PF-06952229, a selective TGF-β-R1 inhibitor: preclinical development and a first-in-human, phase I, dose-escalation study in advanced solid tumors

T A Yap; A D Choudhury; E Hamilton; L S Rosen; K L Stratton; M S Gordon; D Schaer; L Liu; L Zhang; R K Mittapalli; W Zhong; N Soman; A W Tolcher

doi:10.1016/j.esmoop.2024.103653

PF-06952229, a selective TGF-β-R1 inhibitor: preclinical development and a first-in-human, phase I, dose-escalation study in advanced solid tumors

ESMO Open. 2024 Aug 29;9(9):103653. doi: 10.1016/j.esmoop.2024.103653. Online ahead of print.

Authors

T A Yap¹, A D Choudhury², E Hamilton³, L S Rosen⁴, K L Stratton⁵, M S Gordon⁶, D Schaer⁷, L Liu⁸, L Zhang⁹, R K Mittapalli¹⁰, W Zhong¹¹, N Soman¹², A W Tolcher¹³

Affiliations

¹ Department of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston. Electronic address: TYap@mdanderson.org.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston.
³ Breast and Gynecologic Research Program, Sarah Cannon Research Institute, Nashville.
⁴ UCLA Hematology-Oncology, Santa Monica.
⁵ Department of Urology, The University of Oklahoma Health Sciences Center & The Stephenson Cancer Center, Oklahoma City.
⁶ HonorHealth Research Institute, Scottsdale.
⁷ Oncology Translational Science, Pfizer, Pearl River.
⁸ Oncology Translational Science, Pfizer, San Diego.
⁹ Oncology Research Unit, Pfizer, Inc., San Diego.
¹⁰ Clinical Pharmacology, Pfizer Inc., San Diego.
¹¹ Oncology Biostatistics, Pfizer, Cambridge.
¹² Clinical Research, Pfizer, Thousand Oaks.
¹³ Clinical Research, NEXT Oncology, San Antonio, USA.

Abstract

Background: PF-06952229 is a selective small-molecule inhibitor of transforming growth factor-β (TGF-β) receptor 1. We evaluated its antitumor activity in preclinical studies and its safety, tolerability, pharmacokinetics, and pharmacodynamics in a phase I study (NCT03685591).

Patients and methods: In vitro and in vivo preclinical studies were conducted. Patients (aged ≥18 years) received PF-06952229 monotherapy [20-500 mg, oral b.i.d., 7 days on/7 days off, 28-day cycles, Part 1A (P1A)] for advanced/metastatic solid tumors and combination therapy [250/375 mg with enzalutamide, Part 1B (P1B)] for metastatic castration-resistant prostate cancer (mCRPC). Primary endpoints were dose-limiting toxicity (DLT), adverse events (AEs), and laboratory abnormalities. Efficacy, pharmacokinetic parameters, and biomarker modulation were assessed.

Results: PF-06952229 showed activity in preclinical murine tumor models including pSMAD2 modulation in tumors. The study (NCT03685591) enrolled 49 patients (P1A, n = 42; P1B, n = 7). DLTs were reported in 3/35 (8.6%) P1A patients receiving PF-06952229 375 mg (anemia, intracranial tumor hemorrhage, and anemia and hypertension, all grade 3, n = 1 each). The most frequent grade 3 treatment-related AEs (TRAEs) were alanine aminotransferase increased and anemia (9.5% each). There were no grade 4-5 TRAEs. Plasma PF-06952229 exposures were dose proportional between 80 and 375 mg. Pharmacodynamic studies confirmed target modulation of pSMAD2/3 (peripheral monocytes). One P1A patient with prostate cancer receiving PF-06952229 375 mg monotherapy achieved confirmed partial response (31-month duration of response). A total of 8 patients (P1A, n = 6; P1B, n = 2) achieved stable disease.

Conclusions: Antitumor activity of PF-06952229 was observed in preclinical studies. PF-06952229 was generally well tolerated with manageable toxicity; a small group of patients achieved durable responses and/or disease stabilization.

Keywords: TGF-β signaling; TGF-β-R1 inhibitor; advanced solid tumors; epithelial–mesenchymal transition; metastatic castration-resistant prostate cancer.

Associated data

ClinicalTrials.gov/NCT03685591