Tucatinib in Combination with Trastuzumab Deruxtecan in Patients with Previously Treated HER2+ Unresectable Locally Advanced or Metastatic Breast Cancer: an Open-Label Phase 2 Study.

INTRODUCTION:Recent advances in HER2-directed therapies have improved outcomes for patients with HER2+ advanced/metastatic breast cancer (a/mBC), but disease progression ultimately occurs in most cases. Dual targeting of HER2 with tyrosine kinase inhibitors and antibody-drug conjugates has the potential for non-cross-resistant treatments that improve disease control. METHODS:HER2CLIMB-04, a single-arm, open-label, phase 2 study, evaluated tucatinib plus trastuzumab deruxtecan (T-DXd) in patients with HER2+ a/mBC who experienced disease progression on or were intolerant of previous HER2-directed therapy and a taxane. Patients with stable or progressing brain metastases (BMs) were permitted. The primary endpoint was confirmed objective response rate (cORR) by the investigator. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:A total of 70 patients (median age 57 years, median 2 prior lines for a/mBC) received tucatinib 300 mg orally BID and T-DXd on day 1 of each 21-day cycle. The cORR was 51.4% with a median DOR of 11.9 months (95% CI, 6.0-not estimable); median PFS was 11.5 months, and OS was 28.4 months. The most common treatment-emergent adverse events were diarrhea (80.0%), nausea (77.1%), and fatigue (72.9%). Antidiarrheal prophylaxis, introduced for 44 patients, was associated with reduced any grade diarrhea. Survival outcomes in patients with or without BMs are described. CONCLUSION:Although the addition of tucatinib to T-DXd did not demonstrate a clear benefit compared with previously demonstrated T-DXd monotherapy efficacy, when given with antidiarrheal prophylaxis, the combination was tolerable and showed clinical activity in patients with HER2+ a/mBC. CLINICAL TRIAL NUMBER:NCT04539938.