Phase I trial of neratinib plus palbociclib in advanced cancers with HER family alterations.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.