Invited discussant of the C-144-01 study,1 Jason J. Luke, MD, Associate Professor of Medicine and Director of the Cancer Immunotherapeutics Center, University of Pittsburgh Hillman Cancer Center, Pittsburgh, noted that lifileucel is “clearly an active regimen in the post–PD-1/CTLA-4 setting and one that differentiates mechanistically from other systemic approaches.”
As Dr. Luke pointed out, for 10 years or so, tumor-infiltrating lymphocyte (TIL)-based therapy has been of interest as a potential treatment of melanoma. A meta-analysis of relapsed patients treated with lifileucel plus high-dose interleukin-2 (IL-2) showed the pooled overall objective response rate to be 43%, with a complete response rate of 14%.2 Of 28 complete responders, 27 remained in remission during follow-up, for a median of 40 months. Most of these patients were treated before the era of BRAF inhibitors and checkpoint blockade; in the post–PD-1 setting, a response rate of 23% has been reported, he added.
Jason J. Luke, MD
Dr. Luke emphasized the key findings of the current study: the “impressive” median duration of response (not reached at 33 months), the objective response rate of 36.5% (similar to the 29% seen with pembrolizumab plus low-dose ipilimumab post–PD-1 therapy), the greater activity among patients with less prior exposure to anti–PD-1, and responses among patients lacking PD-L1 expression. These findings raise questions about the mechanism of action of lifileucel, and they beg the question of the drug’s place—second or third line—in the treatment algorithm.
Also, aside from the lactate dehydrogenase level and duration of prior anti–PD-1 exposure (which impacted the duration of response), there is little to go on in terms of patient selection, noted Dr. Luke. “These points will be important as we think about how to use this therapy in the future.”
Potential Optimal Approach to Metastatic Melanoma
With another impressive treatment on the horizon—the LAG-3 blocker relatlimab, which was effective in combination with nivolumab in the RELATIVITY trial presented at the 2021 ASCO Annual Meeting3—Dr. Luke proposed that the following could be the optimal approach to metastatic melanoma: front-line treatment with nivolumab plus relatlimab; upon disease progression, TIL harvesting, followed by treatment with anti–PD-1 and low-dose anti–CTLA-4; upon further disease progression, manufacturing of lifileucel and infusion in patients fit enough to undergo lymphodepletion and IL-2.
DISCLOSURE: Dr. Luke holds stock or other ownership interests in Actym Therapeutics, Alphamab Oncology, Arch Oncology, Kanaph Therapeutics, Mavu Pharmaceutical, Onc.AI, Pyxis, and Tempest Therapeutics; has served as a consultant or advisor to 7 Hills Pharma, AbbVie, Alnylam, Alphamab Oncology, Astellas Pharma, Bayer, Bristol Myers Squibb, C-Stone Pharmaceuticals, Checkmate Pharmaceuticals, Crown Bioscience, Eisai, EMD Serono, Flame Biosciences, Genentech, Immunocore, Incyte, Inzen, Janssen, Kadmon, KSQ Therapeutics, Merck, Mersana, Nektar, Novartis, Partner Therapeutics, Pfizer, Reflexion Medical, Regeneron, Ribon Therapeutics, Rubius, Silicon Therapeutics, Spring Bank, Synlogic, Tempest Therapeutics, Tesaro, TRex Bio, Werewolf, Xencor, and Xilio; has received research funding from Agios, Array BioPharma, Astellas Pharma, BioNTech AG, EMD Serono, FStar, Genmab, Ikena Oncology, Immatics, Kadmon, KAHR Medical, Moderna Therapeutics, Nektar, Numab, Replimmune, Rubius Therapeutics, Scholar Rock, Spring Bank, Synlogic, Takeda, Tizona Therapeutics, and Trishula Therapeutics; has received institutional research funding from AbbVie, Bristol Myers Squibb, Corvus Pharmaceuticals, Incyte, MacroGenics, Merck, and Xencor; holds intellectual property in “Serial #15/612,657 (cancer immunotherapy)” and “Serial #PCT/US18/36052 (microbiome biomarkers for anti–PD-1/PD-L1 responsiveness: diagnostics, prognostic and therapeutic uses thereof); and has been reimbursed for travel, accommodations, or other expenses by Array BioPharma, Bristol Myers Squibb, EMD Serono, Janssen, Merck, Mersana, Novartis, Pyxis, Reflexion Medical, and Xilio.
REFERENCES
1. Larkin J, Sarnaik A, Chesney JA, et al: Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma. 2021 ASCO Annual Meeting. Abstract 9505. Presented June 4, 2021.
2. Dafni U, Michielin O, Lluesma SM, et al: Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma. Ann Oncol 30:1902-1913, 2019.
3. Lipson EJ, Tawbi HAH, Schadendorf K, et al: Relatlimab plus nivolumab versus nivolumab in first-line advanced melanoma. 2021 ASCO Annual Meeting. Abstract 9503. June 4, 2021.
