Background
Phase 2 RCT (Lung-MAP S1800A); N=136 advanced NSCLC previously treated with immunotherapy (sequential or combined with platinum chemo) with progression ≥84 days after ICI initiation; last chemo ≥1 year before progression.
Interventions and follow up
Arm A: Ramucirumab 10 mg/kg + pembrolizumab 200 mg IV q21d
Arm B: Investigator's choice SOC (docetaxel ± ramucirumab, gemcitabine, or pemetrexed)
Primary endpoint: overall survival
mFollow up: 17.9mo
Arm B: Investigator's choice SOC (docetaxel ± ramucirumab, gemcitabine, or pemetrexed)
Primary endpoint: overall survival
mFollow up: 17.9mo
Results
mOS: 14.5mo vs 11.6mo, arm A vs B; HR 0.69, 80%CI 0.51-0.92
mPFS: 4.5mo vs 5.2mo, HR 0.86, 80%CI 0.66-1.14
ORR: 22% vs 28%
mPFS: 4.5mo vs 5.2mo, HR 0.86, 80%CI 0.66-1.14
ORR: 22% vs 28%
Adverse events
Vascular: hypertension 13% vs 3%
Fatal: treatment-related deaths n=3 vs n=4
Class effects (ramucirumab): wound dehiscence, arterial thrombosis > VTE, GI perforation, bleeding, diarrhea, RPLS; monitor thyroid function and infusion reactions in early cycles
Fatal: treatment-related deaths n=3 vs n=4
Class effects (ramucirumab): wound dehiscence, arterial thrombosis > VTE, GI perforation, bleeding, diarrhea, RPLS; monitor thyroid function and infusion reactions in early cycles
Conclusions
Ramucirumab plus pembrolizumab significantly improved OS versus SOC in NSCLC progressing ≥3 months after prior immunotherapy, without a PFS or ORR advantage.
Key Limitations
Phase 2, 80% CI used; OS benefit despite no PFS/ORR improvement; SOC arm heterogeneous; not powered for definitive practice change.
Clinical Context
Hypothesis-generating signal for VEGF/PD-1 re-challenge in the post-ICI setting; the larger confirmatory Pragmatica-Lung (S2302) phase 3 was launched to validate. Not yet a guideline standard.