinib,[19] and tecemotide (MUC1 antigen-specific immunotherapy) [20] have not shown an improvement in OS.[Level of evidence: 1iiA]

The role of consolidation systemic therapy after concurrent chemotherapy and radiation therapy for unresectable NSCLC remains unclear. Phase III trials of consolidation systemic therapy including conventional chemotherapy (docetaxel),[18] tyrosine kinase inhibitors (gefitinib),[19] and immunotherapy (tecemotide: MUC1 antigen-specific immunotherapy) [20] have not shown an improvement in OS.[Level of evidence: 1iiA]

Radiation therapy alone

For treatment of locally advanced unresectable tumor in patients who are not candidates for chemotherapy

Radiation therapy alone, administered sequentially or concurrently with chemotherapy, may provide benefit to patients with locally advanced unresectable stage III NSCLC. However, combination chemoradiation therapy delivered concurrently provides the greatest benefit in survival with an increase in toxic effects.

Prognosis:

Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[21]

Evidence (radiation therapy for locally advanced unresectable tumor):

1. One prospective randomized clinical study showed the following:
   • Radiation therapy given as three daily fractions improved OS compared with radiation therapy given as one daily fraction.[22][Level of evidence: 1iiA]
   • Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

For patients requiring palliative treatment

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as the following:

• Tracheal, esophageal, or bronchial compression.
• Pain.
• Vocal cord paralysis.
• Hemoptysis.
• Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[23]

Evidence (radiation therapy for palliative treatment):

1. A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with external-beam radiation therapy (EBRT) or laser therapy.[24]
   • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[24][Level of evidence: 1iiC]
   • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.
   • Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.
   • Although different multifraction regimens appear to provide similar symptom relief,[25-30] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as shown in the National Cancer Institute of Canada Clinical Trials Group trial (NCT00003685).[27][Level of evidence: 1iiC]
   • Evidence of a modest increase in survival in patients with better PS given high-dose radiation therapy is available.[25,26][Level of evidence: 1iiA]

Patients with stages IIIB or IIIC disease with poor PS are candidates for chest radiation therapy to palliate pulmonary symptoms (e.g., cough, shortness of breath, hemoptysis, or pain).[21][Level of evidence: 3iiiC] (Refer to the PDQ summaries on Cardiopulmonary Syndromes and Cancer Pain for more information.)

Treatment Options Under Clinical Evaluation

Because of the poor overall results, patients with stages IIIB or IIIC NSCLC are candidates for clinical trials, which may lead to improvement in the control of disease.

Treatment options under clinical evaluation include the following:

1. New fractionation schedules.
2. Radiosensitizers (NCT02186847).
3. Combined-modality approaches.
4. Incorporation of targeted agents into combined modality therapy in patients with EGFR-mutant or ALK-translocated tumors (RTOG-1306 [NCT01822496]; 11-464 [NCT01553942]).
5. Adaptive radiation therapy using positron emission tomography–based response assessment during treatment (RTOG-1106/ACRIN-6697 ).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Wisnivesky JP, Yankelevitz D, Henschke CI: Stage of lung cancer in relation to its size: part 2. Evidence. Chest 127 (4): 1136-9, 2005. [PUBMED Abstract]
2. Mountain CF: Revisions in the International System for Staging Lung Cancer. Chest 111 (6): 1710-7, 1997. [PUBMED Abstract]
3. Deslauriers J, Brisson J, Cartier R, et al.: Carcinoma of the lung. Evaluation of satellite nodules as a factor influencing prognosis after resection. J Thorac Cardiovasc Surg 97 (4): 504-12, 1989. [PUBMED Abstract]
4. Urschel JD, Urschel DM, Anderson TM, et al.: Prognostic implications of pulmonary satellite nodules: are the 1997 staging revisions appropriate? Lung Cancer 21 (2): 83-7; discussion 89-91, 1998. [PUBMED Abstract]
5. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311 (7010): 899-909, 1995. [PUBMED Abstract]
6. Rowell NP, O'rourke NP: Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002140, 2004. [PUBMED Abstract]
7. Aupérin A, Le Péchoux C, Pignon JP, et al.: Concomitant radio-chemotherapy based on platin compounds in patients with locally advanced non-small cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 17 (3): 473-83, 2006. [PUBMED Abstract]
8. Furuse K, Fukuoka M, Kawahara M, et al.: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol 17 (9): 2692-9, 1999. [PUBMED Abstract]
9. Curran WJ Jr, Paulus R, Langer CJ, et al.: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 103 (19): 1452-60, 2011. [PUBMED Abstract]
10. Fournel P, Robinet G, Thomas P, et al.: Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Français de Pneumo-Cancérologie NPC 95-01 Study. J Clin Oncol 23 (25): 5910-7, 2005. [PUBMED Abstract]
11. Zatloukal P, Petruzelka L, Zemanova M, et al.: Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer 46 (1): 87-98, 2004. [PUBMED Abstract]
12. Rosenman JG, Halle JS, Socinski MA, et al.: High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys 54 (2): 348-56, 2002. [PUBMED Abstract]
13. Socinski MA, Blackstock AW, Bogart JA, et al.: Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer: CALGB 30105. J Clin Oncol 26 (15): 2457-63, 2008. [PUBMED Abstract]
14. Bradley JD, Bae K, Graham MV, et al.: Primary analysis of the phase II component of a phase I/II dose intensification study using three-dimensional conformal radiation therapy and concurrent chemotherapy for patients with inoperable non-small-cell lung cancer: RTOG 0117. J Clin Oncol 28 (14): 2475-80, 2010. [PUBMED Abstract]
15. Bradley JD, Paulus R, Komaki R, et al.: Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 16 (2): 187-99, 2015. [PUBMED Abstract]
16. Vokes EE, Herndon JE 2nd, Kelley MJ, et al.: Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 25 (13): 1698-704, 2007. [PUBMED Abstract]
17. Antonia SJ, Villegas A, Daniel D, et al.: Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377 (20): 1919-1929, 2017. [PUBMED Abstract]
18. Hanna N, Neubauer M, Yiannoutsos C, et al.: Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 26 (35): 5755-60, 2008. [PUBMED Abstract]
19. Kelly K, Chansky K, Gaspar LE, et al.: Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 26 (15): 2450-6, 2008. [PUBMED Abstract]
20. Butts C, Socinski MA, Mitchell PL, et al.: Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 15 (1): 59-68, 2014. [PUBMED Abstract]
21. Langendijk JA, ten Velde GP, Aaronson NK, et al.: Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 47 (1): 149-55, 2000. [PUBMED Abstract]
22. Komaki R, Cox JD, Hartz AJ, et al.: Characteristics of long-term survivors after treatment for inoperable carcinoma of the lung. Am J Clin Oncol 8 (5): 362-70, 1985. [PUBMED Abstract]
23. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990. [PUBMED Abstract]
24. Ung YC, Yu E, Falkson C, et al.: The role of high-dose-rate brachytherapy in the palliation of symptoms in patients with non-small-cell lung cancer: a systematic review. Brachytherapy 5 (3): 189-202, 2006 Jul-Sep. [PUBMED Abstract]
25. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004. [PUBMED Abstract]
26. Lester JF, Macbeth FR, Toy E, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (4): CD002143, 2006. [PUBMED Abstract]
27. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002. [PUBMED Abstract]
28. Erridge SC, Gaze MN, Price A, et al.: Symptom control and quality of life in people with lung cancer: a randomised trial of two palliative radiotherapy fractionation schedules. Clin Oncol (R Coll Radiol) 17 (1): 61-7, 2005. [PUBMED Abstract]
29. Kramer GW, Wanders SL, Noordijk EM, et al.: Results of the Dutch National study of the palliative effect of irradiation using two different treatment schemes for non-small-cell lung cancer. J Clin Oncol 23 (13): 2962-70, 2005. [PUBMED Abstract]
30. Senkus-Konefka E, Dziadziuszko R, Bednaruk-Młyński E, et al.: A prospective, randomised study to compare two palliative radiotherapy schedules for non-small-cell lung cancer (NSCLC). Br J Cancer 92 (6): 1038-45, 2005. [PUBMED Abstract]

Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC Treatment

In This Section

• Determinants of treatment
  • Histology
  • Age versus comorbidity
  • Performance status
• Standard Treatment Options for Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC (First-line Therapy)
  • Cytotoxic combination chemotherapy
  • Combination chemotherapy with monoclonal antibodies
  • Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)
  • EGFR tyrosine kinase inhibitors
  • ALK inhibitors (for patients with ALK translocations)
  • ROS1 inhibitors (for patients with ROS1 rearrangements)
  • BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations)
  • NTRK inhibitors (for patients with NTRK fusions)
  • Immune checkpoint inhibitors with or without chemotherapy
  • Local therapies and special considerations
• Treatment Options Under Clinical Evaluation for Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC (First-line Therapy)
• Current Clinical Trials

Forty percent of patients with newly diagnosed non-small cell lung cancer (NSCLC) have stage IV disease. Treatment goals are to prolong survival and control disease-related symptoms. Treatment options include cytotoxic chemotherapy, targeted agents, and immunotherapy. Factors influencing treatment selection include comorbidity, performance status (PS), histology, and molecular and immunologic features of the cancer. Therefore, assessment of tumor-genomic changes and programmed death-ligand 1 (PD-L1) expression is critical before initiating therapy. Radiation therapy and surgery are generally used in selective cases for symptom palliation.

Determinants of treatment

Randomized controlled trials of patients with stage IV disease and good PS have shown that cisplatin-based chemotherapy improves survival and palliates disease-related symptoms.[1][Level of evidence: 1iiA] Patients with nonsquamous cell histology, good PS, no history of hemoptysis or other bleeding, or recent history of cardiovascular events may benefit from the addition of bevacizumab to paclitaxel and carboplatin. Patients with tumors harboring sensitizing mutations in exons 19 or 21 of EGFR, particularly those from East Asia, never smokers, and those with adenocarcinoma may benefit from EGFR tyrosine kinase inhibitors (TKI) as an alternative to first- or second-line chemotherapy. Patients with tumors harboring anaplastic lymphoma kinase (ALK) translocations or ROS1rearrangements may benefit from ALK or ROS1 inhibitors as an alternative to first- or second-line chemotherapy. Patients with tumors expressing PD-L1 (>50% by immunohistochemistry) have improved survival with pembrolizumab. The addition of pembrolizumab to carboplatin plus pemetrexed chemotherapy for nonsquamous advanced lung cancer improves survival irrespective of PD-L1 expression.[2][Level of evidence: 1iiA] Second-line systemic therapy with nivolumab, docetaxel, pemetrexed, or pembrolizumab for PD-L1-positive tumors also improves survival in patients with good PS (who have not received the same or a similar agent in the first-line setting).[1][Level of evidence: 1iiA]

The role of systemic therapy in patients with an Eastern Cooperative Oncology Group PS below 2 is less certain.

Histology

Patients with adenocarcinoma may benefit from pemetrexed [3] and bevacizumab as well as from combination chemotherapy with pembrolizumab.

Age versus comorbidity

Evidence supports the concept that elderly patients with good PS and limited comorbidity may benefit from combination chemotherapy. Age alone should not dictate treatment-related decisions in patients with advanced NSCLC. Elderly patients with a good PS enjoy longer survival and a better quality of life when treated with chemotherapy compared with supportive care alone. Caution should be exercised when extrapolating data for elderly patients (aged 70–79 years) to patients aged 80 years or older because only a very small number of patients aged 80 years or older have been enrolled on clinical trials, and the benefit in this group is uncertain.[4,5]

Evidence (age vs. comorbidity):

1. Platinum-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care or single-agent therapy; however, such treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Approximately two-thirds of patients with NSCLC are aged 65 years or older, and approximately 40% are aged 70 years or older.[6] Surveillance, Epidemiology, and End Results (SEER) data suggest that the percentage of patients aged older than 70 years is closer to 50%.
2. A review of the SEER Medicare data from 1994 to 1999 found a much lower rate of chemotherapy use than expected for the overall population.[7] The same data suggested that elderly patients may have more comorbidities or a higher rate of functional compromise that would make study participation difficult, if not contraindicated; lack of clinical trial data may influence decisions to treat individual patients with standard chemotherapy.
3. Single-agent chemotherapy and combination chemotherapy clearly benefit at least some elderly patients. In the Elderly Lung Cancer Vinorelbine Italian Study, 154 patients who were older than 70 years were randomly assigned to vinorelbine or supportive care.[8]
   • Patients who were treated with vinorelbine had a 1-year survival rate of 32%, compared with 14% for those who were treated with supportive care alone. Quality-of-life parameters were also significantly improved in the chemotherapy arm, and toxic effects were acceptable.
4. A trial from Japan compared single-agent docetaxel with vinorelbine in 180 elderly patients with good PS.[9]
   • Response rates (22% vs. 10%) and progression-free survival (PFS) rates (5.4 months vs. 3.1 months) were significantly better with docetaxel, but median survival rates (14.3 months vs. 9.9 months) and 1-year survival rates (59% vs. 37%) did not reach statistical significance.
5. Retrospective data analyzing and comparing younger (age <70 years) patients with older (age ≥70 years) patients who participated in large randomized trials of doublet combinations have also shown that elderly patients may derive the same survival benefit, but with a higher risk of toxic effects in the bone marrow.[4,5,10-13]

Performance status

PS is among the most important prognostic factors for survival of patients with NSCLC.[14] The benefit of therapy for this group of patients has been evaluated through retrospective analyses and prospective clinical trials.

