KEY TAKEAWAYS
- The PYNNACLE phase 1, 2 trial aimed to assess PC14586’s efficacy in advanced ovarian cancer patients across various doses in a subgroup analysis.
- PC14586 shows promising efficacy and safety in heavily pre-treated advanced ovarian cancer patients.
Mutations in the TP53 gene, resulting in p53 inactivation, are prevalent in human cancers. PC14586, a pioneering p53 reactivator, specifically targets the mutated p53 Y220C protein, restoring wild-type (WT) function. Phase 1 findings from the PYNNACLE trial (NCT04585750) revealed that PC14586, with a favorable safety profile, elicited responses in heavily pre-treated patients across various tumor types, including ovarian cancer.
Alison Schram and the team aimed to assess the efficacy of PC14586 in patients with advanced ovarian cancer treated within the effective dose range.
The study enrolled patients who had locally advanced or metastatic ovarian cancer with a TP53 Y220C mutation. PC14586 was administered orally continuously. Initial efficacy was evaluated using investigator-assessed RECIST v1.1 radiographic response and CA-125 response (defined as >50% decrease at two separate time points, four weeks apart). Safety within the effective dose range was assessed across various tumor types. Next-generation sequencing (NGS) determined TP53 Y220C and KRAS tumor mutation status.
The median age of ovarian cancer patients (N=22) was 66 years (range 49–81 years). At baseline, 20 had high-grade serous ovarian cancer, and 2 had endometrioid cancer; 3 had a BRCA2 mutation, 2 had a BRCA1 mutation, and 17 lacked a BRCA1/2 mutation; 8 were homologous recombination deficiency (HRD) positive, 10 were HRD negative, and 4 had unknown HRD status; all were KRAS wild-type. The median number of prior lines of systemic therapy was 4 (range 1–9). At study entry, 19 patients were platinum-resistant, 2 were refractory, and 1 was platinum-sensitive.
Among the 15 patients with measurable disease at baseline and at least one post-baseline tumor assessment, 7 achieved a confirmed partial response (PR), 7 had stable disease (SD), and 1 had progressive disease. The median duration of response was 7 months. Of the 15 patients with measurable serum CA-125 at baseline, 6 had a CA-125 response. Among these, 4 patients achieved radiographic PR, and 2 had SD. In the overall population, 67 patients, including this subset of patients with ovarian cancer, were assessed.
The most frequent treatment-related adverse events (TRAEs) were nausea (51%), vomiting (43%), and increased blood creatinine (27%). The frequency and severity of TRAEs were similar in the ovarian cancer population compared with the overall population. Administration of PC14586 with food improved nausea and vomiting.
The study demonstrated the promising efficacy of PC14586 in heavily pre-treated patients with advanced ovarian cancer carrying the TP53 Y220C mutation, accompanied by a favorable safety profile.
The upcoming PYNNACLE Phase 2 trial, a tumor-agnostic registrational study, will evaluate PC14586 monotherapy, including an ovarian cancer cohort, at the recommended Phase 2 dose of 2000 mg QD with food, specifically targeting patients with TP53 Y220C and KRAS wild-type advanced solid tumors.
The trial was sponsored by PMV Pharmaceuticals, Inc.
Source: https://sgo.planion.com/Web.User/AbstractDet?ACCOUNT=SGO&ABSID=577155&CONF=AM2024&CKEY=
Clinical Trial: https://clinicaltrials.gov/study/NCT04585750
Schram A, Shapiro GI, Thompson JA, et al. (2024) “Phase I analysis from the PYNNACLE phase I/II study of PC14586 in the subgroup of patients with advanced ovarian cancer harboring a TP53 Y220C mutation.” Presented at SGO 2024.
