Although survival for patients with unresectable advanced or recurrent gastric cancer remains poor, the advent of several novel later-line therapeutic options may extend survival and improve outcomes for individuals suffering these refractory diseases.
In a recent review article, a pair of researchers from Cambridge University Hospital in Cambridge, England explained that an increasing number of gastric cancer patients are expected to benefit from such individualized, evidence-based approaches to later-line therapy.
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Gastric cancer. Source: Getty
Reporting in Therapeutic Advances in Medical Oncology, the authors noted that while surgical resection of gastric cancer may be curative (particularly at early stages), disease relapse nevertheless affects the majority of patients. To make matters worse, approximately half of such patients will have already developed locally advanced or metastatic gastric cancer by the time they are diagnosed.
“Until recently, there have been no good-quality data to support third-line treatment in metastatic gastric cancer,” they wrote. This changed in the past year, however, when findings from three trials of emerging third-line therapy options in metastatic gastric cancer became available, illustrating that further treatment may prolong survival in some patients after the failure of second-line therapy.
The first of these, the phase-III randomized, double-blind, placebo-controlled ATTRACTION-2 trial, was performed at 49 clinical sites in Japan, South Korea, and Taiwan between November 4, 2014 and February 26, 2016. The study comprised 493 patients who had previously been treated with at least two chemotherapy regimens; 330 received the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) and 63 received placebo intravenously every two weeks.
The study found that while the objective response rate among nivolumab patients was a modest 11.2%, the median overall survival was significantly increased relative to those receiving placebo (5.3 months vs 4.1 months; HR 0.63; 95% CI: 0.51-0.78; P < .0001). Moreover, treatment-related adverse events led to death in 2% (n=5) of nivolumab patients and 1% (n=2) of those taking placebo.
Despite the strength of the findings, the authors of the review also noted that the ATTRACTION-2 trial was limited to an Asian population, where gastric cancer tumors exhibit distinct gene-expression signatures related to T-cell function compared with non-Asian patients. “These differences should be taken into consideration when discussing the potential effectiveness of nivolumab as a treatment for advanced gastric cancer in a non-Asian population,” they wrote.
By comparison, the randomized, double-blind, placebo-controlled, phase-III TAGS study was a global effort (110 sites in 17 countries), comparing the efficacy and safety of the oral cytotoxic chemotherapy trifluridine/tipiracil with placebo. The 507 participants all had metastatic gastric cancer and had been pretreated with at least two prior chemotherapeutic regimens.
It was found that trifluridine/tipiracil met the trial’s primary endpoint of improving overall survival: 5.7 months vs 3.6 months (HR 0.69; 95% CI: 0.56-0.85; P = .0003). Secondary endpoints showed that median progression-free survival was significantly longer with trifluridine/tipiracil (2.0 months vs 1.8 months; HR 0.57; 95% CI: 0.47-0.70; P < .0001).
The TAGS study demonstrated that a chemotherapy-based approach with trifluridine/tipiracil provides and improvement in median overall survival that is comparable with that seen in immunotherapy-based approaches using nivolumab or pembrolizumab in patients with advanced or metastatic gastric cancer. “However, for the small proportion of patients who respond to immune-checkpoint blockade, responses may be more durable,” the review authors wrote.
One phase-II study has also delved into the issue: KEYNOTE-059 was a non-randomized, open-label, single-arm, trial that evaluated the safety and efficacy of the monotherapy with the PD-1 inhibitor pembrolizumab in 259 patients with previously treated advanced gastric or gastro-esophageal junction cancer.
The study found an objective response rate for pembrolizumab of 11.6% in the overall study population after a median follow up of 5.8 months. In patients whose tumors were microsatellite unstable-high, the objective response rate was 9.0%.
The investigation also found that objective response rates were better for PD-L1-positive patients than for their PD-L1-negative counterparts: 15.5% vs 6.4%. Similarly, median response duration was longer for patients who were PD-L1-positive (16.3 vs 6.9 months).
Based on the results of the study, the FDA granted accelerated approval to pembrolizumab for patients with recurrent locally advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma whose tumors express PD-L1.
“Insights and clinical experience from the use of nivolumab, pembrolizumab and trifluridine/tipiracil in previously-licensed indications should help healthcare professionals to use these drugs effectively and to minimize the risk of treatment-related adverse events when adopting them as a new armamentarium for third-line therapy in metastatic gastric cancer,” the authors wrote.
