Background
Phase III KEYNOTE-789; N=289 EGFR-mutant metastatic NSCLC progressing on EGFR-TKI; double-blind. Evaluated adding pembrolizumab to chemotherapy after TKI failure.
Interventions and follow up
Arm A: Pembrolizumab 200 mg IV Q3W + platinum (carboplatin or cisplatin) + pemetrexed Q3W ×4, then pembrolizumab + pemetrexed maintenance
Arm B: Placebo IV Q3W + same chemo, then placebo + pemetrexed maintenance
Primary endpoint: PFS and OS
mFollow up: ~14mo
Arm B: Placebo IV Q3W + same chemo, then placebo + pemetrexed maintenance
Primary endpoint: PFS and OS
mFollow up: ~14mo
Results
mPFS: 5.6 vs 5.5mo, HR 0.90, 95% CI 0.73–1.12, P=.37 (NS)
mOS: 15.9 vs 14.7mo, HR 0.88, 95% CI 0.66–1.18, P=.39 (NS)
ORR: 35.1% vs 33%
PR: ~35% vs 33%; no CR reported
mOS: 15.9 vs 14.7mo, HR 0.88, 95% CI 0.66–1.18, P=.39 (NS)
ORR: 35.1% vs 33%
PR: ~35% vs 33%; no CR reported
Adverse events
Overall: Grade ≥3 AEs 43.7% vs 38.6%.
Hematologic: anemia and neutropenia rates similar between arms.
Hematologic: anemia and neutropenia rates similar between arms.
Conclusions
Adding pembrolizumab to chemotherapy did not significantly improve PFS or OS in EGFR-TKI–resistant NSCLC. Chemo-immunotherapy offers no clear benefit here, underscoring the need for alternative strategies after EGFR-TKI failure.
Key Limitations
Negative trial (no benefit); no bevacizumab arm; PD-L1 not enriched; modest N for subgroup inference.
Clinical Context
Reinforces that single-agent PD-1 + chemo (without anti-VEGF) is not effective in EGFR-mutant post-TKI NSCLC. ESMO does not recommend chemo-immunotherapy in this setting; platinum-doublet chemo remains the standard, with amivantamab combinations emerging.
References