Study Details

In this open-label trial, 1,034 patients from 202 sites in 24 countries who had progressive disease after platinum therapy (and EGFR and ALK inhibitors if appropriate) and PD-L1 expression on ≥ 1% of tumor cells were randomly assigned 1:1:1 between August 2013 and February 2015 to receive pembrolizumab at 2 mg/kg (n = 345), pembrolizumab at 10 mg/kg (n = 346), or docetaxel at 75 mg/m² (n = 343) every 3 weeks. 

Roy S. Herbst, MD, PhD

The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on ≥ 50% of tumor cells. Significance thresholds were P < .00825 (one-sided) for analysis of overall survival and P < .001 for progression-free survival. Patients in the docetaxel group were not permitted to cross over to receive pembrolizumab.

In the total population, the three groups were generally balanced for age (median, 62–63 years), sex (61%–62% male), race (72%–73% white, 21% Asian), region (not east Asia for 81%–82%), Eastern Cooperative Oncology Group performance status (0 or 1 in >99%), histology (nonsquamous in 70%–71%), smoking status (never for 17%–20%), stable brain metastases (14%–16%), wild-type EGFR (83%–86%), ALK translocation (1%), previous systemic therapy (adjuvant in 1%–2%, neoadjuvant in < 1%), previous lines of treatment for advanced disease (1 in 68%–71%), 2 in 19%–22%, ≥ 3 in 8%–10%), and previous systemic treatment for advanced disease (chemotherapy in 97%–99%, immunotherapy in < 1%, EGFR inhibitor in 12%–16%, ALK inhibitor in 1%). Overall, 139 patients (40%) in the pembrolizumab at 2 mg/kg group, 151 (44%) in the 10mg/kg group, and 152 (44%) in the docetaxel group had PD-L1 expression ≥ 50%. Other baseline characteristics in these subgroups were similar to those in the total population. 

Outcomes in Total Population

At data cutoff in the total population, median overall survival was 10.4 months with pembrolizumab at 2 mg/kg (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.58–0.88, P = .0008) and 12.7 months with pembrolizumab at 10 mg/kg (HR = 0.61, 95% CI = 0.49–0.75, P < .0001) vs 8.5 months with docetaxel. Overall survival at 1 year was 43.2% and 52.3% vs 34.6%. 

Additional treatment after discontinuation of study treatment was received by 40%, 38%, and 44% of patients, including chemotherapy in 35%, 29%, and 27%; an EGFR inhibitor in 8%, 7%, and 12%; and immunotherapy in 1%, 2%, and 13% (pembrolizumab in 0.9%). 

Median progression-free survival in the total population was 3.9 months (HR = 0.88, 95% CI = 0.74–1.05, P = .07 [not significant]) and 4.0 months (HR = 0.79, 95% CI = 0.66–0.94, P = .004 [not significant]) vs 4.0 months. The investigators noted that the overall survival benefit despite absence of progression-free survival benefit was also observed in the CheckMate 057 trial of nivolumab (Opdivo) vs docetaxel in nonsquamous NSCLC.² 

Responses (all partial) were observed in 18% (P = .0005) of patients receiving pembrolizumab at 2 mg/kg and 18% (P = .0002) of those receiving pembrolizumab at 10 mg/kg vs 9% of those receiving docetaxel at 75 mg/m².

PD-L1 Expression ≥ 50%

Among the patients with ≥ 50% of tumor cells expressing PD-L1, median overall survival was 14.9 months (HR = 0.54, 95% CI = 0.38–0.77, P = .0002) and 17.3 months (HR = 0.50, 95% CI = 0.36–0.70, P < .0001) vs 8.2 months. Median progression-free survival was significantly prolonged with pembrolizumab, at 5.0 months (HR = 0.59, 95% CI = 0.44–0.78, P = .0001) and 5.2 months (HR = 0.59, 95% CI = 0.45–0.78, P < .0001) vs 4.1 months. Responses occurred in 30% and 29% (both P < .0001) vs 8% of patients. 

Subgroup analysis of overall survival with pooled pembrolizumab groups in the total population showed that hazard ratios favored pembrolizumab for all subgroups examined, including histology and age of tumor sample for PD-L1 testing. Hazard ratios were 0.53 (95% CI = 0.40–0.70) among patients with PD-L1 expression ≥ 50% and 0.76 (95% CI = 0.60–0.96) among those with expression of 1% to 49%. The benefit of pembrolizumab among the 86 patients with EGFR-mutant status (HR = 0.88, 95% CI = 0.45–1.70) was not as great as in other subgroups. 

Subgroup analysis of progression-free survival in the total population showed that hazard ratios favored pembrolizumab in most subgroups; hazard ratios were 0.59 (95% CI = 0.46–0.74) among patients with PD-L1 expression ≥ 50% and 1.04 (95% CI = 0.85–1.27) in those with lower expression levels. The hazard ratio among patients with EGFR-mutant status was 1.79 (95% CI = 0.94–3.42). 

Adverse Events

As determined by investigators, treatment-related adverse events of any grade occurred in 63%, 66%, and 81% of patients, and those of grade ≥ 3 occurred in 13%, 16%, and 35% (including neutropenia in 0% of the pembrolizumab groups and 12% of the docetaxel group). Potential immune-related adverse events of any grade irrespective of investigator-assessed causality were observed in 20% of the pembrolizumab at 2 mg/kg group and 19% of the 10 mg/kg group, with the most common being hypothyroidism (8% in both), hyperthyroidism (4% and 6%), and pneumonitis (5% and 4%). The most common potential immune-mediated events of grade ≥ 3 were pneumonitis (2% in both) and severe skin reactions (1% and 2%).

The investigators concluded: “Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.” ■

Disclosure: The study was funded by Merck & Co. For full disclosures of the study authors visit www.thelancet.com.

References

1. Herbst RS, Baas P, Kim D-W, et al: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial. Lancet 387:1540-1550, 2016.

2. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627-1639, 2015.