Abstract CT159: Phase I Trial of Trastuzumab Deruxtecan in Combination with Neratinib in Solid Tumors with HER2 Alterations (NCI 10495)

Abstract Background: Human epidermal growth factor receptor 2 (HER2) overexpression, amplification, or mutation occurs across a variety of solid tumors. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has been approved by the FDA for HER2-overexpressed advanced breast, gastroesophageal cancers, HER2-low breast cancer, and HER2-mutated non-small cell lung cancer. However, some patients do not derive clinical benefit from T-DXd, and drug resistance is inevitable. Preclinical studies demonstrated that neratinib, an oral irreversible pan-HER tyrosine kinase inhibitor, can increase uptake of HER2-targeting ADCs, including ado-trastuzumab emtansine and T-DXd, in vivo. Enhanced uptake of ADC is postulated to be secondary to hindering HSP90 binding to the HER2 receptor, thereby inducing receptor ubiquitination and internalization. This finding was further confirmed in patient-derived xenograft models from two patients with HER2-mutated, but non-amplified, low-expressing advanced breast cancer. Therefore, we hypothesized that the combination of T-DXd and neratinib in patients with advanced solid tumors with a HER2 alteration will enhance the efficacy of T-DXd. As T-DXd and neratinib may have overlapping toxicities in patients, a phase I study to establish the safety of the combination is warranted. Methods: This is a multi-center, phase I clinical trial (NCT05372614, NCI 10495) with a 3+3 design to study the safety and tolerability of T-DXd and neratinib. The trial is supported by the National Cancer Institute Experimental Therapeutics Clinical Trials Network. Eligible patients have advanced solid tumors with HER2 overexpression, amplification by ISH/NGS, or an activating HER2 mutation. Up to 18 evaluable patients will be enrolled in the dose escalation portion (Part 1), and 12 patients will be enrolled in the pharmacodynamic cohort (Part 2). During Part 1, the maximum tolerated dose and recommended phase 2 dose will be determined for neratinib. The dose of T-DXd is fixed at 5.4 mg/kg. We are actively enrolling patients in Part 1. The primary endpoint is dose-limiting toxicities of the combination during the first 2 cycles of treatment (42 days). Key secondary objectives of the study include T-DXd payload (DXd/MAAA-1181a) in tumor tissue obtained before and after co-treatment with neratinib to assess the potential enhanced payload concentration with the combination and quantitative HER2 assessed by mass spectrometry using multiplex reaction monitoring. Citation Format: Andrew A. Davis, Ecaterina E. Dumbrava, Aparna Kalyan, Nataliya V. Uboha, Haider S. Mahdi, Reema A. Patel, Farshid Dayyani, Jessica Porzel, Whitney L. Hensing, Cynthia X. Ma, Ron Bose, Haeseong Park. Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT159.