SAN FRANCISCO — Patients with refractory advanced gastroesophageal cancer (AGOC) have a poor prognosis, with limited options following failure of second-line therapy. New data showing improved survival suggest that regorafenib (Stivarga) may offer a new treatment option in these patients.

“Regorafenib significantly improves survival compared with placebo in patients with refractory AGOC, delaying deterioration in global quality of life,” said lead author Nick Pavlakis, PhD, MBBS, Royal North Shore Hospital, St. Leonards, Australia. “There were also no new toxicity signals.”

He emphasized that benefit was consistent in all preplanned subgroups. “This offers a new treatment option in this setting,” Pavlakis said.

He presented the findings here at the Gastrointestinal Cancers Symposium 2023.

Regorafenib is an oral multi-kinase inhibitor targeting kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-β, FGFR), and oncogenesis (RAF, RET, and KIT). It is already approved for several indications including metastatic colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma. 

AGOC could be a new indication for the drug. Use in this patient population was explored in an earlier trial, Pavlakis commented.

“We previously demonstrated the regorafenib prolonged progression-free survival in the INTEGRATE phase 2 trial,” he said. “Based on those results, we undertook the phase 3 INTEGRATE II study. The goal was to examine if regorafenib improves overall survival after failure of at least two lines of treatment.”

However, Pavlakis noted that during the conduct of this study, there was a change of practice in gastric cancer. “There was an evolution of new evidence in support of additional chemotherapy and immune checkpoint inhibitors such as nivolumab, and very interesting data on the combination of nivolumab and regorafenib from a study being conducted in Japan,” he explained. “So we amended the protocol and evolved the INTEGRATE II to INTEGRATE IIa, to continue evaluating regorafenib versus placebo, and then to evolve to the INTEGRATE IIb study to evaluate regorafenib plus nivolumab vs chemotherapy,” he explained.

The results he presented at the meeting came from the phase 3 INTEGRATE II part of this trial. The other part of the trial, INTEGRATE IIb, is still accruing, he said.  

A total of 251 patients were enrolled from five countries and stratified by tumor location, geographic location (Asia vs “rest of the world”), and prior treatment with VEGF inhibitors.

The cohort was randomly assigned to receive 160 mg regorafenib and best supportive care (BSC) or placebo plus BSC.

After 238 events, the overall survival hazard ratio (HR) was 0.68. “The survival benefit of regorafenib was best observed in the 12 month survival of 19% vs 6%,” said Pavlakis.

The median overall survival for regorafenib vs placebo was 4.5 vs 4.0 months (HR, 0.70; P = .011).

After pre-planned adjustment for multiplicity, there were no statistically significant differences across regions (Asia vs non-Asia) or other prespecified subgroups.

In the pooled analysis, which included study populations from both the INTEGRATE and INTEGRATE IIa populations, the median overall survival was 5.0 v 4.1 (HR, 0.70; P = .001).  

Regorafenib also improved progression-free survival (median PFS 1.8 vs 1.6 months (HR, 0.52; P < .0001) and it delayed deterioration in global quality of life as compared to placebo (P = .0043).

Toxicity was similar to that previously reported in other studies, and adverse events were mostly grade 1 and 2.

A Building Block?

Approached for comment, Pamela Kunz, MD, director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital and Yale Cancer Center, New Haven, Connecticut, said that she would consider the results with regorafenib in this setting as statistically significant, but with questionable clinical significance.

“The median overall survival difference 0.5 months or about 2 weeks is very modest, especially when taking into consideration the side effect profile,” she said. “I think that regorafenib as a building block for the additional phase III study is more interesting.”

“There is data that suggests synergy between VEGF inhibitors and immune checkpoint inhibitors, so I am eager to see the results of INEGRATE IIb [exploring regorafenib use with nivolumab],” Kunz added.

The study is sponsored by the Australasian Gastro-Intestinal Trials Group. Pavlakis reported relationships with Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Merck KGaA, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda.

2023 ASCO Gastrointestinal Cancers Symposium: Abstract LBA294. Presented January 19, 2023.

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.
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