EU Panel Recommends Ruxolitinib for Acute or Chronic Graft-Vs-Host Disease

The European Medicines Agency’s Committee for Medical Products for Human Use has recommended the approval of ruxolitinib (Jakafi) for the treatment of patients with acute or chronic graft-vs-host disease (GVHD) who are aged 12 years or older and who have inadequate response to corticosteroids or other systemic therapies.¹

The positive opinion is based on findings from the phase 3 REACH2 (NCT02913261) and REACH3 (NCT03112603) trials, in which the agent was found to have superiority over best available therapy (BAT) in patients with steroid-refractory and -dependent acute and chronic GVHD, respectively.^2,3

Specifically, ruxolitinib was found to produce and overall response rate (ORR) of 62.3% at day 28 vs 39.4% with BAT in patients with steroid-refractory or dependent acute GVHD (odds ratio [OR], 2.64; 95% CI, 1.65-4.22; P < .001), according to data from REACH2. Among the subsets of patients who continued to respond to treatment by day 56, the ORRs in the investigative and control arms were 40% and 22%, respectively (OR, 2.38; 95% CI, 1.43-3.94; P < .001).

Ruxolitinib also showed superior ORR vs BAT in those with steroid-refractory or dependent chronic GVHD at week 24, with rates of 49.7% and 25.6%, respectively (OR, 2.99; 95% CI, 1.86-4.80; P < .0001), according to findings from REACH3. The best overall response (BOR) rate at any time up to week 24 was observed in 76.4% and 60.4% of patients in the investigative and control arms, respectively (OR, 2.17; 95% CI, 1.34-3.52; risk ratio, 1.24; 95% CI, 1.07-1.43; P = .001).

“For many hematologic diseases, allogeneic transplant is the only treatment with the potential to be curative; however, half will go on to develop acute or chronic GVHD,” Robert Zeiser, MD, of the Department of Haematology, Oncology and Stem Cell Transplantation at the University Hospital Freiburg, stated in a press release. “It is encouraging that we may soon have a new standard of care for patients with this other debilitating condition who do not adequately respond to first-line corticosteroids or other systemic therapies.”

REACH2 enrolled patients who were at least 12 years of age, were recipients of allogeneic stem cell transplantation, and had grade II to IV glucocorticoid-refractory acute GVHD that involved the use of systemic immunosuppressive therapy. If patients experienced a relapse following any allogeneic stem cell transplantation in the prior 6 months, had relapsed primary cancer after undergoing transplantation, received more than 1 prior treatment for glucocorticoid-refractory acute GVHD, received JAK inhibitor therapy for any indication, or they had active, uncontrolled infection, they were excluded.

Study participants in the investigative arm (n = 154) received oral ruxolitinib at a twice daily dose of 10 mg. Those in the control arm (n = 155) received BAT, which was chosen by the study investigator and could have included any of the following: antithymocyte globulin, extracorporeal photopheresis, mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil, mTOR inhibitor in the form of everolimus (Afinitor) or sirolimus (Rapamune), etanercept (Enbrel), or infliximab (Remicade).

Crossover from the control arm to the investigative arm was allowed if patients did not experience a response to treatment at day 28 or if they experienced loss of response thereafter and were given additional systemic therapy and did not exhibit evidence of chronic GVHD. Notably, standard supportive therapy was permitted in both arms in addition to the continued use of calcineurin inhibitors and glucocorticoids.

The primary end point of the trial was overall response at day 28, and a key secondary end point was durable overall response at day 56. Other secondary end points included duration of response, BOR, failure-free survival (FFS), overall survival (OS), and cumulative glucocorticoid use until day 56. Safety was also evaluated.

Among the 309 total patients, the median age was 54.0 years (range, 12-73), and 59% of patients were male and 69% were White. Thirty-four percent of patients had grade II acute disease, 44% had grade III disease, and 20% had grade IV disease. The most common initial control treatment was extracorporeal photopheresis, which was given to 27% of patients.

Thirty-two percent of those on the control group crossed over to the ruxolitinib arm on, or after, day 28. The median follow-up was 5.04 months (range, 0.03-24.02) in the investigative arm, and 3.58 months (range, 0.03-23.62) in the investigative arm. The data cutoff date was July 25, 2019.

Additional data published in the New England Journal of Medicine showed that 34% of patients in the investigative arm experienced a complete response (CR) to treatment vs 19% of those in the control arm. The percentage of patients who responded proved to be highest among those with grade II acute GVHD at baseline, with percentages of 75% with ruxolitinib vs 51% with BAT, and those with grade III disease, with rates of 56% and 38%, respectively. The odds ratio for response was highest among those with grade IV acute disease at baseline, with rates of 53% with ruxolitinib and 23% with BAT (OR, 3.76; 95% CI, 1.24-11.38).

