Phase I Study to Assess the Combination of Afatinib With Trastuzumab in Patients With Advanced or Metastatic HER2-Positive Breast Cancer
Mené sur 18 patientes atteintes d'un cancer du sein HER2+ de stade avancé ou métastatique, cet essai de phase I évalue la dose maximale tolérée et l'activité clinique de l'afatinib en combinaison avec du trastuzumab
Purpose: The HER2 monoclonal antibody, trastuzumab, is standard therapy for patients with HER2-positive breast cancer (BC) before acquired resistance. Afatinib, an irreversible, oral, small-molecule ErbB-family blocker, shows clinical activity in trastuzumab-refractory HER2-positive BC. Experimental Design: This phase I study utilized a 3+3 dose escalation to determine the maximum tolerated dose (MTD) of oral once-daily afatinib in combination with the recommended dose of intravenous trastuzumab (4 mg/kg week 1; 2 mg/kg/week thereafter). Adult women with confirmed advanced/metastatic HER2-positive BC were eligible. Results: Of 18 patients treated, 16 received daily afatinib 20 mg and two 30 mg. Overall, 4/13 and 2/2 patients receiving afatinib 20 mg and 30 mg, respectively, experienced dose-limiting toxicity (DLT; all CTCAE grade 3 diarrhea). Most frequent treatment-related adverse events were diarrhea (94%), rash (56%), and fatigue (56%). Overall pharmacokinetic profiles of afatinib and trastuzumab in combination were consistent with the known characteristics of each alone. Overall objective response and disease control rates were 11% and 39%, respectively, with median progression-free survival 111.0 days (95% confidence interval, 56.0-274.0). Conclusions: The MTD of afatinib was 20 mg daily combined with the recommended weekly dose of trastuzumab, with 1/6 patients showing DLTs in the dose escalation. However, additional DLTs occurred in the dose expansion phase meaning that this MTD cannot be recommended for phase II development without strict diarrhea management. There was no evidence suggesting relevant pharmacokinetic drug-drug interactions. Signs of clinical activity were seen in trastuzumab-resistant HER2-positive BC, suggesting further investigation with optimal diarrhea management is warranted.