PC14586 Shows Preliminary Activity, Safety in p53 Y220C–Mutant Solid Tumors

Article
Pipeline Report: July 2022

The first-in-class p53 reactivator, PC14586, induced a response in approximately 1 of 4 patients with advanced solid tumors harboring p53 Y220C mutations and showcased an acceptable safety profile consisting primarily of grade 1 and 2 events.

Ecaterina Elena Dumbrava, MD

Ecaterina Elena Dumbrava, MD

The first-in-class p53 reactivator, PC14586, induced a response in approximately 1 of 4 patients with advanced solid tumors harboring p53 Y220C mutations and showcased an acceptable safety profile consisting primarily of grade 1 and 2 events, according to findings from the phase 1/2 PYNNACLE trial (NCT04585750) that were presented at the 2022 ASCO Annual Meeting.

Among response-evaluable patients (n = 33/41), the investigator-assessed objective response rate (ORR) per RECIST v1.1 criteria was 24.2% (n = 8) and included 6 partial responses (PRs) and 2 unconfirmed PRs; also reported were 15 cases of stable disease (SD), 7 cases of progressive disease (PD), and 3 cases that were not evaluable.

“Preliminary efficacy in patients across solid tumor types harboring [a] TP53 Y220C mutation was demonstrated, and enrollment at dose(s) below the maximum tolerated dose [MTD] to support recommended phase 2 dose [RP2D] determination is ongoing,” Ecaterina Elena Dumbrava, MD, of the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, said in a presentation of the data.

TP53 is a tumor suppressor gene, which when mutated, leads to p53 inactivation and tumor oncogenesis. TP53 mutations are the most common genomic events across all human cancers, and approximately 30% comprise hot-spot mutations. P53 Y220C is a key hot-spot TP53 missense mutation that destabilizes p53 and is found in approximately 1% of all solid tumors.

PC14586 is an oral small molecule designed to selectively bind to the pocket within the p53 Y220C–mutant protein and stabilize the mutant protein in the wild-type p53 conformation, resulting in renewed transcription and tumor-suppression function.

The study, which consists of 2 phases, enrolled patients at least 12 years of age with locally advanced or metastatic solid tumors harboring p53 Y220C mutations.

In phase 1, the investigators employed a modified toxicity probability interval design in which intrapatient dose-escalation and backfill enrollment was allowed. Eight dosing cohorts were evaluated: 150 mg daily (cohort 1, n = 3), 300 mg daily (cohort 2, n = 3), 600 mg daily (cohort 3, n = 4), 1150 mg daily (cohort 4, n = 5), 2000 mg daily (cohort 5, n = 7), 2500 mg daily (cohort 6, n = 4), 1500 mg twice daily (cohort 7, n = 10), and 1500 mg daily (cohort 8, n = 5).

The primary objective of phase 1 was to determine the MTD, select the RP2D, and evaluate the safety and tolerability of the agent. Secondary objectives included the analysis of pharmacokinetic (PK) and preliminary efficacy.

As of data cutoff on May 10, 2022, 41 patients had been enrolled to the first phase of the research.

Phase 2, which has an estimated enrollment of 100 patients, will evaluate the ORR by blinded independent central review as its primary objective, with secondary objectives of ORR by investigator assessment, time to response, duration of response, disease control rate, progression-free survival, overall survival, safety, and quality of life.

Exploratory objectives in both phases include biomarker analysis.

Regarding patient demographics, the median age was 62 years (range, 32-84), and most patients were female (n = 25; 61%) and White (n = 31; 76%). Most patients had an ECOG performance status of 1 (n = 23; 56%), received at least 3 prior lines of therapy (n = 23; 57.5%; median, 3 [range, 1-9]), and tested negative for a germline TP53 Y220C mutation (n = 38; 93%).

The predominant cancer type in those enrolled was ovary (n = 11; 26.8%), followed by pancreas (n = 8; 19.5%), breast (n = 6; 14.6%), prostate (n = 5; 12.2%), colon (n = 5; 12.2%), endometrial (n = 2; 4.9%), head and neck (n = 2; 4.9%), small cell lung (n = 1; 2.4%), and germ cell (n = 1; 2.4%).

Additional results showed that when broken down by dose level, no responses were seen in response-evaluable patients who received between 150 mg and 600 mg daily (n = 8/10); 4 cases each of SD and PD occurred.

Among response-evaluable patients who received the agent at doses ranging from 1150 mg daily to 1500 mg twice daily (n = 25/31), the ORR was 32.0% (n = 8) and included 6 PRs and 2 unconfirmed PRs; also reported were 11 cases of SD, 3 cases of PD, and 3 cases that were not evaluable. 

Regarding duration of therapy, 13 patients remained on treatment at data cutoff, and treatment was ongoing in 6 of 8 responders.

PK analysis, which was based on day 15 samples collected from 29 patients, demonstrated dose-proportional increases in Cmax and the area under the curve at steady state, with a median half-life of 19 hours.

“PC14586 exposure is generally dose proportional over a wide dose range and supports once daily dosing,” Dumbrava noted.

Notably, a greater reduction in patients’ target lesion was seen in the higher dose cohorts (cohorts 4-8).

Additionally, reductions in patients’ circulating tumor cells (CTCs) and Y220C variant allele fraction in circulating tumor DNA (ctDNA) were shown from baseline to weeks 2 and 3, suggesting CTC and ctDNA could be potential biomarkers of antitumor activity.

In terms of safety, the most common treatment-related adverse effects occurring in at least 15% of patients included nausea (n = 18; 43.9%), vomiting (n = 11; 26.8%), aspartate (AST)/alanine (ALT) aminotransferase increase (n = 17; 41.5%), anemia (n = 7; 17.1%), blood creatinine increase (n = 7; 17.1%), and fatigue (n = 7; 17.1%).

Dose-limiting toxicities of grade 3 AST/ALT increase and grade 3 acute kidney injury occurred in 2 patients who received the agent at the 1500-mg twice-daily dose. The MTD was reached at 1500 mg twice daily, and the RP2D has not yet been determined.

Included at the end of the presentation was a case study of a 71-year-old woman with extensive-stage small cell lung cancer who progressed after 2 prior lines of therapy and radiotherapy for brain metastasis with worsening dyspnea and complete occlusion of the left bronchus with atelectasis.

Following detection of a TP53 Y220C mutation via next-generation sequencing, the patient was started on PC14586 at 1150 mg once daily, which resulted in a rapid and sustained PR after 6 weeks coupled with relief of respiratory symptoms. Notably, the 60% reduction is the patient’s target lesions at week 6 increased to 70% at week 12. Moreover, a correlation was noted between radiographic tumor shrinkage and Y220C ctDNA decrease.

The patient was subsequently increased to 2000 mg daily at week 30, which was well tolerated with transient treatment-related grade 3 neutropenia. The patient received ongoing treatment for over 9 months.

Reference

  1. Dumbrava EE, Johnson ML, Tolcher AW, et al. First-in-human study of PC14586, a small molecule structural corrector of Y220C mutant p53, in patients with advanced solid tumors harboring a TP53 Y220C mutation. J Clin Oncol. 2022;40(suppl 16):3003. doi:10.1200/JCO.2022.40.16_suppl.3003
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