The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Outside of a clinical trial setting, chemotherapy should be given only to patients with good PS and evaluable tumor lesions, who desire this treatment after being fully informed of its anticipated risks and limited benefits.

Evidence (PS):

1. The Cancer and Leukemia Group B trial (CLB-9730 [NCT00003117]), which compared carboplatin and paclitaxel with single-agent paclitaxel, enrolled 99 patients with a PS of 2 (18% of the study's population).[12]
   • When compared with patients with a PS of 0 to 1, who had a median survival of 8.8 months and a 1-year survival rate of 38%, the corresponding median survival figures for patients with a PS of 2 were 3.0 months and a 1-year survival rate of 14%; this demonstrates the poor prognosis conferred by a lower PS. These differences were statistically significant.
   • When patients with a PS of 2 were analyzed by treatment arm, those who received combination chemotherapy had a significantly higher response rate (24% vs. 10%), longer median survival (4.7 months vs. 2.4 months), and a superior 1-year survival rate (18% vs. 10%), compared with those who were treated with single-agent paclitaxel.[12]
2. A phase III trial compared single-agent pemetrexed with the combination of carboplatin and pemetrexed in 205 patients with a PS of 2 who had not had any previous chemotherapy.[15][Level of evidence: 1iiA]
   • Median overall survival (OS) was 5.3 months for the pemetrexed-alone group and 9.3 months for the carboplatin-and-pemetrexed group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.46–0.83; P = .001).
   • Median PFS was 2.8 months for the pemetrexed-alone group and 5.8 months for the carboplatin-and-pemetrexed group (P < .001).
   • The response rates were 10.3% for the pemetrexed-alone group and 23.8% for the carboplatin-and-pemetrexed group (P = .032).
   • Side effects were more frequent in the combination arm, as expected.
   This study, which was performed in eight centers in Brazil and one center in the United States, reported rates of OS and PFS that were higher than has historically been noted in most, although not all, other published studies. This may indicate differences in patient selection.
3. A subset analysis of 68 patients with a PS of 2 from a trial that randomly assigned more than 1,200 patients to four platinum-based regimens has been published.
   • Despite a high incidence of adverse events, including five deaths, the final analysis showed that the overall toxic effects experienced by patients with a PS of 2 was not significantly different from that experienced by patients with a PS of 0 to 1.
   • An efficacy analysis demonstrated an overall response rate of 14%, median survival time of 4.1 months, and a 1-year survival rate of 19%; all were substantially inferior to the patients with PS of 0 to 1.
4. A phase II randomized trial (E-1599 [NCT00006004]) of attenuated dosages of cisplatin plus gemcitabine and carboplatin plus paclitaxel included 102 patients with a PS of 2.[16]
   • Response rates were 25% in the cisplatin-plus-gemcitabine arm and 16% in the carboplatin-plus-paclitaxel arm; median survival times were 6.8 months in the cisplatin-plus-gemcitabine arm and 6.1 months in the carboplatin-plus-paclitaxel arm; 1-year survival rates were 25% in the cisplatin-plus-gemcitabine arm and 19% in the carboplatin-plus-paclitaxel arm. None of these differences was statistically significant, but the survival figures were longer than expected, based on historical controls.
5. Results from two trials suggest that patients with a PS of 2 may experience symptom improvement.[17,18]

Standard Treatment Options for Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC (First-line Therapy)

Standard treatment options for patients with newly diagnosed stage IV, relapsed, and recurrent disease include the following:

1. Cytotoxic combination chemotherapy with platinum (cisplatin or carboplatin) and paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, protein-bound paclitaxel, or pemetrexed.
   • Combination chemotherapy.
   • Drug and dose schedule.
2. Combination chemotherapy with monoclonal antibodies.
   • Bevacizumab.
   • Cetuximab.
   • Necitumumab.
3. Maintenance therapy following first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy).
   • Maintenance therapy following first-line chemotherapy.
   • Pemetrexed following first-line platinum-based combination chemotherapy.
   • Maintenance erlotinib following platinum-based doublet chemotherapy.
4. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) (for patients with EGFR mutations).
   • Osimertinib.
   • Gefitinib.
   • Erlotinib.
   • Afatinib.
5. Anaplastic lymphoma kinase (ALK) inhibitors (for patients with ALK translocations).
   • Alectinib.
   • Crizotinib.
   • Ceritinib.
6. ROS1 inhibitors (for patients with ROS1 rearrangements).
   • Crizotinib.
7. BRAFV600E and MEK inhibitors (for patients with BRAF V600E mutations).
   • Dabrafenib and trametinib.
8. Neurotrophic tyrosine kinase (NTRK) inhibitors (for patients with NTRK fusions).
   • Larotrectinib.
9. Immune checkpoint inhibitors with or without chemotherapy.
   • Pembrolizumab plus chemotherapy.
   • Pembrolizumab alone.
10. Local therapies and special considerations.
    • Endobronchial laser therapy and/or brachytherapy (for obstructing lesions).[19]
    • External-beam radiation therapy (EBRT) (primarily for palliation of local symptomatic tumor growth).[20-22]
    • Treatment of second primary tumor.
    • Treatment of brain metastases.

Cytotoxic combination chemotherapy

Combination chemotherapy

The type and number of chemotherapy drugs to be used for the treatment of patients with advanced NSCLC has been extensively evaluated in randomized controlled trials and meta-analyses.

Several randomized trials have evaluated various drugs combined with either cisplatin or carboplatin in previously untreated patients with advanced NSCLC. On the basis of meta-analyses of the trials, the following conclusions can be drawn:

• Certain three-drug combinations that add so-called targeted agents may result in superior survival.
• EGFR inhibitors may benefit selected patients with EGFR mutations.
• Maintenance chemotherapy after four cycles of platinum combination chemotherapy may improve PFS and OS.
• Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, protein-bound paclitaxel, and pemetrexed yield similar improvements in survival. Types and frequencies of toxic effects differ, and these may determine the preferred regimen for an individual patient. Patients with adenocarcinoma may benefit from pemetrexed.
• Cisplatin and carboplatin yield similar improvements in outcome with different toxic effects. Some, but not all, trials and meta-analyses of trials suggest that outcomes with cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.
• Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.
• Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.

Evidence (combination chemotherapy):

1. The Cochrane Collaboration reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.[23] Sixty-five trials (13,601 patients) were identified.
   • In the trials that compared a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (odds ratio [OR], 0.42; 95% CI, 0.37–0.47; P < .001) and 1-year survival (OR, 0.80; 95% CI, 0.70–0.91; P < .001) in favor of the doublet regimen. The absolute benefit in 1-year survival was 5%, which corresponds to an increase in 1-year survival from 30% with a single-agent regimen to 35% with a doublet regimen. The rates of grades 3 and 4 toxic effects caused by doublet regimens were statistically increased compared with rates after single-agent therapy, with ORs ranging from 1.2 to 6.2. Infection rates did not increase in doublet regimens.
   • There was no increase in 1-year survival (OR, 1.01; 95% CI, 0.85–1.21; P = .88) for triplet regimens versus doublet regimens. The median survival ratio was 1.00 (95% CI, 0.94–1.06; P = .97).
2. Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior, with variable results.[24-26] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[24]
   • The objective response rate (ORR) was higher for patients treated with cisplatin (30%) than for patients treated with carboplatin (24%); (OR, 1.37; 95% CI, 1.16–1.61; P < .001).
   • Carboplatin treatment was associated with a nonstatistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR, 1.07; 95% CI, 0.99–1.15; P = .100).
   • In patients with nonsquamous cell tumors and in patients treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR, 1.12; 95% CI, 1.01–1.23 in patients with nonsquamous cell tumors and HR, 1.11; 95% CI, 1.01–1.21 in patients treated with third-generation chemotherapy).
   • Treatment-related toxic effects were also assessed in the meta-analysis. More thrombocytopenia was seen with carboplatin than with cisplatin (12% vs. 6%; OR, 2.27; 95% CI, 1.71–3.01; P < .001), but cisplatin caused more nausea and vomiting (8% vs. 18%; OR, 0.42; 95% CI, 0.33–0.53; P < .001) and renal toxic effects (0.5% vs. 1.5%; OR, 0.37; 95% CI, 0.15–0.88; P = .018).
   • The authors concluded that treatment with cisplatin was not associated with a substantial increase in the overall risk of severe toxic effects. This comprehensive individual-patient meta-analysis is consistent with the conclusions of other meta-analyses that were based on essentially the same clinical trials but which used only published data.
3. Three literature-based meta-analyses have trials that compared platinum with nonplatinum combinations.[27-29]
   1. The first meta-analysis identified 37 assessable trials that included 7,633 patients.[27]
      • A 62% increase in the OR for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46–1.8; P < .001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs. 29%; OR, 1.21; 95% CI, 1.09–1.35; P = .003).
      • No statistically significant increase in 1-year survival was found when platinum therapies were compared with third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96–1.28; P = .17).
      • The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting but not for neurologic toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.
   2. The second meta-analysis identified 17 trials that included 4,920 patients.[28]
      • The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (relative risk [RR], 1.08; 95% CI, 1.01%–1.16%; P = .03) and a better partial response (RR, 1.11; 95% CI, 1.02–1.21; P = .02), with a higher risk of anemia, nausea, and neurologic toxic effects.
      • In subanalyses, cisplatin-based doublet regimens improved survival at 1 year (RR, 1.16%; 95% CI, 1.06–1.27; P = .001), complete response (RR, 2.29; 95% CI, 1.08–4.88; P = .03), and partial response (RR, 1.19; 95% CI, 1.07–1.32; P = .002), with an increased risk of anemia, neutropenia, neurologic toxic effects, and nausea.
      • Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR, 0.95; 95% CI, 0.85–1.07; P = .43).
   3. The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[29] Experimental arms were gemcitabine and vinorelbine (n = 4), gemcitabine and taxane (n = 7), gemcitabine and epirubicin (n = 1), paclitaxel and vinorelbine (n = 1), and gemcitabine and ifosfamide (n = 1). This meta-analysis was limited to the set of 11 phase III studies that used a platinum-based doublet (2,298 patients in the platinum-based arm and 2,304 patients in the nonplatinum arm).
      • Patients treated with a platinum-based regimen benefited from a statistically significant reduction in the risk of death at 1 year (OR, 0.88; 95% CI, 0.78–0.99; P = .044) and a lower risk of being refractory to chemotherapy (OR, 0.87; CI, 0.73–0.99; P = .049).
      • Forty-four (1.9%) toxic-related deaths were reported for platinum-based regimens and 29 (1.3%) toxic-related deaths were reported for nonplatinum regimens (OR, 1.53; CI, 0.96–2.49; P = 0.08). An increased risk of grade 3 to 4 gastrointestinal and hematologic toxic effects for patients treated with platinum-based chemotherapy was statistically demonstrated. There was no statistically significant increase in the risk of febrile neutropenia (OR, 1.23; CI, 0.94–1.60; P = .063).

Drug and dose schedule

Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, with the exception of carboplatin, pemetrexed, and pembrolizumab for patients with nonsquamous tumor histology.

