Non-Small Cell Lung Cancer Treatment (PDQ®) 5/5 —Health Professional Version - National Cancer Institute

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

Non-Small Cell Lung Cancer Treatment (PDQ®)–Health Professional Version

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 (CNS) 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]

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).[66]
   • 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 duration of response 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.[66][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 FDA-approved dose of brigatinib is 90 mg qd for 7 days; if tolerated, the dose is increased to 180 mg qd.

Lorlatinib

Evidence (lorlatinib):

1. In an open-label ongoing phase II study with multiple cohorts, patients with metastatic ALK-rearranged NSCLC were enrolled into six ALK expansion (EXP) cohorts based on their ALK status and treatment history.[67] They received lorlatinib 100 mg once daily continuously in 21-day cycles. The primary endpoint was objective tumor response and intracranial tumor response by independent central review, as assessed in key pooled subgroups.[67][Level of evidence: 3iiiDiv]
   1. The number of patients treated, the ORRs, and the intracranial response rates in each cohort or pooled cohorts are as follows:
      1. EXP1 (n = 30, treatment naïve).
         • RR = 90.0%; 95% CI, 73.5‒97.9.
         • Intracranial (n = 3), RR = 66.7%; 95% CI, 9.4‒99.2.
      2. EXP2 (n = 27, previous crizotinib only) and EXP3A (n = 32, previous crizotinib and chemotherapy), RR = 69.5%; 95% CI, 56.1‒80.8.
         • Intracranial (n = 23), RR = 87.0%; 95% CI, 66.4‒97.2.
      3. EXP3B (n = 28, one previous second-generation ALK inhibitor with or without chemotherapy), RR = 32.1%; 95% CI, 15.9‒52.4.
         • Intracranial (n = 9), RR = 55.6%; 95% CI, 21.2‒86.3.
      4. EXP4 (n = 65, two previous ALK inhibitors with or without chemotherapy) and EXP5 (n = 46, three previous lines of ALK inhibitors, with or without chemotherapy), RR = 38.7%; 95% CI, 29.6‒48.5.
         • Intracranial (n = 49), RR = 53.1%; 95% CI, 38.3‒67.5.
   2. The median duration of response has not been reached for any of the pooled cohorts.
   3. The most common adverse event was hypercholesterolemia (16% grade 3-4), and 3% of patients discontinued treatment due to adverse events.

ROS1 inhibitors (for patients with ROS1 rearrangements)

ROS1 rearrangements occur in approximately 1% of patients with NSCLC.[68]

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.[69] 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).[69][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.[70] 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.[70][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), 36 patients with previously untreated 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.[71] 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.[71][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.[72,73] 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.[74] 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.[74][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 programmed cell death-ligand 2 (PD-L2).[75]

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).[75] 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.[76]
   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.[75][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,[77-82] 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.[22,83][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.[84]
   • Better overall symptom palliation and fewer re-treatments were required in previously untreated patients using EBRT alone.[84][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.[85,86]

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.[87,88] Unresectable brain metastases in this setting may be treated with stereotactic radiosurgery.[89]

