Belumosudil Combination Therapy in Refractory Chronic Graft-Versus-Host Disease

Background: There are now 3 FDA approved oral drugs for chronic graft-versus-host disease (cGVHD) after 1-2 or more prior lines of therapy- ibrutinib, ruxolitinib and belumosudil. Encouraging overall response rates have been reported for all 3 agents; however, complete responses are rare and there are still a large number of patients who do not respond or lose the response over time. One of the approaches to overcome potential resistance to single agent use is to combine the new agents with each other or with other therapies (such as extracorporeal photopheresis (ECP), sirolimus, MMF) as there can be synergy across agents with different mechanisms of action. The 3 new drugs are all kinase inhibitors that block lymphocyte activation pathways and the production of proinflammatory cytokines. Preclinical studies showed their potential effects in cGVHD. Since the FDA approvals, it has been possible to use these drugs in various combinations for cGVHD treatment in daily clinical practice. In this retrospective review, we summarize our institution's real-world practice of using the ROCK2-inhibitor belumosudil in combination therapies since its FDA approval in July 2021.

Methods: We conducted a retrospective chart review of patients treated with belumosudil in combination with other therapeutic agents at the Stanford Cancer Institute from July 2021 to July 2022. We collected descriptive statistics of standard outcomes of response as defined by the 2014 NIH Consensus Project on Criteria for Clinical Trials in cGVHD. Refractory cGVHD was defined as steroid-refractory or steroid-dependent cGVHD.

Results: A cohort of 26 patients were evaluated (Table 1). The most common organ affected was skin (n = 20), followed by mouth (n = 19), eyes (n = 15) and joints/fascia (n=15). Patients were treated with a median number of 3 lines of prior therapies before initiating belumosudil. Combination therapies with belumosudil included several 3-4 drug combinations with concurrent use of ruxolitinib, ECP, prednisone, sirolimus or CNI. In instances in which belumosudil was combined with ruxolitinib, belumosudil was the add-on drug. The median follow-up period following initiation of belumosudil was 213.5 days. The overall response rate (ORR) following the addition of belumosudil was 77% (20/26). Responses to belumosudil used in combination were based on organ symptom scoring and global rating by clinician assessment according to the 2014 NIH Consensus Criteria and were seen in 85% (17/20) patients with skin involvement; 53% (8/15) patients with joint/fascial involvement, 33% (5/15) patients with eye involvement, 30% (3/10) patients with lung involvement, 11% (2/19) patients with mouth involvement, and 13% (1/8) patients with liver involvement (Table 2). No responses were seen in patients with GI (lower tract) involvement. No clinically evident adverse drug reactions occurred in the belumosudil combinations although variable dosing of the combined agents was used with the approved belumosudil dose of 200 mg po daily. Infectious adverse events occurred in 42% (11/26) of patients, consistent with the immunosuppressive effects of cGVHD therapies. Of these, 36% (5/14) was due to SARS-CoV2 infection, 29% (4/14) cytomegalovirus reactivation, 21% (3/14) bacterial infection, 7% (1/14) rhinovirus infection, and 7% (1/14) respiratory syncytial virus. The number of infection events with the new agent combination of belumosudil plus ruxolitinib was reviewed separately and was not increased over the other belumosudil combinations. No deaths have occurred in this cohort of 26 patients to date.

Conclusion: In our institutional practice, administration of belumosudil in combination therapy appears safe, tolerable, and effective in patients with established, refractory cGVHD. The results of our retrospective study highlight the feasibility of the next phase of belumosudil research for combination therapy in this difficult-to-treat population.

Shizuru:Jasper Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; rBio: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Shoreline BioSciences: Current equity holder in private company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Shiraz:Kite, a Gilead company: Research Funding. Lowsky:Orca Bio: Research Funding. Frank:Allogene Therapeutics: Research Funding; Kite/Gilead: Honoraria, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Research Funding; Roche/Genentech - Wife: Current equity holder in private company, Current holder of stock options in a privately-held company. Negrin:BioEclipse Therapeutics: Current equity holder in private company, Current holder of stock options in a privately-held company; University of Pennsylvania: Other: DSMB or Advisory Board; CoImmune: Current equity holder in private company, Current holder of stock options in a privately-held company; Amgen: Consultancy; UptoDate: Honoraria; Novartis: Consultancy; Kuur: Consultancy; Garuda: Consultancy; Magenta: Consultancy, Current equity holder in publicly-traded company. Miklos:Kite, a Gilead Company: Research Funding; Bristol Meyers Squibb: Consultancy; Adaptive Biotech: Consultancy; Novartis: Consultancy; Fosun Kite: Consultancy, Honoraria; Allogene: Research Funding; Pharmacyclics: Patents & Royalties: cGVHD Ibrutinib patent ; Janssen: Consultancy, Honoraria. Arai:Kadmon: Membership on an entity's Board of Directors or advisory committees.