The combination of ramucirumab and paclitaxel resulted in a significant prolongation in survival and gains in quality of life when compared to paclitaxel alone for the second-line treatment of patients with metastatic gastric cancer.
Hansjochen Wilke, MD
According to phase III data presented at a press conference held in advance of the 2014 Gastrointestinal Cancers Symposium, the combination of ramucirumab and paclitaxel resulted in a significant prolongation in survival and gains in quality of life when compared to paclitaxel alone for the second-line treatment of patients with metastatic gastric cancer.
The ramucirumab combination prolonged the primary endpoint of overall survival (OS) by greater than 2 months when compared to paclitaxel alone. Additionally, patients experienced a near doubling in the secondary endpoints of progression-free survival (PFS) and overall response rate (ORR) with the combination. Despite a higher incidence of neutropenia with the combination, febrile neutropenia rates were comparable between the two arms.
“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,” said 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. “This difference was not only statistically significant but also clinically meaningful.”
In the phase III study, 665 patients with gastroesophageal junction (GEJ) and gastric adenocarcinoma were randomized in a 1:1 ratio to receive ramucirumab plus paclitaxel (n = 330) or placebo plus paclitaxel (n = 335). Patients enrolled in the study were treated with first-line platinum/fluoropyrimidine-based chemotherapy.
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/m2on days 1, 8, and 15 of a 4-week cycle.
The median OS with ramucirumab plus paclitaxel was 9.63 months compared with 7.36 months with paclitaxel plus placebo (hazard ratio [HR] = 0.807; 95% CI, 0.678-0.962;P= .0169). For the ramucirumab-paclitaxel combination and paclitaxel plus placebo, the 6-month OS rate was 72% and 57% and the 12-month OS rate was 40% and 30%, respectively. The median PFS was 4.40 months with ramucirumab compared with 2.86 months for paclitaxel (HR = 0.635; 95% CI, 0.536-0.752;P< .0001).
For the ramucirumab-paclitaxel combination and paclitaxel plus placebo, respectively, the median time to progression was 5.5 months versus 3.0 months (P< .0001) and ORR was 28% compared with 16% (P= .0001). The disease control rate with ramucirumab was 80% compared with 64% with paclitaxel (P< .0001).
The fully human monoclonal antibody ramucirumab is an antagonist directed against VEGFR-2, which mediates several of the downstream effects of angiogenesis. Many of the additional adverse events experienced with the combination were directly associated with this mechanism of action.
The most common greater than grade 3 adverse events with the combination were neutropenia, leukopenia, hypertension, anemia, fatigue, abdominal pain, and asthenia. Greater than grade 3 neutropenia occurred in 40.7% of patients in the combination arm compared with 18.8% for the paclitaxel plus placebo. Rates of febrile neutropenia were 3.1% with the combination compared with 2.4% with paclitaxel plus placebo.
“This largest gastric cancer second-line trial clearly demonstrates that an effective second-line therapy improves survival of patients with metastatic or advanced gastric cancer,” Wilke noted in the press conference. “We expect that these results and other recently published randomized trial data will lead to a situation where more patients will now be routinely treated in a second-line treatment situation, if they are fit for treatment.”
Recently, based on data from the phase III REGARD study, the FDA assigned a priority review designation to ramucirumab as a single-agent for the second-line treatment of patients with advanced gastric cancer. In this study, 355 patients with advanced gastric cancer or GEJ adenocarcinoma were randomized in a 2:1 ratio to receive best supportive care plus either ramucirumab (n=238) or placebo (n=117).
The median OS in the ramucirumab arm was 5.2 months compared with 3.8 months for patients in the placebo arm (HR = 0.776; 95% CI, 0.603-0.998;P= .047). The median PFS was 2.1 months compared with 1.3 months for ramucirumab and placebo, respectively (HR = 0.483; 95% CI, 0.376-0.620;P< .0001). ORR was 3.4% for ramucirumab and 2.6% for placebo, and disease control rates were 48.7% and 23.1%, respectively.
Taken together, these trials show an advantage for administering ramucirumab both in combination and as monotherapy for the second-line treatment of patients with advanced gastric cancer.
“We’re excited to have what appears to be an active drug for the second-line setting that can be used instead of best supportive care or in addition to chemotherapy for patients who can tolerate chemotherapy,” said Smitha Krishnamurthi, MD, the moderator of the ASCO press conference and a medical oncologist and associate professor of medicine at University Hospitals Case Medical Center and Case Western Reserve University. “We are anxiously awaiting the word from the FDA about the approval of ramucirumab, which is expected later this year.”
A decision from the FDA on ramucirumab as a second-line single-agent is anticipated in the spring of 2014. Eli Lilly and Company is developing the drug, following a 2008 acquisition of ImClone Systems. Ramucirumab is also being explored in phase III trials as a treatment for colorectal cancer, hepatocellular carcinoma, and lung cancer.