The combination of RBN-2397 and pembrolizumab has been dosed in the first patient with squamous cell carcinoma of the lung who is enrolled in a new phase 1b/2 clinical trial.
The selective PARP7 agent, RBN-2397, in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab (Keytruda) has been dosed in the first patient with squamous cell carcinoma of the lung (SCCL) who is enrolled in a phase 1b/2 clinical trial (NCT05127590).1
Following a multicenter, single-arm design, the study aims to determine if the combination can restore the response to patients with SCCL who were previously treated with a PD-1 or PD-L1 inhibitor but later developed disease progression.2
“RBN-2397 is a selective PARP7 inhibitor designed to activate the type I interferon response in tumor cells and overcome a major limitation of immune checkpoint inhibitors (ICI). Combining RBN-2397 with an anti-PD-1 ICI is expected to treat a variety of tumor types including SCCL, a devastating disease representing the second most common form of non-small cell lung cancer,” said Prakash Raman, PhD, president and chief executive officer, Ribon Therapeutics, in a press release.1 “The initiation of the phase 1b/2 study of RBN-2397 with pembrolizumab will enable us to further understand the potential utility of this combination therapy.”
Preclinically, PARP7 inhibition achieved complete tumor regress in a lung xenograft. It also induced tumor-specific adaptive immune memory in an immuno-competent model. Based on these findings, investigators believe that PARP7 trigger antitumor immunity.3
In part 1 of the study of RBN-2397 with pembrolizumab, investigators will assess the safety of the combination with the primary end point of determining the recommended phase 2 dose of RBN-2397/pembrolizumab. Part 2 of the study will evaluate the anti-tumor activity of RBN-2397 plus pembrolizumab with the primary end point of overall response rate and the secondary end points of safety determined by treatment-emergent adverse events, maximum plasma concentration of RBN-2397, time to maximum plasma concentration of RBN-2397, area under the curve of RBN-2397, and terminal half-life of RBN-2397.2
To be eligible for inclusion, patients must have a confirmed diagnosis of advanced/metastatic NSCLC of squamous cell histology, have received and responded to a prior PD-1/PD-L1 therapy, and experienced progressive disease. Patients are required to undergo a tumor biopsy, have an ECOG performance status of 0 to 1, have a measurable target lesion shown on CT or MRI within 28 days of the start of study treatment, have normal organ and bone marrow function, and agree to use contraception during the study.
The study excluded individuals with non-squamous histology NSCLC, central nervous system metastases, known history of a prior malignancy, history of prior prolonged QT syndrome, active autoimmune disease, active systemic infection, active Hepatitis B or C, a known physiatrist disease or substance abuse disorder, and interstitial lung disease. Patients are not permitted to have received prior treatment with systemic therapy for SCCL, radiation within 2 weeks of cycle 1 day 1 in the study, live-virus vaccination within 30 days, herbal medicines within 3 weeks, systemic therapeutic doses of corticosteroids with in 2 weeks.
Patients with SCCL who have unresolved AEs from prior treatments are also excluded from the study.
Currently, patients are being recruited at 2 out of 20 total locations. Those recruiting include Sarah Cannon Research Institute in Nashville, TN, Helen F. Graham Cancer Center in Newark, DE. Site not yet recruiting patients are located in Georgia, Louisiana, Israel, Spain, and the United Kingdom.
“PARP7 is amplified and highly expressed in SCCL and certain other solid tumors. We have seen encouraging results from our ongoing Phase 1 trial of RBN-2397 as a monotherapy, which is currently evaluating a number of defined expansion cohorts, including patients with SCCL,” said Sudha Parasuraman, MD, chief medical officer, Ribon Therapeutics, in a press release.1 “The RBN-2397- pembrolizumab combination is anticipated to drive activated T cells into tumors with the potential to overcome resistance to ICIs. We look forward to evaluating this biology-driven combination in the clinical setting for patients with SCCL who are in need of new therapeutic options.”
1. Ribon Therapeutics announces initiation of phase 1b/2 study of RBN-2397 in combination with pembrolizumab in patients with squamous cell carcinoma of the lung. News release. Ribon Therapeutics. March 29, 2022. Accessed April 1, 2022. https://bit.ly/3tZD3lV
2. RBN-2397 in combination with pembrolizumab in patients with SCCL. Clinicaltrials.gov. Updated March 31, 2022. Accessed April 1, 2022. https://clinicaltrials.gov/ct2/show/NCT05127590?term=RBN-2397&draw=2&rank=1
3. Gozgut JM, Vasbinder MM, Abo RP, et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Cancer Cell. 2021;13;39(9):1214-1226.e10. doi: 10.1016/j.ccell.2021.06.018. https://bit.ly/35v5L4v