A first-in-human phase 1 study of a novel PARP7 inhibitor RBN-2397 in patients with advanced solid tumors.

Abstract

3000 Background: Targeting cytosolic nucleic acid sensing pathways and the Type I interferon (IFN) response is an emerging therapeutic strategy in oncology. PARP7 is a member of the monoPARP class of enzymes and a newly identified negative regulator of nucleic acid sensing in tumor cells. PARP7 expression is increased by cellular stress and aromatic hydrocarbons, and the PARP7 gene is amplified in multiple cancers. RBN-2397 is a potent, selective inhibitor of PARP7. In preclinical models, RBN-2397 restored Type I IFN signaling in tumors, caused complete tumor regressions, and induced adaptive immunity. Methods: Patients (pts) with advanced solid tumors were treated with RBN-2397 on either a continuous or 14-of-21-day intermittent schedule using a 3+3 dose escalation design. Primary objective: establish MTD and/or RP2D. Secondary obj.: safety, activity, PK of unmicronized/micronized tablets. Exploratory obj.: Pd. Results: As of 4 January 2021, 47 pts were treated: 25 pts in the intermittent schedule (25 to 500 mg BID) and 22 patients in the continuous schedule (100 to 400 mg BID). The most frequent RBN-2397-related AEs (all grades) were dysgeusia (26%), decreased appetite (13%), fatigue (11%), and diarrhea (11%). Gr 3/4 RBN-2397-related AEs all occurred in 7 pts (15%) at doses ≥ 200 mg: diarrhea (2 pts, 4%), increased ALT, AST, and bilirubin (1 pt, 2%), and fatigue, anemia, neutropenia, and thrombocytopenia in 1 pt (2%) each. The 2 DLTs were Gr 3 febrile neutropenia (400 mg continuous schedule) and Gr 4 increase in ALT/AST (500 mg intermittent schedule). Plasma exposures generally increased dose dependently with the majority at or above the projected efficacious range based on animal studies. All evaluable baseline tumor biopsies showed evidence of PARP7 expression as measured by mRNA in situ hybridization (n = 11; Median tumor H score: 128). In 5 evaluable tumor biopsy pairs, increases in interferon-stimulated gene expression were observed post RBN-2397, consistent with activation of Type I IFN. CXCL10 mRNA increased in all evaluable on-treatment biopsies (1.5 to 8-fold). Several on-treatment biopsies showed enrichment for immune response gene sets that was accompanied by an increase in CD8+ T cells and Granzyme B expression, evidence for induction of an adaptive immune response post RBN-2397. This increase in immune response related genes and CD8+ T cells was observed in a pt with metastatic squamous NSCLC who has been on study for 16+ months. 1 pt with HR+, HER2- breast cancer achieved a confirmed PR at 100 mg and 8 pts had SD for ≥18 weeks (RECIST 1.1). Conclusions: To date, RBN-2397 is well tolerated and demonstrates dose dependent increases in plasma exposures, evidence of target inhibition, and preliminary signs of clinical activity. Determination of MTD/RP2D is imminent and study expansion is planned to evaluate safety and efficacy in squamous NSCLC, HNSCC, HR+ breast cancer, and PARP7 amplified tumors. Clinical trial information: NCT04053673.