Dr. Charles S. Fuchs presents Abstract 5 during Oral Abstract Session A.
“I wouldn’t purport that ramucirumab should be a first-line therapy,” said Charles S. Fuchs, MD, of the Smilow Cancer Hospital and Yale New Haven Health, who presented the RAINFALL findings. There are no plans to pursue regulatory approval of ramucirumab for a first-line indication.
Ramucirumab is the only biologic with proven efficacy both as a single agent and in combination with paclitaxel in the second-line setting in metastatic G-GEJ adenocarcinoma based on results from the REGARD and RAINBOW trials, in which ramucirumab yielded modest but significant increases in overall survival (OS). Investigators reasoned that ramucirumab might also confer benefit when used earlier in treatment-naive patients with metastatic G-GEJ adenocarcinoma, for which the standard of care in many parts of the world involves combination chemotherapy with a fluoropyrimidine plus a platinum agent.
To evaluate this hypothesis, RAINFALL was designed to compare ramucirumab with placebo in previously untreated patients with metastatic, HER2-negative G-GEJ adenocarcinoma who had an Eastern Cooperative Oncology Group performance status of 0 or 1. All patients received cisplatin combined with capecitabine (or fluorouracil for patients unable to swallow capecitabine). Cisplatin was administered for a maximum of six cycles; capecitabine with ramucirumab or with placebo was continued until patients experienced disease progression or intolerable toxicity.
The intent-to-treat study population consisted of 645 patients with median ages of 60 and 62 years in the ramucirumab and placebo arms, respectively. The majority of patients were white (81%), male (approximately 67%), resided in Europe or North America (76%), and had gastric adenocarcinoma (approximately 75%). Most patients had two or fewer metastatic sites (approximately 75%) and no peritoneal metastasis (approximately 62%).
RAINFALL met the primary study endpoint by demonstrating a modest but significant increase in median PFS for ramucirumab plus chemotherapy versus placebo plus chemotherapy in the intent-to-treat population (5.85 vs. 5.55 months; HR 0.75, 95% CI [0.61, 0.94]; p = 0.011. Trends toward benefit with ramucirumab were seen across nearly every subgroup evaluated.
The PFS improvements observed with ramucirumab did not extend to the other efficacy endpoints evaluated. There was no difference in median OS between the ramucirumab and placebo arms (11.17 vs. 10.74 months; HR 0.96, 95% CI [0.80, 1.16]; p = 0.68)—a finding that held true across several sensitivity analyses. Nor were there significant differences between ramucirumab and placebo in the overall response rate (41% vs. 36%; p = 0.17) or the disease control rate (82% vs. 77%; p = 0.10).
No new or unexpected safety findings emerged with the addition of ramucirumab to chemotherapy. Grade 3 or higher adverse events that occurred more often with ramucirumab than with placebo included hypertension (9.9% vs. 1.6%), hand-foot syndrome (8.7% vs. 3.8%), thrombocytopenia (7.7% vs. 3.5%), decreased appetite (6.5% vs. 3.2%), and gastrointestinal perforation (4.0% vs. 0.3%), whereas vomiting occurred less often (6.5% vs. 9.8%).
After discontinuation of study therapy because of disease progression or unacceptable toxicity, approximately half of the patients in each arm received subsequent therapy. Although paclitaxel was the most common agent used in the second-line setting and beyond, 12% of patients in the ramucirumab arm continued to receive the VEGFR-2 inhibitor outside of the RAINFALL trial, as did 17% of patients in the placebo arm.
Exploratory analysis revealed that the median OS was longer for patients who received ramucirumab after study therapy was discontinued, regardless of the originally assigned arm (14.9 months with first-line placebo; 16.2 months with first-line ramucirumab) compared with patients who did not receive ramucirumab after study discontinuation (13.0 months with first-line placebo; 13.2 months with first-line ramucirumab).
Discussant Stephen Leong, MD, of the University of Colorado Cancer Center, agreed with Dr. Fuchs’ assessment that ramucirumab added to chemotherapy will not replace the current first-line standard of care in metastatic G-GEJ adenocarcinoma based on the very modest PFS improvement reported. He underscored this point by illustrating that the 9-day improvement with added ramucirumab carries a price tag of approximately $90,000 according to the median duration of therapy in RAINFALL—and that excludes infusion-related costs.
Although regulatory approval of first-line ramucirumab will not be sought, Dr. Leong noted that the National Comprehensive Cancer Network will meet soon to debate whether the G-GEJ cancer guidelines should be amended to include ramucirumab as an option in combination with chemotherapy for patients with newly diagnosed metastatic disease.
–Kara Nyberg, PhD