First-Line Ofatumumab Plus Prednisone Demonstrates Promising Efficacy, Safety for Chronic GVHD

Aleksandr Lazaryan, MD, PhD, MPH, Moffitt Cancer Center, Tampa, FL, discusses findings from a phase 2 study which explored the efficacy and safety of ofatumumab and prednisone as initial therapy for patients with chronic graft-versus-host disease (GVHD).

The study found that ofatumumab combined with glucocorticoid therapy for chronic GVHD resulted in 62.5% overall response rate (ORR) at 6 months and 53% failure-free survival (FFS) at 12 months. In addition, the combination demonstrated acceptable safety in these patients.

Transcript:

As a brief introduction, I'm an associate member and a professor in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at the Lee Moffitt Cancer Center and Research Institute in Tampa, Florida. I'm an associate professor of Oncologic Sciences at the University of South Florida, and my clinical research is focused on immunotherapies and their complications, such as chronic graft-versus-host disease.

Oncology Learning Network: What existing data led you and your co-investigators to conduct this research?

Chronic graft-versus-host is a common immune-mediated disorder and a complication of allogeneic stem cell transplantation. It affects about 40% to 50% of our patients. It is a leading cause of late transplant related morbidity and mortality, impairing quality of life, causing disability and prolonged duration of immunosuppressive therapy in many of our patients. Therefore, it has a significant adverse impact on the life and wellbeing of the patients we treat.

Insights into chronic GVHD pathogenesis continue to accumulate. B lymphocyte targeted agents, specifically including anti-CD20 antibodies and BTK inhibitors such as ofatumumab, have shown promise in the prevention and therapy of chronic GVHD. Standard treatment in upfront setting includes high dose glucocorticoids commonly used at 1 milligram per kg of daily prednisone or equivalent, with or without calcineurin inhibitor or mTOR inhibitors, are still in practice. Although current combination therapies have not demonstrated superiority to glucocorticoids, trials of concurrent therapies with steroids are critical for limiting cumulative steroid exposure and side effects.

Our prior experience with the use of anti-CD20 monoclonal antibody ofatumumab was based on a phase 1 pilot trial testing prednisone and ofatumumab combination for initial chronic GVHD therapy, with the pilot results published back in 2015 in BBMT. The phase 1 portion of that trial identified ofatumumab at the 1000 milligram dose given at baseline and at day 14 after a combination therapy with prednisone. It did demonstrate the safety of the recommended phase 2 dose for further testing, which was accomplished by this current phase 2 trial, which enrolled 38 patients.

OLN: Could you briefly describe the study and methods used?

This was a prospective phase 2 single arm clinical trial, so all of the patients got the combination regimen with ofatumumab, as I mentioned earlier, at 1000 milligram administered on day 1 and day 14 of the study, along with the prednisone that was given at the conventional dose, starting at one milligram per kg of prednisone equivalent. We, basically, did find that the overall severity of chronic GVHD according to NIH scale in our trial population was moderate in about 63% of the patients or severe in about 37% of enrolled patients. 74% of our patients were affected by what we call the overlap subtype of chronic GVHD, and 82% of our patients had prior acute graft-versus-host disease.

We found that the observed 6 months clinician reported in 2014 NIH-defined overall response rate, which included complete and partial responses, was 62.5%, which actually was not superior to the pre-specified historic benchmark of 60% that we deemed to be acceptable at the time when we were designing this particular trial. However, when we compared our findings in a post-hoc analysis with more contemporaneous NIH-based benchmark of 48.6%, and these data are mostly driven from the large BMT CTN 0801 clinical trial, our combination regimen of ofatumumab and prednisone appeared to be superior to that conventional benchmark.

The baseline chronic GVHD features, in terms of organ involvement, severity, and initial immune suppression agents, were not significantly associated with 6 months overall response rate. The median time to initiation of second line therapy was 5.4 months. Important outcomes such as failure-free survival in our trial was 64.2% at 6 months, 53.1% at 12 months, whereas the failure-free survival with CR and PR at 12 months was 33.5%, which actually exceeded the benchmark of about 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months, which is a very meaningful outcome. The odds ratio for the likelihood of greater discontinuation of steroids that we found was eightfold of the difference.

OLN: Were any outcomes particularly surprising?

Although our trial did not meet its primary endpoint of hypothesized 20% improvement in the overall response rate at 6 months, it demonstrated potential clinical benefit in secondary and exploratory analysis using contemporaneous definitions, as I mentioned earlier, of responses and overall clinical benefit, according to 2014 NIH response criteria. Failure-free survival with ongoing CR and PR at 12 months was also appearing to be superior. That's, in a way, unexpected, but certainly data revealed in a post-hoc analysis that we think are pertinent and do reflect more contemporaneous data.

Our observed 6 months NIH CR and PR rate suggest that combination ofatumumab with prednisone has potential activity as an initial therapy for chronic GVHD, and compares favorably with current best estimates of response, such as those reported in the benchmark BMT CTN 0801 trial. In fact, the 6 months NIH overall response benchmark from the BMT CTN trial was set at 40%, whereas the 6 months overall response rate was 48.6% in a 2-drug arm, and 50% in a 3-drug arm. That's why these estimates are certainly pertinent for the post-hoc analysis that was performed in this particular trial.

Similarly, in the more recent INTEGRATE phase 3 clinical trial, which compared combination of ibrutinib and prednisone to the prednisone alone, the 6 months overall response rate was 47%. So, as you can see, in both of these more contemporaneous trials, they employed an age-based response assessment, and they did demonstrate the benchmark responses of either 48% range or 47% range.

That's why we believe that our post-hoc analysis was meaningful, and it did demonstrate the potential superiority of the ofatumumab prednisone combination. We acknowledge, however, that these comparisons were post-hoc, and that they're inherent heterogeneous in patient populations across clinical trials. Although FFS was comparable to the current best estimate in the initial therapy setting, the FFS with CR and PR at 12 months appears to be beneficial to existing benchmarks.

OLN: What are the significance of these findings? 

Our data do support that in the subgroup of patients treated with prednisone in the combination with ofatumumab, this combination can achieve durable responses and freedom from treatment failure, yet the limited study population didn't afford clear insights into patient and current GVHD level variables that would be associated with durable treatment successes.

OLN: Do you and your co-investigators intend to expand on this research, and if so, how?

Prior data with the use of CD20 directed agents such as rituximab were reported by others, such as by French colleagues. In their phase 2 clinical trial, the combination of rituximab with steroid did demonstrate some efficacy, however, there were some infectious complications such as PML that were not observed in our trial.

I believe that, taken together, the CD20 targeting frontline therapy of chronic GVHD certainly warrants future randomized trials of potentially steroid-free combination regimens, according to the recently proposed NIH guidelines on chronic GVHD therapy. These future therapeutic strategies may offer similar clinical benefits in initial chronic GVHD therapy, while they might importantly spare the steroid-related toxicities, which is very important for our patients.

Rationally applying the right interventions to patients with the greatest likelihood of benefiting, in other words, within the framework of personalized therapies represents an important future goal, and we all realize that. Given the signal of benefit in our trial, and the wealth of published data supporting the role of B-cell targeted therapies in chronic GVHD, I do believe that ofatumumab or other B-cell targeting agents should be considered in these novel treatment paradigms.

Source:

Kater AP, Levin MD, Dubois J, et al. A phase 2 multicenter trial of ofatumumab and prednisone as initial therapy for chronic graft-versus-host disease. Blood Adv. 2022;6(1):259-269. doi:10.1182/bloodadvances.2021005552.