Background
Phase III open-label RCT, N=305, untreated stage IV NSCLC, PD-L1 TPS ≥50% (22C3 assay). Excluded EGFR/ALK alterations, untreated brain mets, autoimmune disease requiring treatment. PD-L1 ≥50% seen in ~30% of advanced NSCLC.
Interventions and follow up
Arm A: Pembrolizumab 200 mg q3wk x35 cycles (2 yr)
Arm B: Investigator-choice platinum-based chemotherapy x4-6 cycles (crossover to pembrolizumab allowed)
Primary endpoint: PFS
Secondary endpoints: OS, ORR, safety
mFollow up: 11.2 mo (primary); 25.2 mo and 59.9 mo (updates)
Arm B: Investigator-choice platinum-based chemotherapy x4-6 cycles (crossover to pembrolizumab allowed)
Primary endpoint: PFS
Secondary endpoints: OS, ORR, safety
mFollow up: 11.2 mo (primary); 25.2 mo and 59.9 mo (updates)
Results
mPFS: 10.3 vs 6.7 mo (A vs B); HR 0.50, 95%CI 0.37-0.68; P<.001
6-mo OS: 80.2% vs 72.4%; HR 0.60, 95%CI 0.41-0.89; P=.005
ORR: 44.8% vs 27.8%
Update (PMID 30620668, mFU 25.2 mo): mOS 30.0 vs 14.2 mo; HR 0.63, 95%CI 0.47-0.86; one-sided P=.002
1-yr OS: 70.3% vs 54.8%
2-yr OS: 52.5% vs 34.5%
5-yr update (PMID 33872070): mOS 26.3 vs 13.4 mo; HR 0.62, 95%CI 0.48-0.81
5-yr OS: 31.9% vs 16.3%
6-mo OS: 80.2% vs 72.4%; HR 0.60, 95%CI 0.41-0.89; P=.005
ORR: 44.8% vs 27.8%
Update (PMID 30620668, mFU 25.2 mo): mOS 30.0 vs 14.2 mo; HR 0.63, 95%CI 0.47-0.86; one-sided P=.002
1-yr OS: 70.3% vs 54.8%
2-yr OS: 52.5% vs 34.5%
5-yr update (PMID 33872070): mOS 26.3 vs 13.4 mo; HR 0.62, 95%CI 0.48-0.81
5-yr OS: 31.9% vs 16.3%
Adverse events
Overall (A vs B): Grade 3-4 31.2% vs 53.3%; discontinuation 13.6% vs 10.7%
GI: diarrhea 16.2% vs 14.0%; nausea 9.7% vs 43.3%
Constitutional: fatigue 14.3% vs 28.7%
Hematologic: anemia 5.2% vs 44.0%
Immune-related: hypothyroidism, pneumonitis more frequent with pembrolizumab
GI: diarrhea 16.2% vs 14.0%; nausea 9.7% vs 43.3%
Constitutional: fatigue 14.3% vs 28.7%
Hematologic: anemia 5.2% vs 44.0%
Immune-related: hypothyroidism, pneumonitis more frequent with pembrolizumab
Conclusions
First trial to show OS benefit with first-line anti-PD-1 monotherapy in NSCLC (TPS ≥50%), with a favorable AE profile vs chemotherapy.
Key Limitations
Restricted to TPS ≥50% (no benefit established here for lower expressers). EGFR/ALK and untreated CNS mets excluded. ~50% crossover from chemo to immunotherapy may dilute OS difference.
Clinical Context
FDA approved pembrolizumab monotherapy first-line for metastatic NSCLC with TPS ≥50%, no EGFR/ALK (Oct 2016). ESMO guidelines endorse single-agent pembrolizumab as a preferred first-line option for high PD-L1 expressers. Platinum* options: carbo/cis + pemetrexed, gemcitabine, or paclitaxel; pemetrexed maintenance only in nonsquamous.