Tucatinib in Combination With Trastuzumab Demonstrates Safety, Efficacy in Patients With HER2-Mutated Breast Cancer

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Key Takeaways

Tucatinib and trastuzumab demonstrated significant efficacy in HER2-mutated metastatic breast cancer, achieving a 41.9% overall response rate and durable responses.
The combination therapy resulted in a median progression-free survival of 9.5 months and a median overall survival of 20.1 months.
Common treatment-related adverse events included diarrhea, nausea, and hypertension, with no treatment-related mortalities reported.
These findings underscore the importance of targeted therapies in improving outcomes for patients with HER2-mutated metastatic breast cancer.

Tucatinib is an oral HER2-targeting tyrosine kinase inhibitor that was approved by the FDA in 2020.

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 metastatic breast cancer (MBC).

Breast cancer cells | Image Credit: © Jack - stock.adobe.com

Mutations in the HER2 gene can lead to abnormal activation of HER2 receptors, driving uncontrolled cell proliferation and contributing to the development of various cancers, including MBC. Development of targeted therapies have greatly improved the efficacy and safety of treatments, and subsequent health outcomes for patients.¹

Tucatinib is an oral HER2-targeting tyrosine kinase inhibitor that received FDA approval in combination with capecitabine (Xeloda; Cheplapharm Arzneimittel GmbH) for patients with advanced unresectable or metastatic HER2-positive BC in 2020. This decision was based on data from the HER2CLIMB trial (NCT02614794), where tucatinib therapy resulted in statistically significant improvements in overall survival, progression-free survival (PFS), and overall response rate (ORR).^2,3

In the SGNTUC-019 (NCT04579380), an open-label, phase 2 basket study, researchers aimed to determine the benefit of tucatinib in combination with trastuzumab across various HER2-mutated solid tumors divided into cohorts. The HER2 MBC cohort included 31 heavily pretreated female patients, of which 87% were hormone-receptor positive. The primary end point was ORR, with secondary end points including duration of response (DOR) and PFS.^1,4

Patients receiving tucatinib and trastuzumab achieved an ORR of 41.9% (90% confidence interval (CI): 26.9–58.2), including 2 complete responses. The researchers reported a median DOR of 12.6 months (90% CI: 4.7 to not estimable), with a median time to first response of 1.4 months (range 1.2–6.2).¹

The median PFS was 9.5 months (90% CI: 5.4–13.8), with 65.0% of patients (90% CI: 48.3–77.5) remaining progression-free at 6 months and 45.0% (90% CI: 28.8–60.0) at 12 months. The median OS was 20.1 months (90% CI: 15.9 to not estimable), with an estimated 12-month OS rate of 74.2% (90% CI: 58.6–84.7).¹

The most reported treatment-related adverse events (TEAEs) were diarrhea (65%), nausea (35%), vomiting and pruritus (29%), and infusion-related reaction (26%). The most common grade 3 or higher events were increased levels of alanine aminotransferase and hypertension (10%). Additionally, there were no treatment-related mortalities.¹

These findings suggest the clinical benefit of tucatinib and trastuzumab as an effective treatment option for patients with HER2-mutated MBC, particularly those who have progressed after prior therapies. The combination demonstrated a clinically meaningful efficacy and tolerability, offering durable responses and manageable safety profiles. As precision medicine advances, these results reinforce the importance of identifying HER2 mutations and tailoring treatment strategies to improve outcomes.

REFERENCES

1. Okines AFC, Curigliano G, Mizuno N, et al. Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial. Nat Med. January 17, 2025. doi:10.1038/s41591-024-03462-0

2. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. April 17, 2020. Accessed January 24, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer

3. A study of tucatinib vs. placebo in combination with capecitabine & trastuzumab in patients with advanced HER2+ breast cancer (HER2CLIMB). Updated August 14, 2023. Accessed January 24, 2025. https://clinicaltrials.gov/study/NCT02614794

4. Basket study of tucatinib and trastuzumab in solid tumors with HER2 alterations. Updated November 13, 2024. Accessed January 24, 2025. https://clinicaltrials.gov/study/NCT04579380?term=NCT04579380&rank=1