Dr Lazaryan Discusses ROCKstar Study Results 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 the phase 2b ROCKstar study of belumosudil, a selective ROCK2 inhibitor, in patients with chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy.

Transcript

First of all, I would like to thank the Oncology Learning Network for the invitation to share my perspective on the recent data from KD025, 2013 ROCKstar trial published recently in Blood within conventionally through the FDA approval of second-targeted agents in steroid-refractory cGVHD after the initial approval of ibrutinib back in 2017 by FDA.

As a brief introduction, I'm an associate member and professor at the Department of Blood Marrow Transplant and Cellular Immunotherapy at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida, USA. I'm an associate professor of oncologic sciences at the University of South Florida. My clinical research is focused on immunotherapies and their complications, such as cGVHD.

cGVHD is a leading cause of morbidity and mortality, and disability following allogeneic stem cell transplantation. It is an immune-mediated inflammatory and fibrotic disorder characterized by these regulated immune homeostasis leading to a production of inflammatory cytokines and concurrent reduction of regulatory T-cell, which limits the ability of immune system to calibrate and control inflammation.

Rho-associated coiled-coil kinase, or ROCK, plays an important role in inflammation and fibrosis by regulating transcription of profibrotic genes and production of major profibrotic mediators. Belumosudil—now, FDA approved as of July 16, 2021—is an oral ROCK2 inhibitor.

In murine model of chronic GVHD, belumosudil downregulated inflammatory STAT3 pathway, responsible for IL-17 and IL-21 production in upregulated more tolerogenic STAT5 pathway control and regulatory T-cells thereby leading to re-establishment of immune homeostasis.

All this provided the strong rationale for testing of this drug in the clinical trial that we're about to discuss.

As I said, based on this compelling preclinical data and initial phase 2a KD025-208 trial that was published earlier this year in JCO, established an initial safety and efficacy of belumosudil in patients with steroid-refractory dependent chronic GVHD with up to 3 prior lines of therapy.

Our subsequent multi-center, pivotal, randomized, phase 2b clinical trial, also known as a ROCKstar clinical trial that we're discussing today, randomized 1-to-1 a total of 132 patients with up to 5 prior lines of therapy to 200 mg daily or twice a day dose of belumosudil.

The results of the ROCKstar trial were just published in July 16 issue of Blood, which is a leading journal in our society. Primary endpoint of the ROCKstar trial was the overall response rate composed of complete and partial responses for 2014 NIH consensus criteria. Key secondary end points included duration of response, corticosteroid, dose reduction, failure-free survival, and quality-of-life outcomes as measured by the changes in the Lee Symptom Scale score.

Belumosudil was given every 28 days on a daily basis until disease progression or unacceptable toxicity. Sixty-seven percent of patients in the ROCKstar trial had severe graft-versus-host disease. About half of the patients have more than 3 prior organs involved, and over 70 percent had chronic GVHD refractory to their last line of therapy.

The best overall response rate in the ROCKstar trial was 76% across both 200 mg once a day and twice a day dose arms with no significant differences in efficacy or toxicity between dose levels, thereby justifying the approval of 200 mg once a day dose of belumosudil for commercial use.

Similarly, overall response rates were not significantly affected by chronic GVHD severity. The number of organs involved or prior lines of therapy, including prior use of ibrutinib in 34 percent of the patients, or ruxolitinib in 29 percent of the patients in the ROCKstar trial.

Remarkably, patients with prior ruxolitinib had 68 percent overall response rate while patients with prior ibrutinib had 74 percent overall response rate, which was also similar to what was observed among heavily pretreated patients with more than 3 prior line of systemic therapy.

On the patient's level, most of the responses were partial responses. That's an important message from this trial. With only 7 patients in a ROCKstar trial achieving complete response in all affected organs.

However, organ-specific complete responses were achieved across all affected organs, including difficult to treat chronic GVHD involving joint and facia, cutaneous, sclerosis, and even lungs with 13 percent of the patients normalizing their FEV1 and lung age scoring in a ROCKstar trial.

Overall, given the severity and extent of fibrotic chronic GVHD manifestations among the trial participants, achieving CR in all organs might be hampered by occasional irreversible advanced fibrotic manifestations, especially those involving eyes or lung.

Responses were overall rapid, with about 90 percent of all responses achieved within 6 months in the ROCKstar trial. The median duration of response was almost 55 weeks among responders in the ROCKstar trial with approximately 60% of the responders maintaining the response for over 20 weeks.

Therapy with belumosudil was associated with quality-of-life improvements as well. About two-thirds of the patients were able to reduce their steroid dose, and about 20 percent of the patients were able to completely discontinue corticosteroids.

Last but not least, an outcome called failure-free survival, which represents a composite endpoint of recurrent malignancy, non-relapse mortality, and absence of subsequent therapy, was estimated to be around 56 percent at 12 months in the ROCKstar trial, which was fairly satisfactory.

Overall, the rates of non-relapse mortality and relapse were low, while most common failure event would be observed a failure-free survival was the initiation of new systemic cGVHD therapy.

The real applications are such that belumosudil has now been FDA approved for the use in chronic graft-versus-host disease in adult and pediatric patients, 12 years or older, with cGVHD after failure of at least 2 prior lines of systemic therapy.

This will certainly offer an opportunity for so many patients around the world to potentially benefit from the use of this drug. Future studies certainly will be looking at potentially expanding the use of the drug to different patients subsets or perhaps combining this drug with other active agents.

The next step is going to be gaining more mature data, and pediatric patient population.

As I mentioned, expanding it to potential use in combination with other agents and ultimately moving toward steroid-free treatment paradigms in cGVHD, which would benefit a lot of patients who experienced toxicity with the use of steroids on a day-to-day basis battling cGVHD.

For all in ROCKstar trial, as in the prior trial, which was the KD025-208, belumosudil was really well-tolerated with most of the adverse effects consistent with those that are expected in a population of patients with advanced cGVHD who receive steroids.

While serious adverse events were reported in about 40% of the trial, less than 10% of the patients had pneumonia and only 1 patient in a ROCKstar trial had CMV reactivation. We had no CMV reactivation in the prior 208 trial.

Cytopenias, which are low blood counts, were overall rare with less than 4 percent of grade 3 or above.

Overall, the drug was fairly well-tolerated with some lab abnormalities that overall were fairly tolerable. We're certainly optimistic that this drug might represent an opportunity for the patients who are severely immunosuppressed to get the drug that has potential activity with no significant excess risk of infections and no significant excess risk in dropping blood counts further for those patients.