PARP7 inhibitor shows promising results in first-in-human trial

RBN-2397 is a potent, selective inhibitor of PARP7 that could potentially release the brake on the anti-tumour immunity. It was 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 anti-tumour immunity and is, therefore, a potential novel therapeutic target. RBN-2397 is a potent, selective inhibitor of PARP7 that could potentially release the brake on the anti-tumour 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 (NCT04053673) of RBN-2397 in patients with solid tumours [2]. Patients (n=47) were treated with RBN-2397 on either a continuous or 14-of-21-day intermittent schedule using a 3 plus 3 dose-escalation design; 25 patients were treated with the intermittent schedule (25 to 500 mg twice daily) and 22 patients with the continuous schedule (100 to 400 mg twice daily). 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). The 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 anti-tumour activity, and to examine pharmacokinetics of micronised 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). The maximum tolerated dose was 400 mg twice daily on a continuous dosing schedule, recommended phase 2 dose was 200 mg twice daily on a continuous dosing schedule with micronised 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. An increase was observed in immune response-related genes and CD8+ T cells in a patient with metastatic squamous non-small cell lung cancer (NSCLC) who has been on study for >16 months. One patient with HR-positive, HER2-negative breast cancer achieved a confirmed partial response at 100 mg RBN-2397, and 9 patients had stable disease for over 4 months. At data cut-off, 3 patients had an ongoing response. In the expansion phase, which is currently ongoing, patients with squamous NSCLC, HR-positive breast cancer, and PARP7-amplified tumours are included.

1. Vasbinder MM, et al. Tumour Biol. 2020;80: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. Abstract 3000, ASCO 2021 Virtual Meeting, 4–8 June.

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Posted on 12 August 202115 February 2024