This phase 2 basket study investigated the combination of tucatinib and trastuzumab as second-line treatment for patients with HER2-positive biliary tract cancer.
The optimal second-line therapy for patients with advanced biliary tract cancer (BTC) remains unclear. Current second-line treatment options, such as FOLFOX and S-1, have modest clinical benefit with limited overall response rates (ORRs) and suboptimal median overall survival (OS).1-3 Targeted therapies, such as those targeting HER2, are of increasing interest as second-line treatment options for patients with actionable mutations.4 HER2 overexpression or amplification is observed in up to 20% of patients with BTC, and some case studies and single-arm prospective studies have suggested therapeutic potential with HER2-targeted therapy.1,4 Tucatinib is an oral HER-selective tyrosine kinase inhibitor currently approved for HER2-positive metastatic breast cancer and metastatic colorectal cancer following progression on previous therapy.5 Yoshiaki Nakamura, MD, PhD, presented findings from the SGNTUC-019 (NCT04579380) study, which investigated tucatinib with trastuzumab in patients with previously treated metastatic HER2-positive BTC, at the ASCO 2023 annual meeting.6
Yoshiaki Nakamura, MD, PhD, presented findings from the SGNTUC-019 (NCT04579380) study, which investigated tucatinib with trastuzumab in patients with previously treated metastatic HER2-positive BTC.
SGNTUC-019 is an open-label, phase 2 basket study that evaluated the antitumor activity and safety of tucatinib and trastuzumab in patients with HER2-altered solid tumors.6 Enrolled patients had unresectable locally advanced or metastatic cancer previously treated with ≥1 prior lines of systemic therapy with no history of HER2-directed treatment.6 Patients with BTC who had HER2 overexpression or amplification were assigned to cohort 3.6 Treatment consisted of a 21-day cycle with tucatinib 300 mg orally twice a day and trastuzumab intravenously every 3 weeks.6 The primary end point was confirmed ORR, and key secondary end points included safety, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and OS.6
A total of 30 patients with BTC were enrolled, all of whom received ≥1 doses of tucatinib or trastuzumab.6 The mean study follow-up was 10.8 months. Of the 30 patients, 8 had extrahepatic cholangiocarcinoma (CCA), 7 had intrahepatic CCA, and 15 had gallbladder cancer.6 Patients had an average of 2 prior lines of therapy in any setting.6 The confirmed ORR was 46.7%, 1 patient had a complete response, and 13 had a partial response.6 The median DOR was 6 months, the median time to first response was 2.1 months, the DCR was 76.7%, and 70% of patients had a reduction in tumor size.6 The median PFS was 5.5 months and median OS was 15.5 months.6 All patients had ≥1 treatment-emergent adverse event (TEAE), 18 patients had a grade ≥3 TEAE, and 13 patients had a serious TEAE.6 Most grade ≥3 and serious TEAEs were not related to tucatinib (7 patients with tucatinib-related grade ≥3 TEAEs, 3 patients with tucatinib-related serious AEs).6 The most common grade ≥3 TEAEs were nausea, decreased appetite, and cholangitis, each in 3 patients.6 In addition, 3 patients had a TEAE leading to discontinuation of any study treatment (3 tucatinib, 1 trastuzumab), and there were no TEAEs leading to death.6
Overall, the combination of tucatinib and trastuzumab demonstrated antitumor activity in patients with previously treated HER2-positive BTC, with an ORR of 46.7%.6 Tucatinib plus trastuzumab was well tolerated with low rates of discontinuation and no treatment-related deaths.6 Results from this study indicate that HER2 is an actionable target in BTC and should be further explored in larger studies.
References
- Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX. New horizons for precision medicine in biliary tract cancers. Cancer Discov. 2017;7(9):943-962.
- Suzuki E, Ikeda M, Okusaka T, et al. A multicenter phase II study of S-1 for gemcitabine-refractory biliary tract cancer. Cancer Chemother Pharmacol. 2013;71(5):1141-1146.
- Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021;22(5):690-701.
- Harding JJ, Piha-Paul SA, Shah RH, et al. Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers. Nat Commun. 2023;14(1):630.
- TUKYSA [package insert]. Bothell, WA: Seagen Inc; 2023.
- Nakamura Y. Tucatinib and trastuzumab for previously treated HER2-positive metastatic biliary tract cancer (SGNTUC-019): a phase 2 basket study. Presented at: ASCO 2023 Annual Meeting, June 2-6, 2023; Chicago, IL.