Abstract B060: Neratinib in combination with antibody–drug conjugates for patients with metastatic cancer

Abstract Antibody–drug conjugates, such as T-DXd and T-DM1, have improved clinical outcomes in patients with a variety of tumor types, including HER2-positive (HER2+) breast cancer (BC). The effectiveness of an ADC relies on its ability to bind to the target antigen on the cell surface and subsequent internalization into the cell via receptor-mediated endocytosis. Combining ADCs with other therapies, including targeted agents, can enhance ADC efficacy through multiple mechanisms. Neratinib, an irreversible, oral pan-HER inhibitor approved for the treatment of patients with HER2+ early and metastatic BC (MBC), has been evaluated in combination with ADCs. Preclinical studies have shown synergy between neratinib + T-DXd and T-DM1. Neratinib enhances uptake of T-DM1 and T-DXd via increased endocytosis in vitro and in vivo in the patient-derived xenograft lines WHIM51 and WHIM64 from BCs with HER2-activating mutations; this does not occur with reversible inhibitors like lapatinib and tucatinib. Clinical studies have investigated combinations of neratinib with ADCs in patients with metastatic cancer as a means of enhancing ADC internalization and/or combating treatment resistance. The phase 1 NCI 10495 study (NCT05372614) is examining neratinib + T-DXd at different neratinib dose levels (DLs 1–3) in 20 patients with HER2-mutated/amplified advanced solid tumors. Patients at all dose levels received T-DXd 5.4 mg/kg IV q3w; the neratinib recommended phase 2 dose (RP2D) was 120 mg/d on D1–7, 160 mg/d on D8–14, and 240 mg/d on D15 onward. Thus far, there have been 3 confirmed PRs and 1 unconfirmed PR. NSABP FB-10 (NCT02236000) is a phase 1b/2 study of the safety and efficacy of neratinib + T-DM1 in patients with HER2+ MBC previously treated with trastuzumab + pertuzumab (phase 1b, n=27; phase 2, n=22); the RP2D was 160 mg/d neratinib + 3.6 mg/kg T-DM1. The phase 1 objective response rate (ORR) was 63% (12/19) and in phase 2 was 32% (7/22). In the phase 2 TBCRC 022 study (NCT01494662), cohort 4 evaluated the safety and efficacy of neratinib + T-DM1 in patients with HER2+ BC with brain metastases, all of whom received neratinib 160 mg/d and T-DM1 3.6 mg/kg q21d. Patients in cohort 4A (n=6) had no prior central nervous system (CNS)-directed therapies; patients in cohorts 4B (n=17) and 4C (n=21) had prior CNS-directed treatments: 4B had no prior T-DM1 and 4C had prior T-DM1. The CNS ORR in cohorts 4A, 4B, and 4C was 33.3%, 35.3%, and 28.6%, respectively. No new safety signals were observed in any of these studies. All patients received mandatory diarrhea prophylaxis and patients in NCI 10495 received dose-escalated neratinib, which has been shown to reduce the occurrence of diarrhea. The combination of neratinib with the ADCs, T-DM1 and T-DXd, appears to be tolerable with preliminary signals of response. There is a strong rationale for further studies of these combinations in patients with metastatic tumors harboring HER2 mutations or amplifications. Citation Format: Ron Bose, Haeseong Park, Ecaterina E. Dumbrava, Rachel Freedman, Jame Abraham, Andrew A. Davis. Neratinib in combination with antibody–drug conjugates for patients with metastatic cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B060.