Reference Detail

Ref Type

abstract

PMID

Authors

R. Guo A. Dowlati, I. Dagogo-Jack, J. Vibert, A.I. Spira, V. Moreno Garcia, S. Punekar, E. Calvo, G.P. Sonpavde, M. Awad, J.W. Riess, T.C. Hernandez Guerrero, B. Herzberg, A. Italiano, A. Swalduz, P. Lorusso, E.F. Smit, E.B. Garon, W. Novotny, T.A. Yap

Title

603O First clinical results from a phase I trial of PRT3789: A first-in-class intravenous SMARCA2 degrader, in patients with advanced solid tumors with a SMARCA4 mutation

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	35	Supplemental 2	September 2024

URL

https://www.annalsofoncology.org/article/S0923-7534(24)02189-6/fulltext

Abstract Text

Background Genes encoding subunits of the SWI/SNF chromatin remodeling complex are among the most highly mutated in cancer, occurring in 20-24% of all human cancers. The SWI/SNF complex contains either 1 of 2 ATP enzymatic subunits, SMARCA2 or SMARCA4, which function interchangeably. PRT3789 is a potent SMARCA2 degrader with > 1000-fold selectivity for SMARCA4 mutated cancer cell compared to wild-type cells. We hypothesize that selective SMARCA2 degradation through synthetic lethality with PRT3789 will be an effective therapy for SMARCA4 mutated cancer. Methods This is a phase 1 dose escalation study with backfill cohorts added at active doses. Patients with any solid tumor and any SMARCA4 mutation (loss-of-function or missense) are eligible. PRT3789 is given intravenously weekly. Primary objectives are safety and determination of a recommended phase 2 dose. Results As of 7 Mar 2024, 40 pts have been enrolled (NSCLC [18], pancreatic [5], breast [3], esophageal [2], other [12]); 55% have loss-of-function mutations. Dose escalation has proceeded through 6 levels, from 24-212 mg, with 2 backfill cohorts opened. No DLTs or study drug-related SAEs have been reported. The most common AEs reported, of any grade or relatedness, are nausea (25.0%), constipation and dyspnea (each 17.5%), decreased appetite and fatigue (each 15.0%), and anemia (12.5%). Dose-related increases in AUC were observed. Dose dependent decreases in SMARCA2 levels were seen at all doses with a trend for increasing depth and duration with increasing doses; minimal effects on SMARCA4 levels were seen. Clinical activity of PRT3789 therapy noted to date includes RECIST partial responses, tumor shrinkage and prolonged stable disease (longer than response to most recent therapy) in patients with advanced, heavily pretreated esophageal cancer and NSCLC. A complete analysis of PK, PD, biomarkers, safety, and efficacy will be presented at ESMO. Conclusions PRT3789, a first-in-class SMARCA2 degrader, at doses studied to date appears to be well tolerated, with excellent pharmacodynamic effect, and with encouraging signs of anti-tumor activity, even during early dose escalation. Dose escalation and backfill cohorts are ongoing.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
SMARCA4 mutant	esophageal cancer	predicted - sensitive	PRT3789	Case Reports/Case Series	Actionable	In a Phase I trial, PRT3789 treatment was well tolerated and resulted in partial responses, tumor shrinkage, and prolonged stable disease in patients with advanced esophageal cancer (N=2) or non-small cell lung cancer (N=18) harboring SMARCA4 mutations (Ann Oncol (2024) 35 (suppl_2): S483-S484; NCT05639751).	detail...
SMARCA4 mutant	lung non-small cell carcinoma	predicted - sensitive	PRT3789	Phase I	Actionable	In a Phase I trial, PRT3789 treatment was well tolerated and resulted in partial responses, tumor shrinkage, and prolonged stable disease in patients with advanced esophageal cancer (N=2) or non-small cell lung cancer (N=18) harboring SMARCA4 mutations (Ann Oncol (2024) 35 (suppl_2): S483-S484; NCT05639751).	detail...