Tucatinib and trastuzumab in advanced cancers with HER2 mutations or amplifications: a molecular screening and therapeutics (MoST) program substudy

Tucatinib is a small molecule with activity in human epidermal growth factor ERBB2 (erythroblastic oncogene B gene – ERBB2/HER2) amplified breast and colorectal cancer. Its efficacy in other solid tumours and ERBB2 mutant cancers is less well characterised. Dual targeting of ERBB2 with tucatinib and trastuzumab augments the efficacy of each agent alone. We performed a single-arm phase II non-randomised trial (ACTRN12620000767909, Date of registration 27/7/2020), evaluating the combination of tucatinib and trastuzumab in cancers with ERBB2 amplification (ERBB2amp) or mutation (ERBB2mut) detected by comprehensive genomic profiling. Two cohorts of 16 patients, ERBB2amp or ERBB2mut were treated. The overall response rate (ORR) was 6/16 (38%, ERBB2amp group) and 1/16 (6%, ERBB2mut group), respectively. The median PFS was 7.4mo in the ERBB2amp and 4.0 mo in the ERBB2mut group. The median OS was 17.2 mo in the ERBB2amp group and 14.8 mo in the ERBB2mut group, respectively. No unexpected safety signals were detected. Responses were detected in novel populations including thyroid carcinoma ( n = 1) and KRAS co-mutated colon cancer ( n = 1). The protocol defined threshold of activity of cohorts with ≥3/16 responding participants, considered sufficient to estimate a true response rate via Mehta-Cain criteria, was reached in ERBB2 amplified but not ERBB2 mutated cancers.