The combination of tucatinib and trastuzumab, along with fulvestrant for hormone receptor-positive (HR+) cases, has shown promising clinical activity in patients with heavily pretreated HER2-mutated metastatic breast cancer (MBC). Data from the phase 2 SGNTUC-019 basket trial, presented at the 36th EORTC-NCI-AACR Symposium, indicate a confirmed objective response rate (cORR) of 41.9% and a median duration of response (DOR) of 12.6 months, offering a potential chemotherapy-free option for this patient population.
Efficacy in Heavily Pretreated Patients
The SGNTUC-019 trial enrolled 31 patients with HER2-mutated MBC who had progressed during or after at least one prior line of systemic therapy. The median number of previous lines of therapy was four. The study excluded patients with HER2+ MBC. The primary endpoint, cORR, was 41.9% (90% CI: 26.9–58.2), including two complete responses. The median time to first response was 1.4 months. The disease control rate was 80.6% (90% CI: 65.3–91.2).
Median progression-free survival (PFS) was 9.5 months (90% CI: 5.4–13.8), with a 6-month PFS rate of 65.0% and a 12-month PFS rate of 45.0%. Median overall survival (OS) was 20.1 months (90% CI: 15.9 to not estimable), with a 12-month OS rate of 74.2%.
Safety and Tolerability
The combination of tucatinib and trastuzumab was well-tolerated. Treatment discontinuations due to treatment-emergent adverse events (TEAEs) were uncommon (4.1%). The most common TEAEs were diarrhea (65%), nausea (35%), and infusion-related reactions (26%). Grade 3 diarrhea occurred in 13% of patients, manageable with standard clinical care. No treatment-related TEAEs led to death.
Biomarker Analysis
Exploratory biomarker analyses showed responses in patients with various HER2 mutations, including those in the tyrosine kinase and extracellular domains. The most commonly mutated amino acid residues were Leu755 and Ser310. Response rates were similar in patients with HER2-low expression and those without HER2 expression, suggesting the HER2 mutation is an oncogenic driver in these patients.
Agreement between local and central testing methods for HER2 mutations was moderate to strong, indicating that both tissue-based and blood-based NGS can identify patients who may benefit from this treatment.
Expert Commentary
Dr. Yoshiaki Nakamura from the National Cancer Center Hospital East in Kashiwa, Japan, noted that the study results support including this drug combination in guidelines for patients with previously treated HER2-positive bile duct cancer and suggest potential benefits for metastatic breast cancer patients with HER2-mutated tumors.
Study Limitations
The study's limitations include the small cohort size (31 patients) and the lack of a comparator arm. The duration of follow-up was also relatively short, and conclusions based on exploratory biomarker data are limited by the small cohort size and data availability across multiple central testing methods.
Clinical Implications
These findings suggest that tucatinib and trastuzumab, combined with fulvestrant in HR+ cases, represent a promising chemotherapy-free regimen for patients with heavily pretreated HER2-mutated MBC, warranting further investigation in larger, controlled trials.
