Background
Phase III, double-blind RCT (RELAY); N=449; treatment-naive EGFR-mutated (ex19del/L858R) metastatic NSCLC; excluded CNS metastases; randomized 1:1.
Interventions and follow up
Arm A: Erlotinib 150 mg PO daily + ramucirumab 10 mg/kg IV q2wk
Arm B: Erlotinib 150 mg PO daily + placebo
Primary endpoint: investigator-assessed PFS
mFollow up: 20.7 mo
Arm B: Erlotinib 150 mg PO daily + placebo
Primary endpoint: investigator-assessed PFS
mFollow up: 20.7 mo
Results
mPFS: 19.4 mo vs 12.4 mo; HR 0.59 (95%CI 0.46–0.76); P<.0001
OS: immature at primary analysis
OS: immature at primary analysis
Adverse events
Cardiovascular: hypertension
GI: stomatitis
Renal: proteinuria
Skin/bleeding: alopecia, epistaxis
Vascular: peripheral edema
Lab changes: LFT elevation, anemia, thrombocytopenia, neutropenia
Infections: reported (events ≥20% and ≥2% higher than placebo arm)
GI: stomatitis
Renal: proteinuria
Skin/bleeding: alopecia, epistaxis
Vascular: peripheral edema
Lab changes: LFT elevation, anemia, thrombocytopenia, neutropenia
Infections: reported (events ≥20% and ≥2% higher than placebo arm)
Conclusions
Adding ramucirumab to erlotinib improved PFS but not (mature) OS in first-line EGFR-mutant NSCLC; consistent with EGFR+VEGF combinations improving PFS only.
Key Limitations
No mature OS benefit; excluded CNS metastases; comparator erlotinib (not osimertinib); added VEGF-related toxicity (hypertension, proteinuria).
Clinical Context
Ramucirumab + erlotinib FDA approved first-line for EGFR ex19del/L858R metastatic NSCLC (2020). ESMO/ASCO list it as an option but osimertinib remains preferred first-line; combination reserved for selected patients.