Phase III Misses Primary End Point of Improved ORR for Treatment of Acute GVHD

The overall response rate (ORR) was improved with itacitinib (INCB039110) plus corticosteroids compared with placebo plus corticosteroids in patients with treatment-naïve acute graft-versus-host disease (GVHD) in the phase III GRAVITAS-301 (NCT03139604) trial. However, the difference in ORR for the treatment arm compared with the placebo arm was not statistically significant, missing the trial’s primary end point, according to a press release from the Incyte Corporation, developer of itacitinib.¹

The primary end point of improved ORR was defined as the proportion of patients with a complete response, very good partial response, or partial response. At 28 days, itacitinib plus corticosteroids led to an ORR of 74.0% versus 66.4% in the placebo arm (P= .08), but these were not statistically significant. A key secondary end point of the trial was non-relapse mortality at month 6, which was defined by the proportion of patients who died due to causes other than relapse. This end point was also missed.

The toxicity profile for the combination observed in the GRAVITAS-301 study was consistent with previously reported studies. The most common toxicities included thrombocytopenia, which was seen in 34.9% of patients with the combination versus 34.7% in the control, and anemia, noted in 29.8% versus 25.0%, respectively.

GRAVITAS-301 was a randomized, double-blinded, placebo-controlled pivotal phase III trial that evaluated itacitinib in combination with corticosteroids or placebo as a frontline treatment of patients with acute GVHD. Another secondary measurable end point was duration of response.

To be included in the trial, patients had to have undergone 1 allogeneic hematopoietic stem cell transplant (allo-HSCT), have grade II to IV acute GVHD as per MAGIC (Mount Sinai Acute GVHD International Consortium) criteria, evidence of myeloid engraftment, and serum creatinine of ≤ 2.0 mg/dL or creatinine clearance ≥ 40 mL/min. Patients were excluded from the study if they received more than 1 allo-HSCT, received more than 2 days of systemic corticosteroids for acute GVHD, had GVHD overlap syndrome, an active uncontrolled infection, or known human immunodeficiency virus infection.

Itacitinib is a novel, selective JAK1 inhibitor. The agent is currently under investigation in ongoing clinical trials for the frontline treatment of patients with acute and chronic GVHD.

“The result of this study is disappointing,” Steven Stein, MD, chief medical officer at Incyte, said in a press release. “However, we remain committed to building on the success of the REACH program for ruxolitinib (Jakafi), which showed positive results in steroid-refractory acute GVHD. 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.”

Ruxolitinib, which was also developed by Incyte, was previously grantedan FDA approval for the treatment of adult and pediatric patients at least 12 years old with steroid-refractory acute GVHDin May 2019. The combination of the JAK inhibitor plus corticosteroids led to a 57% ORR at day 28 and a 31% complete remission rate in the phase II REACH1 trial. This was the first FDA-approved treatment for patients with steroid-refractory acute GVHD.²

REACH1 was a part of the REACH clinical trial program, which is evaluating ruxolitinib as treatment of patients with steroid-refractory GVHD versus the best available therapy. The program also includes randomized pivotal phase III clinical trials, such as REACH2 and REACH3, which both evaluated the agent in steroid-refractory acute and chronic GVHD.

Incyte will inform investigators of the GRAVITAS-301 trial of the data and conclude the study in a way that is in the best interest of each individual patient that is on trial. Incyte will submit the data for potential presentation at an upcoming meeting.

References:

1. Incyte Announces Results of Phase 3 Study of Itacitinib in Patients with Treatment-Naïve Acute Graft-Versus-Host Disease [new release]. Wilmington, DE: Incyte Corporation; January 2, 2020. https://bit.ly/37KOXls. Accessed January 7, 2020.
2. FDA Approves Jakafi (ruxolitinib) for the Treatment of Patients with Acute Graft-Versus-Host Disease. Incyte. Published May 24, 2019. https://bit.ly/2WiRktX. Accessed May 24, 2019.