Abstract LB_A25: 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
Authors: Schram Alison M , Shapiro Geoffrey I , Johnson Melissa L , Tolcher Anthony W. , Thompson John A , El-Khoueiry Anthony B , Vandross Andrae L , Kummar Shivaani , Parikh Aparna R , Shepard Dale R , Garczarek Ursula , LeDuke Kim , Sheehan Lisa , Fellous Marc , Alland Leila , Dumbrava Ecaterina E 
Published: December 2023

Abstract
Background: Mutations in the TP53 gene leading to p53 inactivation are the most common mutational event across human cancers. PC14586 is a first-in-class p53 reactivator that selectively binds to the mutated p53 Y220C protein and restores p53 wild-type activity. Preclinical data support potential for activity of PC14586 across TP53 Y220C-bearing tumors, with enhanced activity in KRAS wild-type (WT) models, consistent with the important parallel roles for p53 inactivation and oncogenic KRAS in tumorigenesis. Preliminary analysis of Phase 1 data from the Phase 1/2 PYNNACLE trial (NCT04585750) evaluating PC14586 in patients with advanced TP53 Y220C solid tumors showed that PC14586 was well tolerated with preliminary clinical activity across multiple tumor types in the efficacious dose range (1150 mg QD to 1500 mg BID). This updated Phase 1 analysis assesses PC14586 in patients treated across the efficacious dose range. Methods: Eligible patients (≥12 years) with locally advanced or metastatic solid tumors with a TP53 Y220C mutation received increasing oral doses of PC14586 to evaluate safety, PK, and preliminary efficacy via RECIST v1.1, and to determine the Recommended Phase 2 Dose (RP2D). Tumor molecular profiling was assessed for the impact of KRAS status on response. Results: As of 1 May 2023, 61 patients were treated in the efficacious dose range (safety population): median age 63 (range 32-84) years, 62% female, and median of 3 (range 1–9) prior lines of systemic therapy. The most frequent treatment-related adverse events (TRAEs) (≥10%) were nausea (42.3%), vomiting (35.2%), diarrhea (19.7%), increased creatinine (18.3%), fatigue (14.1%), and increased AST and ALT (12.7% each); 3% of patients discontinued PC14586 due to TRAEs. Most TRAEs were grade 1 or 2; the most common grade 3 TRAEs were anemia (4.2%) and increased ALT (2.8%). PC14586 administered with food led to improvement in nausea and vomiting. Dose proportional and linear PK was observed with a median half-life of 19 hours. Among patients with measurable disease, 36 patients had KRAS WT and 15 patients had KRAS mutated tumors. A total of 12 PRs (ORR 33.3%) were observed (9 confirmed and 3 unconfirmed - pending confirmation) in patients with KRAS WT disease across multiple tumor types including ovarian, breast, prostate, small-cell lung, and endometrial cancer. The median duration of confirmed response was 7 months. In patients with a KRAS mutation, there were no confirmed responses, although clinical activity was observed. At 2000 mg QD, the ORR was 46.2% in patients with TP53 Y220C and KRAS WT tumors (n=13). A RP2D of 2000 mg QD was selected based on overall safety, PK and preliminary efficacy. Conclusions: PC14586 was well-tolerated with a favorable safety profile. Efficacy was achieved in heavily pre-treated patients across multiple tumor types. The PYNNACLE registrational Phase 2 trial will assess PC14586 as monotherapy at the RP2D of 2000 mg QD in patients with TP53 Y220C and KRAS WT advanced solid tumors. Additional/updated data will be presented at the conference.
Citation Format: Alison M Schram, Geoffrey I Shapiro, Melissa L Johnson, Anthony W. Tolcher, John A Thompson, Anthony B El-Khoueiry, Andrae L Vandross, Shivaani Kummar, Aparna R Parikh, Dale R Shepard, Ursula Garczarek, Kim LeDuke, Lisa Sheehan, Marc Fellous, Leila Alland, Ecaterina E Dumbrava. 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 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A25.