The median FFS proved to be longer with ruxolitinib vs BAT, at 5.0 months vs 1.0 month, respectively (HR, 0.46; 95% CI, 0.35-0.60). The cumulative incidence of cancer relapse or progression at 18 months was 13% and 19% in the investigative and control arms, respectively; the cumulative incidence of non–relapse-related death at this time point was 49% and 51%, respectively. The median OS in the ruxolitinib and BAT arms was 11.1 months and 6.5 months, respectively (HR, 0.83; 95% CI, 0.60-1.15).

REACH3 enrolled patients who were at least 12 years of age, had undergone allogeneic stem cell transplantation, and had moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. Those with prior receipt of JAK inhibitors for acute GVHD were allowed to enroll if treatment had resulted in a CR or partial response (PR), and if they discontinued the agent at least 8 weeks prior to their first dose of ruxolitinib or BAT on the trial. Those who received 2 or more prior systemic therapies for chronic GVHD in addition to glucocorticoids with or without calcineurin inhibitors were excluded, as were those who experienced relapse of the primary cancer, those who had graft loss within 6 months prior to treatment initiation, or those with active, uncontrolled infection.

Study participants were randomized 1:1 to receive ruxolitinib at a twice-daily dose of 10 mg (n = 165) or therapy chosen by investigators (n = 164), which could have included extracorporeal photopheresis, low-dose methotrexate, mycophenolate mofetil, mTOR inhibitor, infliximab, rituximab (Rituxan), pentostatin (Nipent), imatinib (Gleevec), or ibrutinib (Imbruvica).

The primary end point of REACH3 was overall response at week 24, and 2 key secondary end points comprised FFS and response on the modified Lee Symptom Scale at week 24. Other end points included subgroup analyses of overall response, individual organ responses, BOR at any time up to week 24, DOR, change in glucocorticoid dose over time, OS, changes in quality of life, and safety.

Patient characteristics were noted to be well balanced between the 2 treatment arms. The median age of the 329 total patients was 49 years (range, 12-76), and 61.1% were male. Additionally, 42.9% of patients had moderate chronic disease and 56.5% had severe chronic disease. Notably, 71.4% of patients were glucocorticoid refractory, and 28.6% had glucocorticoid-dependent disease per investigator assessment.

The most common control therapy used was, again, extracorporeal photopheresis (34.8%), followed by mycophenolate mofetil (22.2%), and ibrutinib (17.1%). About 50% of patients received calcineurin inhibitors while on the trial.

The data cutoff for the trial was May 8, 2020, and the median follow-up time was 57.3 weeks. Additional data published in the The New England Journal of Medicine showed that CRs were achieved by 6.7% of those who received ruxolitinib and 3.0% of those who received BAT. Notably, a higher overall response was reported with the JAK inhibitor vs the control treatment irrespective of the organs involved.

Here, ruxolitinib also resulted in a longer FFS vs control treatment, with a median FFS of greater than 18.6 months vs 5.7 months, respectively (HR, 0.37; 95% CI, 0.27-0.51; P < .001). The median FFS was not yet reached in the investigative arm but was estimated to be 18.6 months. The probability of FFS at 6 months, estimated utilizing the Kaplan-Meier method was noted to be higher with the JAK inhibitor vs control treatment, at 74.9% (95% CI, 67.5%-80.9%) and 44.5% (95% CI, 36.5%-52.1%), respectively.

Response on the modified Lee Symptom Scale at week 24 was also higher with ruxolitinib vs the control treatments, with rates of 24.2% and 11.0%, respectively (OR, 2.65; 95% CI, 1.42-4.82; risk ratio, 2.19; 95% CI, 1.31-3.65; P = .001).

Among responders, the estimated probability of maintaining response at 12 months was higher in the investigative arm vs the control arm, at 68.5% (95% CI, 58.9%-76.3%) vs 40.3% (95% CI, 30.3%-50.2%), respectively.

The 61 patients who crossed over from the control arm to the investigative arm also experienced responses, with a BOR of 78.7% at the time of data cutoff; this included 4 CRs and 44 PRs.

OS data were not found to be mature at the data cutoff, and it had not yet been reached in either treatment arm (HR, 1.09; 95% CI, 0.65-1.82). The estimated 12-month OS was 81.4% (95% CI, 74.1%-86.8%) with ruxolitinib vs 83.8% (95% CI, 76.5%-89.0%) with the control therapy.

“This positive CHMP opinion of [ruxolitinib] in GVHD brings us 1 step closer to approval in Europe, for a condition where patients often experience severe and life-threatening symptoms,” Susanne Schaffert, PhD, president of Novartis Oncology, added in the release. “With this exciting news, we may change the way GVHD is treated as about half of patients do not respond to previous corticosteroids or other systemic treatment.”

References

1. Novartis receives positive CHMP opinon for Jakafi to treat acute and chronic graft-versus-host disease. News release. Novartis Pharama AG; March 25, 2022. Accessed March 25, 2022. https://yhoo.it/3qy0q3B
2. Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635
3. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228-238. doi:10.1056/NEJMoa2033122