Aleksandr Lazaryan, MD, Discusses Belumosudil as Effective Therapy for cGVHD

Aleksandr Lazaryan, MD, MPH, PhD, Associate Member, Department of Blood & Marrow Transplant and Cellular Immunotherapy at H. Lee Moffitt Cancer Center, Tampa, Florida, discusses a phase 2a study of belumosudil in patients with chronic graft-versus-host disease (cGVHD) given 1 to 3 prior lines of therapy.

Transcript

I am Dr. Aleksandr Lazaryan and I am an Associate Member at the Department of Blood & Marrow Transplant and Cellular Immunotherapy at H. Lee Moffitt Cancer Center and Research Institute in Tampa, FL. and an Associate Professor at the Department of Oncologic Sciences at the University of South Florida. Prior to joining Moffitt in 2018, I held a position in Blood and Marrow Transplantation at University of Minnesota for over 6 years.

As a brief introduction to the topic, chronic graft-versus-host disease is the leading cause of morbidity and mortality, as well as impaired quality of life (QOL) after an allogeneic hematopoietic cell transplantation with an incidence of approximately 5,000 patients per year. It is an immune-mediated inflammatory and fibrotic disorder, and it is characterized by an imbalance between effector and regulatory arms of the immune system.

Expansion of alloreactive donor TH17 cells that are critical to the pathogenesis of cGVHD results in over production of inflammatory cytokines including IL-17 and IL-21. In the meantime, a persistent reduction in the number of regulatory T (Treg) cells limits the ability of the immune system to re-calibrate this pro-inflammatory environment thereby fueling up cGVHD.

Rho-associated coiled-coil kinases (ROCK) play critical role in controlling inflammation and fibrosis through downstream regulation of major pro-fibrotic mediators and transcription of pro-fibrotic genes.

KD025, also known as belumosudil, is an orally available ROCK2 selective inhibitor. In murine model of cGVHD, KD025 down-regulated inflammatory STAT3 pathway responsible for IL-17 and IL-21 production and increased tolerogenic STAT5 pathway resulting in upregulation of regulatory T cells and re-establishment of immune homeostasis.

Based on the biological rationale and compelling preclinical data, a phase 2a KD208 trial published earlier this year in JCO, enrolled 54 patients across 7 US centers in 3 sequential dose-specific cohorts of 200 mg of the drug daily, 200 mg used BID twice a day, or 400 mg daily to assess the safety and efficacy of belumosudil in patients with steroid refractory or dependent cGVHD with up to 3 prior lines of therapy.

Treatment was continued in 28 day cycles until disease progression or prohibitive toxicity. The primary endpoint was overall response rate (ORR) defined as the proportion of patients who achieved either a complete response (CR) or partial response (PR), per the 2014 NIH cGVHD Consensus Criteria. Secondary end points included duration of response, corticosteroid (CS) dose reductions, failure-free survival (FFS), changes in Lee Symptom Scale, among others.

Seventy-eight percent of the patients had severe cGVHD, 50% had more than 4 organs involved, 73% had cGVHD refractory to their last LOT, and 50% had received more or equal 3 prior LOTs. So, this patient population was more reflrectve of what we call “real-life” patient population with very advanced features of cGVHD.

After median follow up of 29 months the ORR for all patients across 3 cohorts was 65% (in fact, up to 69% in the second cohort) and it was not significantly affected by prior lines of therapy, number organs involved, or cGVHD severity.

Although all responses at the patient level were partial, organ-specific CRs were achieved across all affected organs, including difficult to treat cGVHD involving joint/facia, cutaneous sclerosis, with the exception of the lungs, where the partial response was the best observed. However, given the severity and extent of fibrotic cGVHD manifestations in our patient population, achieving CR in all organs was not entirely expected, as some advanced fibrotic changes may be permanent.

Responses were generally rapid, with 75% of all responses achieved by the first response assessment at 2 months follow up.

The median duration of response was 35 weeks with 51% of responders maintaining response for over 20 weeks. Therapy with belumosudil was  associated with quality-of-life improvements and 67% of patients reduced CS dose while 19% were able to completely discontinued CS.  

Last but not least, FFS, which represents a composite endpoint of recurrent malignancy, non-relapse mortality, and absence of subsequent therapy was 54% at 12 months and our estimate for FFS with CR at 12 months was almost two-folds higher compared to prior historic benchmarks of 12% range.

The drug was overall well tolerated with most of adverse events consistent with those expected in a population of patients with advanced cGVHD receiving CS. Cytopenias were rare and there were no unexpected adverse events and no apparent increased risk of infection, such as with cytomegalovirus, which was reported with other agents active against cGVHD, such as ruxolitinib.

Finally, as a proof of concept, in exploratory analyses of peripheral blood the percentage of regulatory T cells demonstrated an increasing trend throughout trial with belumosudil.

Belumosudil clearly holds promise as a novel effective therapy for patients with steroid refractory or dependent cGVHD who failed multiple prior lines of therapy. In fact, the FDA has already granted Breakthrough Therapy Designation to belumosudil for cGVHD after failure of 2 or more lines of systemic therapy as well as Orphan Drug Designation to belumosudil for the treatment of cGVHD.

We hope that this and subsequent trial data will lead toward final approval to broaden access to belumosudil of patients in need for effective therapies.

The results of this initial trial have already been expanded to the subsequent randomized phase 2 trial (also known as the RockStar Trial) which evaluated belumosudil 200 mg daily dose among 66 patients vs. 200 mg twice a day dose among another 66 patients in subjects with cGVHD who had received 2 or up to 5 prior lines of systemic therapy. This trial results have been presented at 2020 ASH annual meeting and are currently in submission for the publication. Rockstar Trial has further confirmed safety and efficacy of belumosudil with an ORR of 75% across all organs and prior failures to ibrutinib and ruxolitinib, which are commonly used to treat cGVHD.

In addition, an expansion trial among children is currently also underway.

We are all excited about the development of this agent in the field of cGVHD, and because of its unique mechanism of action, belumosudil may have much broader therapeutic potential across many other immune disorders. Further studies comparing belumosudil with current best standard of care therapy for steroid refractory cGVHD as well those trial designed to use it earlier in the course of cGVHD treatment are certainly being considered.