A phase 2 basket trial of ado-trastuzumab emtansine for patients with HER2 amplified cancers.

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3020 Background: The HER2 gene is commonly amplified (amp) across a variety of tumor types. Ado-trastuzumab emtansine (TDM1) is a potent antibody-drug conjugate targeting HER2 that is approved in HER2+ breast cancer. The efficacy of TDM1 in other HER2 -amp solid tumors is unknown. Methods: We conducted a single-arm, phase 2 basket trial of TDM1 in which patients (pts) were enrolled in one of 5 HER2- amp cohorts: non-small cell lung cancer (NSCLC), colorectal cancer, endometrial cancer, salivary gland cancer, or other solid tumor. HER2 amp was identified through next generation sequencing by MSK-IMPACT, defined as two-fold change, or by in-situ hybridization (ISH) with HER2 / CEP17 ratio ≥2.0 in a CLIA-certified laboratory. In tumors sequenced by MSK-IMPACT, precise level of the ERBB2 amplification (i.e. integer copy number) was assessed and correlated with clinical response. All pts received TDM1 3.6mg/kg IV every 21 days. The primary endpoint was overall response rate (ORR). For each cohort, a Simon two-stage optimal design was used. In the first stage, 7 pts were accrued in each cohort; if 0/7 responses, the cohort was closed. Otherwise, up to 11 additional pts were accrued. Cohorts 1, 3, and 4 were expanded by up to 5 pts (max 23 pts) due to durable responses seen early on. Response and progression of disease was evaluated using RECIST version 1.1. Modified PERCIST was allowed if pts did not have RECIST measurable disease. Toxicity was graded as per CTCAE v4.1. Circulating tumor DNA was collected pre-, post-, and on-treatment for all pts when feasible. Results: 88 pts were accrued between 2016 and 2023. The ORR by cohort is listed in Table 1. The most common toxicities were decreased platelet count and elevated ALT. There was one incident of grade 5 pneumonitis in a patient in cohort 1. Median time on treatment was 2.5 months (range 0.03 – 53.7 months); in pts with salivary gland tumors, median time on treatment was 17.6 months (0.3 – 53.7). Conclusions: TDM1 demonstrated efficacy in multiple HER2- amp tumor types. The highest ORR was seen in salivary gland tumors, with a median time on treatment of about 1.5 years. More work is needed to understand the enhanced efficacy of TDM1 in these tumors. Clinical trial information: NCT02675829 . Response rate by cohort and disease site. Cohort RECIST-only ORR Combined* ORR 1: HER2 -amp lung 4/18 (22.2%) 4/19 (21.1%) 2: HER2 -amp colorectal 0/7 (0.0%) 0/7 (0.0%) 3: HER2 -amp endometrial 5/23 (21.7%) 5/23 (21.7%) 4: HER2 -amp salivary 8/10 (80.0%) 14/16 (87.5%) 5: Other HER2- amp solid tumors 2/23 (8.7%) 2/23 (8.7%) Biliary 1/8 (12.5%) 1/8 (12.5%) Bladder & urinary tract 0/5 (0.0%) 0/5 (0.0%) Cervical 0/2 (0.0%) 0/2 (0.0%) Ovarian 1/7 (14.3%) 1/7 (14.3%) Pancreatic 0/1 (0.0%) 0/1 (0.0%) TOTAL 19/81 (23.5%) 25/88 (28.4%) ORR=overall response rate. *Combined: RECIST when available, PERCIST if non-RECIST-evaluable.

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