On August 8, the U.S. Food and Drug Administration (FDA) approved denileukin diftitox-cxdl (Lymphir), a novel immunotherapy for the treatment of adult patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL) who have received at least one prior systemic therapy. Denileukin diftitox is the only CTCL therapy that targets the interleukin-2 (IL-2) receptor found on malignant and regulatory T cells.
More on CTCL
CTCL is a rare and often debilitating chronic non-Hodgkin lymphoma that primarily affects the skin. Approximately 2,500 to 3,000 patients are diagnosed with the disease each year, with an estimated 40,000 living with the condition. Patients with relapsed or refractory CTCL have limited treatment options, and no universally defined single treatment is used to treat these patients with incurable cancer. Patients typically cycle through several skin-directed therapies before the cancer becomes resistant and/or progressive, at which point systemic agents are needed to achieve effective disease control.
Reducing and controlling skin plaques and itching without cumulative toxicity is a primary goal of CTCL treatment. Systemic medicines are prescribed until the disease progresses again or when dose-limiting toxicity occurs, after which practitioners prescribe a different systemic medicine. Denileukin diftitox offers a novel mechanism of action designed to target and eradicate malignant T-cells while preserving healthy tissue.
"As a treating oncologist, I have seen the profound negative effect on the quality of life in patients with relapsed or refractory CTCL. 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 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, Professor of Hematology and Director of the Multidisciplinary T-cell Lymphoma Program at Yale Cancer Center.
Study 302
The approval of denileukin diftitox is based on results from the phase III Study 302 (ClinicalTrials.gov identifier NCT01871727) of patients with CTCL who had previously received at least one systemic treatment (median number of prior therapies = 4; minimum =1, maximum = 18). The primary efficacy population included 69 patients with stage I to III CTCL who were treated with denileukin diftitox at 9 μg/kg/d.
The primary efficacy outcome measure was objective response rate as assessed by an independent review committee. The objective response rate was 36.2% (95% confidence interval [CI] = 25.0%–48.7%), with 8.7% of patients achieving a complete response.
The median time to response was rapid, at 1.41 months, with the majority of responders (about 70%) seeing results after one or two cycles of treatment. Duration of response was at least 6 months for 52.0% of the patients. Approximately 84% (54/64) of skin-evaluable subjects had a decrease in skin tumor burden, and 12.5% (8/64) saw complete clearing of skin disease. Pruritus was evaluated as an exploratory endpoint, with 31.7% of patients demonstrating clinically significant pruritus improvement. Importantly, no cumulative toxicity was observed in patients receiving denileukin diftitox.
Across three studies of 119 patients with CTCL receiving a - μg dose of denileukin diftitox, the most common (occurring in ≥ 20% of patients) adverse reactions, including laboratory abnormalities, were increased transaminases, decreased albumin, nausea, edema, decreased hemoglobin, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, and capillary leak syndrome. The U.S. prescribing information for denileukin diftitox contains a boxed warning that capillary leak syndrome, including life-threatening or fatal reactions, can occur in patients receiving the drug.
This approval includes a postmarketing requirement from the FDA to characterize the risk of visual impairment in patients with CTCL treated with denileukin diftitox. The manufacturer of the agent will continue to monitor all safety data as it emerges.
