! I’m your host today, Courtney Flaherty.

, which provides oncology professionals with the resources and information they need to provide the best patient care. In both digital and print formats, OncLive covers every angle of oncology practice, from new technology to treatment advances to important regulatory decisions.

In today’s episode, sponsored by PMV Pharmaceuticals, we had the pleasure of speaking with Shivaani Kummar, MBBS, FACP, about the ongoing investigation of the first-in-class p53 reactivator rezatapopt (PC14586) for patients with 

 Y220C–mutated advanced solid tumors. Dr Kummar is the Margaret and Lester DeArmond Endowed Chair of Cancer Research, professor, and division head in the Division of Hematology/Medical Oncology at the Oregon Health & Science University School of Medicine in Portland. She is also the codirector of the Center for Experimental Therapeutics and the co-deputy director of the Knight Cancer Institute.

The development of tumor-agnostic agents, such as rezatapopt, is revolutionizing cancer treatment by focusing on specific molecular targets across different tumor types rather than histologic classification. Rezatapopt has activity in advanced solid tumors harboring this mutation, particularly ovarian, breast, lung, and endometrial cancers, with notable response rates and manageable adverse effects.

Updated results from the phase 1/2 PYNNACLE trial (NCT04585750) revealed a 38% confirmed overall response rate (ORR) with rezatapopt monotherapy administered at the recommended phase 2 dose (RP2D) of 2000 mg daily in patients with 

 wild-type tumors (n = 16). Within the ovarian cancer cohort, partial responses were achieved by 7 of the 15 patients with measurable disease at baseline, and 7 patients achieved stable disease. These early data support further investigation of rezatapopt in the phase 2 segment of the trial, which is currently assessing the efficacy of rezatapopt at the RP2D across various cohorts of patients with 

In our exclusive interview, Dr Kummar discussed the significance of targeting 

 Y220C in solid tumors, early efficacy and safety data reported with rezatapopt in 

 Y220C–mutant solid tumors, and directions for future development of TP53-directed drugs both alone and in combination regimens.

That’s all we have for today! Thank you for listening to this episode of 

, sponsored by PMV Pharmaceuticals. Check back on Mondays and Thursdays for exclusive interviews with leading experts in the oncology field.

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Podcasts

Dr Kummar discusses the significance of targeting TP53 Y220C in solid tumors and early data reported with rezatapopt in TP53 Y220C–mutant solid tumors.

Kummar on the Investigation of Rezatapopt in TP53 Y220C–Mutated Advanced Solid Tumors

Dr Kummar on the Evaluation of Rezatapopt in 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 

 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 

Y220C–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 

 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 

 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.

 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 

 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.

Videos

Shivaani Kummar, MD, FACP, discusses the evaluation of rezatapopt in patients with advanced solid tumors.

Shivaani Kummar, MBBS, FACP

Articles

Kummar on the Investigation of Rezatapopt in TP53 Y220C–Mutated Advanced Solid Tumors

Dr Kummar on the Evaluation of Rezatapopt in Advanced Solid Tumors