Ramucirumab prolongs PFS in metastatic gastric/gastroesophageal junction cancer
The addition of ramucirumab, a fully human IgG1 monoclonal antibody receptor antagonist, to chemotherapy, prolonged progression-free survival (PFS) in individuals with previously untreated metastatic gastric or gastroesophageal junction (G-GEJ) adenocarcinoma, findings from the phase III RAINFALL* trial show.
“In treatment-naïve patients with metastatic G-GEJ adenocarcinoma, the addition of ramucirumab to first-line chemotherapy conferred a significant 25 percent reduction in the risk of disease progression or death,” said study author Professor Charles Fuchs from the Smilow Cancer Hospital and Yale Cancer Center in New Haven, Connecticut, US, who presented the findings at the ASCO 2018 Gastrointestinal Cancers Symposium (ASCO GI 2018).
Researchers randomized 645 patients with treatment-naïve metastatic G-GEJ adenocarcinoma and ECOG status 0–1 to receive intravenous ramucirumab (8 mg/kg on days 1 and 8, n=326, median age 60 years, 66 percent male, 79 percent Caucasian) or placebo (n=319, median age 62 years, 67 percent male, 83 percent Caucasian) every 21 days in addition to intravenous cisplatin (80 mg/m2 on day 1 for up to six cycles) plus either oral capecitabine (1,000 mg/m2 BID on days 1–14) or intravenous 5-FU (800 mg/m2/day on days 1–5) until disease progression or intolerable toxicity.
Patients on ramucirumab and placebo were treated for a median 19.0 and 18.8 weeks, respectively.
Patients on ramucirumab demonstrated longer PFS compared with patients on placebo be it investigator-assessed PFS (n=508, median, 5.72 vs 5.39 months, hazard ratio [HR], 0.75, 95 percent confidence interval [CI], 0.61–0.94; p=0.011) or intention-to-treat PFS (n=645, median, 5.85 vs 5.55 months, HR, 0.75, 95 percent CI, 0.63–0.91; p=0.0024). [ASCO GI 2018, abstract 5]
Overall survival (OS) did not differ between patients on ramucirumab and placebo (median, 11.17 vs 10.74 months, HR, 0.96, 95 percent CI, 0.80–1.16; p=0.68), nor did overall response or disease control rates (41 percent vs 36 percent; p=0.17 and 82 percent vs 77 percent; p=0.10, respectively).
Grade ≥3 adverse events (AEs) affecting ≥5 percent of patients that were more common among patients on ramucirumab than placebo were hand-foot syndrome (8.7 percent vs 3.8 percent), thrombocytopenia (7.7 percent vs 3.5 percent), and decreased appetite (6.5 percent vs 3.2 percent), while febrile neutropenia occurred more frequently among patients on placebo (5.1 percent vs 3.7 percent).
Among AEs related to vascular endothelial growth factor receptor inhibition, grade ≥3 hypertension, proteinuria, and gastrointestinal perforation also occurred more frequently in the ramucirumab arm compared with placebo (9.9 percent vs 1.6 percent, 2.5 percent vs 0.6 percent, and 4.0 percent vs 0.3 percent, respectively).
Sixty and 70 percent of patients on ramucirumab and placebo, respectively, discontinued treatment due to disease progression, while 11 and 7.5 percent of patients, respectively, discontinued treatment due to adverse events.
Patients who received ramucirumab after treatment discontinuation demonstrated longer OS compared with those who did not receive ramucirumab (median, 14.9 vs 13.0 months among those who received first-line placebo and 16.2 vs 13.2 months among those who received first-line ramucirumab).
Deaths due to AEs occurred in 5.6 and 4.8 percent of patients on ramucirumab and placebo, respectively.
“Ramucirumab did meet its endpoints of PFS; however, it was disappointing not to see some survival or response rate benefit. There were no new or unexpected toxicities and ramucirumab’s role in the first-line setting is still debatable,” said discussant Associate Professor Stephen Leong from the University of Colorado Cancer Center in Aurora, Colorado, US, who acknowledged that it is unlikely that ramucirumab would replace current standard-of-care treatment for G-GEJ adenocarcinoma in this setting.
While ramucirumab will not be acquiring FDA approval for use in the first-line setting, it remains to be seen if it will be added to the National Comprehensive Cancer Network guidelines for use in combination with chemotherapy for patients with previously untreated metastatic G-GEJ adenocarcinoma, he said.