FDA Greenlights Lifileucel for Unresectable, Metastatic Melanoma Via Accelerated Approval


Iovance’s tumor infiltrating lymphocyte (TIL) therapy is the first cellular therapy to earn this indication, with the phase 3, confirmatory TILVANCE-301 trial set to verify its clinical benefit.

Peter Marks, MD, PhD, director of the FDA's Center for Biologics Evaluation and Research,

Peter Marks, MD, PhD

Credit: FDA

The FDA has granted accelerated approval to Iovance Biotherapeutics for its tumor-derived autologous T cell immunotherapy lifileucel (branded now as Amtagvi) for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, or treated with a BRAF inhibitor with or without a MEK inhibitor in the instance that the patient is if BRAF V600 positive.1,2 It is the first cellular therapy to receive this indication. Iovance said on an investor call that the cost for Amtagvi would be $515,000 yearly.

The agency’s director of the Center for Biologics Evaluation and Research, Peter Marks, MD, PhD, expressed in a statement that this approval “represents the culmination of scientific and clinical research efforts leading to a novel T cell immunotherapy for patients with limited treatment options” for a form of cancer that is aggressive and potentially fatal.2

According to the FDA, the prescribing information for the therapy contains a Boxed Warning for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment.

“The accelerated approval of Amtagvi is the first step in realizing Iovance’s ambition to usher in the next generation of cell therapy by bringing this breakthrough to patients with advanced solid tumors,” Frederick Vogt, PhD, JD, the interim CEP and president of Iovance, said in a statement.3 “Given the significant unmet needs in the advanced melanoma community, we are proud to offer a personalized, one-time therapeutic option for these patients. We are continuing our development efforts to address additional unmet medical needs in patients with solid tumor cancers, making our novel cell therapies available to more patients with melanoma and other types of cancers.”

Lifileucel is a tumor-infiltrating lymphocyte (TIL) therapy, and the biologics license application (BLA) for it was supported by the phase 2 C-144-01 (NCT02360579) clinical trial. Data from C-144-01 were presented by Amod A. Sarnaik, MD, FACS, of Moffitt Cancer Center and the University of South Florida, at the Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting, held November 8-12, 2022, in Boston, Massachusetts.4 The data were also published in the Journal for ImmunoTherapy of Cancer.5

All told, the multicenter study consisted of 4 cohorts and is the largest such study of a TIL therapy in advanced melanoma for patients previously treated with immune checkpoint inhibitors. At SITC 2022, Sarnaik presented pooled data—which had a cutoff date of July 15, 2022—that came from patients in cohorts 2 (n = 66) and 4 (n = 87). Among the key efficacy results were an independent review committee-assessed objective response rate (ORR) of 31.4%, with 9 complete responses and 39 partial responses; a median overall survival (OS) of 13.9 months; and a 12-month OS rate of 54% (95% CI, 45.6-61.6).4

“The FDA approval of Iovance’s TIL therapy is a historic milestone for patients and for the oncology field at large,” Jason Bock, PhD, cofounder and CEO of Cell Therapy Manufacturing Center, said in a statment issued to CGTLive®. “The approval of this first in a new class of cell therapies for solid tumors defines a regulatory path for TIL, which will unlock more innovation in the industry and ultimately benefit patients with cancer.”

READ MORE:Iovance’s NSCLC Trials Push Second TIL Therapy Closer to Submission

The full dataset, published in December 2022,5 also showed an ORR of 31.4% (95% CI, 24.1-39.4), but with 8 complete responses and 40 partial responses, and a median duration of response that was not reached at a median follow-up of 27.6 months. Overall, 41.7% of the responses were maintained for at least 18 months. The median OS and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status showed elevated lactate dehydrogenase (LDH) and target lesion sum of diameters (SOD) above the median were independently correlated with ORR (P = .008). Those with normal LDH and SOD lower than the median had greater likelihood of response than those with either (OR, 2.08) or both (OR, 4.42) risk factors.

As for safety, the most common grade 3/4 treatment-emergent adverse events (AEs) occurring at or above a rate of 30%) were thrombocytopenia (76.9%), anemia (50.0%), and febrile neutropenia (41.7%).

“The approval of Amtagvi offers hope to those with advanced melanoma who have progressed following initial standard of care therapies, as the current treatment options are not effective for many patients,” Samantha R. Guild, JD, President, AIM at Melanoma Foundation, said in a statement.3 “This one-time cell therapy represents a promising innovation for the melanoma community, and we are excited by its potential to transform care for patients who are in dire need of additional therapeutic options.”

In addition to the C-144-01 study, lifileucel is also being evaluated in a randomized phase 3 clinical trial, TILVANCE-301 (NCT05727904). Iovance Biotherapeutics had previously noted that if lifileucel received accelerated approval, TILVANCE-301 may transition into a confirmatory trial to support the therapy’s full approval. The FDA’s announcement of the approval decision reiterated that data from TILVANCE-301 would be utilized as such.2

According to Iovance,3 the treatment is manufactured with its proprietary process that collects and expands a patient’s unique T cells from a portion of their tumor. The treatment then returns billions of the cells back to the body to fight their cancer. Lifileucel will be administered at Authorized Treatment Centers (ATCs) as part of a treatment regimen that includes lymphodepletion and a short course of high-dose aldesleukin (Proleukin), a recombinant form of human interleukin-2.

1. FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. News release. FDA. February 16, 2024. Accessed February 16, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma
2. FDA Approves First Cellular Therapy to Treat Patients with Unresectable or Metastatic Melanoma. News release. FDA. February 16, 2024. Accessed February 16, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma
3. Iovance’s AMTAGVI™ (lifileucel) Receives U.S. FDA Accelerated Approval for Advanced Melanoma. News release. Iovance. February 16, 2024. Accessed February 16, 2024. https://ir.iovance.com/news-releases/news-release-details/iovances-amtagvitm-lifileucel-receives-us-fda-accelerated
4. Sarnaik A. Lifileucel TIL cell monotherapy in patients with advanced melanoma after progression on immune checkpoint inhibitors (ICI) and targeted therapy: Pooled analysis of consecutive cohorts (C-144-01 study). Presented at: Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting November 8-12, 2022; Boston, Massachusetts. #789
5. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022;10:e005755. doi:10.1136/jitc-2022-005755
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