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.