Background
Phase III double-blind RCT, N=559, untreated metastatic squamous NSCLC, EGFR/ALK wt, any PD-L1 (≥1% in 63.3%, <1% in 34.2%, Arm A). Excluded symptomatic CNS mets (~7-9% had brain mets), prior pneumonitis, active autoimmune disease. Randomized 1:1.
Interventions and follow up
Arm A: Carboplatin AUC 6 + paclitaxel 200 mg/m2 (or nab-paclitaxel 100 mg/m2 d1, d8, d15)* x4 cycles + pembrolizumab 200 mg q3wk x31 cycles (~24 mo)
Arm B: Same platinum couplet* x4 cycles + placebo
Primary endpoints: OS and PFS
mFollow up: 7.8 mo (primary); 14.3 mo (update PMID 32599071)
Arm B: Same platinum couplet* x4 cycles + placebo
Primary endpoints: OS and PFS
mFollow up: 7.8 mo (primary); 14.3 mo (update PMID 32599071)
Results
mOS all: 15.9 vs 11.3 mo (A vs B); HR 0.64, 95%CI 0.49-0.85; P<.001
mOS PD-L1 <1%: 15.9 vs 10.2 mo; HR 0.61, 95%CI 0.38-0.98
mOS PD-L1 1-49%: 14.0 vs 11.6 mo; HR 0.57, 95%CI 0.36-0.90
mOS PD-L1 ≥50%: NR vs NR; HR 0.64, 95%CI 0.37-1.10
mPFS all: 6.4 vs 4.8 mo; HR 0.56, 95%CI 0.45-0.70; P<.001
mPFS PD-L1 <1%: 6.3 vs 5.3 mo; HR 0.68, 95%CI 0.47-0.98
mPFS PD-L1 1-49%: 7.2 vs 5.2 mo; HR 0.56, 95%CI 0.39-0.80
mPFS PD-L1 ≥50%: 8.0 vs 4.2 mo; HR 0.37, 95%CI 0.24-0.58
ORR: 57.9% vs 38.4%
Update (PMID 32599071, mFU 14.3 mo): mOS 17.1 vs 11.6 mo; HR 0.71, 95%CI 0.58-0.88
12/18/24-mo OS: 64.7%/48.0%/37.5% vs 49.6%/36.5%/30.6%
mOS PD-L1 <1%: 15.9 vs 10.2 mo; HR 0.61, 95%CI 0.38-0.98
mOS PD-L1 1-49%: 14.0 vs 11.6 mo; HR 0.57, 95%CI 0.36-0.90
mOS PD-L1 ≥50%: NR vs NR; HR 0.64, 95%CI 0.37-1.10
mPFS all: 6.4 vs 4.8 mo; HR 0.56, 95%CI 0.45-0.70; P<.001
mPFS PD-L1 <1%: 6.3 vs 5.3 mo; HR 0.68, 95%CI 0.47-0.98
mPFS PD-L1 1-49%: 7.2 vs 5.2 mo; HR 0.56, 95%CI 0.39-0.80
mPFS PD-L1 ≥50%: 8.0 vs 4.2 mo; HR 0.37, 95%CI 0.24-0.58
ORR: 57.9% vs 38.4%
Update (PMID 32599071, mFU 14.3 mo): mOS 17.1 vs 11.6 mo; HR 0.71, 95%CI 0.58-0.88
12/18/24-mo OS: 64.7%/48.0%/37.5% vs 49.6%/36.5%/30.6%
Adverse events
Overall (A vs B): grade ≥3 69.8% vs 68.2%; discontinuation due to AE 13.3% vs 6.4%
Immune-related: more frequent with pembrolizumab (hypothyroidism, pneumonitis, hyperthyroidism)
Hematologic: anemia, neutropenia common in both (chemotherapy backbone)
Immune-related: more frequent with pembrolizumab (hypothyroidism, pneumonitis, hyperthyroidism)
Hematologic: anemia, neutropenia common in both (chemotherapy backbone)
Conclusions
Adding pembrolizumab to carboplatin-taxane significantly improved OS and PFS in metastatic squamous NSCLC across all PD-L1 strata.
Key Limitations
Squamous-only (nonsquamous via KEYNOTE-189). High crossover from placebo to immunotherapy. No comparison to pembrolizumab monotherapy in high PD-L1 expressers. ≥50% subgroup CI crosses 1 due to small numbers.
Clinical Context
FDA approved pembrolizumab + carboplatin + paclitaxel/nab-paclitaxel first-line for metastatic squamous NSCLC (Oct 2018). ESMO endorses chemo-immunotherapy as a preferred first-line standard for squamous histology regardless of PD-L1. Squamous counterpart to KEYNOTE-189.