Rezatapopt Takes Aim at Previously Untargetable p53 Allele to Treat Advanced Solid Tumors

The first-in-class p53 Y220C reactivator rezatapopt (formerly PC14586) has the potential to turn the p53 Y220C mutation, which had previously been termed undruggable, into a tumor-agnostic target for patients with advanced solid tumors. The agent is currently under evaluation in the phase 1/2 PYNNACLE study (NCT04585750).^1,2

“p53 has a variety of different hotspot mutations that cause a loss of function, it’s a tumor suppressor gene,” Tom Karasic, MD, explained in an interview with OncologyLive. “Y220C is found in [approximately] 1% of all cancers and it’s more common in ovarian cancer, [occurring in approximately] 3% [of patients]. It’s important not because it is any different in terms of its usual cancer behavior, but because it can be targeted [with a] small molecule inhibitor. Targeting it and reactivating it provides p53 function again; it generally loses function and that leads to growth or proliferation of the cancer.”

Karasic is the director of the Developmental Therapeutics Program at Abramson Cancer Center, as well as an assistant professor of medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania, in Philadelphia.

Rezatapopt is an orally available small molecule that is designed to bind selectively to the pocket within the p53 Y220C mutant protein. In preclinical study, rezatapopt has shown the ability to inhibit tumor proliferation across all Y220C-expressing cell lines. Notably, increased sensitivity to the agent has been correlated with the absence of a RAS pathway mutation.²

“This is the first time that we’ve been able to inhibit a particular p53-mutant allele,” Aparna Parikh, MD, an oncologist at Massachusetts General Hospital in Boston, Massachusetts, said in a separate interview with OncologyLive. “There have been a lot of different approaches that have tried to indirectly target p53, [such as] MDM2 inhibitors. [Rezatapopt] binds to a pocket that is only [present] in the p53 Y220C alteration. It stabilizes [the protein] in the wild type, not the mutant form, and by keeping it in the wild-type conformation [the agent] restores p53 activity.”

PYNNACLE Set to Evaluate Rezatapopt

PYNNACLE is an open-label, multicenter study that is examining the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of rezatapopt in patients with locally advanced or metastatic solid tumors harboring with a TP53 Y220C mutation. To be eligible for the trial, patients must be at least 18 years old, or 12 to 17 years old with safety review committee approval, have an ECOG performance status of 1 or less, have experienced disease progression following 1 prior line of therapy, have adequate organ function, and measurable disease per RECIST v1.1. There will also be a phase 1b cohort that will receive the agent in combination with pembrolizumab (Keytruda); patients in this group need to be anti–PD-1/PD-L1 inhibitor naive or have experienced disease progression on treatment.¹

During phase 1, rezatapopt will be administered orally at multiple dose levels given daily to establish the recommended phase 2 dose (RP2D) and maximum tolerated dose (MTD) and pembrolizumab will be given intravenously every 3 weeks at a dose of 200 mg in the combination group. Phase 2 will include ovarian cancer, lung cancer, breast cancer, endometrial cancer, and other solid tumors cohorts who will all be treated with daily oral rezatapopt at the RP2D.

The coprimary end points in phase 1 are safety, establishing the RP2D and the MTD of rezatapopt, both as monotherapy and a combination component; the primary end point in phase 2 is overall response rate (ORR) per RECIST v1.1 by independent review. Secondary end points include pharmacokinetics, disease control rate, progression-free survival, overall survival, and duration of response (DOR).

“As the study moves into phase 2, there are more and more sites that are open that hopefully are closer to patients than when [the trial] was only in phase 1,” Karasic noted. “The bigger challenge is making sure that clinicians are aware that this is a targetable alteration. As data have emerged, it hasn’t necessarily made it to everyone. We think of p53 as something that can sometimes [indicate] a poor prognosis, but [not as something that is] necessarily targetable. Having clinicians recognize that this specific mutation is targetable is important.”

Rezatapopt Displays Early Signals of Efficacy, Tolerability

During the 2023 AACR-NCI-EORTC International Congress on Molecular Targets and Cancer Therapeutics, investigators presented updated findings from the phase 1 portion of PYNNACLE. The results included 67 patients treated with rezatapopt monotherapy in the efficacious dose range of 1150 mg daily to 1500 mg twice daily. The median age was 63 years (range, 32-84); most patients were White (76%), had an ECOG performance status of 1 (67%), had received at least 3 prior therapies (55%), and were KRAS wild type (75%). The update included data from patients with ovarian (n = 22), pancreatic (n = 12), breast (n = 9), colon (n = 5), prostate (n = 6), head and neck (n = 2), small cell lung (n = 2), endometrial (n = 1), and other (n = 8) cancers.³

At the September 5, 2023, data cutoff, efficacy-evaluable patients who were treated at a dose of 1150 mg daily to 1500 mg twice daily (n = 38) achieved an ORR of 34%. The ORRs among patients with ovarian (n = 7), breast (n = 3), small cell lung (n = 1), endometrial (n = 1), and other (n = 1) cancers were 47%, 38%, 50%, 100%, and 8%, respectively.

