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GRAVITAS-301: improved complete aGVDH response

Presented by
Prof. Robert Zeiser, University Hospital Freiburg, Germany
EHA 2020
Phase 3, GRAVITAS-301
Although GRAVITAS-301 missed its primary endpoint, post-hoc analysis showed a significant effect of itacitinib in complete response at day 28 in patients with treatment-naive acute graft-versus-host disease (aGVHD).

Prof. Robert Zeiser (University Hospital Freiburg, Germany) presented the results and a post-hoc analysis from the phase 3 randomised, double-blind GRAVITAS-301 trail [1]. GRAVITAS-301 evaluated itacitinib, a JAK-1 inhibitor in combination with corticosteroids in patients with treatment-naïve aGVHD. The primary endpoint was improvement of overall response rate (ORR) at day 28. The key secondary endpoint was 6-month non-relapse mortality (NRM).

Included were adult patients (n=439) receiving allogeneic haematopoietic stem cell transplant (HSCT) for a haematologic malignancy who developed grade II–IV GVHD per MAGIC criteria. Patients were stratified by standard versus high aGVHD risk status and randomised 1:1 to oral itacitinib 200 mg once daily or placebo, both plus corticosteroids (methylprednisolone 2 mg/kg/day, prednisone equivalent, or an appropriate dose per local treatment guidelines).

At day 28, the ORR for itacitinib in combination with corticosteroids compared with placebo plus corticosteroids was 74.0% versus 66.4%, respectively (P=0.08), thereby missing the primary endpoint. Among patients with high-risk aGVHD, day 28 ORR was 61% in the itacitinib group and 56% in the placebo group; for standard risk, ORR was 78% and 70%, respectively. Additionally, there was no difference observed in NRM between the treatment and placebo arm; 6-month estimates of NRM were 18% and 19%, respectively. With a median follow-up of 267 days, 1-year estimates of overall survival were 70% (95% CI 62%−76%) for itacitinib and 66% (95% CI 58%−72%) for placebo. Cumulative incidence of chronic GVHD (cGVHD) was 19% for itacitinib and 27% for placebo.

Post-hoc analysis of day 28 complete response rates showed a significant difference in favour of itacitinib versus placebo when stratified by aGVHD risk status (OR 1.66; 95% CI 1.14‒2.44; P=0.008). Median time to first response was 8 days for both itacitinib (range 5–55) and placebo (range 5–41). Median duration of response was 180 (range 1−587) days for itacitinib and 174 (range 1–633) days for placebo; 6-month event-free probability estimate was 83% for itacitinib and 83% for placebo.

The safety profile observed in GRAVITAS-301 was consistent with previous observations in studies of itacitinib in combination with corticosteroids. The most commonly reported adverse events were thrombocytopenia (29% for itacitinib vs 26% for placebo) and anaemia (10% vs 8%, respectively).

In conclusion, itacitinib added to corticosteroids for the initial treatment of aGVHD did not significantly improve day 28 ORR, 6-month NRM, or overall survival when compared with placebo plus corticosteroids; however, post-hoc analysis showed significant association with day 28 complete response rates. It remains unclear whether this result will translate into clinical benefit.

  1. Zeiser R, 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 EHA25 Virtual, 11-21 June 2020, Abstract S256.

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