Evidence (drug and dose schedule):

1. One meta-analysis of seven trials that included 2,867 patients assessed the benefit of docetaxel versus vinorelbine.[30] Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial.
   • The pooled estimate for OS showed an 11% improvement in favor of docetaxel (HR, 0.89; 95% CI, 0.82–0.96; P = .004). Sensitivity analyses that considered only vinorelbine as a comparator or only the doublet regimens showed similar improvements.
   • Grade 3 to 4 neutropenia and grade 3 to 4 serious adverse events were less frequent with docetaxel-based regimens (OR, 0.59; 95% CI, 0.38–0.89; P = .013) versus vinca alkaloid-based regimens (OR, 0.68; 95% CI, 0.55–0.84; P < .001).
2. Two randomized trials compared weekly versus every 3 weeks' dosing of paclitaxel and carboplatin, which reported no significant difference in efficacy and better tolerability for weekly administration.[31,32] Although meta-analyses of randomized controlled trials suggest that cisplatin combinations may be superior to carboplatin or nonplatinum combinations, the clinical relevance of the differences in efficacy must be balanced against the anticipated tolerability, logistics of administration, and familiarity of the medical staff in making treatment decisions for individual patients.
3. A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naïve patients with stage IIIB/IV NSCLC and a PS of 0 to 1.[3] Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.
   • OS for cisplatin and pemetrexed (median survival, 10.3 months) was noninferior to cisplatin and gemcitabine (median survival, 10.3 months; HR, 0.94; 95% CI, 0.84%–1.05%).
   • In patients with adenocarcinoma (n = 847), OS was statistically superior for cisplatin and pemetrexed (12.6 months) versus cisplatin and gemcitabine (10.9 months); in patients with large cell carcinoma (n = 153), OS was statistically superior for cisplatin and pemetrexed (10.4 months) versus cisplatin and gemcitabine (6.7 months).
   • In contrast, in patients with squamous cell histology (n = 473), there was a significant improvement in survival with cisplatin and gemcitabine (10.8 months) versus cisplatin and pemetrexed (9.4 months). For cisplatin and pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.
   • The results of this study suggested that the cisplatin and pemetrexed doublet is another alternative doublet for first-line chemotherapy for advanced NSCLC and also suggested that there may be differences in outcome depending on histology.

Combination chemotherapy with monoclonal antibodies

Bevacizumab

Evidence (bevacizumab):

1. Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy.
   1. In a randomized study of 878 patients with recurrent or advanced stage IIIB/IV NSCLC, 444 patients received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab.[33] Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or PS (Eastern Cooperative Oncology Group PS >1) were excluded.
      • Median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (HRdeath, 0.79; P = .003).
      • Median PFS was 6.2 months in the group assigned to chemotherapy plus bevacizumab (HR for disease progression, 0.66; P < .001), with a 35% response rate (P < .001), and 4.5 months in the chemotherapy-alone group (HR for disease progression, 0.66; P < .001), with a 15% response rate (P < .001).
      • Rates of clinically significant bleeding were 4.4% in the group assigned to chemotherapy plus bevacizumab and 0.7% in the chemotherapy-alone group (P < .001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage.
      • For this subgroup of patients with NSCLC, the addition of bevacizumab to paclitaxel and carboplatin may provide survival benefit.[33][Level of evidence: 1iiA]
   2. Another randomized, phase III trial investigated the efficacy and safety of cisplatin-gemcitabine plus bevacizumab.[34] Patients were randomly assigned to receive cisplatin (80 mg/m2) and gemcitabine (1,250 mg/m2) for up to six cycles, plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The primary endpoint was amended from OS to PFS during the course of the study. A total of 1,043 patients were accrued (placebo group, n = 347; low-dose group, n = 345; high-dose group, n = 351).
      • PFS was significantly prolonged with the addition of bevacizumab; the HRs for PFS were 0.75 in the low-dose group (median PFS, 6.7 months vs. 6.1 months for placebo group; P = .03) and 0.82 in the high-dose group compared with the placebo group (median PFS, 6.5 months vs. 6.1 months for placebo group; P = .03).[34][Level of evidence: 1iiB]
      • ORRs were also improved with the addition of bevacizumab, and they were 20.1% for placebo, 34.1% for low-dose bevacizumab, and 30.4% for high-dose bevacizumab plus cisplatin/gemcitabine.
      • Incidence of grade 3 or greater adverse events was similar across arms.
      • Grade 3 or greater pulmonary hemorrhage rates were 1.5% or less for all arms, despite 9% of patients receiving therapeutic anticoagulation.
      • These results support the addition of bevacizumab to platinum-containing chemotherapy, but the results are far less impressive than when the carboplatin-paclitaxel combination was used.
      • Furthermore, no significant difference in survival was shown in this study, as reported in abstract form.
      • Altogether, these findings may suggest that the backbone of chemotherapy may be important when bevacizumab is added.

Cetuximab

Evidence (cetuximab):

1. Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[35,36]
   1. In the first trial, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC, without restrictions by histology or EGFRexpression, received cetuximab with taxane (paclitaxel or docetaxel with carboplatin) or combination chemotherapy.[35]
      • The addition of cetuximab did not result in a statistically significant improvement in PFS, the primary study endpoint, or OS.
      • Median PFS was 4.40 months for patients in the cetuximab-chemotherapy arm versus 4.24 months for patients in the taxane-carboplatin arm (HR, 0.902; 95% CI, 0.761–1.069; P = .236).
      • Median OS was 9.69 months for patients in the cetuximab-chemotherapy arm versus 8.38 months for patients in the chemotherapy-alone arm (HR, 0.890; 95% CI, 0.754–1.051; P = .169).
      • No significant associations were found between EGFR expression, EGFRmutation, EGFR copy number, or KRAS mutations and PFS, OS, and response in the treatment-specific analyses.[37]
   2. The second trial was composed of 1,125 chemotherapy-naïve patients with advanced EGFR-expressing stage IIIB/IV NSCLC treated with cisplatin-vinorelbine chemotherapy plus cetuximab or chemotherapy alone.[36]
      • The primary study endpoint, OS, was longer for patients treated with cetuximab and chemotherapy (median 11.3 months vs. 10.1 months; HRdeath, 0.871; 95% CI, 0.762–0.996; P = .044).
      • A survival benefit was seen in all histological subgroups; however, survival benefit was not seen in nonwhite or Asian patients. Only the interaction between the treatment and the ethnic origin was significant (P = .011).
      • The main cetuximab-related adverse event was acne-like rash (grade 3, 10%).
   3. It is not clear whether the differences in outcome in these two studies are the result of differences in the study populations, tumor characterization for EGFR expression, or chemotherapy regimens.

Necitumumab

Evidence (necitumumab):

1. Two phase III trials have evaluated the addition of the second-generation, recombinant, human immunoglobulin G1 EGFR antibody, necitumumab, to platinum-doublet chemotherapy in the first-line treatment of patients with advanced nonsquamous cell and squamous cell NSCLC.[38,39]
   1. The SQUIRE (NCT00981058) trial randomly assigned 1,093 patients with advanced squamous NSCLC to receive either first-line chemotherapy with cisplatin and gemcitabine or the same regimen with the addition of necitumumab (800 mg on day 1 and day 8 of each cycle).[39]
      • Median OS was prolonged with the addition of necitumumab (11.5 months vs. 9.9 months; P = .01).
      • PFS was also prolonged with the addition of necitumumab (5.7 months vs. 5.5 months); however, ORR was similar in both groups (31% vs. 28%).
      • Grades 3 and 4 adverse events were higher in the necitumumab-containing arm (72% vs. 62%).
      • Necitumumab is associated with higher toxicity and relatively modest benefit.
   2. The INSPIRE (NCT00982111) trial randomly assigned 633 patients with advanced nonsquamous NSCLC to receive either first-line chemotherapy with cisplatin and pemetrexed or to cisplatin and pemetrexed with the addition of necitumumab (800 mg on day 1 and day 8 of each cycle).[38]
      • This study showed no benefit from the addition of necitumumab to standard first-line chemotherapy for advanced nonsquamous NSCLC.
      • OS was 11.3 months (95% CI, 9.5–13.4) for patients in the necitumumab-containing arm versus 11.5 months (95% CI, 10.1–13.1) for patients in the chemotherapy alone arm; P = .96. Similarly, there was no difference between the arms in terms of ORR or PFS.
      • Serious adverse events and rates of grades 3 and 4 adverse events, including thromboembolic events, were higher in patients in the necitumumab-containing arm; the incidence of treatment-related deaths was also higher (5% vs. 3%).
      • On the basis of these results, necitumumab is not recommended as combination therapy with standard first-line chemotherapy for patients with advanced nonsquamous NSCLC.

Maintenance therapy after first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)

One extensively investigated treatment strategy in NSCLC is maintenance therapy after initial response to chemotherapy. Options for maintenance therapy that have been investigated include the following:

• Continuing the initial combination chemotherapy regimen.
• Continuing only single-agent chemotherapy.
• Introducing a new agent as maintenance.

Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.

Evidence (maintenance therapy following first-line chemotherapy):

1. None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles. For patients with nonsquamous NSCLC, two studies have demonstrated improved PFS and OS with either switch or continuous maintenance chemotherapy (e.g., maintenance pemetrexed after initial cisplatin and gemcitabine or maintenance pemetrexed after initial cisplatin and pemetrexed).[40]
2. Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy.[41-43]
3. No consistent improvement in quality of life was reported.[42,44,45]
4. Chemotherapy-related toxicities were greater with prolonged chemotherapy.[44,45]

These data suggest that PFS and OS for patients with nonsquamous NSCLC may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events including additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of combination cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy before disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.[41,42,44,45] For patients with nonsquamous NSCLC who have a response or stable disease after four to six cycles of platinum combination chemotherapy, maintenance chemotherapy with pemetrexed should be considered.[40]

Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):

1. The findings of two randomized trials (NCT00102804 and NCT00789373) have shown improved outcomes with the addition of pemetrexed after standard first-line platinum-based combination chemotherapy.[43,46]
   1. In the first trial, 663 patients with stage IIIB/IV disease who had not progressed on four cycles of nonpemetrexed platinum–based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed or placebo until disease progression.[46]
      • Both the primary endpoint of PFS and the secondary endpoint of OS were statistically significantly prolonged with the addition of maintenance pemetrexed (median PFS, 4.3 months vs. 2.6 months; HR, 0.50; 95% CI, 0.42–0.61; P < .0001; median OS, 13.4 months vs. 10.6 months; HR, 0.79; 95% CI, 0.65–0.95; P = .012).
      • Benefit was not seen in patients with squamous histology.
      • Higher than grade 3 toxicity and treatment discontinuations that resulted from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.
      • No pemetrexed-related deaths occurred.
      • Relatively fewer patients in the pemetrexed group than in the placebo group received systemic postdiscontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).
      • Quality of life during maintenance therapy with pemetrexed was similar to placebo, except for a small increase in loss of appetite and significantly delayed worsening of pain and hemoptysis as assessed using the Lung Cancer Symptom Scale.[47] The quality-of-life results require cautious evaluation because there was a high degree of censoring (> 50%) with the primary quality-of-life endpoint, which was time to worsening of symptoms.
      • Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.
   2. In the second trial, 539 patients with nonsquamous NSCLC with nonprogression after treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[43]
      • There was a statistically significant improvement in the primary endpoint of PFS (4.1 months vs. 2.8 months, HR, 0.62; 95% CI, 0.49–0.79) and in the secondary endpoint of OS (13.9 months vs. 11 months, HR, 0.78; 95% CI, 0.64–0.96).[40,43][Level of evidence: 1iDiii]

Evidence (maintenance erlotinib following platinum-based doublet chemotherapy):

1. One trial (NCT00556712) reported favorable outcomes with maintenance erlotinib after four cycles of platinum-based doublet chemotherapy in patients with stable disease.[48]
   1. In this trial, 889 patients with NSCLC but without progressive disease were randomly assigned to receive erlotinib (150 mg/day) or placebo until they experienced progressive disease or unacceptable toxicity.[48]
      • Median PFS was significantly longer with erlotinib than with placebo: 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for patients in the placebo group (HR, 0.71; 95% CI, 0.62–0.82; P < .0001).
      • In the overall population, patients whose tumors had activating EGFRmutations derived the greatest PFS benefit from maintenance erlotinib treatment (n = 49; HR, 0.10; P < .0001).
      • Patients whose tumors were wild-type EGFR also obtained significant PFS (HR, 0.78) and OS (HR, 0.77) improvements.
      • In the subgroup of patients with stable disease whose tumors did not have activating EGFR mutations (n = 217), both PFS (HR, 0.72; 95% CI, 0.54–0.96; P = .0231) and OS (HR, 0.65; 95% CI, 0.48–0.87; P = .0041) were significantly prolonged with erlotinib.
      • In patients whose tumors had activating EGFR mutations (n = 30), OS was also improved with erlotinib (HR, 0.48; 95% CI, 0.14–1.62) but was not statistically significant in this analysis.[49]
      • EGFR immunohistochemistry, EGFR fluorescence in situ hybridization (FISH), KRAS mutation, and EGFR CA-simple sequence repeat in intron 1 repeat length status were not predictive for erlotinib efficacy.[50] KRASmutation status was a significant, negative prognostic factor for PFS.[50][Level of evidence: 1iDiii]

EGFR tyrosine kinase inhibitors

Selective patients may benefit from single-agent EGFR TKIs. Randomized controlled trials of patients with chemotherapy-naïve NSCLC and EGFR mutations have shown that EGFR inhibitors improved PFS but not OS and have favorable toxicity profiles compared with combination chemotherapy.

