PF-07265028 / Pfizer - LARVOL DELTA

Discovery of PF-07265028, A Selective Small Molecule Inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1) for the Treatment of Cancer. (PubMed, J Med Chem) - P1 | "Key components of the discovery effort included optimization of potency through mitigation of ligand strain as guided by the use of cocrystal structures, mitigation of ADME liabilities (plasma instability and fraction metabolism by CYP2D6), and optimization of kinase selectivity, particularly over immune-modulating kinases with high homology to HPK1. Structure-based drug design via leveraging cocrystal structures and lipophilic efficiency analysis proved to be valuable tools that ultimately enabled the delivery of a clinical-quality small molecule inhibitor of HPK1."

Journal • Oncology

Design of PF-07265028, a small molecule HPK1 inhibitor as a novel oncology immunotherapy (ACS-Fall 2024) - "Significant effort was invested in enhancing selectivity over highly homologous kinases, MST1-4 and MAP4K2-5. Lipophilic efficiency analysis and structure-based drug design were leveraged as tools in the optimization effort to deliver PF-07265028, a potent and selective HPK1 inhibitor which a clinical candidate that was progressed to a phase 1 clinical trial."

Oncology

PF-07265028 As Single Agent And In Combination With Sasanlimab in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=18 | Terminated | Sponsor: Pfizer | Trial completion date: Jan 2028 ➔ Oct 2023 | Active, not recruiting ➔ Terminated | Trial primary completion date: Jul 2026 ➔ Oct 2023; Study terminated based on internal business considerations and was not based on safety reasons

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Trial termination • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

PF-07265028 As Single Agent And In Combination With Sasanlimab in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=17 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=240 ➔ 17

Combination therapy • Enrollment change • Enrollment closed • Metastases • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

PF-07265028 As Single Agent And In Combination With Sasanlimab in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=240 | Recruiting | Sponsor: Pfizer | Trial completion date: Jul 2027 ➔ Dec 2027 | Trial primary completion date: Jan 2026 ➔ Jun 2026

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

PF-07265028 As Single Agent And In Combination With Sasanlimab in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=240 | Recruiting | Sponsor: Pfizer | Trial completion date: Mar 2027 ➔ Jul 2027 | Trial primary completion date: Sep 2025 ➔ Jan 2026

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

A highly-selective HPK1 inhibitor enhances T cell receptor signaling and T cell activation potential, increasing antigen recognition and efficacy of PD-1 therapy (SITC 2022) - "Conclusions Based on its ability to enhance multiple axes of T cell activation, PF-07265028 has the potential to improve anti-tumor responses in patients resistant to immunotherapy. Therefore, a phase one study has thus been initiated to evaluate the safety and efficacy of PF-07265028 alone and in combination with PD-1 blockade in patients with advanced solid tumors."

Clinical • IO biomarker • Oncology • Solid Tumor • CD4 • CD8 • LCP2 • TMB

PF-07265028 As Single Agent And In Combination With Sasanlimab in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=240 | Recruiting | Sponsor: Pfizer | Trial completion date: Oct 2026 ➔ Feb 2027 | Trial primary completion date: Apr 2025 ➔ Aug 2025

Combination therapy • Trial completion date • Trial primary completion date • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer