RBN-2397 is a potent, selective inhibitor of PARP7 that could potentially release the brake on the antitumour immunity, is well tolerated, and demonstrated proof of mechanism in a first-in-human trial.
Targeting cytosolic nucleic acid sensing pathways and the Type I interferon response, is an emerging therapeutic strategy in oncology. PARP7 is a member of the poly-ADP-ribose polymerases (PARP) enzymes and acts as a brake on the cellular stress response by negatively regulating the Type I interferon response. PARP7 expressed in cancer cells blocks antitumour immunity and therefore a potential novel therapeutic target. RBN-2397 is a potent, selective inhibitor of PARP7 that could potentially release the brake on the antitumour immunity. In preclinical models, RBN-2397 restored Type I interferon signalling in tumours, caused complete tumour regressions, and induced adaptive immunity.1
Dr Gerald Falchook (Sarah Cannon Research Institute at HealthONE, CO, USA) presented the results of the first-in-human phase 1 study of RBN-2397 in patients with solid tumours2. Patients were treated with RBN-2397 on either a continuous or 14-of-21-day intermittent schedule using a 3 plus 3 dose-escalation design. A total of 47 patients were included in the study and treated: 25 patients in the intermittent schedule (25 to 500 mg BID) and 22 patients in the continuous schedule (100 to 400 mg BID).
Most common cancer types were breast cancer (n=8), lung cancer (n=7), endometrial cancer (n=4), colon cancer (n=4), and pancreatic cancer (n=4). Primary objective was to establish maximum tolerated dose, dose-limiting toxicity, and the recommended phase 2 dose. Secondary objectives were to characterise the safety profile of RBN-2397, preliminary antitumour activity, and examine pharmacokinetics of unmicronized/micronized tablets.
The most frequent treatment-related adverse events (all grades) were dysgeusia (36%), decreased appetite (16%), fatigue (14%), and nausea (12%). Grade 3/4 treatment-related adverse events all occurred in 8 patients (16%) at doses ≥200 mg: diarrhoea (n=2 ), anaemia (n=2), fatigue (n=1), increased AST(n=1), neutropenia (n=1), and thrombocytopenia (n=1). Maximum tolerated dose was 400 mg BID on a continuous dosing schedule, recommended phase 2 dose was 200 mg BID on a continuous dosing schedule with micronized tablets. In 5 evaluable tumour biopsy pairs, increases in interferon-stimulated gene expression were observed post RBN-2397, consistent with activation of Type I interferon. Increase in immune response-related genes and CD8+ T cells was observed in a patient with metastatic squamous non-small cell lung cancer (NSCLC) who has been on study for 16+ months.
One patient with HR+, HER2- breast cancer achieved a confirmed partial response at 100 mg RBN-2397, 9 patients had stable disease for over 4 months. At data cut-off, 3 patients had ongoing response. Based on these results, Dr Falchook concluded that single-agent RBN-2397 is well tolerated and demonstrated proof of mechanism by increasing tumoral Type I interferon signalling and immune cells. In the expansion phase, which is currently ongoing, patients with squamous NSCLC, HR-positive breast cancer, and PARP7-amplified tumours are included.
References:
1. Vasbinder MM, et al. AACR Annual Meeting 2020, abstract DDT02-01
2. Falchook GS, et al. A first-in-human phase 1 study of a novel PARP7 inhibitor RBN-2397 in patients with advanced solid tumours. ASCO 2021 Virtual Meeting, abstract 3000.