Osimertinib

Evidence (osimertinib):

1. A phase III, multicenter, randomized, double-blind, controlled trial (FLAURA[NCT02296125]) compared osimertinib with standard of care EGFR TKIs (gefitinib or erlotinib) as first-line treatment of patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R), advanced NSCLC, as detected by a U.S. Food and Drug Administration (FDA)-approved test.[51] The 556 patients were randomly assigned in a 1:1 ratio.
   • Investigator-assessed PFS, the primary endpoint, was significantly longer with osimertinib (18.9 months vs. 10.2 months; HR, 0.46; 95% CI, 0.37–0.57, P < .0001).[51][Level of evidence: 1iDiii]
   • The objective response rate was similar for both groups (80% for the osimertinib group vs. 76% for the standard EGFR TKI group).
   • The median duration of response was 17.2 months (95% CI, 13.8–22.0) with osimertinib versus 8.5 months (95% CI, 7.3–9.8) with standard EGFR TKIs.
   • Data on OS are immature.
   • Adverse events of grade 3 or higher were less frequent with osimertinib (34%) than with standard TKIs (45%).

Osimertinib was approved by the FDA for first-line treatment of EGFR-mutant NSCLC (exon 19 deletion or L858R).

Gefitinib

Evidence (gefitinib):

1. A phase III, multicenter, randomized trial compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia who had advanced adenocarcinoma of the lung and had never smoked or were former light smokers.[52]
   1. The study met its primary objective of demonstrating the superiority of gefitinib compared with the carboplatin-paclitaxel combination for PFS (HR for progression or death, 0.74; 95% CI, 0.65–0.85; P < .001).
   2. The median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group.[52][Level of evidence: 1iDiii]
   3. Following the time that chemotherapy was discontinued and while gefitinib was continued, the PFS curves clearly separated and favored gefitinib.
      • The 12-month PFS rates were 24.9% with the gefitinib group and 6.7% with the carboplatin-paclitaxel group.
   4. More than 90% of the patients in the trial with mutations had either del19 or exon 21 L858R mutations, which have been shown to be sensitive to EGFR inhibitors. In the subgroup of patients with a mutation, PFS was significantly longer among those who received gefitinib (HR, 0.48; 95% CI, 0.36–0.64; P < .001); however, in the subgroup of patients who were negative for a mutation, PFS was significantly longer in those who received the carboplatin-paclitaxel combination (HR with gefitinib, 2.85; 95% CI, 2.05–3.98; P < .001). There was a significant interaction between treatment and EGFR mutation with respect to PFS (P < .001).[52]
   5. OS was similar for patients who received gefitinib and carboplatin-paclitaxel, with no significant difference between treatments overall (HR, 0.90; 95% CI, 0.79–1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76–1.33; P= .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86–1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to the carboplatin-paclitaxel regimen received subsequent EGFR TKIs. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34–0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09–7.09).
2. Two phase III trials from Japan prospectively confirmed that patients with NSCLC and EGFR mutations have improved PFS but not OS when treated with gefitinib.[53,54]
   1. In the first trial, 230 chemotherapy-naïve patients with metastatic NSCLC and EGFR mutations were randomly assigned to receive gefitinib or carboplatin-paclitaxel.[53]
      • In the planned interim analysis of data for the first 200 patients, PFS was significantly longer in the gefitinib group than in the standard-chemotherapy group (HRdeath or disease progression with gefitinib, 0.36; P < .001), resulting in early termination of the study.
      • The gefitinib group had a significantly longer median PFS (10.8 months vs. 5.4 months in the chemotherapy group; HR, 0.30; 95% CI, 0.22–0.41; P< .001).[53][Level of evidence: 1iiDiii] The median OS was 30.5 months in the gefitinib group and 23.6 months in the standard chemotherapy group (P = .31).
   2. In the second trial, the West Japanese Oncology Group conducted a phase III study (WJTOG3405) in 177 chemotherapy-naïve patients aged 75 years or younger and diagnosed with stage IIIB/IV NSCLC or postoperative recurrence harboring EGFR mutations (either the exon 19 deletion or L858R-point mutation).[54]
      • Patients were randomly assigned to receive either gefitinib or cisplatin plus docetaxel (administered every 21 days for three to six cycles). The primary endpoint was PFS.
      • The gefitinib group had significantly longer PFS than the cisplatin-plus-docetaxel group, with a median PFS of 9.2 months (95% CI, 8.0–13.9) versus 6.3 months (range, 5.8–7.8 months; HR, 0.489; 95% CI, 0.336–0.710, log-rank; P < .0001).[54][Level of evidence: 1iiDiii]

Erlotinib

Evidence (erlotinib):

1. In an open-label, randomized, phase III trial (NCT00874419) from China, 165 patients older than 18 years with histologically confirmed stage IIIB/IV NSCLC and a confirmed activating mutation of EGFR (i.e., exon 19 deletion or exon 21 L858R-point mutation) received either oral erlotinib (150 mg/day) until they experienced disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin.[55]
   • Median PFS was significantly longer in erlotinib-treated patients than in patients treated with chemotherapy (13.1 months [95% CI, 10.58–16.53] vs. 4.6 months [range, 4.21–5.42 months]; HR, 0.16; 95% CI, 0.10–0.26; P < .0001).[55][Level of evidence: 1iiDiii]
2. In a European study (EURTAC [NCT00446225]), 1,227 patients with advanced NSCLC were screened for EGFR mutations. Of these, 174 patients with EGFR mutations were randomly assigned to receive erlotinib or platinum-based chemotherapy.[56] The primary endpoint was PFS.
   • In an interim analysis of the first 153 patients, PFS in the chemotherapy arm was 5.2 months (95% CI, 4.5–5.8) compared with 9.7 months (95% CI, 8.4–12.3) in the erlotinib arm (HR, 0.37; P < .0001). Median survival was 19.3 months in patients in the chemotherapy arm and 19.5 months in patients in the erlotinib arm (HR, 0.80; P = .42).[57][Level of evidence: 1iiDiii]

Afatinib

Evidence (afatinib):

1. In an open-label, randomized, phase III study (LUX-Lung 3 [NCT00949650]), 345 Asian (72%) and white (26%) patients with stage IIIB/IV NSCLC and confirmed EGFRmutations (i.e., exon 19 deletion, L858R, or other [38 of 345 patients had other less-common mutations]) were screened, and 340 patients received at least one dose of study medication, which was either 40 mg of oral afatinib, an irreversible EGFR/human epidermal receptor (HER) TKI, daily or up to six cycles of cisplatin and pemetrexed for first-line treatment.[58]
   1. The primary endpoint was PFS. In this study, the afatinib group had significantly longer PFS than the cisplatin-plus-pemetrexed group, with a median PFS of 11.1 months for afatinib and 6.9 months for chemotherapy (HR, 0.58; 95% CI, 0.43–0.78; P = .001).[58][Level of evidence: 1iiDiii]
   2. Assessment of OS was a secondary endpoint and was reported separately.[59] Similar to the PFS analysis, OS was stratified based on EGFR-mutation type and ethnic origin.
      • With a median follow-up of 41 months, median OS was 28.2 months in patients in both arms (HR, 0.88; 95% CI, 0.66–1.17; P = .39).
      • In patients harboring common EGFR mutations (i.e., exon 19 deletion and L858R), survival did not differ significantly between treatment arms (HR, 0.78; 95% CI, 0.58–1.06; P = .11). However, prespecified subgroup analyses demonstrated a survival advantage with afatinib compared with chemotherapy in patients with tumors harboring the EGFR del19 mutation (median OS, 33.3 months vs. 21.1 months; HR, 0.54; 95% CI, 0.36–0.79; P = .0015) but no significant difference between treatment arms in patients with tumors harboring the L858R mutation (median OS, 27.6 months vs. 40.3 months; HR, 1.30; 95% CI, 0.80–2.11; P = .29).
      • First-line afatinib was associated with a significant survival advantage compared with chemotherapy in patients with NSCLC-harboring EGFRdel19 mutations but not in patients with EGFR L858R mutations or in the overall EGFR–mutation-positive patient population.[59][Level of evidence: 1iiA]
2. In an open-label, randomized, phase III study (LUX-Lung 6 [NCT01121393]), 364 East Asian patients with stage IIIB/IV NSCLC and confirmed EGFR mutations (i.e., exon 19 deletion, L858R, or other) were randomly assigned (2:1 ratio) to 40 mg of afatinib daily or gemcitabine and cisplatin for up to six cycles for first-line treatment.[60]
   1. The primary endpoint was PFS. Median PFS was significantly longer in the afatinib group (11.0 months; 95% CI, 9.7–13.7) than in the gemcitabine and cisplatin group (5.6 months, [range, 5.1–6.7 months]; HR, 0.28; 95% CI, 0.20–0.39; P < .0001).[60][Level of evidence: 1iiDiii]
   2. Assessment of OS was a prespecified secondary endpoint and was reported separately.[59] Similar to the PFS analysis, OS was stratified based on EGFR-mutation type and ethnic origin.
      • With a median follow-up of 33 months, median OS was 23.1 months in patients in the afatinib arm and 23.5 months in patients in the chemotherapy arm (HR, 0.93; 95% CI, 0.72–1.22; P = .61).
      • In patients harboring common EGFR mutations (i.e., exon 19 deletion and L858R), survival did not differ significantly between treatment arms (HR, 0.83; 95% CI, 0.62–1.09; P = .18). However, prespecified subgroup analyses demonstrated a survival advantage with afatinib compared with chemotherapy in patients with tumors harboring the EGFR del19 mutation (median OS, 31.4 months vs. 18.4 months; HR, 0.64; 95% CI, 0.44–0.94; P = .023), but no significant difference between treatment arms was seen in patients with tumors harboring the L858R mutation (median OS, 19.6 months vs. 24.3 months; HR, 1.22; 95% CI, 0.81–1.83; P= .34).
      • First-line afatinib was associated with a significant survival advantage compared with chemotherapy in patients with NSCLC-harboring EGFRdel19 mutations but not in patients with EGFR L858R mutations or in the overall EGFR-mutation-positive patient population.[59][Level of evidence: 1iiA]

ALK inhibitors (for patients with ALK translocations)

Alectinib

Evidence (alectinib):

1. In an open-label, randomized, phase III study (the ALEX trial [NCT02075840]), 303 patients with previously untreated, advanced ALK-rearranged NSCLC received either alectinib (600 mg bid) or crizotinib (250 mg bid).[61] The primary endpoint was investigator-assessed PFS.
   • The rate of PFS was significantly higher with alectinib than crizotinib; the 12-month event-free survival was 68.4% for the alectinib group (95% CI, 40.4–56.9) compared with 48.7% for the crizotinib group (95% CI, 40.4–56.9) (HR, 0.47; 95% CI, 0.34–0.65; P < .001). The median PFS was not reached with alectinib. The results of independent review committee-assessed PFS were consistent.[61][Level of evidence: 1iiDiii]
   • Central nervous system progression events were less frequent with alectinib (12%) than with crizotinib (45%) (HR, 0.16; 95% CI, 0.10–0.28; P <.001).
   • The response rate was similar for both groups, 82.9% for the alectinib group compared with 75.5% for the crizotinib group (P = .09).
   • Grade 3 to 5 adverse events were less frequent with alectinib (41%) than with crizotinib (50%).
2. A second, open-label, randomized, phase III trial (J-ALEX) recruited 207 ALK-inhibitor–naïve Japanese patients with ALK-positive NSCLC who were chemotherapy-naïve or had received one previous chemotherapy regimen. Patients were randomly assigned in a 1:1 ratio to receive alectinib (300 mg bid, which is the dose approved in Japan and is lower than the 600 mg twice daily dose approved elsewhere) versus crizotinib (250 mg bid).[62] The primary endpoint was PFS-assessed by an independent review committee.
   • At data cutoff for the second primary interim analysis, the independent data monitoring committee determined that the primary endpoint was met (HR, 0.34; 99.7% CI, 0.17–0.71; P <.0001) and recommended immediate release of the data. Median PFS had not been reached with alectinib but was reached at 10.2 months with crizotinib.
   • Grade 3 or 4 adverse events occurred less frequently with alectinib (26% occurrence rate) than with crizotinib (52% occurrence rate).

Crizotinib

Evidence (crizotinib):

1. In an open-label, randomized, phase III study, 343 patients with stage IIIB/IV NSCLC harboring translocations in ALK received either 250 mg of crizotinib orally twice a day or the combination of pemetrexed and cisplatin or carboplatin for up to six cycles.[63] At the time of disease progression, patients on the chemotherapy arm were allowed to cross over to crizotinib; 60% of patients in the chemotherapy arm subsequently received crizotinib. The primary endpoint of this study was PFS.
   • The study met its primary endpoint and demonstrated that crizotinib is superior to chemotherapy in prolonging PFS (median, 10.9 months vs. 7.0 months; HR, 0.454; 95% CI, 0.346–0.596; P < .0001).[64][Level of evidence: 1iiDiii]

Ceritinib

Evidence (ceritinib):

1. In an open-label, randomized, phase III study, 376 patients with stage IIIB/IV ALK-rearranged nonsquamous NSCLC received either oral ceritinib 750 mg daily or platinum-based chemotherapy (cisplatin or carboplatin and pemetrexed) every 3 weeks for four cycles, followed by maintenance pemetrexed.[65] The primary endpoint was PFS and crossover from chemotherapy to ceritinib was allowed upon documented progression.
   • Median PFS, assessed by blinded independent review, was 16.6 months in the ceritinib group and 8.1 months in the chemotherapy group (HR, 0.55; 95% CI, 0.42–0.73; P < .00001).
   • The median OS was not reached with ceritinib, and it was 26.2 months with chemotherapy (HR, 0.73; 95% CI, 0.50–1.08; P = .056).[65][Level of evidence: 1iiDiii]

ROS1 inhibitors (for patients with ROS1 rearrangements)

ROS1 rearrangements occur in approximately 1% of patients with NSCLC.[66]

Crizotinib

Evidence (crizotinib):

1. In an expansion cohort of a phase I study of crizotinib, 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement were treated with oral crizotinib 250 mg twice daily.[67] ROS1 rearrangements were identified using break-apart FISH or reverse-transcriptase-polymerase-chain-reaction assay. Seven patients (14%) had not had any previous treatment for advanced disease, 21 patients (42%) had one prior treatment, and 22 patients (44%) had more than one prior treatment. The primary endpoint was response rate.
   • The overall response rate was 72% (95% CI, 58–84). Six percent of patients had a complete response, 66% had a partial response, and 18% had stable disease as their best response.
   • Median PFS was 19.2 months (95% CI, 14.4–not reached). The estimated duration of response was 17.6 months (95% CI, 14.5–not reached).[67][Level of evidence: 3iiiDiv]
2. In a phase II, open-label, single-arm trial, 127 East Asian patients with ROS1-positive NSCLC were treated with crizotinib 250 mg twice daily.[68] Twenty-four patients (18.9%) had not had any previous treatment for advanced disease, 53 patients (41.7%) had one previous treatment, and 50 patients (39%) had two or three previous treatments. The primary endpoint was objective response rate by independent review.
   • The objective response rate was 71.7% (95% CI, 63.0–79.3). Response rates were similar, irrespective of the number of previous therapies. Complete responses occurred in 13.4% of patients, while 58.3% of patients had partial responses, and 16.5% of patients had stable disease as their best response.[68][Level of evidence: 3iiiDiv]
   • Median PFS was 15.9 months (95% CI, 12.9–24). The duration of response was 19.7 months (95% CI, 14.1–not reached).
   • OS was 32.5 months (95% CI, 32.5–not reached).

Crizotinib was approved for patients with metastatic NSCLC whose tumors are ROS1-positive, regardless of the number of previous systemic therapies.

BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations)

BRAFV600E mutations occur in 1% to 2% of lung adenocarcinomas.

Dabrafenib and trametinib

Evidence (dabrafenib and trametinib):

1. In a phase II multi-center, non-randomized, open-label study (NCT01336634), 36 patients with previously untreated metastatic NSCLC who tested positive for BRAFV600E mutations were treated with dabrafenib (a BRAF inhibitor) 150 mg bid and trametinib (a MEK inhibitor) 2 mg qd.[69] BRAFV600E mutations were identified by the Oncomine Dx Target Test (ThermoFisher Scientific). The primary endpoint was investigator-assessed overall response.
   • The overall response rate was 64% (95% CI, 46–79). Six percent of patients had a complete response, and 58% of patients had a partial response.
   • The median investigator-assessed PFS was 10.9 months (95% CI, 7.0–16.6 months). The estimated median duration of response was 10.4 months (95% CI, 8.3–17.9). At data cutoff, 47% of patients had died, and the median OS was 24.6 months (95% CI, 12.3–not estimable).
   • Sixty-nine percent of patients had at least one grade 3 or 4 adverse event, of which the most common were pyrexia, alanine aminotransferase increase, hypertension, or vomiting. Adverse events led to permanent discontinuation in 22% of patients, dose interruption or delay in 75% of patients, and dose reduction in 39% of patients.[69][Level of evidence: 3iiiDiv]

The combination of dabrafenib and trametinib received approval in the treatment of patients with NSCLC whose tumors harbor BRAFV600E mutations as detected by an FDA-approved test.

NTRK inhibitors (for patients with NTRK fusions)

Somatic gene fusions in NTRK occur across a range of solid tumors including in fewer than 0.5% of NSCLC tumors.[70,71] These fusions appear to occur more frequently in nonsmokers with lung adenocarcinoma.

Larotrectinib

Evidence (larotrectinib):

1. Larotrectinib was studied in three protocols: a phase I study involving adults, a phase I/II study involving children, and a phase II study involving adolescents and adults.[72] Fusions were confirmed in the tumors using either FISH or next-generation sequencing methods. The primary endpoint for the combined analysis was objective response rate by independent review and was conducted with input from regulators with the goal of excluding a lower bound of less than 30% for response rate. In total, 55 patients with a median age of 45 years (range, 4 months‒76 years) were enrolled across 17 different NTRK fusion positive tumor types. All patients had either metastatic disease (82%) or locally advanced unresectable disease (18%). Enrolled patients had received a median of two previous systemic therapies.
   • The objective response rate was 75% (95% CI, 61%‒75%) and 73% of these responses lasted at least 6 months.[72][Level of evidence: 3iiiDiv]
   • Treatment was well tolerated with 93% of adverse events being grade 1 to 2; the most common grade 3 to 4 adverse events were anemia (11% of patients), transaminitis (7%), and neutropenia (7%).

The FDA has approved larotrectinib for the treatment of patients who have locally advanced or metastatic tumors that harbor an NTRK gene fusion without a known acquired resistance mutation, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment.

Immune checkpoint inhibitors with or without chemotherapy

Pembrolizumab is a humanized monoclonal antibody that inhibits the interaction between the PD-1 coinhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells and its ligands, PD-L1 and PD-L2.[73]

Pembrolizumab plus chemotherapy

Evidence (pembrolizumab plus chemotherapy):

1. A phase III double-blind trial (KEYNOTE-189 [NCT02578680]) randomly assigned, in a 2:1 ratio, 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFRmutations or ALK rearrangements who had received no previous treatment for metastatic disease. Patients received pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance.[2] Crossover to pembrolizumab monotherapy was permitted after verified progression among patients in the placebo-containing combination group. The primary endpoints were OS and PFS as assessed by blinded independent central committee radiologic review.
   • After a median follow-up of 10.5 months, the estimated rate of OS at 12 months was 69.2% (95% CI, 64.1–73.8) in the pembrolizumab combination group compared with 49.4% (95% CI, 42.1–56.2) in the placebo combination group (HR, 0.49; 95% CI, 0.38–0.64; P < .001).[2][Level of evidence: 1iA]
   • Improvement in survival was seen across all PD-L1 categories.
   • Median PFS was 8.8 months in the pembrolizumab combination group compared with 4.9 months in the placebo combination group (HR, 0.52; 95% CI, 0.43–0.64; P < .001).
   • Adverse events of grade 3 or higher occurred with similar frequency in both treatment groups (67.2% in the pembrolizumab combination group vs. 65.8% in the placebo combination group).

Pembrolizumab alone

Evidence (pembrolizumab alone):

1. A phase III, open-label study (KEYNOTE-024) randomly assigned 305 patients with previously untreated, advanced NSCLC with PD-L1 expression on 50% or more tumor cells and no sensitizing EGFR mutations or ALK translocations to either intravenous pembrolizumab (200 mg every 3 weeks for up to 35 cycles) or platinum-based chemotherapy (4–6 cycles, investigator’s choice; pemetrexed maintenance was allowed for nonsquamous tumors).[73] The primary endpoint was PFS.
   1. PD-L1 expression was centrally assessed using the PD-L1 immunohistochemistry 22C3 pharmDx assay (Dako North America). PD-L1 tumor expression of 50% or more was found in 30.2% of 1,653 patient samples that were examined.
   2. Pembrolizumab demonstrated significant improvement in median PFS (10.3 months vs. 6.0 months; HR, 0.50; 95% CI, 0.37–0.68; P < .001). The overall response rate (44.8% vs. 27.8%), the median duration of response (not reached, [range 1.9+–14.5+ months] vs. 6.3 months [range, 2.1+–12.6+ months]), and the estimated rate of OS at 6 months (80.2% vs. 72.4%; HR, 0.60; 95% CI, 0.41–0.89; P = .005) were all higher with pembrolizumab than with chemotherapy.
   3. Further follow up of this study confirmed an OS advantage in favor of pembrolizumab; the median OS for patients who received pembrolizumab was 30 months (95% CI, 18.3 months–not reached) versus 14.2 months for patients who received chemotherapy, with a 75% crossover to immunotherapy afterwards, suggesting the crossover did not impact survival.[74]
   4. Adverse events (any grade) were less frequent with pembrolizumab than with chemotherapy (73.4% vs. 90.0%).
      • Grade 3–5 adverse events occurred in 26.6% of patients treated with pembrolizumab and 53.3% of patients treated with chemotherapy.
      • Grade 3 or 4 immune-related events occurred in 9.7% of patients treated with pembrolizumab and 0.7% of patients treated with chemotherapy.
      • The most common grade 3 or 4 immune-related events associated with pembrolizumab were severe skin reactions (3.9%), pneumonitis (2.6%), and colitis (1.3%).
      • There were no grade 5 immune-related events.
   5. Pembrolizumab treatment demonstrated significant improvement in PFS, OS, and duration of response with less frequent adverse events compared with chemotherapy treatment.[73][Level of evidence: 1iiDiii]

Pembrolizumab in combination with pemetrexed and carboplatin received FDA approval as first-line treatment of patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Pembrolizumab also received approval as a first-line monotherapy for patients with NSCLC whose tumors express PD-L1 (≥50% staining as determined by a test approved by the FDA). Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapies before receiving pembrolizumab (refer to the FDA label for pembrolizumab).

