FDA Approves Denileukin Diftitox for Patients With R/R Cutaneous T-Cell Lymphoma

On August 8, 2024, the US Food and Drug Administration (FDA) granted approval to denileukin diftitox-cxdl, a novel immunotherapy, for the treatment of patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL), a rare and chronic cancer characterized by debilitating skin lesions and severe itching, after at least 1 prior systemic therapy.

“Given the long-term nature of the disease, pruritus, ulceration of the tumors, and secondary pyogenic skin infection, it is vital to get this skin involvement under control. [Denileukin diftitox-cxdl] is the first therapeutic option in many years to offer hope of reducing skin disease, bringing us one step closer to filling the need for [patients with] CTCL, particularly those that are not able to complete or continue prior therapies,” stated Francine Foss, MD, Yale Cancer Center, New Haven, Connecticut.

The approval was based on results from the phase 3 open-label, single-arm, multicenter Pivotal Study 302 which included patients with R/R stage I to IV CTCL who had previously received at least 1 systemic treatment. Eligible trial participants were required to have expression of CD25 on ≥ 20% of biopsied malignant cells by immunohistochemistry. Patients received denileukin diftitox-cxd at 9 mcg/kg as an intravenous infusion daily from day 1 through day 5 of each 21-day cycle and continued to receive treatment until disease progression or unacceptable toxicity. 

The primary efficacy population included 69 patients with stage 1 to 3 CTCL who were treated with denileukin diftitox-cxdl (9 μg /kg/day). The primary efficacy outcome measure was objective response rate (ORR), as assessed by an Independent Review Committee (IRC). This measured as 36.2%, (95% [confidence interval] CI, 25 to 48.7), with 8.7% of patients achieving a complete response (CR). It was noted that the median number of prior therapies for these patients was 4 (range: 1 to 18), which included both skin-directed and systemic therapies. Prior therapies included photodynamic therapy (56%), total skin electron beam therapy (42%), systemic retinoids (49%), methotrexate/pralatrexate (49%), histone deacetylase inhibitor (35%), brentuximab vedotin (26%) and mogamulizumab (12%).

Results demonstrated that the median time to response was 1.41 months, with ~70% of responders seeing results after 1 to 2 cycles of treatment. The duration of response was at least 6 months for 52% of the patients. Additionally, 84.4% (54 out of 64) of skin evaluable subjects had a decrease in skin tumor burden and 12.5% (8 out of 64) of patients saw a complete clearing of skin disease. Pruritis was evaluated as an exploratory end point with 31.7% of patients demonstrating clinically significant pruritus improvement. Overall, no cumulative toxicity was observed in patients receiving denileukin diftitox-cxdl.

Investigators noted the safety profile is consistent with the known safety profile for denileukin diftitox. Across 3 studies of 119 patients with CTCL who received a 9 μg dose of denileukin diftitox, the most frequent (greater than or equal to 20%) treatment-related adverse reactions, including laboratory abnormalities, were increased transaminases, albumin decreased, nausea, edema, hemoglobin decreased, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, and capillary leak syndrome (CLS).

Due to these adverse events, the US Prescribing Information for denileukin diftitox-cxdl contains a boxed warning that CLS, including life-threatening or fatal reactions, can occur in patients receiving this immunotherapy. Additionally, the approval includes an FDA postmarketing requirement advising of the risk of visual impairment for patients with CTCL receiving this treatment.

Source:

Citius pharmaceuticals receives FDA approval for LYMPHIR™ (denileukin diftitox-cxdl) immunotherapy for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma. PR Newswire. Published online August 8, 2024. https://www.prnewswire.com/news-releases/citius-pharmaceuticals-receives-fda-approval-for-lymphir-denileukin-diftitox-cxdl-immunotherapy-for-the-treatment-of-adults-with-relapsed-or-refractory-cutaneous-t-cell-lymphoma-302217630.html