The National Comprehensive Cancer Network (NCCN) has added denileukin diftitox-cxdl (Lymphir) to its Clinical Practice Guidelines in Oncology as a category 2A recommendation for patients with cutaneous T-cell lymphoma (CTCL). This decision, announced September 5, 2024, follows the FDA's recent approval of denileukin diftitox for relapsed or refractory CTCL after at least one prior systemic therapy and is poised to expand access to this important treatment option.
The inclusion of denileukin diftitox in the NCCN guidelines underscores the clinical evidence supporting its use. According to Leonard Mazur, CEO of Citius Pharma and Citius Oncology, this recognition will further support healthcare professionals in considering denileukin diftitox as part of the recommended treatment protocols for CTCL.
Pivotal Study 302 Data
The NCCN's decision was influenced by the pivotal phase 3 Study 302 (NCT01871727), a multicenter, open-label trial that evaluated the efficacy and safety of denileukin diftitox in patients with relapsed or refractory CTCL. The study enrolled patients aged 18 years or older with stage I to IV CTCL who expressed CD25 on at least 20% of biopsied malignant cells.
The results showed that treatment with denileukin diftitox (n = 69) led to an objective response rate (ORR) of 36.2% (95% CI, 25.0%-48.7%) per independent review committee (IRC) assessment, including a complete response (CR) rate of 8.7%. The median time to response was 1.41 months, and the 6- and 12-month duration of response (DOR) rates were 52.0% and 20.0%, respectively. Notably, 84.4% of skin-evaluable patients (n = 64) experienced a decrease in skin tumor burden, with complete clearance of skin disease in 12.5% of these patients.
Dosing and Patient Characteristics
In Study 302, patients received intravenous denileukin diftitox at 9 µg/kg over 60 minutes on days 1 to 5 every 21 days for up to 8 cycles. The primary efficacy endpoint was ORR per IRC assessment based on Global Response Score. Secondary endpoints included DOR, time to response, skin response, safety and tolerability, pharmacokinetics, and immunogenicity.
The median patient age was 64 years (range, 28-87), and most patients had an ECOG performance status of 0 (56.5%). The median number of prior lines of therapy was 4.0 (range, 1-18), including photodynamic therapy (56%), total skin electron beam therapy (42%), systemic retinoids (49%), and histone deacetylase inhibitors (35%).
Safety Profile
Regarding safety, 98.6% of patients experienced at least one treatment-emergent adverse effect (TEAE). The most frequent TEAEs were nausea (43.5%), fatigue (31.9%), increased alanine aminotransferase, chills, and peripheral edema (27.5% each). Treatment-related AEs of special interest included capillary leak syndrome, hepatotoxicity, infusion reaction, and visual impairment, predominantly grade 1/2.
Implications for Clinical Practice
Denileukin diftitox is a targeted immune therapy that eliminates immunosuppressive regulatory T lymphocytes from the tumor microenvironment and exerts antitumor activity through a direct cytocidal effect on IL-2R–expressing tumors. It is the only CTCL therapy that targets the IL-2 receptor.
The addition of denileukin diftitox to the NCCN guidelines is expected to influence treatment practices and payor reimbursement in the US. Mazur believes that this inclusion may aid adoption and ease reimbursement, particularly for patients who qualify for Center for Medicare and Medicaid coverage, potentially improving outcomes for CTCL patients.
