Rezatapopt Revolutionizes Research Directions in TP53-Mutated Solid Tumors

Commentary
Article
Supplements and Featured PublicationsTargeting TP53 Mutations in Advanced Solid Tumors
Volume 1
Issue 1

Shivaani Kummar, MBBS, FACP, discusses the mechanism of action of the TP53-directed agent rezatapopt and efficacy data with this agent in solid tumors.

Shivaani Kummar, MBBS, FACP

Shivaani Kummar, MBBS, FACP

Phase 1 data with rezatapopt (PC14586) in patients with TP53 Y220C–mutated advanced solid tumors have demonstrated early signals of clinical efficacy with this agent and support the continued investigation of rezatapopt in this patient population, according to Shivaani Kummar, MBBS, FACP.

“TP53 is a tumor suppressor gene and mutations in TP53 that result in p53 inactivation have been contribute to oncogenesis. Rezatapopt is a first-in-class p53 reactivator that binds to the pocket created by the TP53 Y220C mutation, restoring p53 function,” Kummar said in an interview with OncLive®. “That’s the rationale behind testing [this agent] in patients with advanced solid tumors that carry this mutation in the TP53 gene.”

The phase 1/2 PYNNACLE trial (NCT04585750) is investigating rezatapopt in patients with TP53 Y220C–mutated advanced solid tumors.1 The primary end point of the phase 1 portion of the trial was to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of rezatapopt monotherapy. Updated phase 1 findings demonstrated that the agent elicited a 38% confirmed overall response rate (ORR) when administered at the RP2D of 2000 mg daily in patients with TP53 Y200C–mutant, KRAS wild-type solid tumors (n = 16).2 Additionally, findings from the PYNNACLE ovarian cancer patient cohort showed that of the 15 patients with baseline measurable disease, 5 patients achieved a radiographic partial response (PR) and 1 patient had stable disease (SD).3

The ongoing phase 2 portion of the trial is evaluating the efficacy of rezatapopt at the RP2D across cohorts of patients with TP53 Y200C–mutant, KRAS wild-type solid tumors, including a cohort of patients with ovarian cancer.1

In the interview, Kummar discussed the mechanism of action of rezatapopt; early efficacy data observed with this agent across solid tumors, including in patients with ovarian cancer; and potential next steps for the future evaluation of TP53-directed drugs in solid tumors.

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, where she is also the codirector of the Center for Experimental Therapeutics and the co-deputy director of the Knight Cancer Institute.

OncLive: What is the value of investigating tumor-agnostic agents across solid tumors?

Kummar: The reason we are approaching cancer not just with the traditional histology-based classification, but more based on the presence of a target, is because now we understand specific molecular targets can be present across histologic types and we can design drugs against these targets. We are trying to evaluate whether [directing agents at targets that are present] across [tumor types] will result in clinical benefit for patients. Clinical trial designs now include basket trials where we enroll patients with tumors carrying the molecular target of interest and evaluate a therapeutic agent.

What is the significance of targeting TP53 Y220C in solid tumors, and what is known about its mechanism of action?

We have known for a long time that TP53 is a tumor suppressor gene. Mutations within this gene lead to inactivation of p53, which has been demonstrated to be a key step in oncogenesis. TP53 Y220C is a hotspot mutation found in approximately 1% of solid tumors. In ovarian cancer, it has the highest incidence. In approximately 2.9% of tested [ovarian cancer] samples, we demonstrated the presence of this mutation.

When the TP53 Y220C mutation is present, it destabilizes the p53 protein, leading to its inactivation. Rezatapopt is a first-in-class p53 reactivator that has been designed to specifically bind to the pocket that’s created when TP53 Y220C mutations happen in the TP53 gene. This binding results in restoration of p53 activity, at least based on preclinical data.

In what advanced solid tumors has rezatapopt begun to show activity?

Data from the [PYNNACLE] trial were reported at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. Data from the first 67 patients who were evaluable for safety and the first 51 patients who were evaluable for efficacy were reported. Of these patients, in the subset that had the TP53 Y220C mutation but did not have a mutation in KRAS [n = 38], there were a total of 13 confirmed responses, [translating to] an ORR of 34%. This ORR was observed across multiple tumor types, such as ovarian cancer, breast cancer, small cell lung cancer, and endometrial cancer.