Local therapies and special considerations

Endobronchial laser therapy and/or brachytherapy (for obstruction lesions)

Radiation therapy may be effective in palliating symptomatic patients with local involvement of NSCLC with any of the following:

• Tracheal, esophageal, or bronchial compression.
• Pain.
• Vocal cord paralysis.
• Hemoptysis.
• Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy have been used to alleviate proximal obstructing lesions.[19]

EBRT (primarily for palliation of local symptomatic tumor growth)

Although EBRT is frequently prescribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief,[75-80] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCT00003685 trial.[20][Level of evidence: 1iiC] Evidence of a modest increase in survival in patients with a better PS given high-dose radiation therapy is available.[22,81][Level of evidence: 1iiA] In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

Evidence (radiation therapy):

1. A systematic review identified six randomized trials of high-dose rate endobronchial brachytherapy (HDREB) alone or with EBRT or laser therapy.[82]
   • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[82][Level of evidence: 1iiC]
   • HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

Treatment of second primary tumor

A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Whether the new lesion is a new primary cancer or a metastasis may be difficult to determine. Studies have indicated that in most patients the new lesion is a second primary tumor, and after its resection, some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected, if possible.[83,84]

Treatment of brain metastases

Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged disease-free survival with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy.[85,86] Unresectable brain metastases in this setting may be treated with stereotactic radiosurgery.[87]

Approximately 50% of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment.[88] In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiation surgery.[87,88] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[89][Level of evidence: 3iiiDiii]

Treatment Options Under Clinical Evaluation for Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC (First-line Therapy)

Treatment options under clinical evaluation for newly diagnosed stage IV, recurrent, and relapsed NSCLC (first-line therapy) include the following:

• Clinical trials can be considered as first-line therapy.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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61. Peters S, Camidge DR, Shaw AT, et al.: Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med 377 (9): 829-838, 2017. [PUBMED Abstract]
62. Hida T, Nokihara H, Kondo M, et al.: Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet 390 (10089): 29-39, 2017. [PUBMED Abstract]
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71. Gatalica Z, Xiu J, Swensen J, et al.: Molecular characterization of cancers with NTRK gene fusions. Mod Pathol 32 (1): 147-153, 2019. [PUBMED Abstract]
72. Drilon A, Laetsch TW, Kummar S, et al.: Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378 (8): 731-739, 2018. [PUBMED Abstract]
73. Reck M, Rodríguez-Abreu D, Robinson AG, et al.: Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 375 (19): 1823-1833, 2016. [PUBMED Abstract]
74. Reck M, Rodríguez-Abreu D, Robinson AG, et al.: Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol : JCO1800149, 2019. [PUBMED Abstract]
75. Danson S, Middleton MR, O'Byrne KJ, et al.: Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma. Cancer 98 (3): 542-53, 2003. [PUBMED Abstract]
76. Pfister DG, Johnson DH, Azzoli CG, et al.: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22 (2): 330-53, 2004. [PUBMED Abstract]
77. Smit EF, van Meerbeeck JP, Lianes P, et al.: Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III trial of the European Organization for Research and Treatment of Cancer Lung Cancer Group--EORTC 08975. J Clin Oncol 21 (21): 3909-17, 2003. [PUBMED Abstract]
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Progressive Stage IV, Relapsed, and Recurrent NSCLC Treatment

In This Section

• Standard Treatment Options for Progressive Stage IV, Relapsed, and Recurrent NSCLC (Second-line Therapy)
  • Chemotherapy
  • EGFR-directed therapy
  • ALK-directed tyrosine kinase inhibitors (TKI)
  • ROS1-directed therapy
  • BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations)
  • Immunotherapy
• Treatment Options under Clinical Evaluation for Progressive Stage IV, Relapsed, and Recurrent NSCLC (Second-line Therapy)
• Current Clinical Trials

Standard Treatment Options for Progressive Stage IV, Relapsed, and Recurrent NSCLC (Second-line Therapy)

Standard treatment options for patients with progressive stage IV, relapsed, and recurrent non-small cell lung cancer (NSCLC) (second-line therapy and beyond) include the following:

1. Chemotherapy.
   • Docetaxel.
   • Docetaxel plus ramucirumab.
   • Pemetrexed.
2. Epidermal growth factor receptor (EGFR)-directed therapy.
   1. EGFR-directed therapy after first-line chemotherapy.
      • Erlotinib.
      • Gefitinib.
      • Afatinib.
   2. EGFR-directed therapy for acquired EGFR T790M mutations after prior EGFR-directed therapy.
      • Osimertinib.
3. Anaplastic lymphoma kinase (ALK)-directed tyrosine kinase inhibitors (TKI).
   1. ALK-directed TKI after first-line chemotherapy.
      • Crizotinib.
   2. ALK-directed TKI after prior ALK TKI therapy.
      • Ceritinib.
      • Alectinib.
      • Brigatinib.
4. ROS1-directed therapy.
   • Crizotinib.
5. BRAF V600E and MEK inhibitors (for patients with BRAF V600E mutations).
   • Dabrafenib and trametinib.
6. Immunotherapy.
   • Nivolumab.
   • Pembrolizumab.
   • Atezolizumab.

Chemotherapy

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[1][Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[2,3] Informed patients with good performance status (PS) and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered.

Docetaxel

Evidence (docetaxel):

1. Two prospective randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[4,5] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.[6]
2. A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported.[7] In that analysis, the following was shown:
   • Median survival was 27.4 weeks for patients treated every 3 weeks and 26.1 weeks for patients treated weekly (P = .24, log-rank test).
   • Significantly less severe neutropenia and febrile neutropenia were reported with weekly docetaxel (P < .001 for both); however, no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxic effects.

Docetaxel plus ramucirumab

Evidence (docetaxel plus ramucirumab):

1. In a double-blind, placebo-controlled, phase III study, 1,253 patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1 who had progressive disease after first-line chemotherapy were randomly assigned to receive docetaxel and placebo or docetaxel and ramucirumab.[8][Level of evidence: 1iiA] Ramucirumab is a human immunoglobulin G1 monoclonal antibody that targets the extracellular domain of vascular endothelial growth factor receptor 2. The primary endpoint of the study was overall survival (OS), with secondary endpoints of progression-free survival (PFS) and objective response rate (ORR). The study enrolled patients with either nonsquamous or squamous NSCLC; however, patients with poorly controlled hypertension, gastrointestinal perforation or fistulae, arterial thromboembolic event within 6 months (before random assignment), gross hemoptysis within 2 months, or grade 3 to 4 gastrointestinal bleeding within 3 months were excluded. In addition, the trial did not include patients with tumors that had major blood vessel involvement or intratumor cavitation.
   • The addition of ramucirumab to docetaxel compared with placebo plus docetaxel led to an increase in median OS (10.5 months vs. 9.1 months; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75–0.98), ORR (23% vs. 14%), and PFS (4.5 months vs. 3 months). The improvement in OS from the addition of ramucirumab appeared consistent across subgroups including squamous and nonsquamous histologies.
   • Grade 3 to 4 treatment-related adverse events occurred in 79% of patients who received docetaxel and ramucirumab as compared with 71% of patients who received docetaxel and placebo. Febrile neutropenia, fatigue, and hypertension were among the toxicities that were more common with the addition of ramucirumab to docetaxel. There was no significant difference in the incidence of grades 3 to 4 hemorrhage between the groups.
   • On the basis of this study, the addition of ramucirumab to docetaxel chemotherapy can be considered for patients with good PS with advanced NSCLC who have progressive disease after first-line chemotherapy.

Pemetrexed

Evidence (pemetrexed):

1. A randomized, phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, PFS, or OS.[9][Level of evidence: 1iiA] Of note, patients with squamous histology benefited from docetaxel, and those with nonsquamous histologies appeared to benefit more from pemetrexed.[10]

EGFR-directed therapy

EGFR-directed therapy after first-line chemotherapy

Erlotinib

Evidence (erlotinib):

1. Two randomized, placebo-controlled trials indicated that erlotinib prolongs survival and time to deterioration in symptoms in patients with NSCLC after first-line or second-line chemotherapy compared with placebo [11,12] but does not improve survival compared with standard second-line chemotherapy with docetaxel or pemetrexed.[13]
   1. The trial of erlotinib versus best supportive care included 731 patients; 49% had received two previous chemotherapy regimens, and 93% had received platinum-based chemotherapy.
      • OS was 6.7 months among those who had received two previous chemotherapy regimens and 4.7 months among those who had received platinum-based chemotherapy. The HR was 0.70 (P < .001) in favor of erlotinib.[11][Level of evidence: 1iiA]
   2. In the trial (NCT00556322), which was designed to show the superiority of erlotinib versus standard second-line chemotherapy after disease progression on first-line platinum combination therapy, 424 patients were randomly assigned.
      • There was no difference in the primary endpoint of OS (median OS, 5.3 months vs. 5.5 months; HR, 0.96; 95% CI, 0.78–1.19).[13][Level of evidence: 1iiA]

Gefitinib

Evidence (gefitinib):

1. A randomized phase III trial evaluated gefitinib versus placebo in 1,692 previously treated NSCLC patients and showed the following:
   • Gefitinib does not improve OS.
   • Median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; HR, 0.89; 95% CI, 0.77–1.02; P = .087) or among the 812 patients with adenocarcinoma (6.3 months vs. 5.4 months; HR, 0.84; CI, 0.68–1.03; P = .089).
   • Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than in the placebo group for never-smokers (n = 375; 95% CI, 0.67 [0.49–0.92]; P = .012; median survival 8.9 months vs. 6.1 months) and for patients of Asian origin (n = 342; 95% CI, 0.66 [0.48–0.91]; P = .01; median survival 9.5 months vs. 5.5 months).[14][Level of evidence: 1iiA]
2. In a large, randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy.[15] The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high EGFR gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day PO; n = 733) or docetaxel (75 mg/m2 IV every 3 weeks; n = 733).
   • Noninferiority of gefitinib compared with docetaxel was confirmed for OS (HR, 1.020; 95% CI, 0.905–1.150). However, superiority of gefitinib in patients with high EGFR gene copy number (85 patients vs. 89 patients) was not proven (HR, 1.09; 95% CI, 0.78–1.51; P = .62).
   • In the gefitinib group, the most common adverse events were rash or acne (49% vs. 10%) and diarrhea (35% vs. 25%). In the docetaxel group, neutropenia (5% vs. 74%), asthenia (25% vs. 47%), and alopecia (3% vs. 36%) were most common.
   • This trial established noninferior survival of patients treated with gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced NSCLC.

ORR to erlotinib and gefitinib are higher in patients who have never smoked, in females, in East Asians, and in patients with adenocarcinoma and bronchioloalveolar carcinoma.[16-22] Responses may be associated with sensitizing mutations in the tyrosine kinase domain of the EGFR- [17-19,21,22] and, with the absence of, KRAS mutations.[20-22][Level of evidence: 3iiiDiii] Survival benefit may be greater in patients with EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by fluorescence in situhybridization studies,[21,22] but the clinical utility of EGFR testing by immunohistochemistry has been questioned.[23]

Afatinib

Evidence (afatinib):

1. Afatinib, an irreversible inhibitor of the ErbB-family of receptors, has been compared with erlotinib as second-line treatment in patients with advanced squamous cell carcinoma. In a randomized, controlled, phase III trial (LUX-Lung 8 [NCT01523587]), patients with stage IIIB/IV squamous cell NSCLC with disease progression after frontline platinum-based chemotherapy were randomly assigned in a 1:1 ratio to receive afatinib (398 patients, 40 mg PO qd) or erlotinib (397 patients, 150 mg PO qd).[24][Level of evidence: 1iiDiii] The primary endpoint was PFS. Secondary endpoints included OS and response rate.
   • After a median follow-up of 6.7 months, the PFS was 2.4 months versus 1.9 months (HR, 0.82; 95% CI, 0.68–1.00).
   • After a median follow-up of 18.4 months, the median OS was significantly longer in the afatinib arm (7.9 months vs. 6.8 months; HR, 0.81; 95% CI, 0.69–0.95; P = .007). Survival at 6 months (63.6% vs. 54.6%; P = .009), 12 months (36.4% vs. 28.2%; P = .015), and 18 months (22% vs. 14.4%; P = .013) were all significantly better in patients who received afatinib.
   • There was no significant difference in response rate between the two arms (6% vs. 3%; P = .551).
   • The frequency of adverse events was similar between the two groups with 57% of the patients experiencing a rate of grade 3 or higher adverse events. Grade 3 treatment-related diarrhea and stomatitis occurred more frequently with afatinib; however, grade 3 rash or acne were more common in patients who received erlotinib.
   • Afatinib, as compared with erlotinib, represents another option for the second-line treatment of patients with stage IV squamous cell NSCLC.

