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Targeting TP53 Mutations in Advanced Solid Tumors
Volume 1
Issue 1

Rezatapopt Shows Preliminary Efficacy in TP53 Y220C–Mutated Advanced Ovarian Cancer

Author(s):

Rezatapopt induced responses with acceptable toxicity in heavily pretreated patients with advanced ovarian cancer harboring TP53 Y220C mutations.

Alison Schram, MD

Alison Schram, MD

Rezatapopt (PC14586) elicited responses with a favorable toxicity profile in heavily pretreated patients with advanced ovarian cancer harboring TP53 Y220C mutations, according to data from the phase 1/2 PYNNACLE study (NCT04585750) presented at the 2024 SGO Annual Meeting on Women’s Cancer.1

When given at an efficacious dose range from 1150 mg once daily to 1500 mg twice daily, rezatapopt evoked an objective response rate (ORR) of 47% in evaluable patients who had measurable disease at baseline and had at least 1 post-baseline assessment (n = 15). Specifically, 7 patients had a partial response (PR), and 7 had stable disease (SD). A total of 6 patients had a CA125 response, which included 5 patients with a radiographic PR and 1 with SD. The median duration of response (DOR) was 7 months.

Rezatapopt showed promising efficacy in heavily pretreated patients with TP53 Y220C–mutant ovarian cancer,” Alison Schram, MD, a gynecologic oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, New York, said in a late-breaking presentation during the meeting. “[The agent] had a favorable safety profile in the overall population and in [patients with] ovarian cancer.”

Seventy percent of patients with ovarian cancer have TP53 mutations; the incidence of this mutation is even higher in the subset of patients with high-grade serous disease (>96%). Moreover, the hotspot mutation TP53 Y220C is most prevalent in ovarian cancer, occurring in 2.9% of these patients.

“Rezatapopt is a first-in-class p53 reactivator that selectively binds to the mutated p53 Y220C protein and restores wild-type activity,” Schram noted.

PYNNACLE enrolled patients with locally advanced or metastatic solid tumors harboring TP53 Y220C mutations, which were identified utilizing local next-generation sequencing. To be eligible, patients needed to be at least 12 years of age.

In the study, rezatapopt was evaluated at doses ranging from 1150 mg once daily (n = 5), 1500 mg once daily (n = 10), 2000 mg once daily (n = 29), 2500 mg once daily (n = 13), and 1500 mg twice daily (n = 10).

The primary objectives of the study were to identify the maximum tolerated dose, determine the recommended phase 2 dose (RP2D), and to assess the safety and tolerability of the agent. Secondary objectives included evaluating the pharmacokinetic profile of the agent and to examine the preliminary efficacy in the form of ORR. Exploratory objectives included biomarker analysis and evaluating pharmacodynamics.

As of the data cutoff date of September 5, 2023, a total of 67 patients were enrolled in the efficacious dose range; this included 22 patients with ovarian cancer. In this subset, investigators examined ORR by investigator assessment per RECIST v1.1 criteria and serum CA-125 response defined as a greater than 50% decrease at 2 separate time points, 4 weeks apart. Safety was examined across tumor types and in the efficacious dose range for the overall population and in the subset of patients with ovarian cancer.

Earlier data from the PYNNACLE study were previously presented at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.2 Results showed that when rezatapopt was given at the RP2D of 2000 mg daily, it led to an ORR of 38% per RECIST v1.1 criteria in evaluable patients with TP53 Y220C–mutated solid tumors (n = 16), including ovarian, breast, prostate, small cell lung, and endometrial cancers. When given in the efficacious dose range, the ORR achieved with the agent was 34% (n = 13) in evaluable patients (n = 38). The median DOR was 7 months.

At the SGO Annual Meeting, Schram shared data from the ovarian cancer subset. In these 22 patients, the median age was 66 years (range, 49-81). More than half of the patients were White (68%) and had an ECOG performance status of 1 (73%). The majority of patients had high-grade serous ovarian cancer (91%), and the remaining 9% had endometroid histology. Ninety-one percent of patients had measurable disease at baseline.

“No patient had a germline TP53 Y220C alteration. About one-third of patients [who] had homologous recombination deficiency–positive disease, including 2 patients with somatic BRCA2 mutations,” Schram reported. “No patients had a KRAS mutation.”

The median number of prior systemic therapies received was 4 (range, 1-9), with 64% of patients receiving at least 3 or more lines of treatment. Moreover, 86% of patients had platinum-resistant disease, and 5% had platinum-refractory disease; 9% of patients were platinum sensitive.

Schram noted that most patients experienced some degree of tumor shrinkage, and several patients remained on treatment at the time of data cutoff.

Rezatapopt had a favorable safety profile. In the overall population (n = 67), any-grade treatment-related adverse effects (TRAEs) occurred in 89.6% of patients. Grade 1, 2, 3, and 4 TRAEs occurred in 23.9%, 40.3%, 23.9%, and 1.5% of patients, respectively.

The most common TRAEs experienced by patients who received the agent were nausea (grade 1, 32.8%; grade 2, 16.4%; grade 3, 1.5%; grade 4, 0%), vomiting (23.9%; 17.9%; 1.5%; 0%), increased blood creatinine (14.9%; 11.9%; 0%; 0%), diarrhea (17.9%; 0%; 1.5%; 0%), fatigue (11.9%; 7.5%; 0%; 0%), increased alanine aminotransferase (6.0%; 7.5%; 4.5%; 0%), increased aspartate aminotransferase (10.4%; 3.0%; 3.0%; 0%), anemia (1.5%; 9.0%; 4.5%; 0%), decreased appetite (3.0%; 6.0%; 1.5%; 0%), proteinuria (1.5%; 7.5%; 0%; 0%), maculopapular rash (1.5%; 4.5%; 3.0%; 0%), headache (6.0%; 1.5%; 0%; 0%), increased lipase (6.0%; 0%; 1.5%; 0%), decreased platelet count (1.5%; 1.5%; 3.0%; 0%), increased amylase (4.5%; 1.5%; 0%; 0%), and dehydration (0%; 6.0%; 0%; 0%).

“The pivotal global PYNNACLE phase 2 trial is ongoing and will assess rezatapopt as monotherapy in patients with TP53 Y220C and KRAS wild-type advanced solid tumors, including ovarian cancer,” Schram concluded.

Editor’s Note: Dr Schram disclosed serving on advisory boards for Relay Therapeutics, Mersana, Merus, and PMV Pharma; having a consulting role with Blueprint Bio, Flagship Pioneering, and Redona Therapeutics; and being a steering committee member with Merus and Pfizer. Research funding to institution was provided by AstraZeneca, ArQule, BeiGene/SpringWorks, Black Diamond Therapeutics, Elevation Oncology, Kura, Lilly, Merus, Northern Biologics, Pfizer, PMV Pharma, Relay Therapeutics, Revolution Medicine, and Surface Oncology.

References

  1. 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, California.
  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 18, 2024. https://ir.pmvpharma.com/news-releases/news-release-details/pmv-pharmaceuticals-updated-pc14586-phase-1-data-demonstrated
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