The current standard of care for the first-line treatment of patients with advanced biliary tract cancer is chemotherapy combination of gemcitabine plus cisplatin; however, this regimen yields only modest responses, underscoring the need for novel, more active treatments. Human epidermal growth factor receptor (HER) tyrosine kinases are often overexpressed in patients with biliary tract cancers.
A multicenter, phase 1b/2 study is investigating the addition of the reversible, small-molecule pan-HER inhibitor varlitinib to the backbone regimen of gemcitabine plus cisplatin as first-line treatment of Asian patients with advanced biliary tract cancers. The results of the phase 1b portion of the study were presented at the 2022 ASCO GI Cancers Symposium by Do-Youn Oh, MD, PhD, Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, South Korea.
The phase 1b portion of the study included a total of 23 patients in Korea, Singapore, and Taiwan who received oral varlitinib twice daily every day (starting dose, 200 mg twice daily) plus gemcitabine and cisplatin on days 1 and 8 of a 3-week cycle.
The primary objectives were the maximum-tolerated dose of varlitinib plus gemcitabine and cisplatin and the safety profile of this 3-drug regimen. Patients were evaluable for the maximum-tolerated dose if they had ≥80% varlitinib compliance and received 2 doses of the chemotherapy regimen in cycle 1, or if they had a dose-limiting adverse event in cycle 1. The secondary objective was to assess the preliminary antitumor activity of the regimen, as measured by objective response rate (ORR).
The median age of 23 patients was 66 years (range, 47-82 years); 52% were male, 57% had ECOG performance status 1, 43% of the tumors were in the intrahepatic bile duct, 22% in the extrahepatic bile duct, 22% in the gallbladder, and 13% of the tumors were in the ampulla of Vater.
In all, 11 patients received varlitinib 200 mg and 12 patients received varlitinib 300 mg. Of these, 9 patients in the 200-mg cohort and 7 patients in the 300-mg cohort were evaluable for the maximum-tolerated dose.
In the 23 patients evaluable for response, the ORR was 35%, including 8 partial responses and 12 patients with stable disease for ≥12 weeks; the disease control rate was 87%. The median duration of response was 4 months (range, 2.8-11 months), and the median progression-free survival was 6.8 months (range, 5.1-10.7 months).
Dose-limiting adverse events were reported in 2 patients in the 200-mg cohort, including grade 3 unconjugated hyperbilirubinemia, grade 3 increased alanine aminotransferase (ALT), and grade 4 increased aspartate aminotransferase (AST), as well as in 1 patient in the 300-mg dose cohort, who had grade 4 thrombocytopenia, grade 3 febrile neutropenia, and grade 3 AST increase.
In the safety analysis, 36% of the patients in the 200-mg cohort and 67% of the patients in the 300-mg cohort had at least 1 grade ≥3 treatment-related adverse event (TRAE), including fatigue, vomiting, platelet count decreased, AST, neutrophil count decreased, and decreased appetite. In the 200-mg cohort, 36% of patients had 1 or more grade ≥3 TRAEs, including rash, elevated ALT and AST levels, and decreased neutrophil count.
Based on these results, Dr Oh and colleagues concluded that the addition of the pan-HER inhibitor varlitinib to gemcitabine and cisplatin was well-tolerated and yielded antitumor activity in patients with treatment-naïve advanced biliary tract cancers.
Oh DY, Yong WP, Chen LT, et al. Varlitinib in combination with gemcitabine and cisplatin for treatment-naïve advanced biliary tract cancer. Abstract 439.
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