Abstract CT071: Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495)

Abstract Background: Preclinical work demonstrated that neratinib, an oral irreversible pan-HER tyrosine kinase inhibitor, increased uptake of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in patient-derived xenograft models. Therefore, we hypothesized that the combination of T-DXd and neratinib would lead to enhanced anti-tumor effect and a manageable toxicity profile in patients with advanced solid tumors with a HER2 alteration. We present data from the phase I dose escalation clinical trial of this novel drug combination. Methods: This is a multi-center, phase I clinical trial (NCT05372614) with a 3+3 design to evaluate the safety and tolerability of T-DXd in combination with neratinib. The trial is supported by the NCI Experimental Therapeutics Clinical Trials Network. Eligible patients had advanced solid tumors with HER2 IHC3+, amplification by ISH/NGS, or an activating HER2 mutation. Prior T-DXd treatment was not allowed. The dose of T-DXd was fixed at 5.4 mg/kg. The 3 dose levels (DLs) for neratinib all started at 120mg daily for the first week. DL1 remained at 120mg daily, DL2 escalated to 160mg daily in week 2, and DL3 escalated to 240 mg daily by week 3. The primary endpoint was dose-limiting toxicities (DLTs) during the first 2 cycles of treatment (42 days) and the recommended phase 2 dose (RP2D) of the combination of T-DXd and neratinib. Results: Twenty patients received study treatment (DL1 N=7, DL2 N=4, and DL3 N=9). The most common treatment-emergent adverse events (TEAEs) of any grade included nausea (N=13, 65%), diarrhea (N=12, 60%), fatigue (N=10, 50%), and hypokalemia (N=10, 50%). Grade 3 TEAEs that occurred in more than 2 patients included anemia (N=6), diarrhea (N=4), and hypokalemia (N=3). The only Grade 4 treatment-related AE was neutropenia that occurred in 1 patient. One DLT (acute kidney injury) was observed at DL1, 0 DLTs were observed in DL2, and 1 DLT (fatigue leading to early drug discontinuation) occurred in DL3. Three patients developed Grade 1 pneumonitis (2 at DL1 and 1 at DL3). The proportion of reported TEAEs was lower at higher DLs. Of 15 response-evaluable patients by RECIST v1.1, 4 patients had a partial response including patients with gastroesophageal (N=2, one IHC 3+ and one HER2 mutated), pancreatic (N=1, IHC 3+), and ovarian (N=1, IHC 3+) cancers. Notably, 3 of 5 patients with pancreatic cancer were observed to have tumor regression (1 PR, 2 SD with -29.4% and -13.3%). With a data cutoff of 11/1/24, 3 patients at DL3 remain on study. Conclusions: The combination of T-DXd and neratinib had a manageable safety profile. DL3, which consisted of T-DXd at 5.4 mg/kg and neratinib (120 mg Cycle1 Days1-7, 160 mg C1D8-14, and 240 mg C1D15 onward) was selected as the RP2D. Promising signals of activity were observed, including pancreatic cancer. A phase I pharmacodynamic cohort and randomized phase II studies are planned to further assess safety and activity. Citation Format: Andrew A. Davis, Haeseong Park, Ecaterina E. Dumbrava, Nataliya V. Uboha, Aparna Kalyan, Farshid Dayyani, Mili Arora, Miguel A. Villalona-Calero, Haider S. Mahdi, Reema A. Patel, Floor Backes, Jessica Porzel, Whitney L. Hensing, Cheryl Pickett, Cynthia X. Ma, Ron Bose. 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 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT071.