NCCN Adds Denileukin Diftitox to CTCL Clinical Practice Guidelines in Oncology

Leonard Mazur

Denileukin diftitox-cxdl (Lymphir) has been added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology with a category 2A recommendation as an appropriate option for patients with cutaneous T-cell lymphoma (CTCL).¹

“The inclusion of [denileukin diftitox] in the NCCN guidelines is a testament to the clinical evidence supporting this therapy, and further supports health care professionals in considering [denileukin diftitox-cxdl] as part of the recommended treatment protocols for CTCL. We are grateful to the NCCN board for its recognition of [denileukin diftitox-cxdl], paving the way for expanded access to this important treatment option,” Leonard Mazur, CEO of Citius Pharma and Citius Oncology, said in a news release.¹

Denileukin diftitox is a targeted immune therapy that rids the tumor microenvironment of immunosuppressive regulatory T lymphocytes and exerts antitumor activity through a direct cytocidal effect on IL-2R–expressing tumors and is the only CTCL therapy that targets the IL-2 receptor.¹

The addition of the novel immunotherapy to the guidelines comes just one month after receiving regulatory approval from the FDA for the treatment of patients with relapsed/refractory CTCL after at least 1 prior systemic therapy.²

The decision was based on findings from the pivotal phase 3 Study 302 (NCT01871727), in which 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%.2,3 Additionally, 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. Responses also occurred early, with approximately 70% of patients experiencing a response after the first 2 cycles of therapy. Notably, 84.4% of skin-evaluable patients (n = 64) achieved a decrease in skin tumor burden; skin disease cleared entirely in 12.5% of these patients.^2,3

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.4 All patients received intravenous denileukin diftitox over 60 minutes at 9 µg/kg on days 1 to 5 every 21 days for up to 8 cycles.³

The primary efficacy end point of the study was ORR per IRC assessment based on Global Response Score. Secondary end points included DOR, time to response, skin response, safety and tolerability, pharmacokinetics, and immunogenicity.³

A total of 112 patients were enrolled in the study, 69 of whom had stage I to III CTCL and comprised the primary efficacy population. Overall, the median number of prior lines of therapy was 4.0 (range, 1-18). 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 (12%). The median patient age was 64 years (range, 28-87) and most patients had an ECOG performance status of 0 (56.5%). The majority of patients were White (72.5%) and had stage IA/IB/IIA disease (43.5%). The median number of treatment cycles was 6.0 (range, 1-42).^2,3

Additional data from the trial demonstrated that the IRC-assessed clinical benefit rate (CBR) was 49.3% (95% CI, 37.0%-61.6%). Efficacy was also evaluated by investigator assessment (n = 71) and reflected an ORR of 42.3% (95% CI, 30.6%-54.6%), including a CR rate of 8.5%. The CBR was 53.5% (95% CI, 41.3%-65.5%).³

Regarding safety, 98.6% of patients experienced at least 1 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 and were predominantly grade 1/2.³

“NCCN guidelines are widely regarded as the gold standard for clinical decision-making in oncology and hematology, influencing treatment practices and payor reimbursement in the US,” Mazur added.¹ “We believe that [denileukin diftitox-cxdl] has the potential to improve CTCL patient outcomes and expect its addition to the NCCN guidelines may aid adoption and ease reimbursement, particularly for the anticipated patients that qualify for Center for Medicare and Medicaid coverage.”

References

1. Citius Pharmaceuticals, Inc. and Citius Oncology, Inc. announce LYMPHIR (denileukin diftitox-cxdl) added to National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. News release. Citius Pharmaceuticals. September 5, 2024. Accessed September 6, 2024. https://www.prnewswire.com/news-releases/citius-pharmaceuticals-inc-and-citius-oncology-inc-announce-lymphir-denileukin-diftitox-cxdl-added-to-national-comprehensive-cancer-network-nccn-clinical-practice-guidelines-in-oncology-302239014.html
2. 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. September 6, 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
3. Foss FM, Kim YH, Miles Prince HM, et al. Efficacy and safety of E7777 (improved purity denileukin diftitox [ONTAK]) in patients with relapsed or refractory cutaneous T-cell lymphoma: results from Pivotal Study 302. Blood. 2022;140(suppl 1):1491-1492. doi:10.1182/blood-2022-166916
4. A trial of E7777 in persistent and recurrent cutaneous T-cell lymphoma. ClinicalTrials.gov. Updated December 12, 2022. Accessed September 6, 2024. https://clinicaltrials.gov/study/NCT01871727