The addition of ramucirumab (Cyramza), a VEGF inhibitor, to osimertinib (Tagrisso), an EGFR inhibitor, significantly slowed disease progression in patients with untreated EGFR-positive non-small cell lung cancer (NSCLC), according to results from the RAMOSE trial. The study, a randomized phase II trial, showed a 9-month improvement in median progression-free survival (PFS) with the combination therapy compared to osimertinib alone. This suggests a potential new first-line treatment option for this patient population.
Efficacy of Combination Therapy
The RAMOSE trial's interim analysis revealed a median PFS of 24.8 months in the combination arm versus 15.6 months in the osimertinib-only arm. The 12-month PFS rates were 76.7% and 61.9%, respectively. These results indicate a clinically meaningful benefit for patients receiving the dual-inhibition strategy. The study's findings were published in the Journal of Clinical Oncology.
Safety Profile
The safety profile of the combination was consistent with the known adverse events associated with each drug. The rates of adverse events (AEs), treatment-related AEs (TRAEs), and grade 3 TRAEs were similar between the two treatment arms. No grade 5 AEs occurred during the interim analysis. These findings suggest that the combination is generally well-tolerated.
Biological Rationale
Preclinical and clinical evidence suggests that EGFR-mutated NSCLC is particularly sensitive to VEGF inhibition. EGFR signaling increases VEGF expression, which contributes to EGFR TKI resistance. Combining VEGF and EGFR inhibitors has been shown to delay the emergence of resistance in preclinical models. Clinical trials have also demonstrated improved outcomes with anti-VEGF/EGFR TKI combinations in previously untreated EGFR-mutant NSCLC.
Trial Design and Patient Population
The open-label RAMOSE trial enrolled patients with newly diagnosed advanced/metastatic NSCLC and EGFR exon 19 deletion or L858R mutations across 11 sites in the U.S. Patients were randomized 2:1 to receive either osimertinib plus ramucirumab or single-agent osimertinib. The primary endpoint was investigator-assessed PFS. The analysis included 139 evaluable patients.
Key Findings and Limitations
The primary analysis, conducted after 16.6 months of follow-up, demonstrated a 9.2-month difference in median PFS favoring the combination therapy. This translated to a 45% reduction in the hazard for disease progression or death (95% CI 0.32-0.93, P = 0.023). The 12-month PFS rate also favored the combination, with a near-15% absolute difference (P = 0.026). Objective response rate and disease control rate were similar between the treatment arms.
The study authors acknowledged several limitations, including a moderate sample size, potential bias in investigator-assessed PFS, and an imbalance in patients with brain metastases. They also noted that the overall survival (OS) data were immature at the time of the interim analysis, and further follow-up is needed to confirm these findings.
Implications for Clinical Practice
These results add to the growing body of evidence supporting combination strategies to intensify treatment for EGFR-mutated NSCLC. While single-agent osimertinib has become the standard first-line treatment, studies like RAMOSE are exploring ways to further improve outcomes. The findings suggest that the addition of ramucirumab to osimertinib may be a promising approach to delay disease progression and overcome resistance mechanisms in this patient population. Further validation in larger studies is warranted.
