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Ref Type Journal Article
PMID (41223631)
Authors Piha-Paul SA, Tseng C, Tran HT, Fu S, Dumbrava EE, Yap TA, Naing A, Lim J, Murphy MB, Ramirez DL, Soliman PT, Sood AK, Meric-Bernstam F
Title Phase I trial of neratinib plus palbociclib in advanced cancers with HER family alterations.
Journal Vol Issue Date Pages Journal Short Title
ESMO open 10 12 2025 Nov 11 105895 ESMO Open
URL
Abstract Text Aberrations in the human epidermal growth factor receptor (HER) and cyclin-dependent kinase 4/6 pathways drive tumor growth. While neratinib, a pan-HER kinase inhibitor, and palbociclib, a cyclin-dependent kinase 4/6 inhibitor, are effective in targeting these pathways individually, resistance to monotherapy limits durability of benefit. Herein, we sought to determine the feasibility of combining neratinib and palbociclib.This single-center phase I trial enrolled patients with advanced solid tumors harboring HER alterations. Primary objectives were to establish maximum tolerated dose and characterize dose-limiting toxicities. Secondary objectives included pharmacokinetic assessment and preliminary antitumor efficacy.Thirty-five patients were enrolled (median age, 61.5 years; median four prior therapy lines); 74% were female, and all had an Eastern Cooperative Oncology Group performance status of 0-1. Breast cancer was the most common tumor type, with HER2 amplification being the most predominate alteration. Common grade (G) 1-2 treatment-related adverse events included diarrhea (80%), leukopenia (57.1%), neutropenia (48.6%), and thrombocytopenia (48.6%). G ≥3 treatment-related adverse events affecting ≥20% of patients were neutropenia (37.1%) and leukopenia (22.9%). Dose-limiting toxicities were G3 febrile neutropenia and G3 febrile neutropenia with hepatitis. The maximum tolerated dose was neratinib 240 mg daily for 28 days and palbociclib 125 mg daily for a 3 weeks on/1 week off schedule. Among 30 response-assessable patients, the objective response rate was 16.7% (five partial responses) and three patients exhibited prolonged stable disease ≥16 weeks, yielding a clinical benefit rate of 26.7%. Pharmacokinetic analysis indicated a drug-drug interaction between neratinib and palbociclib via the CYP3A4 metabolism pathway, leading to decreased clearance and increased plasma exposure of both drugs.Combination therapy with neratinib and palbociclib demonstrated a favorable safety profile and clinical benefit rate in patients with HER-driven alterations. Pharmacokinetic analysis revealed a CYP3A4-mediated drug-drug interaction, leading to reduced clearance and increased plasma exposure of both agents, underscoring the importance of considering metabolic interactions in future clinical development.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB3 G284R Her2-receptor positive breast cancer predicted - sensitive Neratinib + Palbociclib Case Reports/Case Series Actionable In a Phase I trial, treatment with the combination of Nerlynx (neratinib) and Ibrance (palbociclib) resulted in an objective response rate of 16.7% (5/30, all partial responses) and clinical benefit rate of 26.7% in patients with advanced solid tumors harboring HER alterations, including a partial response in a patient with ESR1-positive, ERBB2 (HER2)-positive breast cancer harboring ERBB3 G284R (PMID: 41223631; NCT03065387). 41223631