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Adding itacitinib to corticosteroids does not improve the objective response rate in the initial treatment of patients with acute graft-versus-host disease

In a previously reported phase I trial, the Janus kinase 1 (JAK1) inhibitor itacitinib demonstrated preliminary efficacy in patients with corticosteroid-refractory or corticosteroid–naïve acute graft-versus-host disease. However, the phase III GRAVITAS-301 trial failed to reproduce this finding. In fact, in this randomized trial adding itacitinib to corticosteroids did not result in a significant improvement in the day 28 objective response rate, nor did it improve the 6-months non-relapse mortality or the overall survival (OS) compared to placebo plus corticosteroids.


About 35-60% of patients who require initial acute graft-versus-host disease (aGVHD) therapy become refractory to corticosteroids. Moreover, prolonged systemic exposure to corticosteroids is associated with toxicity and significant morbidity. As such, novel treatment strategies to tackle GVHD are urgently needed. Targeting key pathogenic mechanisms underlying the aGVHD pathogenesis may improve outcomes for a large proportion of patients. Itacitinib is a potent, selective JAK1 inhibitor that was well tolerated and showed preliminary efficacy in a phase I study of patients with corticosteroid-refractory or –naïve acute GVHD. The randomised, placebo-controlled phase III GRAVITAS-301 study builds further on these findings and evaluated the efficacy of itacitinib added to corticosteroids as an initial treatment of aGVHD.

Eligible patients for the trial were at least 18 years old and received allogeneic hematopoietic cell transplant (HCT) for a haematological malignancy. All patients developed grade II-IV aGVHD per MAGIC criteria. Patients were excluded if they received more than one HCT, corticosteroids for more than 2 days for aGVHD, previous JAK inhibitor therapy, or had GVHD overlap syndrome. Patients (N=439) were stratified by standard versus high aGVHD risk status and were randomly assigned (1:1) to oral itacitinib (200 mg, once daily) or placebo, both in combination with corticosteroids (methylprednisolone 2 mg/kg/day, prednisone equivalent, or an appropriate dose per local treatment guidelines). Patients received the study treatment until treatment taper was completed, or until treatment failure, or unacceptable toxicity.


The median age of patients in the study was 58 years, 27% of the patients had grade 3/4 aGVHD and 24% presented with high-risk aGVHD. With an objective response rate (ORR) at day 28 of 74.0% for patients in the itacitinib arm versus 66.4% for patients in the placebo arm, the study did not meet its primary endpoint of an improved day 28 ORR with itacitinib versus placebo (Odds ratio [95% CI]: 1.45 [0.959-2.204], p=0.0782). Respectively 53.0% and 40.5% of the patients with an objective response achieved complete remission (CR). In a subsequent subgroup analysis, no differences were seen between the two treatment groups when stratified by patient demographic or baseline disease characteristic factors. Nevertheless, in a post-hoc analysis of day 28 CR rates by GVHD risk status, itacitinib was associated with a significantly higher CR rate compared to placebo (odds ratio [95% CI]: 1.66 [1.14‒2.44], p=0.008). Further analyses are even though required to understand whether or not this finding translates into a clinical benefit for the patients.

Relapse of the underlying malignancy occurred in 27 patients (12.4%) randomised to itacitinib and 24 (10.9%) randomised to placebo. Death owing to malignancy relapse occurred in 4.6% and 7.3% of the patients, respectively. The six-months estimates of non-relapse mortality (NRM) were 18.3% and 18.9% for itacitinib and placebo groups, respectively (p=0.7952). After a median follow-up of 267 days, the 1-year estimates of OS were 70% for itacitinib and 66% for placebo. In addition, the trial revealed that there was no difference in failure-free survival (p=0.3560) between both arms. The median duration of corticosteroids use was 47.0 days in the itacitinib group and 44.0 days in the placebo group. The median time to first response was 8 days in both study arms while the median duration of response was 180 days for itacitinib and 174 days for placebo. There was no difference in six-month event-free probability estimate (83% in both study arms).

Treatment-emergent adverse events (TEAEs) of grade ≥3 occurred in 86% and 82.4% of the patients in the itacitinib and placebo groups, respectively, with no pronounced differences in type or prevalence of adverse events. Itacitinib or placebo-related AEs of interest included thrombocytopenia (36.3% versus 31.5%, respectively), anaemia (18.6% versus 12.0%) and cytomegalovirus infections (8.4% versus 7.4%). Fungal infections of grade ≥3 were reported in 2.3% of the patients in the itacitinib group and in 3.2% of the patients in the placebo group. Fatal TEAEs occurred in 10.2% and 13.4% of the patients enrolled in the itacitinib and placebo arms, respectively.


Itacitinib added to corticosteroids for the initial treatment of acute GVHD was well tolerated but did not significantly improve the day 28 ORR, the 6-months NRM or the OS as compared to placebo plus corticosteroids. One interesting finding came from a post-hoc analysis demonstrating a significant improvement in the day 28 complete response rates with itacitinib. However, further analyses will be required to understand whether or not this finding translates into a clinical benefit for the patients.


Zeiser R, Socié G, Schroeder MA, et al. GRAVITAS-301: a randomized, double-blind phase 3 study of itacitinib or placebo in combination with corticosteroids for initial treatment of patients with acute graft-versus-host disease. Presented at EHA 2020; Abstract S256.

Speaker Robert Zeiser

Robert Zeiser

Robert Zeiser, MD, University Hospital Freiburg, Freiburg im Breisgau, Germany


See: Keyslides


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