Puma Biotechnology Showcases Promising Neratinib Combination Data at AACR Annual Meeting 2025
Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company specializing in the development of innovative cancer treatments, has presented new clinical data on its lead drug candidate, neratinib (NERLYNX®), at the 2025 Annual Meeting of the American Association for Cancer Research (AACR). The presentation, delivered as part of a poster session, detailed the preliminary findings from an early-phase clinical trial evaluating a combination therapy of neratinib and trastuzumab deruxtecan (T-DXd or ENHERTU®) in patients with advanced solid tumors exhibiting HER2 alterations.
The study, entitled “CT071: Phase I trial of trastuzumab deruxtecan in combination with neratinib in solid tumors with HER2 alterations (NCI 10495),” was presented by Dr. Andrew A. Davis, Assistant Professor of Medicine at Washington University School of Medicine. The poster was featured during Session PO.CT01.01, focusing on First-in-Human Phase I Clinical Trials, held at McCormick Place in Chicago, Illinois.
Overview of the NCI 10495 Study
The Phase I trial (ClinicalTrials.gov Identifier: NCT05372614) was conducted under the sponsorship of the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and carried out through the NCI’s Experimental Therapeutics Clinical Trials Network (ETCTN). The primary aim of the trial was to evaluate the safety, tolerability, and determine the recommended Phase II dose (RP2D) for the combination regimen of trastuzumab deruxtecan and neratinib in patients with HER2-positive or HER2-mutated advanced solid tumors.
The study utilized a traditional 3+3 dose escalation design across three dosing cohorts. A total of 20 patients were enrolled and treated at three dose levels. All patients received trastuzumab deruxtecan at a fixed dose of 5.4 mg/kg, while neratinib was administered with stepwise dose escalation across cohorts:
- Dose Level 1 (DL1): Neratinib 120 mg daily continuously
- Dose Level 2 (DL2): Neratinib 120 mg daily in Week 1, escalated to 160 mg in Week 2, and maintained
- Dose Level 3 (DL3): Neratinib 120 mg daily in Week 1, escalated to 160 mg in Week 2 and 240 mg from Week 3 onward
Eligible patients were those with advanced solid tumors characterized by HER2 immunohistochemistry (IHC) 3+, HER2 amplification identified by in situ hybridization or next-generation sequencing, or an activating HER2 mutation. Notably, prior exposure to trastuzumab deruxtecan was not permitted.
Safety and Tolerability Profile
Among the 20 patients treated (DL1: n=7, DL2: n=4, DL3: n=9), the most commonly reported treatment-emergent adverse events (TEAEs) of any grade included:
- Nausea (75%)
- Diarrhea (75%)
- Fatigue (65%)
- Hypokalemia (55%)
Grade 3 TEAEs occurring in more than two patients included:
- Anemia (30%)
- Diarrhea (20%)
- Hypokalemia (15%)
There was one report of a Grade 4 treatment-related adverse event (neutropenia) in a single patient (5%). Dose-limiting toxicities (DLTs) were relatively rare: one case of acute kidney injury at DL1 and one case of fatigue leading to treatment discontinuation at DL3. Importantly, no DLTs were observed at DL2. Additionally, three patients developed Grade 1 pneumonitis or interstitial lung disease (ILD), with two cases at DL1 and one at DL3. Interestingly, the incidence of reported TEAEs appeared to decrease at higher dose levels.
These findings indicate that the combination regimen had a generally manageable safety profile, with toxicities that were consistent with the known side effects of both agents.
Early Signs of Antitumor Activity
Of the 15 patients evaluable for response per RECIST v1.1 criteria, four patients achieved partial responses (PRs). These responses were observed in patients with gastroesophageal cancers (n=2; one with HER2 IHC3+ and one with a HER2 mutation), pancreatic cancer (n=1; HER2 IHC3+), and ovarian cancer (n=1; HER2 IHC3+; unconfirmed PR).
Particularly encouraging were the responses observed in patients with advanced pancreatic cancer—a tumor type traditionally associated with poor prognosis and limited treatment options. Among five evaluable pancreatic cancer patients, three showed evidence of tumor shrinkage:
- One patient achieved a PR lasting more than 13 cycles
- Another had stable disease with a 29.4% tumor reduction over 9 cycles
- A third experienced a 13.3% tumor regression maintained for 8 cycles
These preliminary efficacy results suggest potential benefit of the neratinib and trastuzumab deruxtecan combination in treating HER2-altered tumors beyond breast cancer, especially in hard-to-treat malignancies.
Dose Selection and Future Study Plans
Based on safety and tolerability data, along with early signs of clinical activity, the study identified DL3 as the RP2D. This dosing regimen includes trastuzumab deruxtecan at 5.4 mg/kg in combination with neratinib at 120 mg in Week 1, escalating to 160 mg in Week 2 and 240 mg in Week 3 and beyond.
Following this determination, the study has progressed to Part 2, which began enrollment in March 2025. This second phase will include 12 patients and focus on pharmacodynamic evaluations. Eligible participants will include individuals with any advanced solid tumor harboring HER2 overexpression or mutation.
Expert Commentary and Industry Perspective
“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,” said Dr. Davis. “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.”
Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, expressed optimism about the study’s early results. “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,” said Auerbach. “We look forward to continued evaluation of this combination in the Phase II portion of this study.”
Industry Collaboration and Drug Background
The NCI 10495 trial is supported by both Puma Biotechnology and Daiichi Sankyo, Inc., through Cooperative Research and Development Agreements (CRADAs) with the NCI. This underscores the collaborative efforts across industry and government to advance innovative cancer therapies.
Trastuzumab deruxtecan, developed by Daiichi Sankyo and co-commercialized with AstraZeneca, is a HER2-targeting antibody-drug conjugate (ADC) engineered with a topoisomerase I inhibitor payload (DXd) designed to deliver targeted cytotoxic activity to cancer cells expressing HER2.
Neratinib, Puma Biotechnology’s oral, irreversible pan-HER tyrosine kinase inhibitor, is currently approved for extended adjuvant treatment of early-stage HER2-positive breast cancer and is being investigated in a variety of HER2-altered solid tumors in combination regimens.
The presentation of the NCI 10495 trial at AACR 2025 represents a key milestone in Puma Biotechnology’s ongoing efforts to expand the therapeutic applications of neratinib beyond breast cancer. The combination of neratinib with trastuzumab deruxtecan appears to offer a tolerable safety profile and promising early signals of efficacy in patients with HER2-positive or HER2-mutant tumors, including those with limited existing treatment options.
As Part 2 of the trial progresses, further insights into the pharmacodynamics and long-term efficacy of this combination will be crucial in shaping the future clinical development pathway. The oncology community and investors alike will be watching closely as Puma and its partners move this novel approach through the next phase of clinical validation.