As we went through the dose-escalation [portion of the trial], we established the [rezatapopt] dose of 2000 mg a day [as the RP2D], which is [the dose level of the drug that the ongoing] phase 2 part of the trial [is investigating]. [In the] patients who were treated at this dose in the dose-escalation portion of the trial who had a TP53 Y220C mutation but were KRAS wild type, the ORR was 38%.

In just the patients with ovarian cancer, data were reported at the 2024 SGO Annual Meeting. Of the 15 patients with measurable disease at baseline who had at least 1 post-baseline tumor assessment, 7 patients achieved a confirmed PR, and an additional 7 patients had SD. The median duration of response was 7 months.

We are seeing encouraging activity in the phase 1 portion of the study. As proof-of-mechanism and proof-of-concept, reduction in the variant allele frequency was observed, especially in responders. Now, we are excited about the phase 2 portion, which is adding more patients at this RP2D, to see whether we can continue to find patients who derive clinical benefit from this agent.

What is the safety profile of rezatapopt?

Some of the most common [adverse effects (AEs) associated with rezatapopt] have been nausea and gastrointestinal [GI] toxicities. We found as the trial progressed that if we administer rezatapopt following food, we can reduce the associated GI AEs. The administration of food before patients take the agent has helped with that AE profile.

We have seen elevations in creatinine levels in certain patients, and there have been some increases in liver enzymes. Overall, rezatapopt has been well tolerated, and some of the AEs have been managed by dose modifications. There has been a low rate of drug discontinuation due to treatment-related AEs, [at 3%].

What are the next steps for evaluating rezatapopt in patients with solid tumors? Will combination regimens using this agent be investigated?

[Next steps] depend on what we see in the phase 2 part of the trial. The phase 1b component of the trial evaluated [rezatapopt in combination with] immunotherapy. Those data are still in evolution, and we’ll find out more as we get experience [with rezatapopt]. However, in general, the response rates and promising activity we’re seeing are with rezatapopt as monotherapy. The phase 2 component is what I’m excited about to see whether we can induce durable clinical responses with an oral agent that is relatively well tolerated for this patient population.

What other TP53-targeted agents are in development for patients with solid tumors?

[Rezatapopt] is the first-in-class agent that is the furthest along [in development]. There are ongoing efforts to target other mutations in p53. There are multiple mutations that have different consequences, but most of them lead to increased oncogenesis. Targeting those [will] be important, but we need to develop specific agents that are designed to target those specific mutations, such as [rezatapopt] for TP53 Y220C mutations. I’m excited to see those ongoing efforts come into the clinical space.

What is your main message for community and academic colleagues based on this research with rezatapopt?

There are different levels of excitement. I’ve been doing drug development for over 20 years. I find that at this point, we are at one of the most exciting times in this field, as we can now design molecules against molecular targets within cancer cells, and we have a slew of different types of agents that target the tumor microenvironment and immune cells.

However, the old paradigm of [conducting] phase 1 trials just for safety and finding a dose is no longer completely true. We do find the dose and look for safety for these new drugs [in phase 1 trials]. However, we are seeing response rates and clinical benefits more often when we can develop drugs such as rezatapopt. Considering clinical trials for patients earlier on in their treatment for metastatic cancers, as well as educating patients along the way about participation in clinical trials, even in the neoadjuvant and adjuvant settings, will help deliver good care to individual patients and move the needle as we try to expedite anticancer drug development.

References

  1. The evaluation of PC14586 in patients with advanced solid tumors harboring a TP53 Y220C mutation (PYNNACLE). ClinicalTrials.gov. Updated February 9, 2024. Accessed March 27, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04585750
  2. PMV Pharmaceuticals updated PC14586 phase 1 data demonstrated anti-tumor activity across multiple solid tumor types with a TP53 Y220C mutation. News release. PMV Pharmaceuticals, Inc. October 12, 2023. Accessed March 27, 2024. https://ir.pmvpharma.com/news-releases/news-release-details/pmv-pharmaceuticals-updated-pc14586-phase-1-data-demonstrated
  3. Schram AM, Shapiro GI, Thompson JA, et al. Phase 1 analysis from the PYNNACLE phase 1/2 study of PC14586 in the subgroup of patients with advanced ovarian cancer harboring a TP53 Y220C mutation. Presented at: 2024 SGO Annual Meeting; March 16-18, 2024; San Diego, California.
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