PC14586 Targets Previously “Undruggable” p53 in Treatment of Solid Tumors

Ecaterina E. Dumbrava, MD

Despite previous unsuccessful attempts to target p53, investigators have continued to try to develop novel therapeutics directed at the tumor suppressor gene with the goal of restoring p53 wild-type activity. With the initiation of the phase 1/2 PYNNACLE (NCT04585750) trial, investigators hope to crack the code in order to overcome previous challenges in targeting p53 and add the first-in-class agent PC14586 to the treatment armamentarium for multiple types of advanced solid tumors.

“Mutations in TP53 result in loss of its antitumor activity, creating an oncogenic environment that promotes tumor proliferation, invasion, and drug resistance,” Ecaterina E. Dumbrava, MD, assistant professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with OncologyLive^®. “[Approximately] half of all cancers have a TP53 mutation, and the specific TP53Y220C [mutation] is one of the hot spot mutations that is present in 1% of all solid tumors. Historically, p53 has been undruggable; we did not have any drug that [directly targets] p53. PC14586 is a first-in-class small molecule that reactivates p53. It binds selectively to this protein and stabilizes it in a wild-type configuration and restores its activity. This is the first time that we [have been] able to target p53.”

PC14586 is designed to stabilize the p53 YY20C mutation in which tyrosine is substituted by cysteine at amino acid 220 of the protein. This modification causes a small gap to form in p53, causing it to become thermally unstable and incapable of interacting with DNA effectively.¹

In October 2020, the FDA granted fast track designation to PC14586 for the treatment of patients with locally advanced or metastatic solid tumors that have a TP53 Y220C mutation and the agency noted that there are currently no FDA-approved agents directed at the mutation.²

PYNNACLE Trial Design

PYNNACLE is an open-label multicenter trial enrolling patients with advanced solid tumors with a TP53 Y220C mutation. The phase 1 and 2 portions of the study will assess PC14586 monotherapy, and the phase 1b portion will examine the agent in combination with the PD-1 inhibitor pembrolizumab (Keytruda; FIGURE).³

The study is aiming to enroll approximately 181 patients aged at least 18 years or patients aged 12 to 17 years after adequate safety findings are collected. Patients must also have an ECOG performance status of 1 or less, adequate organ function, and experienced disease progression after previously receiving at least 1 line of anticancer therapy. In phase 1b, patients must also be anti-PD-1/L1 inhibitor naive or have experienced disease progression on treatment.³

Patients who received anticancer therapy within 21 days of treatment with PC14586, those who received radiotherapy within 28 days of treatment, and those with unstable brain metastases are not eligible for enrollment. In the combination phase, those who received prior therapy with an agent directed at another stimulatory or coinhibitory T-cell receptor and were forced to discontinue treatment due to grade 3 or higher immune-related adverse effects (AEs) are also excluded.³

Patients in the phase 1 dose-escalation portion will receive PC14586 daily in an escalating manner to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The phase 1b dose-escalation portion will evaluate multiple dose levels of PC14586 plus intravenous pembrolizumab 200 mg every 3 weeks to determine the MTD and RP2D of PC14586 with the combination. In the phase 1b dose expansion, patients who are PD-1/PD-L1 inhibitor-naive and have relapsed/refractory disease will be divided into 2 cohorts to receive the RP2D of PC14586 in combination with pembrolizumab.³

Phase 2 will consist of 2 dose expansion cohorts. Cohort A will include patients who meet all eligibility criteria and have measurable disease per RECIST 1.1 criteria, and cohort B will consist of patients who did not meet all eligibility criteria, such as those with primary central nervous system tumors, and those who do not have measurable disease.³

The coprimary end points in phases 1 and 2 are characterizing the safety of PC14586 by determining the type and number of AEs and overall response rate (ORR) via RECIST 1.1 criteria per independent review. Investigators will also aim to establish the MTD and RP2D of PC14586 both as monotherapy and in combination with pembrolizumab.³

Early PYNNACLE Data Display Efficacy, Tolerability

During the American Association for Cancer Research–National Cancer Institute–European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics, which took place from October 11 to 15, 2023, in Boston, Massachusetts, investigators presented updated findings from PYNNACLE. At the September 5, 2023, data cutoff 77 patients had been treated with PC14586 monotherapy, including 67 in the efficacious dose range of 1150 mg daily to 1500 mg twice daily.⁴

