Background
Phase III double-blind RCT, N=616, untreated metastatic nonsquamous NSCLC, EGFR/ALK negative, any PD-L1 (≥1% in 63.1%, <1% in 31.0%). Excluded symptomatic CNS mets (~17% had brain mets), prior pneumonitis, active autoimmune disease, >30 Gy chest RT within 6 mo.
Interventions and follow up
Arm A: Pembrolizumab 200 mg + pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 (or carboplatin AUC 5) q3wk x4 cycles, then pembrolizumab + pemetrexed maintenance
Arm B: Placebo + chemotherapy q3wk x4 cycles, then pemetrexed maintenance (crossover to pembrolizumab allowed)
Primary endpoints: OS and PFS
mFollow up: 10.5 mo (primary); 23.1 mo (update)
Arm B: Placebo + chemotherapy q3wk x4 cycles, then pemetrexed maintenance (crossover to pembrolizumab allowed)
Primary endpoints: OS and PFS
mFollow up: 10.5 mo (primary); 23.1 mo (update)
Results
12-mo OS: 69.2% vs 49.4% (A vs B); HR 0.49, 95%CI 0.38-0.64; P<.001
mOS: not reached vs 11.3 mo; HR 0.49, 95%CI 0.38-0.64; P<.001
12-mo OS PD-L1 <1%: 61.7% vs 52.2%; HR 0.59, 95%CI 0.38-0.92
12-mo OS PD-L1 1-49%: 71.5% vs 50.9%; HR 0.55, 95%CI 0.34-0.90
12-mo OS PD-L1 ≥50%: 73.0% vs 48.1%; HR 0.42, 95%CI 0.26-0.68
mPFS: 8.8 vs 4.9 mo; HR 0.52, 95%CI 0.43-0.64; P<.001
ORR: 47.6% vs 18.9%
mDOR: 11.2 vs 7.8 mo
Update (PMID 32150489, mFU 23.1 mo): mOS 22.0 vs 10.7 mo; HR 0.56, 95%CI 0.45-0.70
Update mPFS: 9.0 vs 4.9 mo; HR 0.48, 95%CI 0.40-0.58
mOS: not reached vs 11.3 mo; HR 0.49, 95%CI 0.38-0.64; P<.001
12-mo OS PD-L1 <1%: 61.7% vs 52.2%; HR 0.59, 95%CI 0.38-0.92
12-mo OS PD-L1 1-49%: 71.5% vs 50.9%; HR 0.55, 95%CI 0.34-0.90
12-mo OS PD-L1 ≥50%: 73.0% vs 48.1%; HR 0.42, 95%CI 0.26-0.68
mPFS: 8.8 vs 4.9 mo; HR 0.52, 95%CI 0.43-0.64; P<.001
ORR: 47.6% vs 18.9%
mDOR: 11.2 vs 7.8 mo
Update (PMID 32150489, mFU 23.1 mo): mOS 22.0 vs 10.7 mo; HR 0.56, 95%CI 0.45-0.70
Update mPFS: 9.0 vs 4.9 mo; HR 0.48, 95%CI 0.40-0.58
Adverse events
Overall (A vs B): grade ≥3 67.2% vs 65.8%; discontinuation of all drugs 13.8% vs 7.9%
Renal: acute kidney injury 5.2% vs 0.5% (higher with pembrolizumab + pemetrexed)
Pulmonary: pneumonitis more frequent with pembrolizumab
Immune-related: discontinuation of pembrolizumab vs placebo 20.2% vs 10.4%
Renal: acute kidney injury 5.2% vs 0.5% (higher with pembrolizumab + pemetrexed)
Pulmonary: pneumonitis more frequent with pembrolizumab
Immune-related: discontinuation of pembrolizumab vs placebo 20.2% vs 10.4%
Conclusions
Pembrolizumab + platinum/pemetrexed in metastatic nonsquamous NSCLC significantly prolonged OS and PFS across all PD-L1 strata, including PD-L1 <1%.
Key Limitations
Nonsquamous only (squamous addressed by KEYNOTE-407). High crossover from chemo to pembrolizumab (~50%). No head-to-head vs pembrolizumab monotherapy in high PD-L1 expressers.
Clinical Context
FDA approved pembrolizumab + pemetrexed + platinum first-line for metastatic nonsquamous NSCLC, no EGFR/ALK (Aug 2018). ESMO endorses chemo-immunotherapy as a preferred first-line standard regardless of PD-L1, particularly for low/negative expressers. Confirmatory of phase II KEYNOTE-021G (ORR 55% vs 29%).