In an open-label, phase II basket SGNTUC-019 study, the combination of tucatinib and trastuzumab (with fulvestrant in patients with hormone receptor-positive disease) showed activity in patients with heavily pretreated HER2-mutated metastatic breast cancer (MBC). Moreover, the responses were durable and occurred early.
Clinically meaningful activity was seen despite patients having been heavily pretreated and support further investigation in this population according to Dr. Paula R. Pohlmann of the University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues, who reported the findings on 17 January 2025 in the Nature Medicine.
HER2 is a validated, actionable target, with HER2-targeted therapies showing clinical activity that resulted in regulatory approvals for the treatment of patients with HER2-positive breast, gastric and colorectal cancers. There is a growing interest in HER2 somatic mutations as oncogenic drivers, in the absence of HER2-positive disease, in multiple solid tumours.
In breast cancer, approximately 2-5% of tumours harbour HER2 mutations. HER2-mutated breast cancer is more frequently associated with lobular histology and heavily pretreated patients with metastatic disease. HER2-targeted agents have shown clinical activity in HER2-mutated MBC in basket trials and case reports. However, the efficacy of HER2 therapies in tumours with HER2 mutations has not been widely investigated and currently there are no treatments that have been approved specifically for patients with HER2-mutated MBC.
The authors wrote in the background that tucatinib is an oral tyrosine kinase inhibitor that is highly selective for HER2. Preclinical data have shown that tucatinib in combination with trastuzumab has antitumour activity in HER2-mutated patient-derived xenograft tumour models of multiple solid tumours, suggesting that patients with activating HER2 mutations may derive clinical benefit from the combination.
SGNTUC-019 is an open-label phase II basket study evaluating tucatinib in combination with trastuzumab in patients with HER2-altered solid tumours. In the article published in the Nature Medicine, the study team reported results of the efficacy, safety and exploratory biomarker analyses from the HER2-mutated MBC cohort of tucatinib in combination with trastuzumab (and fulvestrant in patients with hormone receptor-positive disease).
The study included a cohort of 31 heavily pretreated female patients with HER2-mutated MBC who were also HER2-negative per local testing. Patients with hormone receptor-positive tumours also received fulvestrant. The overall response rate, which was a primary endpoint, was 41.9% (90% confidence interval [CI] 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI 4.7 to not estimable) and 9.5 months (90% CI 5.4–13.8), respectively.
Treatment was well tolerated and consistent with the established safety profile of the combination. Diarrhoea was the most commonly reported adverse event; however, most events were grade 1 in severity and manageable with standard clinical care, with a grade 3 occurrence of 13%. Furthermore, antidiarrhoeal prophylaxis was not required on the study and no discontinuations of tucatinib occurred because of diarrhoea. No patients discontinued all study treatments because of an adverse event, highlighting the tolerability of this chemotherapy-free approach in patients with previous exposure to multiple lines of therapy and associated toxicities.
Exploratory biomarker analyses showed that responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. Moderate-to-strong agreement between local and central test methods was observed, suggesting that both tissue-based and blood-based next-generation sequencing may be used to identify patients harbouring HER2 mutations who may respond to treatment with tucatinib and trastuzumab.
A variety of concomitant non-HER2 genomic alterations were observed, including alterations in CDH1 and PIK3CA. Clinical activity was observed across patients with a wide variety of alterations; however, larger datasets are required to draw any conclusions about the impact of concomitant non-HER2 mutations on response.
The authors concluded that clinically meaningful activity in the SGNTUC-019 study was seen despite patients having been heavily pretreated with a median of four previous lines of systemic therapy in any setting and three previous lines in the locally advanced or metastatic setting. The results support further investigation of HER2 therapies in patients with HER2 mutations.
This further adds to the data from the SUMMIT study, which showed that HER2 mutations are potentially actionable targets in MBC; treatment with neratinib in combination with fulvestrant and trastuzumab for patients with hormone receptor-positive, HER2-mutated MBC showed similar clinical activity.
The SGNTUC-019 study was sponsored by Seagen, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Seagen was acquired by Pfizer in December 2023. F. Hoffmann-La Roche provided trastuzumab for the study.
Reference
Okines AFC, Curigliano G, Mizuno N, et al. Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial. Nature Medicine; Published online 17 January 2025. DOI: https://doi.org/10.1038/s41591-024-03462-0