The results from the biliary tract cancer (BTC) cohort of SGNTUC-019 study further validate HER2 as an actionable biomarker in metastatic BTC. The combination of tucatinib and trastuzumab demonstrated clinically meaningful activity and favourable tolerability for patients with HER2-positive metastatic BTC, a population with historically poor outcomes.
The investigators led by Dr. Yoshiaki Nakamura of the International Research Promotion Office/Translational Research Support Office/Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East in Chiba, Japan, who published the study findings on 26 September in the JCO, wrote that additional investigations of HER2-directed agents are warranted in patients with HER2-positive metastatic BTC.
BTC is an aggressive malignancy, with most patients having metastatic or locally advanced disease at diagnosis. First-line systemic treatment for advanced BTC includes gemcitabine plus cisplatin with or without durvalumab, with a median overall survival (OS) of 12.8 months and 11.5 months. A recent report has also shown that pembrolizumab added to gemcitabine and cisplatin results in a significantly longer OS compared with gemcitabine and cisplatin alone in the first-line setting (12.7 months versus 10.9 months). However, for patients whose disease progresses beyond first-line therapy, treatment options are limited and provide modest clinical benefit.
BTC is a heterogeneous group of rare diseases with varied actionable molecular alterations (e.g. FGFR2 and IDH1), and recent reports have shown that several molecular agents targeting specific genomic alterations result in antitumour activity in patients with metastatic BTC. HER2 overexpression/amplification is observed in up to 20% of metastatic BTC, with varying rates based on tumour location. The authors wrote that HER2 is emerging as an important actionable target in this patient population. Investigational anti-HER2 therapies have demonstrated clinical activity in metastatic BTC with reported objective response rates (ORRs) ranging from 12% to 41.3%.
Tucatinib is an oral tyrosine kinase inhibitor highly selective for HER2. Preclinical data have shown that tucatinib and trastuzumab in various HER2-positive tumour types results in superior antitumor activity compared with either agent alone. Consistent with the preclinical data, clinical trials of tucatinib have demonstrated that vertical receptor inhibition of HER2 is highly effective in patients with HER2-positive metastatic cancer.
In the latest article, the authors present the efficacy and safety results of tucatinib and trastuzumab in a cohort of patients with previously treated HER2-positive metastatic BTC from the SGNTUC-019 study. SGNTUC-019 is an open-label phase II basket study evaluating the efficacy and safety of tucatinib and trastuzumab in patients with HER2-altered solid tumours.
In the BTC cohort, patients had previously treated HER2 overexpressing, or amplified tumours identified with local testing with no prior HER2-directed therapy. The primary endpoint was confirmed ORR per investigator assessment. Patients were treated on a 21-day cycle with tucatinib (300 mg orally twice daily) and trastuzumab (8 mg/kg intravenously followed by 6 mg/kg every 3 weeks).
A total of 30 patients were enrolled. As of data cut-off on 30 January 2023, the median duration of follow-up was 10.8 months. Confirmed ORR was 46.7% (90% confidence interval [CI] 30.8 to 63.0), with a disease control rate of 76.7% (90% CI 60.6 to 88.5). The median duration of response and progression-free survival were 6.0 months (90% CI 5.5 to 6.9) and 5.5 months (90% CI 3.9 to 8.1), respectively. At data cut-off, 15 patients (50.0%) had died, and the estimated 12-month OS rate was 53.6% (90% CI 36.8 to 67.8).
The two most common treatment-emergent adverse events (TEAEs) were pyrexia (43.3%) and diarrhoea (40.0%). Grade ≥3 TEAEs were reported in 18 patients (60.0%), with the most common being cholangitis, decreased appetite, and nausea (all 10.0%), which were generally not treatment related. TEAEs led to treatment regimen discontinuation in one patient, and there were no deaths due to TEAEs.
The authors commented that there is currently no consistent HER2 testing guideline for BTC. A comparative analysis of results from local and central testing showed a high level of agreement between central and local and between central HER2 status determination. In addition, confirmed ORR for patients whose samples tested positive for HER2 centrally (IHC/FISH 57.1%, FISH only 57.1%, NGS 63.6%) was similar to the confirmed ORR reported in the overall cohort (46.7%).
The percentage agreement and confirmed ORR data suggest that in clinical setting, various HER2 testing modalities can reliably be used to identify patients with HER2-positive metastatic BTC who may respond to tucatinib and trastuzumab. No responses were seen in patients who tested negative by the central blood-based NGS assay, suggesting clinical utility of this platform in HER2-positive metastatic BTC.
The authors underlined that local and central HER2 test results had a high level of agreement highlighting the importance of HER2 testing for patients with metastatic BTC to optimise clinical treatment, and the testing methods used in this analysis could serve as a framework for future studies involving patients with HER2-positive metastatic BTC or other types of tumours.
The authors also commented that this analysis is limited by a small cohort, short follow-up, lack of control group, and absence of independent central radiology review. Despite the absence of a control arm, the encouraging results from this analysis support that HER2 is an actionable biomarker for HER2-positive metastatic BTC, justifying further investigation of HER2-directed agents in this tumour type.
Most patients enrolled in the BTC cohort were Asian, which is consistent with the global statistics for BTC; Japan and South Korea are known to have some of the highest incidences of the disease. To contextualize data, the authors have referenced previous studies with other HER2-directed agents in similar patient populations while acknowledging the limitations of cross-trial comparisons. They concluded that tucatinib combined with trastuzumab had clinically significant antitumour activity and was well tolerated in patients with previously treated HER2-positive metastatic BTC.
The authors acknowledged the SCRUM-Japan MONSTAR-SCREEN alliance for contribution to the patient recruitment at the Japanese study sites.
The study was supported by Seagen Inc (Bothell, WA, US) in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc (Rahway, NJ, US). F. Hoffmann-La Roche, San Francisco, CA, US provided trastuzumab for the study.
Reference
Nakamura Y, Mizuno N, Sunakawa Y, et al. Tucatinib and Trastuzumab for Previously Treated Human Epidermal Growth Factor Receptor 2–Positive Metastatic Biliary Tract Cancer (SGNTUC-019): A Phase II Basket Study. JCO; Published online 26 September 2023. DOI: 10.1200/JCO.23.00606
