SAN FRANCISCO — In a group of heavily pretreated patients with advanced or recurrent gastric or gastroesophageal junction (GEJ) cancer, immunotherapy with nivolumab (Opdivo, Bristol-Myers Squibb) significantly improved survival, according to new findings presented here at the Gastrointestinal Cancers Symposium (GICS) 2017.
Treatment with nivolumab significantly reduced the risk for death by 37% in patients with unresectable advanced or recurrent advanced gastric cancer in whom two or more previous chemotherapy regimens had failed.
Compared with placebo recipients, patients treated with nivolumab had superior overall survival, response rates, disease control, and progression-free survival (PFS).
"This phase 3 study demonstrated the efficacy and safety of nivolumab as third or later line of treatment in patients with advanced gastric cancer," said lead author Yoon-Koo Kang, MD, PhD, Department of Oncology at the University of Ulsan College of Medicine, Asan Medical Center in Seoul, Korea, who presented the findings at the meeting.
"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," Dr Kang told attendees.
The prognosis for patients with advanced gastric cancer is poor, and there are currently no established treatments for those who progress after receiving two or more lines of treatment, he noted, so novel treatment regimens are needed in this patient population.
As previously reported by Medscape Medical News, early clinical data have already suggested that the programed cell death inhibitors hold promise in the treatment of advanced gastric, esophagus, and GEJ cancers.
The drugs were well tolerated and demonstrated encouraging antitumor activity in these upper gastrointestinal cancers, Dr Kang noted. But the data so far are from phase 1 and 2 trials, and the efficacy of immune checkpoint inhibitors has not yet been established in these GI cancers in a randomized trial.
All Endpoints Met
The ONO-12 trial included 493 patients from 49 centers in Japan, Korea, and Taiwan. All patients had unresectable advanced or recurrent gastric or GEJ cancer, had received at least two prior regimens, and were refractory to and/or intolerant of standard therapy.
The cohort was randomly assigned to receive nivolumab (n = 330), administered 3 mg/kg intravenously every 2 weeks, or placebo (n = 163).
The primary endpoint was overall survival, and secondary endpoints included PFS and objective response rate (ORR).
The median overall survival was 5.32 months for nivolumab vs 4.14 months for placebo (hazard ratio [HR], 0.63; P < .0001), and the 12-month overall survival was 26.6% for nivolumab vs 10.9% for placebo.
The ORR was 11.2% for nivolumab vs 0% for placebo (P < .0001), and the median duration of response was 9.53 months.
Improvement was also seen in PFS, favoring nivolumab (1.61 months vs 1.45 months; HR, 0.60; P < .0001).
Dr Kang explained that the safety profile of nivolumab was consistent with previously reported studies in solid tumors. Treatment-related adverse events of any grade occurred in 42.7% of nivolumab patients vs 26.7% of placebo patients, and grade 3/4 adverse event rates were 10.3% vs 4.3%.
Grade 3/4 events reported in more than 2% of patients included diarrhea, fatigue, decreased appetite, pyrexia, and increased liver enzyme levels (aspartate aminotransferase and alanine aminotransferase) in the nivolumab group.
Similar rates of treatment discontinuation due to adverse events were seen in both groups, at 2.7% and 2.5%, respectively.
"Not all patients benefitted from immunotherapy, so biomarker investigation is underway," said Dr Kang.
Where to Go Next?
In a discussion of the paper, Heinz-Josef Lenz, MD, associate director for adult oncology and co-leader of the Gastrointestinal Cancers Program at the University of Southern California Norris Comprehensive Cancer Center in Los Angeles, noted that the data "are impressive."
"With a hazard ratio of 0.63 you see a highly significant benefit in highly refractory gastric cancer patients," Dr. Lenz said.
He emphasized not to "get stuck at the median, because the median will not give you the full benefit of nivolumab therapy."
The HR is the combined difference between survival curves over the whole course of treatment, he explained: "the cumulative benefit."
The findings also suggest that a subset of patients may be achieving a more significant benefit. This is apparent in the results of PFS, he pointed out.
Even though the median in PFS doesn't look different, the HR is 0.6 "because there is a significant patient subset who benefit in a significant way."
"The big question is — who are these patients?" he asked.
Dr Lenz added that he "couldn't agree more," with the authors that this is a new treatment option and he agreed that "it should not get stuck in third line."
He would like to see more data on the duration of treatment, and another factor to consider is that the study was conducted in three Asian countries. Some data show that the composition and molecular makeup of gastric cancer differ between Asian and white patients, and this factor could "impact the efficacy of immunotherapies," Dr Lenz said.
"We need better patient selection, and we still have no understanding of what the mechanism of resistance to immunotherapies are, which would be the basis for combinations," he noted.
Finally, Dr Lenz emphasized that "we need to move from the third to second and when we have the right patient selection, to the first line. This is a very exciting time for patients with gastric cancers to entertain new treatment options."
The trial was funded by Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb. Dr Kang reports a consulting or advisory role with Lilly/ImClone, Novartis, Ono Pharmaceutical, Roche/Genentech, and Taiho Pharmaceutical and research funding from Bayer, Novartis, and Roche/Genentech. Several coauthors report relationships with industry as noted in the abstract. Dr Lenz reports honoraria from Bayer, Boehringer Ingelheim, Merck Serono, and Roche; a consulting or advisory role with Bayer, Merck Serono, and Roche; and travel, accommodations, expenses from Bayer, Merck Serono, and Roche.
Gastrointestinal Cancers Symposium (GICS) 2017. Abstract 2. Presented January 19, 2017.