Regorafenib may be new kid on the block for advanced gastroesophageal cancer

Adding regorafenib to best supportive care improves outcomes in patients with refractory advanced gastroesophageal cancer who have limited options following failure of second-line therapy, with no new toxicity signals.

This was the key finding from the phase III INTEGRATE IIa trial presented at ASCO GI 2023.

"Regorafenib significantly improved survival vs placebo in patients with refractory advanced gastroesophageal cancer, delaying deterioration in the quality of life and prolonging progression-free survival (PFS),” reported Dr Nick Pavlakis from the Royal North Shore Hospital in St Leonards, New South Wales, Australia. [ASCO GI 2023, abstract LBA294]

The benefit was consistent across all preplanned subgroups. “This offers a new treatment option for advanced gastroesophage al cancer,” he added.

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

Building the evidence case

“We previously demonstrated that regorafenib prolonged PFS in the phase II INTEGRATE trial,” Pavlakis shared. “Based on those results, we undertook the phase III INTEGRATE II study to further examine if regorafenib can improve overall survival (OS) following failure of two lines of treatment.”

However, due to a change in gastric cancer practice, INTEGRATE II was later split into INTEGRATE IIa (comparing regorafenib vs placebo), and INTEGRATE IIb (comparing regorafenib plus nivolumab vs chemotherapy), with the latter currently accruing. [NCT04879368]

“There was new evidence in support of additional chemotherapy and immune checkpoint inhibitors such as nivolumab, and interesting data on the nivolumab-regorafenib combination from a study in Japan,” Pavlakis continued. “So, we amended the protocol and evolved the INTEGRATE II to INTEGRATE IIa, to further evaluate regorafenib vs placebo, and then the INTEGRATE IIb study for regorafenib plus nivolumab vs chemotherapy.”

INTEGRATE IIa comprised 251 patients with advanced gastroesophageal cancer who had received at least two prior lines of therapy, including a platinum agent and a fluoropyrimidine analogue.

Patients were randomly assigned to receive regorafenib (n=169) or placebo (n=82), on top of best supportive care. Baseline characteristics were well balanced between arms.

Superior OS with regorafenib

After 238 events, OS was superior in the regorafenib arm (hazard ratio [HR], 0.68; 95 percent confidence interval [CI], 0.52–0.90; p=0.006). At 12 months, OS rate was 19 percent with regorafenib vs 6 percent with placebo.

The median OS was 4.5 months with regorafenib vs 4.0 months with placebo (HR, 0.70; p=0.011).

In the pooled analysis, which included data from the INTEGRATE and INTEGRATE IIa cohorts, the median OS was 5.0 v 4.1 (HR, 0.70; p=0.001).  

There was also an improvement in PFS with regorafenib (HR, 0.53; 95 percent CI, 0.40–0.70; p<0.0001). Furthermore, deterioration in global quality of life was delayed with regorafenib vs placebo (p=0.0043). 

Toxicity was similar to what was reported in other studies of regorafenib. The most common adverse events were fatigue, palmar-plantar erythrodysesthesia syndrome, and hypertension.

When sought for comment, Dr Pamela Kunz from the Smilow Cancer Hospital and Yale Cancer Center in New Haven, Connecticut, US said there are data to suggest synergy between VEGF inhibitors and immune checkpoint inhibitors. “Hence, I await the results of INTEGRATE IIb.”