A major Japanese intergroup phase III trial is evaluating the efficacy of continuing VEGF blockade with ramucirumab plus irinotecan in patients with advanced gastric cancer who have progressed on prior ramucirumab-containing therapy. The study represents the largest investigation to date of sustained anti-angiogenic treatment in the third-line setting for this challenging malignancy.
Trial Design and Rationale
The randomized, controlled trial compares ramucirumab plus irinotecan against irinotecan monotherapy in patients with advanced gastric cancer (AGC) who have received at least two prior lines of chemotherapy, including platinum agents, fluoropyrimidines, taxanes, and ramucirumab. The study is based on the hypothesis that sustained VEGF blockade might contribute to long-term disease control across various cancer types.
Ramucirumab, a fully human monoclonal IgG1 antibody targeting VEGFR2, has demonstrated survival benefits in two pivotal randomized trials as second-line therapy for advanced gastric cancer. The combination of ramucirumab plus paclitaxel is currently recognized as standard second-line treatment for this indication.
Patient Population and Endpoints
The trial recruits patients from 110 institutions participating in 9 clinical trial groups across Japan, targeting an enrollment of 400 patients. Key eligibility criteria include histologically confirmed gastric or esophagogastric adenocarcinoma, unresectable or recurrent disease, and disease progression during prior ramucirumab-containing chemotherapy. Patients must have adequate performance status (0-1), expected survival of at least 90 days, and no prior exposure to irinotecan.
The primary endpoint is overall survival, with an assumed hazard ratio of 0.77, designed to provide 80% power at a one-sided significance level of 0.05. Secondary endpoints encompass progression-free survival, time to treatment failure, response rate, disease control rate, and safety parameters.
Treatment Protocol
Patients are randomized 1:1 to receive either ramucirumab plus irinotecan or irinotecan alone. Irinotecan is administered at 150 mg/m² every two weeks in both arms, while ramucirumab is given at 8 mg/kg biweekly in the combination arm. Treatment continues until disease progression or unacceptable toxicity.
Enrollment Progress and Supporting Evidence
As of January 31, 2018, the trial had enrolled 87 of the planned 400 patients since opening to accrual in February 2017. The study's feasibility is supported by previous phase II data demonstrating the activity of irinotecan-based combinations in gastric cancer.
A separate phase II trial evaluated biweekly irinotecan plus cisplatin in 18 patients with advanced gastric cancer following S-1 failure. The combination achieved an overall response rate of 16.7%, including 2 complete responses and 1 partial response. The median overall survival reached 282 days, with 72.2% of patients proceeding to third-line therapy.
Safety Considerations
The phase II experience with irinotecan combinations revealed manageable toxicity profiles. The most common grade 3/4 adverse events included neutropenia (22.2%), leukopenia (22.2%), anemia (11.1%), anorexia (11.1%), diarrhea (11.1%), and fatigue (5.6%). These findings support the feasibility of irinotecan-based regimens in the gastric cancer population.
Clinical Significance
This intergroup trial addresses a critical unmet need in advanced gastric cancer, where treatment options become increasingly limited after progression on standard therapies. The investigation of sustained VEGF blockade represents a novel therapeutic strategy that could potentially extend survival in this difficult-to-treat patient population.
The study's large scale and multi-institutional design across Japan's major clinical trial groups positions it to provide definitive evidence regarding the role of continued anti-angiogenic therapy in advanced gastric cancer. Results from this trial may establish a new standard of care for third-line treatment and inform future therapeutic strategies incorporating sustained VEGF inhibition.
