FDA Approves Ramucirumab Plus Paclitaxel for Advanced Gastric Cancer

Richard Gaynor, MD

The FDA has approved the combination of ramucirumab (Cyramza) and paclitaxel as a treatment for patients with previously treated advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, based on data from the phase III RAINBOW trial.

In this trial, the combination of the VEGFR-2 inhibitor ramucirumab and paclitaxel improved overall survival (OS) by 2.3 months over paclitaxel alone, representing a 19% improvement. The FDA initially approved Ramucirumab in April 2014 as a treatment for patients with unresectable gastric cancer or GEJ adenocarcinoma following fluoropyrimidine- or platinum-containing therapy, based on the phase III REGARD trial. In this trial, OS was improved by 1.4 months with ramucirumab compared with placebo.

"This FDA approval of Cyramza represents another milestone for people battling this devastating and difficult-to-treat disease," Richard Gaynor, MD, senior vice president, product development and medical affairs for Lilly Oncology, the manufacturer of the drug, said in a press release. "Lilly is pleased to continue delivering on its commitment to provide new treatment options to people living with cancer and those who care for them."

In the RAINBOW trial, 665 patients with GEJ and gastric adenocarcinoma were evenly randomized to receive ramucirumab plus paclitaxel (n = 330) or placebo plus paclitaxel (n = 335). Patients enrolled in the study were treated with first-line fluoropyrimidine- or platinum-containing therapy. Most patients in the study had an ECOG performance status of 0 or 1. Both ramucirumab and placebo were administered in respective cohorts intravenously at 8 mg/kg on days 1 and 15. In both arms, paclitaxel was administered at 80 mg/m2 on days 1, 8, and 15 of a 4-week cycle.

In the study, the median OS was 9.6 months with ramucirumab plus paclitaxel versus 7.4 months for paclitaxel alone (HR = 0.81; 95% CI, 0.678-0.962; P = .017). The median PFS was 4.4 versus 2.9 months, for the ramucirumab and placebo arms, respectively (HR = 0.64; 95% CI, 0.536-0.752; P <.0001).

The median time to progression was 5.5 months versus 3.0 months (P <.0001) and ORR was 28% compared with 16% (P = .0001), for the ramucirumab combination versus paclitaxel alone, respectively. The disease control rate with ramucirumab was 80% compared with 64% with paclitaxel (P <.0001).

“The survival difference in favor of ramucirumab plus paclitaxel was 9.7 versus 7.4 months, and this differences of 2.3 months is an astonishingly good result in such a challenging patient population,” lead study author Hansjochen Wilke, MD, the director of the Department of Oncology, Hematology and Center of Palliative Care at Kliniken Essen-Mitte in Essen, Germany, said when data from the RAINBOW trial were announced at the 2014 GI Cancers Symposium. “This difference was not only statistically significant but also clinically meaningful.”

In the study, grade 3 or greater neutropenia occurred in 40.7% of patients in the combination arm compared with 18.8% for paclitaxel plus placebo. Rates of febrile neutropenia were 3.1% with the combination compared with 2.4% with paclitaxel plus placebo. Hypertension was 14.1% with the ramucirumab combination compared with 2.4% with paclitaxel alone.

Ramucirumab carries a Boxed Warning regarding increased risk of severe and sometimes fatal hemorrhage. In the REGARD study, hypertension was more common in the ramucirumab arm (16% versus 8%). However, all-grade adverse events were similar between the two groups at 94% compared with 88% for ramucirumab and placebo, respectively.

Results from a number of large studies exploring ramucirumab have been announced in the past year. Most recently, the phase III RAISE trial showed that the combination of ramucirumab and FOLFIRI significantly improved OS and PFS compared with chemotherapy alone as a second-line treatment for patients with metastatic colorectal cancer. Eli Lilly and Company, announced plans to present data from the RAISE trial in 2015. Additionally, the company expects to initiate regulatory submissions in the first half of 2015.