Multikinase inhibitor targets advanced biliary tract tumors

By Naveed Saleh, MD, MS
Published September 22, 2020

Key Takeaways

After gemcitabine and platinum-based chemotherapy fails as a first-line treatment for locally advanced or metastatic biliary tumors, regorafenib significantly boosted progression-free survival (PFS), as well as tumor control, as a second- or third-line agent, according to recent research.

“There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy,” wrote the authors of a clinical study published in the Annals of Oncology. “Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies.”

In this multicenter randomized phase II trial, researchers assessed the efficacy and safety of regorafenib in 66 patients with nonresectable/metastatic biliary tract cancer that progressed following gemcitabine/platinum chemotherapy. The team assigned patients to either regorafenib 160 mg once daily for 3 weeks on/1 week off plus supportive care (n=33) or placebo (n=33) until progression or excess toxicity. The primary endpoints were PFS, with secondary endpoints including response rate, overall survival (OS), and translational analysis.

By 24 months, all patients had progressed and six had survived. The median treatment duration was 11 weeks in the experimental group and 6.3 weeks in the placebo group. In the experimental group, 14 of 33 patients experienced dose reduction, with stable disease rates of 74% (95% CI: 59-90) in the regorafenib group and 34% in the placebo group (95% CI: 18-51; P=0.002). 

In the experimental group, median PFS was 3 months (95% CI: 2.3-4.9) vs 1.5 months (95% CI: 1.2-2.0) in the placebo group, with median overall survival of 5.3 months (95% CI: 2.7-10.5) and 5.1 months (95% CI: 3.0-6.4), respectively (P=0.28). Importantly, no new or unanticipated safety signals occurred.

Benefit occurred in all tumor subgroups

Regorafenib is a multikinase inhibitor indicated for the treatment of metastatic colorectal cancer, unresectable hepatocellular carcinoma, and locally advanced or metastatic gastrointestinal stromal tumors. The drug mitigates angiogenesis via vascular endothelial growth factor (VEGF) receptors 1-3 and TIE2. It also targets oncogenesis via inhibition of the downstream KIT, RET, RAF1, and BRAF pathways. By blocking the activity of the intracellular domain of the platelet-derived growth factor receptor and fibroblast growth factor receptor (FGFR), regorafenib changes the tumor microenvironment, as well as affecting tumor immunity. 

In the current study, 42 of the 66 patients had intrahepatic cholangiocarcinoma, 9 had extrahepatic cholangiocarcinoma, 6 had perihilar cholangiocarcinoma, and 9 had gallbladder carcinoma.

“Although the trial was not designed for subgroup analyses and the sample size did not allow for interaction tests, this clinical benefit was present across all tumor subgroups, and, despite having a higher proportion of IH [intrahepatic] tumors, it is not possible to conclude if this benefit is related to FGFR2 fusions or IH location,” the authors wrote.

Regorafenib did not significantly prolong OS, despite yielding higher median PFS and disease control rates after 24 months of follow-up. Even though the OS was higher than that of historical controls, the estimated survival at 12 months was 30% in the experimental group compared with 60% in the controls. The researchers hypothesized that this paucity of survival benefit could in part be due to the study not being designed to exhibit OS as a primary outcome.

“For example,” the authors noted, “one-half of the patients treated with regorafenib were able to receive subsequent treatments, mainly chemotherapy, compared with one-third of patients treated with placebo, but this difference was not statistically significant and probably did not translate into gains in OS. Moreover, three patients in the regorafenib arm died rapidly from infection (but no angiocholitis) and three of them decided to stop the treatment very early (not due to an adverse event), despite being stabilized under treatment. These six patients (18% of the patients in that arm) may have shortened the observed OS. This may explain the lack of a survival benefit, which was not a designed end point of our study.”

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