The combination of itacitinib and corticosteroids did not induce a statistically significant improvement in overall response rate at day 28 compared with placebo plus corticosteroids in patients with treatment-naïve acute graft-versus-host disease, missing the primary endpoint of the phase III GRAVITAS-301 trial.
Steven Stein, MD
The combination of itacitinib and corticosteroids did not induce a statistically significant improvement in overall response rate (ORR) at day 28 compared with placebo plus corticosteroids in patients with treatment-naïve acute graft-versus-host disease (aGVHD), missing the primary endpoint of the phase III GRAVITAS-301 trial (NCT03139604).1
Specifically, the ORR was 74.0% and 66.4% with and without itacitinib, respectively. Additionally, there was no difference reported in nonrelapse mortality at 6 months between the 2 arms, which was a secondary endpoint of the study.
The safety profile of the JAK1 inhibitor combined with corticosteroids was consistent with what has been reported in previous trials. The most common adverse events were thrombocytopenia (34.9% for itacitinib and 34.7% for placebo, respectively) and anemia (29.8% and 25.0%, respectively).
“The result of this study is disappointing. However, we remain committed to building on the success of the REACH program for ruxolitinib, which showed positive results in steroid refractory acute GVHD,” Steven Stein, MD, chief medical officer of Incyte, the developer of itacitinib, stated in a press release. “Additionally, we will continue to study the role of JAK inhibition in chronic GVHD and in the prophylactic setting, as we seek to develop treatments for patients with this debilitating and often fatal disease.”
Results from the study are expected to be presented at an upcoming medical meeting.
In the double-blind, placebo-controlled, phase III GRAVITAS-301 study, investigators randomized approximately 439 patients with acute GVHD to receive the novel and selective JAK1 inhibitor itacitinib compared with placebo, both in combination with corticosteroids, as a first-line treatment. Corticosteroids included prednisone and methylprednisolone.
To be eligible for enrollment, patients had to have undergone 1 allogeneic hematopoietic stem cell transplant (HSCT) from any donor and any source for a hematologic malignancy or disorder, have grade 2 to 4 aGVHD as per Mount Sinai Acute GVHD International Consortium criteria, have evidence of myeloid engraftment, and have serum creatinine level ≤2.0 mg/dL or creatinine clearance ≥40 mL/min.
Those who receive ≥1 allogeneic HSCT, ≥2 days of systemic corticosteroids, have presence of GVHD overlap syndrome or active uncontrolled infection, have HIV or hepatitis B or C infection, have evidence of relapsed primary disease, and have received JAK inhibitor therapy after transplant for any indication are excluded from enrollment.
The primary endpoint was ORR at day 28, while the key secondary endpoint was nonrelapse mortality at 6 months, which was defined as the proportion of subjects who died due to causes other than malignancy relapse. Duration of response was another secondary endpoint.
An analysis presented at the 2019 ASH Annual Meeting comprised plasma samples from 25 patients with aGVHD, which were previously enrolled on a phase I trial exploring the combination of itacitinib and corticosteroids, to determine potentially predictive biomarkers of response to the treatment. Patients included 10 complete responders (CRs), 1 patient with very good partial response (VGPR), 8 patients who achieved partial responses (PRs), and 6 patients with progressive disease (PD) or died before day 28.
Results showed that patients with the biomarkers MCP3/CCL7, SCF/KIT-L, interleukin-8, and TNFRSF6B demonstrated a significant difference between CR and PD/death cohorts (P <.05); intermediate levels of these markers were associated with VGPR and PRs to itacitinib.2
“Because MCP3, IL8, and TNFRSF6B presumably associate with inflammation, elevation of these biomarkers in the PD/death cohort that poorly respond to a JAK inhibitor is not surprising,” the authors stated in the abstract. “In addition, elevation of SCF in responders to JAK [inhibition] is consistent with supporting hematopoiesis.”
Itacitinib is also being evaluated in combination with corticosteroids compared with placebo and corticosteroids as a frontline therapy for patients with chronic GVHD in the phase III GRAVITAS-309 trial (NCT03584516).