Regorafenib extends survival in refractory advanced gastroesophageal cancer
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Adding regorafenib to best supportive care significantly increased survival rates compared with placebo among patients with refractory advanced gastroesophageal cancer, results of the randomized, phase 3 INTEGRATE IIa trial showed.
Data presented at ASCO Gastrointestinal Cancers Symposium confirmed the consistent survival benefit of regorafenib (Stivarga, Bayer) across regions and racial/ethnic subgroups, “offering a new treatment option in this setting,” according to Nick Pavlakis, MBBS, MMed, PhD, senior staff specialist in the department of medical oncology at Royal North Shore Hospital and professor of medicine at University of Sydney.
In addition to prolonging OS and PFS, regorafenib delayed deterioration in global quality of life, with no new toxicity signals, he told Healio.
Background
There is an unmet need for treatment options among patients with advanced, treatment-refractory gastroesophageal cancers, according to Pavlakis.
His group looked to broaden their experience with regorafenib — an oral multitargeted tyrosine kinase inhibitor — “building on [results of the] INTEGRATE phase 2 study, which showed promising activity with regorafenib in refractory gastric and gastroesophageal junction cancers,” Pavlakis said.
Methodology
The double-blind INTEGRATE IIa study compared the safety and effectiveness of regorafenib with placebo in adults with metastatic or locally advanced gastroesophageal cancer who were refractory to or intolerant of two or more prior lines of therapy with a platinum agent plus fluoropyrimidine.
The investigators randomly assigned 251 patients from five countries — including 157 patients from Korea, Taiwan and Japan — in a 2:1 ratio to receive either regorafenib plus best supportive care (n = 169) or placebo plus best supportive care (n = 82). Researchers stratified patients according to tumor location (gastroesophageal junction vs. gastric), geographic location (Asia vs. non-Asia) and prior use of VEGF inhibitors.
OS in the intent-to-treat population served as the study’s primary endpoint, with OS among the Asian subpopulation included as a key secondary objective. Secondary endpoints included PFS, objective response rate, quality of life and safety.
Key findings
A primary analysis showed significantly longer median OS with regorafenib compared with placebo (4.5 months vs. 4 months; HR = 0.7; 95% CI, 0.56-0.87), in addition to a significantly higher 12-month OS rate (19% vs. 6%; HR = 0.68).
Regorafenib also improved median PFS compared with placebo (1.8 months vs. 1.6 months; HR = 0.53; 95% CI, 0.4-0.7).
Investigators reported no statistically significant regional differences in survival benefit among Asian vs. non-Asian participants or among any other prespecified subgroup.
A pooled analysis of INTEGRATE phase 2/phase 3 data showed median OS of 5 months among those who received regorafenib compared with 4.1 months among the entire study population (HR = 0.69; 95% CI, 0.56-0.87).
Regorafenib significantly delayed global quality-of-life deterioration vs. placebo (P = .0043) and exhibited a toxicity profile similar to earlier reports.
Researchers identified fatigue (9%), palmar-plantar erythrodysesthesia (9%) and hypertension (8%) as the most common grade 3 adverse events among patients treated with regorafenib.
Clinical implications
“Single agent regorafenib should be considered an option for patients with drug-refractory advanced or metastatic gastric and gastroesophageal junction cancer,” Pavlakis told Healio. “The regorafenib survival benefit compared with placebo in [these] patients can best be appreciated by the landmark 12-month survival rates of 19% for regorafenib vs. 6% for those who received placebo.”
Moving forward, Pavlakis said it will be important to identify who is likely to benefit from single-agent regorafenib, which is the subject of an ongoing translational substudy.
Regorafenib is also being evaluated in the ongoing randomized, phase 3 INTEGRATE IIb trial, which is comparing the agent and nivolumab (Opdivo, Bristol Myers Squibb) against standard chemotherapy among patients with pretreated advanced gastroesophageal cancer.
References:
- Pavlakis N, et al. Abstract LBA294. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 19-21, 2023; San Francisco.
- Pavlakis N, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2015.65.1901.
Perspective
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Jennifer Chuy, MD
I applaud the investigators' efforts to conduct this randomized phase 3 study assessing the effects of regorafenib for patients with refractory advanced gastroesophageal cancer. Although the study demonstrated statistically significant survival benefit with regorafenib vs. placebo, the magnitude of benefit was extremely modest. It would be of interest to see if the results of the INTEGRATE IIb trial, designed to assess the combination of regorafenib plus nivolumab (Opdivo, Bristol Myers Squibb) might improve outcomes further for this population.
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Pavlakis N, et al. Abstract LBA294. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 19-21, 2023; San Francisco.
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