KEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation
Adding pembrolizumab to standard chemotherapy roughly halved the risk of death in newly diagnosed non-squamous lung cancer, whatever the PD-L1 level, making chemo-immunotherapy the default first treatment.
Double-blind phase 3 trial of 616 patients with untreated metastatic non-squamous NSCLC without EGFR or ALK alterations, randomised 2:1 to pembrolizumab or placebo plus pemetrexed and a platinum. Primary endpoints were overall survival and PFS.
12-month overall survival was 69.2% vs 49.4% (HR 0.49) and median PFS 8.8 vs 4.9 months (HR 0.52), with benefit in every PD-L1 stratum including below 1%. Together with KEYNOTE-024 (pembrolizumab alone for PD-L1 of 50% or more) it made PD-1 blockade part of first-line treatment for almost all patients with advanced NSCLC. The five-year update showed OS 19.4% vs 11.3%.
- 12-month overall survival 69.2% vs 49.4%; HR 0.49 (95% CI 0.38-0.64).
- Median PFS 8.8 vs 4.9 months; HR 0.52.
- OS benefit in all PD-L1 subgroups: TPS below 1% HR 0.59; 1-49% HR 0.55; 50% or more HR 0.42.
- Objective response 47.6% vs 18.9%.
- Five-year update (2023): OS 19.4% vs 11.3%; median 22.0 vs 10.6 months despite about 57% crossover to immunotherapy.
Most patients with newly diagnosed advanced non-squamous lung cancer that lacks a targetable mutation should receive chemotherapy plus pembrolizumab; those with PD-L1 of 50% or more may reasonably receive pembrolizumab alone. About one in five patients is alive at five years, compared with roughly one in ten with chemotherapy alone. Patients with EGFR or ALK alterations were excluded and should have targeted therapy first.
- Excluded EGFR- and ALK-positive tumours; immunotherapy benefit in driver-mutated lung cancer is much smaller.
- Whether patients with PD-L1 of 50% or more need chemotherapy added to pembrolizumab has never been directly randomised.
- Immune-related adverse events, including pneumonitis and nephritis, were more frequent with pembrolizumab.
- Crossover in the control arm means the true OS effect is probably larger than measured.