Dr Kummar on the Evaluation of Rezatapopt in Advanced Solid Tumors

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Supplements and Featured PublicationsTargeting TP53 Mutations in Advanced Solid Tumors
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Shivaani Kummar, MD, FACP, discusses the evaluation of rezatapopt in patients with advanced solid tumors.

Shivaani Kummar, MBBS, FACP, Margaret and Lester DeArmond Endowed Chair of Cancer Research, Professor and Division Head, Division of Hematology/Medical Oncology, Oregon Health & Science University School of Medicine; co-director, Center for Experimental Therapeutics, co-deputy director, Knight Cancer Institute, discusses the evaluation of rezatapopt (PC14586) in patients with advanced solid tumors.

Rezatapopt is a first-in-class p53 reactivator that binds to the mutated p53 Y220C protein in solid tumors, thereby restoring wild-type p53 function, Kummar says. The phase 1/2 PYNNACLE trial (NCT04585750) is evaluating this agent in patients with TP53Y220C–mutated advanced solid tumors. Data from the phase 1 portion of the trial were presented at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics and included findings from the first 67 safety-evaluable patients. In the subset of evaluable patients with TP53 Y220C mutations and KRAS wild-type disease who received rezatapopt in the efficacious dose range (n = 38), the confirmed overall response rate (ORR) was 34% (n = 13). Additionally, the ORR was 38% (n = 6) in evaluable patients with TP53 Y220C–mutated, KRAS wild-type disease who received the agent at the recommended phase 2 dose (RP2D) of 2000 mg daily (n = 16). Responses were observed across several tumor types, including ovarian cancer, small cell lung cancer, breast cancer, and endometrial cancer, Kummar notes.

TP53 Y220C mutations occur at a higher frequency in ovarian cancer than in other solid tumors, at approximately 2.9% vs 1%, Kummar explains. Data with rezatapopt in the ovarian cancer patient cohort were presented at the 2024 SGO Annual Meeting and showed that among the 15 patients with measurable disease at baseline who underwent 1 or more post-baseline tumor assessments, 7 experienced a radiographic partial response, and 7 had stable disease. The median duration of response was 7 months.

Variant allele frequency decreases in patients who responded to rezatapopt were also observed in the phase 1 proof-of-concept portion of the trial, Kummar emphasizes. The phase 2 portion of the trial has launched and is enrolling patients to receive rezatapopt at the RP2D. The study aims to determine which patients will benefit most from treatment with this agent, Kummar concludes.

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