The PD-1 inhibitor nivolumab extended overall survival versus placebo for patients who were refractory or intolerant to standard therapy with unresectable, advanced, or recurrent gastric cancer, according to topline data from the phase III ONO-4538-12 trial.
The phase III doubled-blind trial was conducted by Ono Pharmaceuticals, which is the company developing nivolumab in Japan, Korea, and Taiwan. The announcement of the results was released by the main developer of the PD-1 inhibitor, Bristol-Myers Squibb (BMS). The primary endpoint of the study was OS, and secondary endpoints focused on progression-free survival (PFS) and objective response rate (ORR). Full findings from the study were not yet announced, and will be prepared for presentation at an upcoming meeting, according to BMS.
“Patients with advanced or recurrent gastric cancer generally have a poor prognosis, and there are currently no standard-of-care treatment options for patients who fail to respond to or who are intolerant of standard chemotherapy," Fouad Namouni, MD, head of development, Oncology, Bristol-Myers Squibb, said in a statement. "With the results from the ONO-4538-12 study, Opdivo is now the first Immuno-Oncology agent to demonstrate a survival benefit for this patient population.”
The multicenter ONO-4538-12 trial began enrolling patients in October 2014. The trial had a target enrollment goal of 480 patients with unresectable advanced gastric or gastroesophageal junction (GEJ) cancer. Patients received nivolumab at 3 mg/kg intravenously every 2 weeks or placebo. All patients had an ECOG performance status between 0 and 1 and confirmed adenocarcinoma. Those with brain metastasis requiring treatment were excluded.
Prior to the phase III study, the phase I/II CheckMate-032 trial demonstrated promise for nivolumab in a cohort of 59 patients with locoregionally advanced or metastatic gastric cancer or GEJ. Nivolumab was administered at 3 mg/kg IV every 2 weeks. This study also assessed the combination of nivolumab and ipilimumab.
In the single-agent arm, the mean age of patients was 57 years, and 76% were male. Seventy-one percent of patients had received 2 to 3 prior regimens. The primary outcome measure for the study was ORR, with secondary endpoints focused on PD-L1 status, PFS, and OS.
In this study, the ORR with nivolumab was 14%, which consisted of 1 complete response and 7 partial responses. Additionally, the stable disease rate was 19%, for a total disease control rate of 32%. The median time to response was 1.6 months and the median duration of response was 7.1 months.
In those with PD-L1 expression on ≥1% of cells (n = 15), the ORR was 27% with nivolumab. In those with PD-L1 expression on <1% (n = 25), the ORR was 12%. When 5% was used as a cutoff, the ORR was 33% in PD-L1-positive patients versus 15% in the negative cohort.
The median OS was 5.03 months with nivolumab (95% CI, 3.35-12.42). The 12-month OS rate was 36%. The median PFS was 1.36 months (95% CI, 1.25-1.51) and the 12-month PFS rate was 7%.
Grade 3/4 treatment-related adverse events (AEs) were experienced by 17% of patients treated with nivolumab. All-grade AEs were experienced by 70% of patients, the most common of which were fatigue (32%), pruritus (17%), diarrhea (15%), decreased appetite (15%), nausea (14%), AST increase (12%), pyrexia (10%), and vomiting (10%).
“Nivolumab monotherapy was well tolerated in patients with metastatic gastric, esophageal, or gastroesophageal junction cancer,” lead author Dung T. Le, MD, an assistant professor of Oncology at Johns Hopkins Kimmel Cancer Center, said when presenting the results at the 2016 Gastrointestinal Cancers Symposium. “PD-L1 expression appears to be numerically associated with a higher objective response rate,” she added.
Nivolumab has gained approvals across a variety of indications for patients with melanoma, lung cancer, renal cell carcinoma, and Hodgkin lymphoma. Additionally, the treatment continues to be assessed across multiple types of cancer.
Janjigian YY, Bendell JC, Calvo E, et al. CheckMate-032: Phase I/II, open-label study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC).J Clin Oncol.