Tucatinib and Trastuzumab in HER3-mutant and HER2-not Amplified Metastatic Breast Cancer

The H3RAKLES trial would allow patients with a progressive metastatic breast cancer to have access to one more line of systemic therapy. Patients included in this trial will have already received at least two lines of chemotherapy (and potentially several lines of endocrine therapy for patients with a HR+ disease). In this setting, few treatments have demonstrated a clinically meaningful benefit, and any additional option is valuable. Furthermore, the pre-clinical and clinical rationale indicate a high probability of clinical benefit, as previously shown in Table 1, with all patients treated with trastuzumab and a TKI targeting HER2 displaying a response. Besides, with several years of hindsight for the combination of lapatinib, trastuzumab and capecitabine, we expect excellent tolerance with the same treatment without capecitabine. The H3RAKLES single-arm phase II trial will evaluate the combination of tucatinib, a HER2 TKI, and trastuzumab, a HER2-directed antibody in patients with a HER2-not amplified metastatic or unresectable breast cancer harboring an activating ERBB3 mutation. To demonstrate the actionability of ERBB3 mutations, all patients will receive a combination of trastuzumab and tucatinib, in 3-weeks cycles.

NCT Number	NCT07193394
Lead Sponsor	Institut Curie Collaborators: Pfizer, Eurofins, UNICANCER
Conditions	Metastatic Breast Cancer ( HER2 Negative), Unresectable Breast Cancer
Enrollment	20 participants
Start Date	2026-01-31
Primary Completion	2028-12-07 (estimated)
Study Completion	2029-06-08 (estimated)
Updated on ClinicalTrials.gov	2026-02-23