EGFR-directed therapy for acquired EGFR T790M mutations after prior EGFR-directed therapy

Osimertinib

Evidence (osimertinib):

1. An open-label, phase III trial (AURA 3 [NCT02151981]) studied osimertinib in NSCLC patients with EGFR-sensitizing mutations whose disease had progressed after first-line EGFR inhibitors and who had the T790M EGFR resistance mutation as determined by the Cobas® EGFR Mutation Test.[25] The trial randomly assigned 419 patients (with a 2:1 ratio) to receive either osimertinib 80 mg PO qd or pemetrexed plus carboplatin or cisplatin IV every 3 weeks for up to six cycles; maintenance pemetrexed was allowed for the chemotherapy group. The primary endpoint was PFS.
   • Osimertinib was superior to chemotherapy in prolonging median PFS (10.1 months vs. 4.4 months; HR, 0.30; 95% CI, 0.23–0.41; P < .001).
   • The ORR was 71% with osimertinib versus 31% with platinum therapy (odds ratio for objective response, 5.39; 95% CI, 3.47–8.48; P < .001).
   • Among 144 patients with central nervous system (CNS) metastases, median PFS duration was 8.5 months with osimertinib versus 4.2 months with platinum therapy (HR, 0.32; 95% CI, 0.21–0.49).
   • Adverse events of grade 3 or greater occurred in 23% of osimertinib-treated patients versus 47% of platinum-treated patients.[25][Level of evidence: 1iiDiii]

ALK-directed tyrosine kinase inhibitors (TKI)

ALK-directed TKI after first-line chemotherapy

Crizotinib

Evidence (crizotinib):

1. A study (NCT00585195) that screened 1,500 patients with NSCLC for ALKrearrangements identified 82 patients with advanced ALK-positive disease who were enrolled in a clinical trial that was an expanded cohort study instituted after phase I dose escalation had established a recommended dose of crizotinib dual and ALK inhibitor of 250 mg bid in 28-day cycles.[26] Most of the patients had received previous treatment.
   • At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses, and one confirmed complete response); 27 patients (33%) had stable disease.[26][Level of evidence: 3iiiD]
   • The estimated probability of 6-month PFS was 72%.
   • 1-year OS was 74% (95% CI, 63–82), and 2-year OS was 54% (40–66).
   • Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls identified from a different cohort given any second-line therapy (median OS not reached [95% CI, 14 months–not reached] vs. 6 months [95% CI, 4–17], 1-year OS, 70% [95% CI, 50–83] vs. 44% [95% CI, 23–64], and 2-year OS, 55% [33–72] vs. 12% [2–30]; HR, 0.36; 95% CI, 0.17–0.75; P = .004).[27][Level of evidence: 3iiiD]
   • Common toxicities were grade 1 or 2 (mild) gastrointestinal side effects.
   • Patients with ALK rearrangements tended to be younger than those without the rearrangements; most of the patients had little or no exposure to tobacco; and the patients had adenocarcinomas.
2. In an open-label, randomized, phase III study, 347 patients with stage IIIB/IV NSCLC-harboring translocations in ALK, who had received one previous regimen of platinum-based chemotherapy, received either crizotinib (250 mg PO twice a day) or chemotherapy (pemetrexed 500 mg/m2 if pemetrexed-naïve or docetaxel 75mg/m2 IV every 21 days).[28]
   • The primary endpoint was PFS. Median PFS was significantly longer in favor of crizotinib (7.7 months vs. 3.0 months, P < .001).[28][Level of evidence: 1iiDiii]
   • OS, a secondary endpoint, was not significantly different, but there was significant crossover in the design.

ALK-directed TKI after prior ALK TKI therapy

Ceritinib

Evidence (ceritinib):

1. A single-arm, open-label trial enrolled 163 patients with ALK-translocated stage IIIB/IV NSCLC who had disease progression while receiving crizotinib or were intolerant to the drug.[29]
   • The primary endpoint was ORR according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) with a secondary endpoint of duration of response (DOR). The ORR by blinded independent review was 43.6% (95% CI, 36–52), and the median DOR was 7.1 months (range, 5.6–not estimable).[29][Level of evidence: 3iiiDiv]
   • Of note, 38% of patients required dose modification because of gastrointestinal toxicity; elevation of alanine transaminase to more than five times the upper limit of normal occurred in 27% of patients.

Alectinib

Evidence (alectinib):

1. A phase II, open-label trial (NCT01871805) enrolled 87 patients with ALK-translocated stage IIIB/IV NSCLC who had disease progression after crizotinib treatment.[30]
   • The primary endpoint was objective response according to RECIST (version 1.1). At the time of primary endpoint analysis of this ongoing study, 48% of patients (95% CI, 36–60) had a confirmed partial response, and 32% had stable disease by blinded independent review. The median DOR was 13.5 months (95% CI, 6.7–not estimable). The estimated median PFS was 8.1 months (95% CI, 6.2–12.6).[30][Level of evidence: 3iiiDiv]
   • Sixteen patients had measurable CNS disease at baseline, of whom 11 had received prior radiation therapy. The CNS ORR was 75% (95% CI, 48–93), with 25% of the patients attaining complete response and 50% of the patients attaining partial response.
   • The most common side effects were grade 1 or 2 in severity; the most frequent adverse events, occurring in 23% to 36% of patients, were constipation, fatigue, myalgia, and peripheral edema. Dose interruption was needed in 36% of patients, and dose reduction occurred in 16%.
2. A second phase II, open-label trial enrolled 138 patients with ALK-positive stage IIIB/IV NSCLC who had disease progression on crizotinib.[31]
   • The primary endpoint was ORR by independent central review. ORR was 50% (95% CI, 41–59). Median DOR was 11.2 months (95% CI, 9.6–not reached). Median PFS was 8.9 months (95% CI, 5.6–11.3).[31][Level of evidence: 3iiiDiv]
   • CNS ORR in 35 patients with measurable CNS lesions was 57% (95% CI, 39–74).
   • Common adverse events that were mainly grade 1 or 2, which occurred in 25% to 33% of patients, were constipation, fatigue, and peripheral edema.

Brigatinib

Evidence (brigatinib):

1. A phase II, open-label trial (NCT02094573) enrolled 222 patients with ALK-translocated locally advanced or metastatic NSCLC who had disease progression after crizotinib treatment. Patients were randomly assigned to receive 90 mg qd (n = 112, 109 treated) or 180 mg qd with a 7-day lead-in at 90 mg qd (n = 110).[32]
   • The primary endpoint assessed by the investigators was ORR. ORR was 45% (97.5% CI, 34–56) for patients who received the 90 mg dose and 54% (97.5% CI, 43–65) for patients who received the 180 mg dose.
   • Median PFS was 9.2 months (95% CI, 7.4–15.6) for patients who received the 90 mg dose and 12.9 months (95% CI, 11.1–not reached) for patients who received the 180 mg dose.
   • At data cutoff, the median DOR was 13.8 months (95% CI, 5.6–13.8) for patients who received the 90 mg dose and 11.1 months (95% CI, 9.2–13.8) for patients who received the 180 mg dose.[32][Level of evidence: 1iiDiv]
   • The CNS ORR in patients with measurable CNS lesions was 42% in patients receiving 90 mg qd (n = 26) and 67% in patients receiving 180 mg qd (n = 18).
   • Common adverse events, which were mainly grade 1 or 2 and occurred in 27% to 38% of patients at the higher dose, were nausea, diarrhea, headache, and cough. A subset of pulmonary adverse events with early onset (median onset, day 2) occurred in 14 of 219 treated patients (all grades, 6% ≥ grade >3, 3%); none occurred after escalation to 180 mg. These events included dyspnea, hypoxia, cough, pneumonia, or pneumonitis. They were managed with dose interruption. Seven of the 14 patients were successfully retreated with brigatinib.
   • The U.S. Food and Drug Administration (FDA)-approved dose of brigatinib is 90 mg qd for 7 days; if tolerated, the dose is increased to 180 mg qd.

ROS1-directed therapy

ROS1 rearrangements occur in approximately 1% of patients with NSCLC.[33]

Crizotinib

Crizotinib was approved for patients with metastatic NSCLC whose tumors are ROS1-positive, regardless of the number of previous systemic therapies.

Evidence (crizotinib):

1. In an expansion cohort of a phase I study of crizotinib, 50 patients with advanced NSCLC who tested positive for ROS1 rearrangement were treated with oral crizotinib 250 mg twice daily.[34] ROS1 rearrangements were identified using break-apart fluorescence in situ hybridization or reverse-transcriptase-polymerase-chain-reaction assay. Seven patients (14%) had not had any previous treatment for advanced disease, 21 patients (42%) had one prior treatment, and 22 patients (44%) had more than one previous treatment. The primary endpoint was response rate.
   • The overall response rate was 72% (95% CI, 58–84). Six percent of patients had a complete response, 66% had a partial response, and 18% had stable disease as their best response.
   • Median PFS was 19.2 months (95% CI, 14.4–not reached). The estimated DOR was 17.6 months (95% CI, 14.5–not reached).[34][Level of evidence: 3iiiDiv]
2. In a phase II, open-label, single-arm trial, 127 East Asian patients with ROS1-positive NSCLC were treated with crizotinib 250 mg twice daily.[35] Twenty-four patients (18.9%) had not had any previous treatment for advanced disease, 53 patients (41.7%) had one previous treatment, and 50 patients (39%) had two or three previous treatments. The primary endpoint was objective response rate by independent review.
   • The objective response rate was 71.7% (95% CI, 63.0–79.3). Response rates were similar, irrespective of the number of previous therapies. Complete responses occurred in 13.4% of patients, while 58.3% of patients had partial responses and 16.5% of patients had stable disease as their best response.[35][Level of evidence: 3iiiDiv]
   • Median PFS was 15.9 months (95% CI, 12.9–24). The duration of response was 19.7 months (95% CI, 14.1–not reached).
   • OS was 32.5 months (95% CI, 32.5–not reached).

BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations)

BRAFV600E mutations occur in 1% to 2% of lung adenocarcinomas.

Dabrafenib and trametinib

Evidence (dabrafenib and trametinib):

1. In a phase II, multicenter, nonrandomized, open-label study (NCT01336634), 57 patients with progression after at least one to three previous platinum-containing regimens for treatment of metastatic NSCLC, who tested positive for BRAFV600Emutations, were treated with dabrafenib (a BRAF inhibitor) 150 mg bid and trametinib (a MEK inhibitor) 2 mg qd.[36] BRAFV600E mutations were ascertained by local testing. The primary endpoint was investigator-assessed overall response.
   • The overall response rate was 63.2% (95% CI, 49.3–75.6), as determined independently by investigator and independent review committee assessments. There were 2 out of 36 complete responses by investigator assessment; all responses were deemed partial by the independent review committee.
   • The median investigator-assessed PFS was 9.7 months (95% CI, 6.9–19.6 months). The estimated median DOR was 9.0 months (95% CI, 6.9–18.3). The OS data are immature.
   • Forty-nine percent of patients had at least one grade 3 or 4 adverse event, the most common of which were neutropenia, hyponatremia, and anemia.[36][Level of evidence: 3iiiDiv]

The combination of dabrafenib and trametinib received approval for patients with NSCLC whose tumors harbor BRAFV600E mutations as detected by an FDA-approved test.

Immunotherapy

Nivolumab is a fully human monoclonal antibody that inhibits the programmed death-1 (PD-1) co-inhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells.[37,38] Pembrolizumab is a humanized monoclonal antibody that inhibits the interaction between the PD-1 co-inhibitory immune checkpoint expressed on tumor cells and infiltrating immune cells and its ligands, PD-L1 and PD-L2.[39] Atezolizumab is a PD-L1–blocking antibody.