Efficacy-evaluable patients treated at the 2000-mg daily dose level achieved an ORR of 38%. The ORRs among patients with ovarian (n = 2), breast (n = 2), endometrial (n = 1), and other (n = 1) cancers were 40%, 67%, 100%, and 17%, respectively.

In terms of safety, treatment-related adverse effects (TRAEs) were mostly grade 1 or 2 in severity, with the most common any-grade TRAEs being nausea (50.7%), vomiting (43.3%), and increased blood creatine (26.9%). Investigators noted that administering rezatapopt with food improved the gastrointestinal toxicities that were observed. Only 1 patient experienced a grade 4 TRAE and 3% of patients were forced to discontinue treatment due to a TRAE.

Study authors concluded that rezatapopt monotherapy displayed a favorable safety profile and displayed clinical efficacy across multiple tumor types. The RP2D was determined to be 2000 mg daily.

“The numbers are relatively small, as they often are in these studies, but certainly [rezatapopt] has notable activity in patients with generally refractory cancers and limited treatment options,” Karasic said. “The ongoing phase 2 expansion of the study will help clarify what the expected response rate is and will [help us] gain additional information about what diseases and what genetic phenotypes it [is effective] in. It seems to have enough activity that it seems likely to become an available agent for patients.”

In March 2024, during the SGO Annual Meeting on Women’s Cancer, a phase 1 analysis from PYNNACLE was presented which encompassed a subgroup of patients with advanced ovarian cancer harboring a TP53 Y220C mutation. The analysis consisted of efficacy and safety findings from 22 patients with a median age of 66 years (range, 49-81). Most patients included in the analysis were White (68%), had an ECOG performance status of 1 (73%), were platinum resistant (86%), had high-grade serous histology (91%), had measurable disease at baseline (91%), and did not have germline BRCA1/2 mutations (59%). The median number of prior lines of therapy was 4 (range, 1-9) with most patients receiving at least 3 (64%); all patients were negative for germline TP53 Y220C and had KRAS wild-type disease.⁴

Among 15 efficacy-evaluable patients treated with rezatapopt across the efficacious dose range, 7 patients achieved a partial response (PR). Seven patients experienced stable disease and 1 patient had disease progression. Additionally, 5 patients with a radiographic PR and 1 patient with stable disease achieved a CA-125 response. The median DOR was 7 months and treatment was ongoing in 4 patients at the data cutoff.

Later in March 2024, PMV Pharmaceuticals, Inc. announced that the first patient had been dosed in the phase 2 portion of PYNNACLE.⁵

“If [the findings in phase 2] are promising, as what we saw with the initial dose escalation, I am optimistic around a path of approval––whether that’s an accelerated approval based on phase 2 will be a conversation with the FDA,” Parikh said in conclusion. “[There have been] certainly encouraging results to date and I am optimistic to potentially have another option for these Y220C patients. Hopefully it opens the door for other p53-targeting strategies that are being explored.”

References

1. The evaluation of PC14586 in patients with advanced solid tumors harboring a TP53 Y220C mutation (PYNNACLE). ClinicalTrials.gov. Updated July 3, 2024. Accessed July 17, 2024. https://clinicaltrials.gov/study/NCT04585750
2. KOL webinar for phase 1/2 PYNNACLE study of PC14586 from the 2023 AACR-NCI-EORTC International Conference. PMV Pharma. October 12, 2023. Accessed July 17, 2024. bit.ly/4bMNtb9
3. Schram AM, Shapiro GI, Johnson ML, et al. Updated phase 1 results from the PYNNACLE phase 1/2 study of PC14586, a selective p53 reactivator, in patients with advanced solid tumors harboring a TP53 Y220C mutation. Mol Cancer Ther. 2023;22(suppl 12):LBA_A25. doi:10.1158/1535-7163.TARG-23-LB_A25
4. 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 on Women’s Cancer; March 16-18, 2024; San Diego, CA.
5. PMV Pharmaceuticals announces first patient dosed in global tumor-agnostic phase 2 PYNNACLE trial for rezatapopt in TP53 Y220C-positive solid tumors. News release. PMV Pharmaceuticals, Inc. March 27, 2024. Accessed July 18, 2024.bit.ly/3WuPowJ