Patients included in the analysis were 12 years or older and received PC14586 monotherapy at a daily dose of 1150 mg (n = 5), 1500 mg (n = 10), 2000 mg (n = 29), and 2500 mg (n = 13). There was also a cohort of 10 patients who received the agent twice daily at a dose of 1500 mg.4

The median patient age across cohorts was 63 years (range, 32-84). Most patients were White (76%), female (61%), had an ECOG performance status of 1 (67%), and had KRAS wild-type disease (75%). Patients were heavily pretreated; the median number of prior lines of therapy was 3 (range, 1-9), and 55% of patients received at least 3 prior lines of systemic therapy, 28% received 2 lines, and 9% received 1 line. The analysis included patients with ovarian (33%), pancreatic (18%), breast (13%), prostate (9%), colon (7%), head and neck (3%), endometrial (1%), small cell lung (3%), and other (12%) cancer.⁴

Fifty-one patients were evaluable for efficacy; 13 patients had TP53 Y220C and KRAS mutations, and 38 had KRASwild-type TP53 Y220C–mutated disease. Reduction of target lesions was seen in both groups of patients; however, confirmed responses were only reported in the group of patients who had KRAS wild-type and TP53 Y220C–mutated disease.⁴

Across all dose levels in the KRAS wild-type and TP53 Y220C–mutated disease population, the ORR was 34%, all partial responses (PRs), with 20 patients achieving stable disease (SD) and 5 experiencing disease progression. Patients treated at the 2000-mg daily dose level (n = 16) achieved an ORR of 38%, with 8 patients experiencing SD and 2 experiencing progression. All responses were also PRs in the 2000-mg cohort. The median time to response among all responders was 1.5 months, and the median duration of response was 7 months.

Patients with ovarian (n = 2), breast (n = 2), small cell lung (n = 0), endometrial (n = 1), and other (n = 1) cancer in the 2000-mg daily dosing cohort experienced ORRs of 40%, 67%, 0%, 100%, and 17%, respectively.⁴

“PC14586 showed preliminary efficacy in multiple advanced cancers,” Dumbrava said. “This brings hope that p53 is now considered a targetable gene and no [longer] undruggable. And if the phase 2 [findings] of the study are positive, I believe that PC14586 would be a valuable addition to the arsenal of tumor-agnostic targeted therapies that would bring hope for patients and improve their outcomes.”

In terms of safety, patients treated in the efficacious dose range experienced any-grade treatment-related AEs (TRAEs) at a rate of 89.6% and the most common included nausea (50.7%), vomiting (43.3%), increased blood creatine level (26.9%), diarrhea (19.4%), and fatigue (19.4%). Grade 3 TRAEs occurred in 23.9% of patients, and there was 1 grade 4 TRAE of immune thrombocytopenia. No grade 5 TRAEs were reported.⁴

“PC14586 has a favorable safety profile; patients are tolerating treatment well,” Dumbrava said. “Nausea, vomiting, and diarrhea improved with administration with food. Also, the study had a low discontinuation rate of 3% because of TRAEs.”

Study authors concluded that PC14586 displayed clinical efficacy as a single agent in heavily pretreated patients across multiple tumor types. The RP2D of the agent as a monotherapy was determined to be 2000 mg daily. Dumbrava noted that the phase 1b portion of PYNNACLE is still enrolling patients and the phase 2 portion will open soon.⁴

PMV Pharmaceuticals, the manufacturer of PC14586, announced plans to initiate a registrational phase 2 trial examining the agent in early 2024.⁵

References

1. PMV pipeline. PMV Pharma. Accessed November 20, 2023. bit.ly/3G67AUn
2. PMV Pharma granted FDA fast track designation of PC14586 for the treatment of advanced cancer patients that have tumors with a p53 Y220C mutation. News release. PMV Pharma. October 13, 2020. Accessed November 20, 2023. bit.ly/3G5UUfY
3. The evaluation of PC14586 in patients with advanced solid tumors harboring a p53 Y220C mutation (PYNNACLE). ClinicalTrials.gov. Updated September 7, 2023. Accessed November 17, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04585750
4. 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. Presented at: American Association for Cancer Research–National Cancer Institute–European Organisation for Research and Treatment of Cancer International Conference on Molecular Targets and Cancer Therapeutics; October 11-15, 2023; Boston, MA.
5. 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. October 12, 2023. bit.ly/40FXq6p