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.[90] In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiation surgery.[89,90] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[91][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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39. Thatcher N, Hirsch FR, Luft AV, et al.: Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 16 (7): 763-74, 2015. [PUBMED Abstract]
40. Paz-Ares LG, de Marinis F, Dediu M, et al.: PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol 31 (23): 2895-902, 2013. [PUBMED Abstract]
41. Brodowicz T, Krzakowski M, Zwitter M, et al.: Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer 52 (2): 155-63, 2006. [PUBMED Abstract]
42. Park JO, Kim SW, Ahn JS, et al.: Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol 25 (33): 5233-9, 2007. [PUBMED Abstract]
43. Paz-Ares L, de Marinis F, Dediu M, et al.: Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 13 (3): 247-55, 2012. [PUBMED Abstract]
44. Socinski MA, Schell MJ, Peterman A, et al.: Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 20 (5): 1335-43, 2002. [PUBMED Abstract]
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46. Ciuleanu T, Brodowicz T, Zielinski C, et al.: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 374 (9699): 1432-40, 2009. [PUBMED Abstract]
47. Belani CP, Brodowicz T, Ciuleanu TE, et al.: Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study. Lancet Oncol 13 (3): 292-9, 2012. [PUBMED Abstract]
48. Cappuzzo F, Ciuleanu T, Stelmakh L, et al.: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11 (6): 521-9, 2010. [PUBMED Abstract]
49. Coudert B, Ciuleanu T, Park K, et al.: Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer (NSCLC) according to response to first-line chemotherapy. Ann Oncol 23 (2): 388-94, 2012. [PUBMED Abstract]
50. Brugger W, Triller N, Blasinska-Morawiec M, et al.: Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 29 (31): 4113-20, 2011. [PUBMED Abstract]
51. Soria JC, Ohe Y, Vansteenkiste J, et al.: Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 378 (2): 113-125, 2018. [PUBMED Abstract]
52. Mok TS, Wu YL, Thongprasert S, et al.: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361 (10): 947-57, 2009. [PUBMED Abstract]
53. Maemondo M, Inoue A, Kobayashi K, et al.: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362 (25): 2380-8, 2010. [PUBMED Abstract]
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55. Zhou C, Wu YL, Chen G, et al.: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12 (8): 735-42, 2011. [PUBMED Abstract]
56. Rosell R, Gervais R, Vergnenegre A, et al.: Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: Interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. [Abstract] J Clin Oncol 29 (Suppl 15): A-7503, 2011.
57. Rosell R, Carcereny E, Gervais R, et al.: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13 (3): 239-46, 2012. [PUBMED Abstract]
58. Sequist LV, Yang JC, Yamamoto N, et al.: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 31 (27): 3327-34, 2013. [PUBMED Abstract]
59. Yang JC, Wu YL, Schuler M, et al.: Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 16 (2): 141-51, 2015. [PUBMED Abstract]
60. Wu YL, Zhou C, Hu CP, et al.: Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 15 (2): 213-22, 2014. [PUBMED Abstract]
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]
63. Solomon BJ, Mok T, Kim DW, et al.: First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 371 (23): 2167-77, 2014. [PUBMED Abstract]
64. Mok T, Kim D, Wu Y, et al.: First-line crizotinib versus pemetrexed-cisplatin or pemetrexed-carboplatin in patients (pts) with advanced ALK-positive non-squamous non-small cell lung cancer (NSCLC): results of a phase III study (PROFILE 1014). [Abstract] J Clin Oncol 32 (Suppl 15): A-8002, 2014.
65. Soria JC, Tan DSW, Chiari R, et al.: First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 389 (10072): 917-929, 2017. [PUBMED Abstract]
66. Kim DW, Tiseo M, Ahn MJ, et al.: Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial. J Clin Oncol 35 (22): 2490-2498, 2017. [PUBMED Abstract]
67. Solomon BJ, Besse B, Bauer TM, et al.: Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol 19 (12): 1654-1667, 2018. [PUBMED Abstract]
68. Gainor JF, Shaw AT: Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 18 (7): 865-75, 2013. [PUBMED Abstract]
69. Shaw AT, Ou SH, Bang YJ, et al.: Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371 (21): 1963-71, 2014. [PUBMED Abstract]
70. Wu YL, Yang JC, Kim DW, et al.: Phase II Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 36 (14): 1405-1411, 2018. [PUBMED Abstract]
71. Planchard D, Smit EF, Groen HJM, et al.: Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol 18 (10): 1307-1316, 2017. [PUBMED Abstract]
72. Farago AF, Le LP, Zheng Z, et al.: Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer. J Thorac Oncol 10 (12): 1670-4, 2015. [PUBMED Abstract]
73. 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]
74. 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]
75. 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]
76. 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]
77. 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]
78. 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]
79. 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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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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26. Kwak EL, Bang YJ, Camidge DR, et al.: Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363 (18): 1693-703, 2010. [PUBMED Abstract]
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 (04/05/2019)

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 Brigatinib as a new subsection.

Added Lorlatinib as a new subsection.

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]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

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: April 5, 2019