According to findings from the phase III ONO-4538-12 trial, treatment with nivolumab (Opdivo) reduced the risk of death by 37% compared with placebo for patients with advanced gastric or gastroesophageal junction (GEJ) cancer following second or later-line chemotherapy.
Yoon-Koo Kang, MD, PhD
According to findings from the phase III ONO-4538-12 trial, treatment with nivolumab (Opdivo) reduced the risk of death by 37% compared with placebo for patients with advanced gastric or gastroesophageal junction (GEJ) cancer following second or later-line chemotherapy. Results of the trial were presented at the 2017 Gastrointestinal Cancers Symposium.
In the double-blind study, which was conducted in Asia, the median overall survival (OS) was 5.32 months (95% CI, 4.63-6.41) with nivolumab versus 4.14 months (95% CI, 3.42-4.86) in the placebo arm (HR, 0.63;P<.0001). The 6-month OS rate was 46.4% with nivolumab versus 34.7% for placebo and the 12-month OS rate was 26.6% (95% CI, 21.1-32.4) with nivolumab compared with 10.9% (95% CI, 6.2-17.0) in the placebo arm.
"This phase III study demonstrated the efficacy and safety of nivolumab as third or later line of treatment in patients with advanced gastric cancer," said lead study investigator Yoon-Koo Kang, MD, PhD, Department of Oncology at the University of Ulsan College of Medicine, Asan Medical Center in Seoul, Korea. "These results indicate that nivolumab could be a new treatment option for patients with heavily pretreated advanced gastric cancer, and also provide a strong rationale to explore nivolumab in earlier lines of treatment for gastric cancer."
The phase III doubled-blind trial was conducted by Ono Pharmaceuticals, which is the company developing nivolumab in Japan, Korea, and Taiwan. In the United States, the PD-1 inhibitor is developed and commercialized by Bristol-Myers Squibb. The primary endpoint of the study was OS, and secondary endpoints focused on progression-free survival (PFS) and objective response rate (ORR).
The trial randomized 493 patients with unresectable advanced or recurrent gastric or GEJ cancer in a 2:1 ratio to receive nivolumab (n = 330) or placebo (n = 163). Nivolumab was administered at 3 mg/kg intravenously every 2 weeks. All patients had an ECOG performance status between 0 and 1, confirmed adenocarcinoma, and were ≥20 years of age. Those with brain metastasis requiring treatment were excluded.
Median PFS with nivolumab was 1.61 (95% CI, 1.54-2.30) versus 1.45 months (95% CI, 1.45-1.54) with placebo, representing a 40% reduction in the risk of progression or death (HR, 0.60; 95% CI, 0.49-0.75;P<.0001). The 12-month PFS rates were 7.6% (95% CI, 4.2-12.2) versus 1.5% (95% CI, 0.3-4.8), for nivolumab and placebo, respectively.
The ORR with nivolumab was 11.2% (95% CI, 7.7-15.6) compared with 0% with placebo (95% CI, 0.0-2.8). The ORR consisted entirely of partial responses. The median duration of response for nivolumab was 9.53 months. Biomarker analyses from the study are still under way, according to Kang.
Treatment-related adverse events (AEs) of any grade were experienced by 42.7% of patients treated with nivolumab compared with 26.7% of those in the placebo arm. Grade 3/4 treatment-related AEs were noted in 10.3% and 4.3% of those in the nivolumab and placebo arms, respectively. The most commonly reported treatment-related grade 3/4 AEs with nivolumab were diarrhea, fatigue, decreased appetite, pyrexia, and increases in AST and ALT. Discontinuation rates due to AEs were similar between the arms (2.7% vs 2.5%).
"OS was superior versus placebo, with long-term survival shown," said Kang. "Nivolumab had superior response rates, disease control, and PFS versus placebo, and was well tolerated with a safety profile comparable to the placebo arm."
“ONO-4538-12 is the first randomized, phase III Immuno-Oncology trial to demonstrate improved survival for patients with previously treated advanced or recurrent gastric cancer," Ian M. Waxman, MD, development lead, Gastrointestinal Oncology, Bristol-Myers Squibb, said in a statement. "We find these results with Opdivo encouraging, as gastric cancer is a leading cause of cancer death globally and unmet needs remain for patients with advanced forms of this disease who become intolerant to chemotherapy or for whom such treatment has failed.”
Kang Y-K, Satoh T, Ryu M-H, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): A double-blinded, randomized, phase III trial. J Clin Oncol. 2017; 35 (suppl 4S; abstract 2).
Since its initial approval in 2014 for metastatic melanoma, nivolumab has added numerous indications across a variety of settings for patients with lung cancer, renal cell carcinoma, Hodgkin lymphoma, and continued indications in combination with ipilimumab (Yervoy) for melanoma. Additionally, the treatment continues to be assessed across multiple types of cancer, including gastrointestinal malignancies.