Lifileucel Approval Signals Progress in Advanced Melanoma Treatment

In a significant stride forward in the treatment landscape for advanced melanoma, the U.S. Food and Drug Administration (FDA) has granted approval to lifileucel, marking the first-ever cellular therapy sanctioned for adult patients grappling with unresectable or metastatic melanoma. The approval comes as a beacon of hope for individuals who have exhausted other therapeutic avenues, such as PD-1 blocking antibodies and BRAF inhibitors or BRAF inhibitors combined with MEK inhibitors. The newly approved lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, involves isolating T cells from a patient's own tumor tissue, subjecting them to further manufacturing processes, and then reintroducing them into the patient's body as a single infusion. Approval of lifileucel was facilitated through the Accelerated Approval pathway, underscoring the urgency and unmet medical need in treating advanced melanoma. This pathway allows for expedited approval of drugs for serious or life-threatening conditions based on surrogate endpoints that are reasonably likely to predict clinical benefit. The safety and efficacy of lifileucel were evaluated in a comprehensive global clinical study involving adult patients with unresectable or metastatic melanoma who had previously undergone systemic therapy, including PD-1 blocking antibodies and BRAF inhibitors. Conducted by a collaborative team across multiple centers, the C-144-01 study (NCT02360579) examined outcomes in 153 patients enrolled in the Phase II cell therapy trial. These patients received a single infusion of lifileucel following a lymphodepletion regimen. The study's primary focus was evaluating the objective response rate (ORR) determined by an independent review committee using RECIST v1.1. Results from the analysis revealed an ORR of 31.5 percent (95% CI: 24.1-39.4) with eight complete responses and 40 partial responses among the treated patients. Furthermore, the median duration of response was not reached during the median study follow-up of 27.6 months, suggesting enduring effectiveness of lifileucel therapy. Impressively, 41.7 percent of responses persisted for ≥18 months, indicating the treatment's potential for long-term benefit. Adjusting for various clinical factors, multivariable analyses indicated that patients with lower tumor burden and normal lactate dehydrogenase levels were more likely to respond to lifileucel therapy. The safety profile of lifileucel was generally favorable with common Grade 3/4 treatment-emergent adverse events, including thrombocytopenia, anemia, and febrile neutropenia, aligning with known profiles of lymphodepletion and interleukin-2 (IL-2) therapy. To gain additional insight into lifileucel and its impact on patients with advanced melanoma, Oncology Times connected with study author, Omid Hamid, MD, Chief of Research/Immuno-Oncology and Co-Director of the Cutaneous Malignancy Program at The Angeles Clinic & Research Institute. Oncology Times: Could you provide insight into the duration of response and its variability in patients treated with lifileucel in the C-144-01 study? Hamid: “These data prove the viability of TIL therapy in advanced melanoma patients established based on objective response rate to treatment and duration of response. Among the 73 patients treated with lifileucel at the recommended dose, the ORR was 31.5 percent, including three patients (4.1%) with a complete response and 20 patients (27.4%) with a partial response. Among patients who were responsive to the treatment, 56.5 percent, 47.8 percent, and 43.5 percent continued to maintain responses without tumor progression or death at 6, 9, and 12 months, respectively, with some ongoing for many years. In addition, 81 percent of patients progressed on anti-CTLA4 therapy and patients had up to 10 lines of therapy. Responses were seen in patients that were primary refractory.” Oncology Times: How does the ORR and duration of response of lifileucel compare to other treatment modalities, such as cytotoxic chemotherapy or retreatment with immune checkpoint inhibitors, in patients with advanced melanoma after progression on ICI and targeted therapy? Hamid: “The response rate (RR) seen here is the highest in the second line response rate seen with any therapy. It is not fair to compare these data as the majority of patients had seen many lines of therapy. When you review the RR of TIL therapy in post PD-1 second-line patients, the RR is 48.8 percent, unmatched even with ipilimumab/nivolumab second line (N Engl J Med 2022; doi: 10.1056/NEJMoa2210233). The durability is significant. There is no role for retreatment with PD-1 therapy alone. More important is the RR seen in hard-to-treat melanoma. The RR in mucosal melanoma was 50 percent (6/12).” Oncology Times: Can you discuss the implications of FDA's accelerated approval of lifileucel for patients with unresectable or metastatic melanoma? Hamid: “The approval provides access to a huge cohort of patients without options. It opens the doors to further investigations with lifileucel, such as for those with brain metastases and in combination with PD-1 therapy (both ongoing). Confirmatory trials (TILVANCE) are looking into combination with PD-1 in untreated patients versus PD-1 for a first-line registration. The real-life experience will inform TILs true benefit. We are currently looking at TIL manipulations such as TIL with PD-1 removed through CRISPR technology. Multiple companies have novel TIL technology forthcoming. We are currently accruing for a trial that looks to replace interleukin (IL-2) with IL-15. Without current approval, the momentum and dedication would have dissipated. “The real power of this approval is the light it will shine on current work with TIL, including lifileucel, in other solid tumors. The data in cervix cancer is paradigm-shifting. Current trials are accruing head and neck squamous cell cancer and non-small cell lung cancer. Work at the NCI has shown responses in breast cancer and colorectal cancer. “Further work will elucidate predictive and prognostic markers. It seeks to decrease the main toxicities associated with TIL-related lymphodepletion by decreasing the conditioning regimen IL-2 toxicity.” Dibash Kumar Das is a contributing writer.