Background
Phase III open-label RCT, N=1,274, untreated locally advanced or metastatic NSCLC, PD-L1 TPS ≥1%. Excluded EGFR/ALK alterations, unstable/untreated CNS mets, prior pneumonitis or autoimmune disease needing steroids, HBV/HCV.
Interventions and follow up
Arm A: Pembrolizumab 200 mg q3wk up to 35 cycles
Arm B: Carboplatin AUC 5-6 + paclitaxel 200 mg/m2 (or pemetrexed 500 mg/m2) x4-6 cycles; pemetrexed maintenance allowed in nonsquamous
Primary endpoint: OS in PD-L1 TPS ≥50%, ≥20%, and ≥1% (hierarchical)
mFollow up: 12.8 mo
Arm B: Carboplatin AUC 5-6 + paclitaxel 200 mg/m2 (or pemetrexed 500 mg/m2) x4-6 cycles; pemetrexed maintenance allowed in nonsquamous
Primary endpoint: OS in PD-L1 TPS ≥50%, ≥20%, and ≥1% (hierarchical)
mFollow up: 12.8 mo
Results
mOS PD-L1 ≥50%: 20.0 vs 12.2 mo (A vs B); HR 0.69, 95%CI 0.56-0.85; P=.0003
mOS PD-L1 ≥20%: 17.7 vs 13.0 mo; HR 0.77, 95%CI 0.64-0.92; P=.002
mOS PD-L1 ≥1%: 16.7 vs 12.1 mo; HR 0.81, 95%CI 0.71-0.93; P=.0018
mOS PD-L1 1-49% (exploratory): 13.4 vs 12.1 mo; HR 0.92, 95%CI 0.77-1.11 (no benefit)
24-mo OS ≥50%: 45% vs 30%
24-mo OS ≥20%: 41% vs 30%
24-mo OS ≥1%: 39% vs 28%
mOS PD-L1 ≥20%: 17.7 vs 13.0 mo; HR 0.77, 95%CI 0.64-0.92; P=.002
mOS PD-L1 ≥1%: 16.7 vs 12.1 mo; HR 0.81, 95%CI 0.71-0.93; P=.0018
mOS PD-L1 1-49% (exploratory): 13.4 vs 12.1 mo; HR 0.92, 95%CI 0.77-1.11 (no benefit)
24-mo OS ≥50%: 45% vs 30%
24-mo OS ≥20%: 41% vs 30%
24-mo OS ≥1%: 39% vs 28%
Adverse events
Overall (A vs B): grade ≥3 treatment-related 18% vs 41%; discontinuation ~9% vs 9%
Pulmonary: grade ≥3 pneumonitis 3% vs 0%
Hematologic: grade ≥3 anemia <1% vs 13%
Immune-related: hypothyroidism, hyperthyroidism, pneumonitis more frequent with pembrolizumab
Pulmonary: grade ≥3 pneumonitis 3% vs 0%
Hematologic: grade ≥3 anemia <1% vs 13%
Immune-related: hypothyroidism, hyperthyroidism, pneumonitis more frequent with pembrolizumab
Conclusions
First-line pembrolizumab monotherapy improved OS across PD-L1 TPS ≥1%, ≥20%, and ≥50%, but benefit was driven by high expressers; the 1-49% subgroup derived no clear advantage.
Key Limitations
≥1% benefit confounded by ≥50% subgroup; no incremental benefit in 1-49%. Open-label; chemotherapy comparator without immunotherapy crossover at randomization. No combination-immunotherapy comparator.
Clinical Context
FDA expanded first-line pembrolizumab monotherapy to PD-L1 TPS ≥1% NSCLC (Apr 2019). ESMO favors single-agent pembrolizumab for TPS ≥50%; for TPS 1-49% it endorses pembrolizumab + chemotherapy over monotherapy given the weak monotherapy signal here.