Abstract CT109: First-in-class first-in-human phase 1 trial and translational study of the mono(ADP-ribose) polymerase-7 (PARP7) inhibitor RBN-2397 in patients with selected advanced solid tumors
Authors: Yap Timothy A. , Cervantes Andres , Falchook Gerald S. , Patel Manish R. , Juric Dejan , Waqar Saiama N. , Schenk Erin L. , Shapiro Geoffrey , Boni Valentina , Perez Cesar A. , Burtness Barbara , Najjar Yana G. , Racca Fabricio , Rojas Katerin , Kuplast-Barr Kristy , McEachern Kristen , Samant Manoj , Bozón Viviana , Parasuraman Sudha , Johnson Melissa 
Published: April 2023

Background: PARP7 is a stress-induced monoART that suppresses the cellular type I interferon (IFN) response following cytosolic nucleic acid sensing. RBN-2397 is a first-in-class PARP7 inhibitor that induces IFN and an adaptive immune response. The tumor-intrinsic immunomodulatory mechanism of RBN-2397 and preliminary antitumor activity in patients (pts) was demonstrated during dose escalation (Falchook, ASCO 2021; Kuplast-Barr, AACR 2022).

Methods: Pts with solid tumors were treated with RBN-2397 at the RP2D of 200 mg BID in 3 expansion cohorts: squamous cell carcinoma of the lung (SCCL), head and neck squamous cell carcinoma (HNSCC), and hormone receptor-positive breast cancer (HR+ BC). Objectives of the expansion phase included safety, pharmacokinetics, pharmacodynamics, and antitumor activity.

Results: As of 2 July 2022, 31 pts have been treated: SCCL (n=13), HNSCC (n=10), and HR+ BC (n=8). RBN-2397-related AEs (all grades &gt;10%) included dysgeusia (42%, n=13), nausea (26%, n=8), fatigue (23%, n=7), with Grade 3 events of nausea and pleural infection (each n=1) and ALT/AST increase (n=2), and no Grade 4 events. No significant chronic toxicities were observed. The disease control rate in response-evaluable pts was 44% in SCCL (stable disease [SD] in 4/9 pts), 71% in HNSCC (RECIST partial response [PR] for 12+ months in 1/7; SD in 4/7), and 29% in HR+ BC (SD in 2/7). Biomarker analyses confirmed PARP7 mRNA expression in all baseline biopsies, with H-scores higher in tumor cells than in stromal cells (n=26, H-score range 66-256, P&lt;0.0001). Four of 17 evaluable pts showed PARP7 focal copy number gains, and 2 had copy number gains that tracked with chromosome 3 copy number. One pt with HPV-negative HNSCC (nonsmoker; paranasal sinus primary) has an ongoing durable RECIST PR (−41%) for 12+ months. Tumor analysis of this responder confirmed PARP7 expression at baseline and SMARCB1 deletion, and demonstrated an excluded immune phenotype by IHC and MIBI-SCOPE. Analyses of paired tumor biopsies confirmed induction of adaptive immunity with ≥2-fold increases in CD8+ T cells and/or granzyme B expression in 10 (63%) of 16 pts across tumor types. Increases in immune checkpoint expression (PD-1 and LAG3 on T cells; PD-L1 on tumor cells) from 30% to 150% were observed in 3 (60%) of 5 pt tumor samples evaluated using MIBI-SCOPE, indicating the potential to prime tumors for immune checkpoint inhibitor therapy. These changes were independent of PARP7 copy number or PARP7 mRNA expression level at baseline.

Conclusions: RBN-2397 was well tolerated at biologically active drug exposures, with preliminary antitumor activity observed. Paired tumor biopsy translational studies demonstrated the immunomodulatory mechanism of RBN-2397 and support the ongoing trial of RBN-2397 in combination with pembrolizumab (NCT05127590).

Citation Format: Timothy A. Yap, Andres Cervantes, Gerald S. Falchook, Manish R. Patel, Dejan Juric, Saiama N. Waqar, Erin L. Schenk, Geoffrey Shapiro, Valentina Boni, Cesar A. Perez, Barbara Burtness, Yana G. Najjar, Fabricio Racca, Katerin Rojas, Kristy Kuplast-Barr, Kristen McEachern, Manoj Samant, Viviana Bozón, Sudha Parasuraman, Melissa Johnson. First-in-class first-in-human phase 1 trial and translational study of the mono(ADP-ribose) polymerase-7 (PARP7) inhibitor RBN-2397 in patients with selected advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT109.