Randomized Phase III trial of Ramucirumab finds benefit for patients with refractory advanced gastric cancer

1. The addition of ramucirumab to irinotecan in patients with ramucirumab-refractory advanced or recurrent gastric or gastroesophageal cancer (AGC) did not confer a survival advantage compared to irinotecan alone. 

2. In patients with AGC with progression on ramucirumab-based chemotherapies, the use of ramucirumab plus irinotecan was associated with improved PFS compared to irinotecan alone.  

Evidence Rating Level: 1 (Excellent)

Study Rundown: Gastric cancer remains one of the leading causes of cancer-related mortality worldwide. Ramucirumab is an important agent approved as second-line management for AGC when used with paclitaxel, and which has shown sustained benefits in other types of cancers when used beyond disease progression. However, it is unknown whether continued use of ramucirumab beyond disease progression confers a survival benefit in patients with AGC. This randomized phase III trial therefore sought to investigate the efficacy of adding ramucirumab to irinotecan in patients with AGC who have previously progressed on ramucirumab-based management. 

Patients with AGC who had progressed on ramucirumab-based chemotherapies but who had no previous exposure to irinotecan were assigned to receive either ramucirumab plus irinotecan (n = 202) or irinotecan monotherapy (n = 200). The median overall survival (OS) was comparable between both groups at 9.4 months in the ramucirumab plus irinotecan group and 8.5 months in the irinotecan monotherapy group. Progression-free survival (PFS) was significantly longer in the ramucirumab plus irinotecan group compared to the irinotecan monotherapy group, with a 6-month PFS rate of 31.5% in the ramucirumab plus irinotecan group and 17.6% in the irinotecan monotherapy group. 

Overall, this study found that among patients with AGC who had experienced disease progression on previous ramucirumab-based chemotherapies, ramucirumab plus irinotecan did not confer survival benefit compared to irinotecan alone but was associated with improved PFS. 

Click to read the study in Journal of Clinical Oncology

Relevant Reading: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial

In-Depth [randomized phase III trial]: Gastric cancer is one of the most common malignancies worldwide and is among the leading causes of cancer-related mortality. Treatment options for patients with AGC revolve around systemic chemotherapy, including agents such as irinotecan, which is used in the third-line or later setting. Ramucirumab is another important agent functioning as an angiogenesis inhibitor and which has been approved as second-line management for AGC when used with paclitaxel. In other cancer types, the use of antiangiogenic agents beyond disease progression has shown clinical benefits. However, whether continued use of ramucirumab beyond disease progression confers a survival benefit in patients with AGC or not is unknown. This randomized phase III trial therefore sought to investigate the efficacy of adding ramucirumab to irinotecan in patients with AGC who have previously progressed on ramucirumab-based management. 393 patients with AGC who had progressed on ramucirumab-based chemotherapies but who had no previous exposure to irinotecan were included in the full analysis set (FAS), with 200 being assigned to ramucirumab plus irinotecan and 193 to irinotecan monotherapy. The median overall survival (OS) was 9.4 months (95% CI, 8.0 to 10.5) in the ramucirumab plus irinotecan group and 8.5 months (95% CI, 8.0 to 9.3) in the irinotecan monotherapy group. When adjusted for stratification factors, the hazard ratio (HR) was 0.92 (95% CI, 0.74 to 1.13; P = 0.49). Progression-free survival (PFS) was significantly longer in the ramucirumab plus irinotecan group compared to the irinotecan monotherapy group (median, 3.8 months [95% CI, 3.4 to 4.6] v 2.8 months [95% CI, 2.2 to 3.5]; HR, 0.73 [95% CI, 0.59 to 0.89]; P = .002.) Disease control rate (DCR) was significantly higher in the ramucirumab plus irinotecan arm compared to the irinotecan monotherapy group (64.4% vs 52.1%; odds ratio, 1.66; P = .03).

Image: PD

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