Clinically meaningful outcomes in patients with chronic graft-versus-host disease were observed with administration of the selective ROCK2 inhibitor KD025, according to interim results of the phase II ROCKstar trial presented at the 2020 Transplant and Cellular Therapies Meetings in Orlando, Florida.
Corey S. Cutler, MD, MPH
Clinically meaningful outcomes in patients with chronic graft-versus-host disease (cGVHD) were observed with administration of the selective ROCK2 inhibitor KD025, according to interim results of the phase II ROCKstar trial presented at the 2020 Transplant and Cellular Therapies Meetings in Orlando, Florida.
The analysis indicated that KD025 produced statistically significant responses in patients treated at 2 different dose levels. In total, 3 patients out of 132 achieved a complete response to therapy.
“Approximately two-thirds of patients had a clinical response, defined as either a PR or CR at this early time point,” Corey S. Cutler, MD, MPH, of the Dana-Farber Cancer Institute, said during a presentation of the results. “There is some expectation that the response rate will continue to rise slightly over time.”
The ongoing trial includes patients aged ≥12 years who had received 2 to 5 prior lines of therapy and for whom systemic therapy for cGVHD was indicated. Patients were treated by 1 of 2 dosing strategies; those in arm A received KD025 mg once daily (n = 66), or the same dose twice per day in arm B (n = 66). The primary end point was overall response rate (ORR) by the 2014 National Institutes of Health (NIH) Response Criteria. By sample size calculations, a 30% clinical response rate was considered meaningful. The trial was designed with a 90% power to exclude 30% as the lower bound of the 95% confidence interval for the ORR. The results presented focus on a protocol-specified interim analysis occurring when the last accrued patient had been followed for 2 full months.
In patients treated on arm A, the ORR was 64% (95% CI, 51%-75%). For arm B, that rate was 67% (95% CI, 54%-78%).
“The results were statistically significant because the lower bounds of the confidence interval exclude 30%,” Cutler said. “In fact, the lower bounds exclude 50%, suggesting that these results are quite robust.”
Evaluating data by key patient subgroups, trends toward better responses were observed in patients with less severe and shorter duration cGVHD, but the number of involved organ sites failed to indicate a significant difference.
“It is worth noting that even with NIH-severe or longer-duration cGVHD, responses were observed in 50% to 60% of subjects,” Cutler said, adding that the lower bounds for the confidence interval in these groups was above 30%.
Stratifying patients by prior therapies, there were no statistically significant differences ­in response based on the number of prior therapies, best response to prior therapy, prior ibrutinib (Imbruvica), or prior ruxolitinib (Jakafi).
At a median duration of follow-up of 5 months, 44 patients in arm A and 43 in arm B remained on therapy. Reasons for discontinuation included progression, adverse events (AEs), decision by the investigators, and death.
The adverse event profile of KD025 was consistent with cGVHD treated with corticosteroids and other immunosuppressants. There was no apparent increased risk of infection and no cytomegalovirus reactivation.
Any-grade adverse events occurred in 95% of the patient population, with 38% and 28% experiencing grade 3/4 and serious AEs, respectively. Drug-related AEs occurred in half of the patients on the study. Five patients died during the study period.
All-grade AEs that occurred in ≥10% of patients included fatigue (24%), diarrhea (21%), nausea (21%), liver-related investigations (20%), peripheral edema (20%), cough (16%), and dyspnea (16%). Grade ≥3 AEs included hypertension in 5% of patients; hyperglycemia and pneumonia in 4% each; and glutathione S-transferase (GST) increase, nausea, and vomiting in 3% each.
Baseline characteristics were evenly distributed between the 2 arms. Overall, patients were a median of 56 years old (range, 21-77), 57% were men, 52% had more ≥4 organ involved, and 66% had NIH severe cGVHD. The median number of prior lines of therapy was 4 with 34% having received prior ibrutinib; 73% were refractory to their prior line of therapy. The median time between diagnosis of cGVHD and enrollment was 28 months.
In describing the rationale for ROCK2 inhibition for cGVHD therapy, Cutler explained the compounds ability to regulate immunity and treat fibrosis.
“While T-cellmediated inflammation is the end point of acute GVHD, fibrosis is often the final outcome of chronic GVHD.”
ROCK, or Rho-associated coiled-coil kinase, is a serine/threonine kinase that is a critical regulator of inflammation of the level of the T follicularhelper and T follicular–regulatory cells. ROCK2 inhibition selectively downregulates Th17 cells via STAT3 signaling while increasing T regulatory cells through enhanced STAT5 signaling.
“The ROCK kinase system is critical as the common final pathway in fibrosis. Pan-ROCK inhibitors, which are in development, can prevent fibrosis in experimental models,” Cutler said. “Selective ROCK2 inhibitors can also prevent collagen deposition, fibrosis, and scarring.”
KD025 has been granted breakthrough therapy designation by the FDA for the treatment of adults with cGVHD after failure of 2 or more lines of systemic therapy.
Primary analysis of the trial will occur 6 months following the completion of enrollment, with a follow-up analysis occurring at 12 months. Secondary end points that will be evaluated include safety, duration of response, failure-free survival, and overall survival.
“After 2 dosing strategies of KD025, we know that excellent tolerance of the study compound and a robust response rates were seen in all patients and patient subgroups,” Cutler concluded.
Cutler CS, Lee S, Arai S, et al. Interim analysis of KD025-213: a phase 2, randomized, multicenter study to evaluate the efficacy and safety of KD025 in subjects with chronic graft versus host disease (cGVHD) after at least 2 prior lines of systemic therapy (The ROCKstar study; NCT03640481). Presented at: 2020 Transplant and Cellular Therapies Meeting; February 19-23, 2020; Orlando, FL. Abstract LBA2. bit.ly/2SQF8Os.