Nivolumab

Evidence (nivolumab):

1. In two phase III clinical trials, one conducted in patients with advanced platinum-pretreated squamous NSCLC and the other trial conducted in patients with nonsquamous NSCLC, nivolumab demonstrated a significant improvement in OS compared with the previous standard treatment of docetaxel chemotherapy.[37,38][Level of evidence:1iiA] In addition, the rates of grade 3 and 4 treatment-related toxicity in both trials were significantly lower with nivolumab than with docetaxel. Of note, all patients enrolled in phase III studies of nivolumab had an ECOG PS of 0 or 1; patients with autoimmune disease, symptomatic interstitial lung disease, or those receiving systemic immunosuppression were excluded from enrollment.
   1. A randomized, open-label, phase III trial randomly assigned 272 advanced squamous cell NSCLC patients who had received one regimen of platinum-containing chemotherapy to receive either nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), administered until disease progression.[37] The primary endpoint of this study was OS.
      • Nivolumab demonstrated a significant improvement in median OS compared with docetaxel (9.2 months vs. 6 months; P < .001). In addition, the ORR (20% vs. 9%; P = .008) and median PFS (3.5 months vs. 2.8 months; P < .001) favored nivolumab.
      • Rates of treatment-related toxicity were significantly lower with nivolumab than with docetaxel (all grades, 58% for nivolumab vs. 86% for docetaxel; grades 3–4, 7% for nivolumab vs. 55% for docetaxel).
   2. A randomized, open-label, phase III trial randomly assigned 582 advanced nonsquamous NSCLC patients who had received one regimen of platinum-containing chemotherapy to receive either nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), administered until disease progression.[38] Previous maintenance chemotherapy after first-line platinum-doublet was allowed; patients with EGFR mutations or ALK translocations were allowed to have received an additional regimen of therapy with a TKI. The primary endpoint of this study was OS.
      • Nivolumab demonstrated a significant improvement in patients in median OS compared with docetaxel (12.2 months vs. 9.4 months; HR, 0.73; 96% CI, 0.59–0.89; P = .002). In this study, ORR (19% vs. 12%; P = .02) but not median PFS (2.3 months for nivolumab vs. 4.2 months for docetaxel) favored nivolumab. The median DOR in patients was 17.2 months for nivolumab and 5.6 months for docetaxel.
      • Rates of treatment-related toxicity were significantly lower with nivolumab than with docetaxel (all grades, 69% for nivolumab vs. 88% for docetaxel; grades 3–4, 10% for nivolumab vs. 54% for docetaxel).
   3. Both of these trials demonstrated long-term clinical benefit at the 2-year outcomes. The OS rates for nivolumab at 2 years compared with docetaxel in squamous NSCLC were 23% (95% CI, 16–30) versus 8% (95% CI, 4–13), and OS rates in nonsquamous NSCLC were 29% (95% CI, 24–34) versus 16% (95% CI, 12–20).[40] Ongoing responses at 2 years were observed in 10 (37%) confirmed responders with squamous NSCLC and 19 (34%) of 56 responders with nonsquamous NSCLC. No patient treated with docetaxel in either study had an ongoing response.

Nivolumab is now considered a standard second-line therapy for patients with metastatic NSCLC with progression on or after first-line platinum-based chemotherapy and is associated with improved survival and lower rates of toxicity than docetaxel. However, clinical trials of nivolumab to date have not enrolled patients with a history of autoimmune disease, interstitial lung disease, or an ECOG PS higher than 1. Patients with active autoimmune conditions cannot be treated with nivolumab. Closely monitoring all patients for autoimmune toxicities from treatment is required. Specific algorithms for the management of autoimmune toxicity are included in the FDA label for nivolumab.

Pembrolizumab

Evidence (pembrolizumab):

1. In a phase I study with multiple expansion cohorts, pembrolizumab demonstrated significant activity with respect to response rate and DOR.[39][Level of evidence: 3iiiDiv]
   • In the study, 495 patients received either pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. No significant differences were seen among the different treatment schedules. Key exclusion criteria were autoimmune disease, history of pneumonitis, requirement for systemic immunosuppressive therapy, and a PS higher than 1. The ORR was 19.4% (95% CI, 16.0–23.2), which included a response rate of 18.0% (95% CI, 14.4–22.2) in 394 previously treated patients and 24.8% (95% CI, 16.7–34.3) in 101 previously untreated patients. Median PFS was 3.7 months (95% CI, 2.9–4.1) for all patients, 3.0 months (95% CI, 2.2–4.0) for previously treated patients, and 6.0 months (95% CI, 4.1–8.6) for previously untreated patients. The median DOR was 12.5 months (range, 1.0–23.3 months) in all patients.
   • The study evaluated the efficacy of pembrolizumab in patients with high levels of PD-L1, as assessed by the anti-PD-L1 antibody clone 22C3. Using the cutoff of membranous staining in at least 50% of tumor cells in a validation group of 73 patients, the response rate was 45.2% (95% CI, 33.5–57.3), and the median PFS in this group was 6.3 months (95% CI, 2.9–12.5). Median OS was not reached at the time of publication.
   • The estimated prevalence of PD-L1 tumor staining from 1,143 screened patients, of whom 824 had evaluable samples, is as follows: 23.2% had 50% or more tumor cells with staining; 37.6% had between 1% and 49% tumor cells with staining; and 39.2% had less than 1% of tumor cells with staining.
   • The most common adverse events were fatigue, pruritus, and decreased appetite. Grade 3 or higher adverse events were reported in 9.5% of patients. Inflammatory and immune-mediated adverse events that occurred in more than 2% of patients were infusion-related reactions (3.0%), hypothyroidism (6.9%), and pneumonitis (3.6%).
2. In a phase II/III randomized clinical trial, patients with previously treated NSCLC with PD-L1 expression on at least 1% of tumor cells were randomly assigned (1:1:1) to receive pembrolizumab (2 mg/kg), pembrolizumab (10 mg/kg), or docetaxel (75 mg/m2) every 3 weeks.[41][Level of evidence: 1iiA] The primary endpoints were OS and PFS in the total population and in patients with PD-L1 expression on at least 50% of tumor cells. This study enrolled 1,034 patients; 345 of them were allocated to pembrolizumab (2 mg/kg); 346 were allocated to pembrolizumab (10 mg/kg); and 343 were allocated to docetaxel.
   • In the total population, median OS was 10.4 months with pembrolizumab (2 mg/kg), 12.7 months with pembrolizumab (10 mg/kg), and 8.5 months with docetaxel. OS was significantly longer for pembrolizumab (2 mg/kg) versus docetaxel (HR 0.71; 95% CI, 0.58–0.88; P = .0008) and for pembrolizumab (10 mg/kg) versus docetaxel (HR, 0.61; CI, 0.49–0.75; P < .0001).
   • In the total population, PFS was not prolonged in the pembrolizumab groups compared with the docetaxel group.
   • Among patients with at least 50% of tumor cells expressing PD-L1, OS was significantly longer with pembrolizumab (2 mg/kg) than with docetaxel (median, 14.9 months vs. 8.2 months; HR, 0.54; 95% CI, 0.38–0.77; P = .0002) and with pembrolizumab (10 mg/kg) than with docetaxel (median, 17.3 months vs. 8.2 months; HR, 0.50; CI, 0.36–0.70; P < .0001).
   • In the group of patients with at least 50% of tumor cells expressing PD-L1, PFS was significantly longer with pembrolizumab (2 mg/kg) than with docetaxel (median, 5.0 months vs. 4.1 months; HR, 0.59; 95% CI, 0.44–0.78; P = .0001) and with pembrolizumab (10 mg/kg) than with docetaxel (median, 5.2 months vs. 4.1 months; HR, 0.59; CI, 0.45–0.78; P < .0001).
   • Grade 3 to 5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given pembrolizumab (2 mg/kg), 55 [16%] of 343 patients given pembrolizumab (10 mg/kg), and 109 [35%] of 309 patients given docetaxel).

Pembrolizumab received accelerated approval as a second-line therapy for patients with NSCLC whose tumors express PD-L1 (>50% staining as determined by an FDA-approved test) with progression on or after first-line chemotherapy. Patients with EGFR or ALKgenomic tumor aberrations should have disease progression on FDA-approved therapies before receiving pembrolizumab (refer to the FDA label for pembrolizumab).

Atezolizumab

Evidence (atezolizumab):

1. Two international, randomized, open-label clinical trials (OAK [NCT02008227] and POPLAR [NCT01903993]) demonstrated efficacy and safety in a total of 1,137 patients with NSCLC who previously received platinum chemotherapy.[42,43][Level of evidence: 1iiA] Compared with docetaxel, treatment with atezolizumab in the intended patient population resulted in improved OS rates of 4.2 months in the OAK study and 2.9 months in the POPLAR study.
   • In the OAK trial, the median OS was 13.8 months in the atezolizumab arm (95% CI, 11.8–15.7) compared with 9.6 months in the docetaxel arm (95% CI, 8.6–11.2) (HR = 0.74; 95% CI, 0.63–0.87; P = .0004).
   • The median OS in the POPLAR trial was 12.6 months in the atezolizumab arm (95% CI, 9.7–16.0) and 9.7 months in the docetaxel arm (95% CI, 8.6–12.0) (HR, 0.69; 95% CI, 0.52–0.92).
   • Although the magnitude of improvement correlated with PD-L1 immunohistochemistry expression on tumor cells and tumor-infiltrating immune cells, survival benefit with atezolizumab was seen in patients with tumors with and without PD-L1 expression.
   • In the POPLAR trial, the most common (≥20%) adverse reactions were in patients treated with atezolizumab and included fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation.
   • The most common (≥2%) grade 3 to 4 adverse events in patients treated with atezolizumab were dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, anemia, musculoskeletal pain, aspartate aminotransferase increase, alanine aminotransferase increase, dysphagia, and arthralgia.
   • Clinically significant immune-related adverse events for patients receiving atezolizumab included pneumonitis, hepatitis, colitis, and thyroid disease.

Treatment Options under Clinical Evaluation for Progressive Stage IV, Relapsed, and Recurrent NSCLC (Second-line Therapy)

Treatment options under clinical evaluation for progressive stage IV, relapsed, and recurrent NSCLC (second-line therapy) include the following:

• Clinical trials can be considered as second-line therapy.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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16. Miller VA, Kris MG, Shah N, et al.: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22 (6): 1103-9, 2004. [PUBMED Abstract]
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18. Lynch TJ, Bell DW, Sordella R, et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350 (21): 2129-39, 2004. [PUBMED Abstract]
19. Pao W, Miller V, Zakowski M, et al.: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101 (36): 13306-11, 2004. [PUBMED Abstract]
20. Pao W, Wang TY, Riely GJ, et al.: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2 (1): e17, 2005. [PUBMED Abstract]
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24. Soria JC, Felip E, Cobo M, et al.: Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 16 (8): 897-907, 2015. [PUBMED Abstract]
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27. Shaw AT, Yeap BY, Solomon BJ, et al.: Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12 (11): 1004-12, 2011. [PUBMED Abstract]
28. Shaw AT, Kim DW, Nakagawa K, et al.: Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 368 (25): 2385-94, 2013. [PUBMED Abstract]
29. Shaw AT, Kim DW, Mehra R, et al.: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370 (13): 1189-97, 2014. [PUBMED Abstract]
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Changes to This Summary (03/01/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC Treatment

Added Neurotrophic tyrosine kinase (NTRK) inhibitors (for patients with NTRK fusions) as a new subsection.

Added new text to state that further follow up of this study confirmed an overall survival (OS) advantage in favor of pembrolizumab; the median OS for patients who received pembrolizumab was 30 months versus 14.2 months for patients who received chemotherapy, with a 75% crossover to immunotherapy afterwards, suggesting the crossover did not impact survival (cited Reck et al. as reference 74).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of non-small cell lung cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Non-Small Cell Lung Cancer Treatment are:

• Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group)
• Patrick Forde, MD (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins)
• Raymond Mak, MD (Harvard Medical School)
• Arun Rajan, MD (National Cancer Institute)
• Eva Szabo, MD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Non-Small Cell Lung Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389304]

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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• Updated: March 1, 2019