Background Options for patients with non-squamous non-small cell lung cancer (NSCLC) whose disease progresses after first-line chemotherapy are limited. This randomized, open-label, international phase 3 study evaluated efficacy and safety of nivolumab versus docetaxel in this patient population after failure of platinum doublet chemotherapy. Methods Patients were randomized to nivolumab 3 mg per kilogram every 2 weeks or docetaxel 75 mg per square meter every 3 weeks. The primary endpoint was overall survival. Results Nivolumab improved overall survival versus docetaxel. Median overall survival was 12.2 months (95% CI, 9.7 to 15.0) for nivolumab (n=292) and 9.4 months (95% CI, 8.1 to 10.7) for docetaxel (n=290) (hazard ratio, 0.73; 96% CI, 0.59 to 0.89; P=0.002). One-year overall survival rates were 51% (95% CI, 45 to 56) for nivolumab and 39% (95% CI, 33 to 45) for docetaxel. Updated efficacy results with additional follow up are available for overall survival only: 18-month overall survival rates were 39% (95% CI, 34 to 45) for nivolumab and 23% (95% CI, 19 to 28) for docetaxel. Response rates were 19% for nivolumab and 12% for docetaxel (P=0.02). Although progression-free survival did not favor nivolumab (2.3 months for nivolumab versus 4.2 months for docetaxel), 1-year progression-free survival was higher for nivolumab (19%) than docetaxel (8%). Nivolumab further improved efficacy across all endpoints at predefined ≥1%, ≥5%, and ≥10% programmed death-1 ligand 1 (PD-L1) tumor membrane expression levels. Grade 3–5 treatment-related adverse events were reported in 10% of nivolumab and 54% of docetaxel-treated patients. Conclusions Compared to docetaxel, nivolumab demonstrated superior overall survival, with PD-L1 expression conferring enhanced efficacy in patients with advanced non-squamous NSCLC after failure of platinum-based chemotherapy. The safety profile of nivolumab was favorable versus docetaxel.

Background Patients with advanced squamous-cell non–small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, as compared with docetaxel in this patient population. Methods We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. Results The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P = 0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group. Conclusions Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.)

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Progression-free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461 .).

BACKGROUNDStandard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC. METHODSIn this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival. RESULTSAfter a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumabcombination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebocombination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%). CONCLUSIONSIn patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435.

Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceut

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Lung cancer is the most frequent cause of cancer-related deaths worldwide. Every year, 1·8 million people are diagnosed with lung cancer, and 1·6 million people die as a result of the disease. 5-year survival rates vary from 4-17% depending on stage and regional differences. In this Seminar, we discuss existing treatment for patients with lung cancer and the promise of precision medicine, with special emphasis on new targeted therapies. Some subgroups, eg-patients with poor performance status and elderly patients-are not specifically addressed, because these groups require special treatment considerations and no frameworks have been established in terms of new targeted therapies. We discuss prevention and early detection of lung cancer with an emphasis on lung cancer screening. Although we acknowledge the importance of smoking prevention and cessation, this is a large topic beyond the scope of this Seminar.