Adding ramucirumab (Cyramza) to first-line cisplatin plus fluoropyrimidine failed to improve survival in patients with metastatic gastric cancer or adenocarcinoma of the gastroesophageal junction, the phase III RAINFALL study found.
While the investigators reported a significant improvement in median progression-free survival (PFS) for the ramucirumab-treated group (5.7 months vs 5.4 months with placebo), the findings did not hold up on independent review (HR 0.96, 95% CI 0.77-1.20, P=0.74), reported Charles S. Fuchs, MD, of Yale Cancer Center in New Haven, Connecticut, and colleagues.
Median overall survival (OS) was also not improved with ramucirumab (11.2 months vs 10.7 months with placebo, HR 0.96, 95% CI 0.80-1.16, P=0.676).
“Similarly, other efficacy parameters did not show significant improvement,” Fuchs’ group wrote in the Lancet Oncology. “On the basis of these efficacy results, ramucirumab in combination with cisplatin-fluoropyrimidine cannot be recommended for first-line treatment.”
In a comment that accompanied the study, Annemieke Cats, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, said it’s unclear why ramucirumab has improved PFS and OS in the second-line setting — in both the REGARD (which led to FDA approval of a single-agent treatment) and RAINBOW trials (which led to approval in combination with paclitaxel) — but has failed to do so in first-line.
Cats added that angiogenesis inhibition for gastric cancer in general has only demonstrated benefit in these later settings.
“The results of the RAINFALL study do not stand alone,” she wrote, pointing to both the AVAGAST and AVATAR trials that showed that adding bevacizumab (Avastin) to upfront chemotherapy for gastric cancer patients also offered no benefit. “In the curative setting, bevacizumab also did not improve survival when added to perioperative chemotherapy with epirubicin, cisplatin, and capecitabine [Xeloda].”
Cats suggested a number of factors could be at play in these findings, including the choice of chemotherapy backbone. “So far, all studies using cisplatin and fluoropyrimidine have underperformed compared with those with paclitaxel or ramucirumab as monotherapy,” she wrote.
Fuchs’ group said as much too, noting that perhaps using a taxane (as was done in the RAINBOW trial) might have improved outcomes. But they also hypothesized that the natural history of these metastatic gastric and gastroesophageal junction cancers “might include a change in the balance between pro-angiogenic and antiangiogenic factors in the second-line setting or a natural selection of tumors more sensitive to ramucirumab.”
In the double-blind, randomized, placebo-controlled RAINFALL study, all 645 patients received first-line fluoropyrimidine and cisplatin, and were then randomized 1:1 to either ramucirumab or placebo. Baseline characteristics were similar between the two groups. Roughly 75% of patients in each arm had gastric cancer while the remaining had adenocarcinoma of the gastroesophageal junction. Most patients ( about 75%) had ≤2 metastatic sites.
The researchers noted that a similar amount of patients in each group received post-discontinuation therapy, and those who did had improved OS.
Common grade 3/4 adverse events (AEs) between the ramucirumab-treated and placebo-treated patients, respectively, included neutropenia (26% vs 27%), anemia (12% vs 14%), hypertension (10% vs 2%), and hand-foot syndrome (9% vs 4%). There were similar rates of serious AEs of any grade (50% with ramucirumab vs 47% with placebo). The most common of these were vomiting (14% with ramucirumab vs 7% with placebo) and diarrhea (3% vs 6%, respectively). Seven deaths occurred in each arm.
AEs leading to treatment discontinuation occurred in 17% and 12% of the ramucirumab and placebo groups, respectively.
The study was funded by Eli Lilly.
Fuchs disclosed relevant relationships with Eli Lilly, Agios, Bain Capital, Bayer, Celgene, CytomX Therapeutics, Dicerna, Five Prime Therapeutics, Gilead-Sciences, Entrinsic Health, Genentech, KEW, Merck, Merrimack Pharmaceuticals, Pfizer, Sanofi, Taiho, and Unum Therapeutics. Co-authors disclosed multiple relevant relationships with industry including Eli Lilly.
Cats disclosed her involvement in the initiation of RAINFALL at the Netherlands Cancer Institute, but was not involved in the conduct of the study.