Background
Phase III, double-blind, placebo-controlled RCT (KEYNOTE-091/PEARLS). N=1177 patients with completely resected stage IB (≥4cm)–IIIA NSCLC, squamous or non-squamous, any PD-L1 level. Adjuvant chemotherapy permitted before randomization. Hierarchical testing: PD-L1 ≥50% first, then all-comers.
Interventions and follow up
Arm A: Pembrolizumab 200 mg IV q3wk × up to 18 cycles (~12 months) (N=590)
Arm B: Placebo IV q3wk × up to 18 cycles (N=587)
Primary endpoint: DFS (hierarchical: PD-L1 ≥50% then ITT)
mFollow up: 35.6 mo
Arm B: Placebo IV q3wk × up to 18 cycles (N=587)
Primary endpoint: DFS (hierarchical: PD-L1 ≥50% then ITT)
mFollow up: 35.6 mo
Results
DFS (PD-L1 ≥50%): HR 0.82, 95% CI 0.57–1.18, P=.28 — NOT significant (hierarchical stopped)
DFS (all-comers): HR 0.76, 95% CI 0.63–0.91, P=.0014
mDFS: 53.6 vs 42.0 months
OS: immature
DFS (all-comers): HR 0.76, 95% CI 0.63–0.91, P=.0014
mDFS: 53.6 vs 42.0 months
OS: immature
Adverse events
Immune-related (grade ≥3): 14.6% vs 1.7%.
Endocrine: hypothyroidism (all grades) 18.6%.
Pulmonary: pneumonitis grade ≥3 3.4%.
Overall: treatment discontinuation 26.3% vs 12.8%.
Endocrine: hypothyroidism (all grades) 18.6%.
Pulmonary: pneumonitis grade ≥3 3.4%.
Overall: treatment discontinuation 26.3% vs 12.8%.
Conclusions
Adjuvant pembrolizumab improved DFS in the all-comers resected NSCLC population (HR 0.76, P=.0014), but the hierarchical primary analysis technically failed because the PD-L1 ≥50% subgroup was not significant. FDA approved adjuvant pembrolizumab for stages IB–IIIA regardless of PD-L1 based on the all-comers result.
Key Limitations
Trial failed pre-specified hierarchical primary (PD-L1 ≥50% not met first) — by strict statistics the all-comers DFS cannot be declared significant at the pre-specified alpha. No OS benefit demonstrated; DFS improvement without OS raises questions about clinical meaningfulness. No biomarker identified to select patients. DFS benefit modest (HR 0.76). High immune-related discontinuation (26%).
Clinical Context
FDA approved adjuvant pembrolizumab 2023 for stage IB–IIIA NSCLC regardless of PD-L1, based on all-comers DFS. Competes with osimertinib (ADAURA, EGFR+) and atezolizumab (IMpower010, PD-L1+). KEYNOTE-091 is unique in enrolling all PD-L1 levels and all stages IB–IIIA. ESMO-MCBS: not favorable given failed hierarchical primary.