On April 28, 2025 Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, reported that clinical data on neratinib were presented in a poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2025 (Press release, Puma Biotechnology, APR 28, 2025, View Source [SID1234652287]). The AACR (Free AACR Whitepaper) Annual Meeting is currently taking place at the McCormick Place in Chicago, Illinois. The poster is entitled, "CT071: Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495)." Andrew A. Davis, Assistant Professor at Washington University School of Medicine, presented the poster during Session PO.CT01.01 – First-in-Human Phase I Clinical Trials 1.

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NCI 10495 is sponsored by the National Cancer Institute, part of National Institutes of Health, and conducted in the NCI funded Experimental Therapeutics Clinical Trials Network (ETCTN). This open label, multi-center, Phase I clinical trial (NCT05372614) enrolled 20 patients in three cohorts treated with three increasing dose levels, or a 3+3 trial design, to evaluate the safety and tolerability of trastuzumab deruxtecan (T-DXd or ENHERTU) in combination with neratinib (NERLYNX). Eligible patients had advanced solid tumors with HER2 immunohistochemistry 3+ (IHC3+), HER2 amplification identified by in situ hybridization or next-generation sequencing, or an activating HER2 mutation. Prior treatment with trastuzumab deruxtecan was not allowed. The dose of trastuzumab deruxtecan was fixed at 5.4 mg/kg. The three dose levels (DLs) for neratinib all started at 120 mg daily for the first week. DL1 remained at 120 mg daily throughout the course of treatment, DL2 escalated to 160 mg daily in week 2 and 200 mg by week 3, and DL3 escalated to 160 mg in week 2 and 240 mg by week 3. The primary endpoints were the determination of the dose-limiting toxicities (DLTs) during the first two cycles of treatment (42 days) and the determination of the recommended Phase II dose of the combination of trastuzumab deruxtecan and neratinib.

Twenty patients received study treatment (DL1 N=7, DL2 N=4, and DL3 N=9). The most common treatment-emergent adverse events of any grade included nausea (N=15, 75%), diarrhea (N=15, 75%), fatigue (N=13, 65%), and hypokalemia (N=11, 55%). Grade 3 treatment-emergent adverse events that occurred in more than 2 patients included anemia (N=6, 30%), diarrhea (N=4, 20%), and hypokalemia (N=3, 15%). The only Grade 4 treatment-related adverse event was neutropenia that occurred in 1 patient (5%). One DLT (acute kidney injury) was observed at DL1, 0 DLTs were observed in DL2, and 1 DLT was observed (fatigue leading to early drug discontinuation) at DL3. Three patients developed Grade 1 pneumonitis or interstitial lung disease (ILD), 2 at DL1 and 1 at DL3. The proportion of reported treatment-emergent adverse events was lower at higher dose levels.

Of 15 response-evaluable patients by RECIST v1.1, 4 patients had a partial response (PR), including patients with gastroesophageal (N=2, one HER2 IHC 3+ and one HER2 mutated), pancreatic (N=1, IHC 3+), and ovarian (N=1, IHC 3+; unconfirmed response) cancers. Notably, 3 of 5 patients with advanced pancreatic cancer were observed to have tumor regression (1 PR for 13+ cycles, 2 with stable disease consisting of one patient with -29.4% tumor regression for 9 cycles and one patient with -13.3% tumor regression for 8 cycles).

Dose level 3, which consisted of trastuzumab deruxtecan at 5.4 mg/kg and neratinib at 120 mg in week 1, 160 mg week 2, and 240 mg week 3 onward, was selected as the recommended Phase II dose. Part 2 of this study, which consists of a pharmacodynamic evaluation of trastuzumab deruxtecan (5.4 mg/kg) and neratinib (RPD2) in 12 patients, opened to enrollment in March 2025. Patients with any advanced solid tumor and HER2 amplification/overexpression or a HER2 mutation will be enrolled.

"Neratinib and trastuzumab deruxtecan showed impressive combination activity in preclinical models of HER2-mutated breast cancers, which prompted evaluation of the combination in this first-in-human clinical trial. I am pleased to report that the combination not only had a manageable safety profile, but we also observed early signs of efficacy across a variety of HER2-altered tumors," said Dr. Davis.

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, added, "We are pleased with the tolerability and potentially promising signals of efficacy of neratinib in combination with trastuzumab deruxtecan, especially in hard-to-treat tumors including pancreatic cancer. We look forward to continued evaluation of this combination in the Phase II portion of this study."

NCI 10495 is also supported by Puma Biotechnology and Daiichi Sankyo, Inc. through Cooperative Research and Development Agreements with NCI.

Trastuzumab deruxtecan is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).