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

FDA

The FDA has approved denileukin diftitox-cxdl (Lymphir) for the treatment of patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL) after at least 1 prior systemic therapy.¹

The approval was supported by data from the phase 3 Study 302 (NCT01871727), which showed that patients treated with denileukin diftitox (n = 69) elicited an objective response rate (ORR) of 36.2% (95% CI, 25.0%-48.7%) per independent review committee assessment, including a complete response rate of 8.7%.

Additionally, the median time to response was 1.41 months, and 52.0% of patients experienced a duration of response of at least 6 months. Notably, 84.4% of skin-evaluable patients (n = 64) achieved a decrease in skin tumor burden, and skin disease completely cleared in 12.5% of these patients.

"[Denileukin diftitox] offers new hope for patients suffering from CTCL, a rare and chronic cancer characterized by debilitating skin lesions and severe itching," Leonard Mazur, chief executive officer of Citius Pharmaceuticals, stated in a news release. "This approval is a significant milestone for [patients with] CTCL."

The multicenter, open-label Study 302 enrolled patients at least 18 years of age with a histopathologic diagnosis of relapsed/refractory stage I to IV CTCL who expressed CD25 on at least 20% of biopsied malignant cells per immunohistochemistry. At least 1 prior therapy was required, and there was no limit on the number of prior therapies.^1,2

Other key inclusion criteria consisted of an ECOG performance status of 0 to 2 in the lead-in portion of the study and 0 to 1 in the main portion of the study; a life expectancy of at least 3 months during the lead-in portion and at least 12 months during the main portion; and adequate bone marrow, hepatic, and renal function.²

Patients with significant cardiac disease or uncontrolled infections were not permitted to enroll.¹

All patients received denileukin diftitox at 9 µg/kg on days 1 to 5 of each 21-day cycle, and treatment continued until disease progression or unacceptable toxicity.

The study's primary end points were the incidence of dose-limiting toxicities and establishing the maximum tolerated dose during the lead-in portion, and ORR during the main portion of the study.²

The efficacy-evaluable population included 69 patients with stage I to III CTCL who had a median age of 64 years (range, 28-87). Sixty-five percent of patients were male, and 73% of patients were White. Disease stages included IA (7%), IB (23%), IIA (13%), IIB (35%), IIIA (12%), and IIIB (10%). Patients received a median of 4 prior lines of therapy (range, 1-18), comprised of 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 (Adcetris; 26%) and mogamulizumab-kpkc (Poteligeo; 12%).¹

Additional data showed that 31.7% of patients experienced a clinically significant improvement in pruritus.

Regarding safety, no cumulative toxicity was observed in patients treated with the study drug. The safety profile of denileukin diftitox was consistent with its known profile. Pooled safety data from 119 patients with CTCL patients treated with 9 μg/kg of denileukin diftitox across 3 studies showed that the most common adverse effects reported in at least 20% of patients included increased aminotransaminases, decreased albumin, nausea, edema, decreased hemoglobin, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, and capillary leak syndrome (CLS).

Denileukin diftitox includes a boxed warning for CLS. Patients receiving the agent should be monitored for signs and symptoms of CLS, and denileukin diftitox should be withheld until CLS resolves or discontinued based on severity.

With the approval, the FDA also included a post-marketing requirement to characterize the risk of visual impairment for patients with CTCL treated with denileukin diftitox.

"We are grateful to the clinicians, patients, and researchers who contributed to the development of [denileukin diftitox]. We believe [denileukin diftitox's] unique IL-2 receptor-targeted treatment, which kills tumor cells directly, and concurrently depletes host regulatory T cells in order to boost the body's immune response, is an important differentiator and offers clinically meaningful benefits to a significant percentage of patients [with relapsed/refractory CTCL]," Myron Czuczman, chief medical officer of Citius Pharmaceuticals, added in a news release. "As the only IL-2 receptor–targeted immunotherapy for CTCL, [denileukin diftitox] provides a novel and non-cross-resistant treatment option without cumulative toxicity for [patients with] stage I to III relapsed/refractory [disease] for whom symptomatic skin involvement interferes with their daily quality of life."

References

1. Citius Pharmaceuticals receives FDA approval for Lymphir (denileukin diftitox-cxdl) immunotherapy for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals. August 8, 2024. Accessed August 8, 2024. https://citiuspharma.com/investors/news-media/news/release-details/2024/Citius-Pharmaceuticals-Receives-FDA-Approval-for-LYMPHIR-denileukin-diftitox-cxdl-Immunotherapy-for-the-Treatment-of-Adults-with-Relapsed-or-Refractory-Cutaneous-T-Cell-Lymphoma/default.aspx
2. A trial of E7777 in persistent and recurrent cutaneous T-cell lymphoma. ClinicalTrials.gov. Updated December 12, 2022. Accessed August 8, 2024. https://clinicaltrials.gov/study/NCT01871727