Dr. Yoon-Koo Kang
“These results suggest that nivolumab could be a new treatment option for patients with heavily pretreated [advanced gastric or gastroesophageal junction cancer] and also provide a strong rationale to explore nivolumab in earlier lines of treatment for [these diseases],” said lead investigator Yoon-Koo Kang, MD, PhD, of the University of Ulsan College of Medicine, in South Korea.
This randomized, double-blind, placebo-controlled phase III trial was conducted in Japan, Korea, and Taiwan in 493 patients with unresectable advanced or recurrent gastric or gastroesophageal junction cancer who had received at least two prior regimens or who were refractory to or intolerant of standard therapy.
Following stratification based on country, Eastern Cooperative Oncology Group performance status (0 vs. 1), and the number of organs with metastases (< 2 vs. ≥ 2), patients underwent random assignment in a 2:1 ratio to receive intravenous nivolumab 3 mg/kg or placebo every 2 weeks. Treatment could be continued beyond traditional definitions of disease progression so long as patients derived clinical benefit and demonstrated suitable tolerability.
The final data analysis revealed that nivolumab significantly prolonged median OS from 4.14 to 5.32 months in this population (HR 0.63, 95% CI [0.50, 0.78]; p < 0.0001)—approximately 80% of whom had received three or more prior regimens. This translated into a 37% reduction in the risk of death with nivolumab versus placebo. Survival rates at 12 months were 26.6% with nivolumab as compared to 10.9% with placebo.
Across all subgroups analyzed, the hazard ratios for OS favored the nivolumab arm.
PFS and ORR outcomes bolstered the survival results. Median PFS extended from 1.45 months with placebo to 1.61 months with nivolumab (HR 0.60, 95% CI [0.49, 0.75]; p < 0.0001). ORR rates reached 11.2% with nivolumab (all partial responses) versus 0% with placebo (p < 0.0001), with the median duration of response lasting 9.53 months among patients whose disease responded to nivolumab.
Dr. Heinz-Josef Lenz
In his critique of the ONO-4538-12 findings, discussant Heinz-Josef Lenz, MD, of the University of Southern California Norris Comprehensive Cancer Center, said that “the data are very impressive. The HR of 0.63 would signal a significant benefit in highly refractory gastric cancer.”
Dr. Lenz continued, “Don’t get stuck on the median, because the median will not reflect fully the benefit of the approach of immunotherapy.” The continuous separation of survival curves points to a subpopulation that derives significant benefit from nivolumab, he said.
Still, whether a 1-month extension in survival justifies the cost of nivolumab remains up for debate, as does whether patients of different ethnicities may exhibit a differential response to nivolumab. Dr. Lenz raised this notion, presenting data suggesting that the molecular profile of advanced gastric/gastroesophageal junction cancer is completely different between Asian and Caucasian populations.
When asked whether the ONO-4538-12 trial should be repeated in the West, both Drs. Lenz and Kang agreed that this was not necessary given ongoing global nivolumab trials that will reveal the agent’s efficacy in different racial and ethnic subgroups.
According to Dr. Lenz, the key question now following the findings of this “beautifully designed phase III trial showing a clear benefit of nivolumab in a highly refractory gastric cancer population … is: Where do we go from here? Certainly we don’t want to be stuck in third-line treatment.”
Toward this end, analyses are needed to identify the subgroup of patients who stand to benefit from nivolumab, as well as which agents may be combined with the agent to increase immunogenicity and treatment response. Focusing nivolumab-based therapy in patients most likely to gain benefit should enhance clinically relevant outcomes and better justify the cost of treatment.
Dr. Kang did indicate that biomarker analyses in a subgroup of patients within ONO-4538-12 are currently underway.
–Kara Nyberg, PhD