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Tucatinib and Trastuzumab Demonstrates Safety, Efficacy in HER2-Mutated Breast Cancer
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Key Takeaways
- Tucatinib and trastuzumab exhibit significant antitumor activity and tolerability in HER2-mutated breast cancer patients.
- HER2 mutations are present in 2% to 5% of breast cancer tumors, making it a critical therapeutic target.
The data showed improvements in overall response rates, progression-free survival, and duration of response.
Tucatinib (Tukysa; Array BioPharma) and trastuzumab (Herceptin; Genentech) demonstrated clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with human epidermal growth factor receptor 2 (HER2)-mutated breast cancer (BC). The data support the continued investigation of these agents for this patient population.
TKI binding to breast cancer cells | This image is AI generated
HER2 has become a key target for BCs harboring this mutation, which can be found in approximately 2% to 5% of tumors. HER2 overexpression and overactivation lead to uncontrolled cell growth and inhibit programmed cell death, or apoptosis. Various agents have been approved for the treatment of patients with BC harboring HER2 mutations; however, some populations continue to progress, become refractory to treatment, or experience disease recurrence. Emerging targeted therapies have greatly improved outcomes for patients, but continued study is needed to understand their safety and efficacy, as well as how these treatments interact with one another in combination regimens.1
The HER2 targeting agents tucatinib and trastuzumab have shown significant efficacy and safety when used in combination to treat patients with HER2-mutated BC. Both agents selectively target and bind to HER2 mutations to trigger an immune response that causes cell death in tumors. Tucatinib is a Tyrosine kinase inhibitor (TKI) that has received FDA approval in both BC and colorectal cancer. Trastuzumab is a monoclonal antibody that has various approved indications to be used alone or in combination with other agents such as docetaxel and carboplatin. Additionally, tucatinib in combination with trastuzumab has received prior approval from the FDA when used with capecitabine (Xeloda; Genentech) for patients with advanced unresectable or metastatic HER2-positive BC. This approval was supported by the HER2CLIMB trial (NCT02614794).1-5
The trial data published in Nature Medicine builds upon prior studies showing the clinical benefits of combining tucatinib with trastuzumab. Investigators performed a phase 2 basket study of tucatinib in combination with trastuzumab in patients with previously treated, locally advanced unresectable or metastatic solid tumors driven by HER2. They aimed to determine the safety and efficacy of these HER2-targeting agents in tumors with HER2 mutations, which has not been extensively investigated.1
The SGNTUC-019 trial (NCT04579380) involved multiple tumor-specific cohorts of patients with HER2 overexpression across various malignancies, including BC, cervical cancer, uterine cancer, biliary tract cancer, urothelial cancer, and non-squamous non-small cell lung cancer.1,6
In the BC cohort, the investigators assessed 31 heavily pretreated female patients with metastatic HER2-mutated BC. The median age of the patients was 64 years. Eighty percent of patients were hormone receptor-positive (HR+). At initial diagnosis, 7 individuals (23%) had stage 4 illness, 3 were in the locally advanced or metastatic setting, and 4 (range: 1-10) in any setting represented the median number of prior lines of therapy. Of the patients included, 17 (55%) had previously been treated with fulvestrant. In the trial, patients who were HR+ received fulvestrant.1
The primary end point was overall response rate (ORR), with key secondary end points including duration of response (DOR) and progression-free survival (PFS). At the median follow-up of 15 months, patients receiving tucatinib with trastuzumab achieved an ORR of 41.9% (90% confidence interval (CI): 26.9–58.2). The DOR and PFS were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4–13.8), respectively. The investigators reported no new safety signals.1
The data shows the clinical benefit of the chemotherapy-free regimen of tucatinib and trastuzumab. Continued studies are needed; however, these initial findings strongly support the use of the combination for this patient population.
