PARP7 Inhibitor RBN-2397 Has Tolerable Safety Profile in Solid Tumors

Timothy Yap, MBBS, PhD, FRCP

RBN-2397, a PARP7 inhibitor, was found to be well tolerated and have preliminary antitumor activity as monotherapy in patients with advanced solid tumors, including head and neck squamous cell carcinoma (HNSCC), breast cancer, and squamous cell carcinoma of the lung (SCCL), according to findings from the first-in-human phase 1 Study RBN-2397-19-001 (NCT04053673).¹

In total, 103 treatment-related adverse effects (TRAEs) occurred with the agent, 75.7% (n = 78) of which were any grade, 15.5% (n = 16) of which were grade 3, and 1.0% (n = 1) of which was grade 4. A best response of partial response (PR) was achieved by 1 patient with breast cancer in the dose-escalation cohort and 1 patient with HNSCC in the dose-expansion cohort.

“Overall, RBN-2397 was well tolerated at the recommended phase 2 dose [of 200 mg twice daily continuously], with biological and antitumor activity at observed exposures,” Timothy Yap, MBBS, PhD, FRCP, of The University of Texas MD Anderson Cancer Center in Houston, said in a presentation during the 2023 ESMO Targeted Anticancer Therapies Congress.

PARP7 is a stress-induced mono-ADP-ribosyltransferase not typically expressed in normal tissues that blocks antitumor immunity and inhibits tumoral Type 1 interferon signaling. The PARP7 gene is highly expressed and/or amplified in a subset of cancers. RBN-2397 is a first-in-class, oral, potent, and selective small molecule PARP7 inhibitor that reactivates interferon signaling and antitumor immunity. In preclinical models, RBN-2397 induced complete tumor regressions as a single agent and in combination with PD-1 inhibitors.²

Study RBN-2397-19-001 consisted of a dose-escalation phase and a dose-expansion phase.¹ The escalation phase had a 3+3 design and enrolled 50 patients, who received RBN-2397 at twice daily doses ranging from 25 mg to 500 mg in either an intermittent dosing schedule of 14 days on and 7 days off, or a continuous dosing schedule of 21-day cycles. The most common tumor types in this phase were breast cancer (n = 8), lung cancer (n = 7), and colon cancer (n = 5). Through this phase, the recommended phase 2 dose was determined to be 200 mg twice daily on a continuous dosing schedule with micronized tablets. The dose-expansion cohort enrolled 53 patients with SCCL (n = 22), HNSCC (n = 17), hormone receptor (HR)–positive breast cancer (n = 14), and PARP7-amplified tumors.

In the escalation cohort, patients had a mean of 4.2 (standard deviation [SD], 2.0) and a median of 4 (range, 2-10) prior lines of therapy. In the expansion cohort, patients had a mean of 3.6 (SD, 1.9) and a median of 3 (range, 1-8) prior lines of therapy.

During the trial, patients in the escalation cohort received a mean of 4.4 (SD, 5.3) and a median of 2.0 treatment cycles. Patients in the expansion cohort received a mean of 3.3 (SD, 3.5) and a median of 2.0 treatment cycles.

At a data cutoff date of January 31, 2023, 100% of patients in the escalation cohort and 90.6% (n = 48) of patients in the expansion cohort had discontinued the study treatment. Patients still receiving treatment included 2 patients in the expansion cohort who had best responses of stable disease (SD), 1 each with HNSCC and SCCL. Reasons for discontinuation in the escalation and expansion cohorts, respectively, were progressive disease (PD; 54.0%; 60.4%), physician decision or withdrawal of consent (20.0%; 15.1%), non–dose-limiting toxicity (DLT) adverse effects (AEs; 4.0%; 3.7%), and other (22.0%; 11.3%).

Of the 37 evaluable patients in the escalation cohort, the best responses with RBN-2397 were PR in 1 patient with breast cancer who received the agent at 100 mg intermittently; SD in 18 patients, 13 of whom had clinical benefit lasting over 4 months from the date of the first dose; and PD in 18 patients.

Of the 44 evaluable patients in the expansion cohort (HNSCC, n = 14; HR-positive breast cancer, n = 11; SCCL, n = 19), the best responses with RBN-2397 were PR in 1 patient with HNSCC; SD in 17 patients, 4 of whom had clinical benefit lasting over 4 months from the date of the first dose; and PD in 24 patients. One patient was not evaluated. One patient with HR-positive breast cancer had a PR in their target lesion before clinical progression.

