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

BackgroundThe HER2-selective tyrosine kinase inhibitor, tucatinib is used with trastuzumab for treatment of HER2 positive metastatic breast and colorectal cancer. Its activity in other metastatic solid tumors with HER2 alterations identified through comprehensive genomic profiling (CGP) is unknown.MethodsThe MoST program is a precision oncology platform for screening patients (pts) by CGP to identify potentially actionable genomic alterations. This multi-center, single arm phase 2 trial (ACTRN12620000767909) enrolled pts with advanced solid tumors (excluding breast or esophago-gastric cancers) with HER2 alterations. The trial recruited 2 groups of 16 pts (1: mutation, 2: amplification). The primary endpoint was objective tumour response (OTR) by RECIST 1.1. The threshold for anti-tumor activity warranting further evaluation was set at >= 3 pts with an OTR in each group. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety.Results31 pts (15 group 1, 16 group 2) had a median age of 59 years; 91% ECOG PS £ 1; 59% female; and median 1 prior line of systemic therapy. The cohort included colorectal cancer (CRC) (n=7); non-small cell lung cancer (NSCLC), cholangiocarcinoma (each n=4); cervical, duodenal (each n=3); pancreas, endometrial cancer (each n=2). At a median follow-up of 16.4 months (mo), the primary endpoint was met in group1; 6/15 pts (40%) achieved an OTR with a median PFS 8.5mo (1.48-NR), median OS 17.2mo (6.3-NR). In group 2, 1/16 pts (6%) achieved an OTR, with a median PFS 3.2mo (2.0-11.3), median OS 16.1mo (7.2-NR). In group 1, 3/4 CRC pts achieved an OTR, including 1 pt with a KRAS co-mutation. In group 2, OTR was observed in a pt with HER2 D769H mutant thyroid cancer; no OTR amongst S310F/Y mutant cancers. SD was achieved in 2/3 NSCLC pts with HER2 exon20 insertions. No new safety signals for the tucatinib/trastuzumab combination were noted.ConclusionsTucatinib plus trastuzumab demonstrates sufficient activity to warrant further trials for cancers with HER2 amplification detected by CGP, but not HER2 mutation. The activity observed in CRC with KRAS co-mutation and HER2 mutant thyroid cancer is novel, and correlation with HER2 status by IHC/ISH is of interest.Clinical trial identificationACTRN12620000767909.Legal entity responsible for the studyNHMRC Clinical Trials Centre, The University of Sydney.FundingSeattle Genetics.DisclosureB.Y. Kong: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca. J. Desai: Financial Interests, Institutional, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Bayer, BeiGene, Boehringer Ingelheim, Daiichi Sankyo Europe GmbH, GSK, Merck KGaA, Novartis, Pierre Fabre, Roche/Genetech; Financial Interests, Institutional, Research Funding: AstraZeneca/MedImmune, BeiGene, Bionomics, Bristol Myers Squibb, GSK, Novartis, Roche. C.K. Lee: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Roche, Janssen, Gilead, MSD, GSK, Novartis, Merck kGA; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Amgen, Merck kGA, Novartis, Roche. D.M. Thomas: Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Pfizer, Eisai, BeiGene, Bayer, Seattle Genetics, Merck, Illumina, Sunpharma, Elevation Oncology, RedX Pharmaceutcals. J. Simes: Financial Interests, Institutional, Advisory Role: FivePhusion ; Financial Interests, Institutional, Research Funding: Bayer, AbbVie, Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, Amgen, Astellas Pharma, MSD, Elevation Oncology, BeiGene. D. Goldstein: Financial Interests, Personal, Other: AstraZeneca, Boehringer Ingelheim, Sun Biopharma; Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Seagen, Sun Biopharma; Financial Interests, Institutional, Research Funding: Amgen, Bayer, Bristol Myers Squibb, Celgene, Pfizer, Zucero Therapeutics. All other authors have declared no conflicts of interest.