SGNTUC-019: A Phase 2 Study of Tucatinib and Trastuzumab in Patients With Previously Treated HER2-Positive Metastatic BTC

The optimal second-line therapy for patients with advanced biliary tract cancer (BTC) remains unclear as current second-line treatment options, including FOLFOX and S-1, have modest clinical benefit with limited overall response rates (ORRs) and suboptimal median overall survival (OS).^1-3 Targeted therapies are of increasing interest as a second-line treatment option for certain patients with actionable mutations, including HER2.⁴ HER2 overexpression or amplification is prevalent in up to almost 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 a HER-selective oral tyrosine kinase inhibitor currently approved for HER2-positive metastatic breast cancer and metastatic colorectal cancer following progression on previous therapy.⁵ At the ASCO 2023 annual meeting, Yoshiaki Nakamura, MD, PhD, presented results from SGNTUC-019 (NCT04579380), which investigated tucatinib and trastuzumab in patients with previously treated HER2-positive metastatic BTC.⁶

SGNTUC-019 is an open-label, phase 2 basket study that investigated the antitumor activity and safety of tucatinib and trastuzumab in patients with HER2-altered solid tumors.⁶ To be enrolled, patients had to have unresectable locally advanced or metastatic cancer previously treated with ≥1 prior lines of therapy; however, no history of HER2-directed treatment was also required.⁶ Cohort 3 consisted of patients with BTC who had HER2 overexpression or amplification.⁶ Patients were treated on 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 TEAE grade ≥3, 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, this study demonstrated antitumor activity with tucatinib and trastuzumab in patients with previously treated HER2-positive BTC, with an ORR of 46.7%.⁶ The combination of tucatinib and trastuzumab was well tolerated with low rates of discontinuation and no treatment-related deaths.⁶ Results from this study further validate that HER2 is an actionable target in certain patients with BTC and should be explored further in larger studies.

References

1. 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.
2. 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.
3. 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.
4. 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.
5. TUKYSA [package insert]. Bothell, WA: Seagen Inc; 2023.
6. 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.