The patient in the expansion cohort who achieved a PR was 50 years old and had paranasal sinus carcinoma. They were a non-smoker, human papillomavirus negative, and had received 5 prior lines of systemic treatment: neoadjuvant carboplatin and paclitaxel; adjuvant cisplatin and pembrolizumab (Keytruda); and pembrolizumab, cetuximab (Erbitux), and pembrolizumab plus an investigational STING agonist in the metastatic setting. A baseline biopsy determined that this patient had high CD8 and Granzyme B density, as well as tumor mutational burden at 2.5 mut/Mb, SMARCB1 deletion, and was microsatellite stable. This patient remained on the study for approximately 16 months.

Baseline biopsies showed detectable levels of PARP7 expression by RNA in situ hybridization (ISH) in all evaluated patients, with more expression in the tumor cells than in the stroma. In on-treatment biopsies, most patients in the expansion cohort had increases in CD8⁺ T cells or Granzyme B in their tumor tissue. These increases were independent of cancer type and clinical response.

Yap provided an example of a patient who had an increase in T cells and macrophages while on treatment. This patient had SCCL and had received prior adjuvant carboplatin/paclitaxel and prior nivolumab (Opdivo) in the metastatic setting. Their best response on RBN-2397 was PD in cycle 3. At baseline, this patient had high PARP7 mRNA expression by RNA ISH, with a tumor H-score of 230. They also had PARP7 amplification as identified by FoundationOneCDx and confirmed by fluorescence ISH. An on-treatment biopsy of this patient’s tumor showed increases in immune cell populations like CD8⁺ T cells, macrophages, and monocytes. This patient also had increases in checkpoint proteins such as PD-1 on T cells and PD-L1 on tumor cells.

Overall, the most common TRAEs were dysgeusia (any grade, 37.9%), fatigue (any grade, 20.4%; grade 3, 1.9%), nausea (any grade, 17.5%; grade 3, 1.0%), decreased appetite (any grade, 13.6%), diarrhea (any grade, 9.7%; grade 3, 1.9%), weight decrease (any grade, 7.8%), aspartate aminotransferase (AST) increase (any grade, 7.8%; grade 3, 2.9%; grade 4, 1.0%), alanine aminotransferase (ALT) increase (any grade, 6.8%; grade 3, 1.9%; grade 4, 1.0%), anemia (any grade, 5.8%; grade 3, 2.9%), constipation (any grade, 4.9%), and pruritis (any grade, 4.9%). Other grade 3 AEs that occurred in 1 patient each were bilirubin increase, febrile neutropenia, neutropenia, thrombocytopenia, pleural infection, and pneumonitis. No other grade 4 AEs were reported.

In total, treatment-related serious AEs occurred in 4.9% of patients (n = 5). In the escalation cohort, 2 patients experienced these AEs. One patient, who received RBN-2397 at 500 mg twice daily intermittently, had grade 4 ALT and AST increases, and 1 patient, who received the agent at 400 mg twice daily continuously, had grade 3 febrile neutropenia; both AEs were also DLTs. Three patients in the expansion cohort experienced treatment-related serious AEs. One each had grade 2 pneumonitis, grade 3 pleural infection plus grade 1 post-obstructive pneumonia, and grade 3 pneumonitis.

Additionally, 27.2% of patients (n = 28) experienced treatment interruptions because of AEs, including 26.0% (n = 13) of the escalation cohort and 28.3% (n = 15) of the expansion cohort. Treatment discontinuation because of AEs occurred in 11.7% of patients (n = 12), 6 each in the escalation and expansion cohorts.

“Overall, we believe that these data validate PARP7 as a novel anticancer therapeutic target and confirm proof of the mechanism of RBN-2397,” Yap concluded.

RBN-2397 is currently under investigation in a phase 1/2 trial with pembrolizumab (NCT05127590) and a trial with nivolumab (jRCT2031210373).

Editor’s Note: Dr Yap reports receiving grant/research support (to institution) from Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace, and Zenith; having consultancies for AbbVie, AstraZeneca, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper-Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, Xinthera, Zai Labs, and ZielBio; and being a stockholder in Seagen.

References

1. Yap TA, Cervantes A, Falchook G, et al. First-in-class first-in-human phase I trial of RBN-2397 in patients with advanced solid tumors validate PARP7 as a novel anticancer therapeutic target. Ann Oncol. 2023;8(suppl_2):100903. doi:10.1016/esmoop/esmoop100903
2. Gozgit JM, Vasbinder MM, Abo RP, et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor activity. Cancer Cell. 2021;39(9):1214-1226.e10. doi:10.1016/j.ccell.2021.06.018