Despite the fact that we have made significant progress in metastatic melanoma with immune checkpoint inhibitors—now the standard of care—most patients experience disease progression and are left without approved treatments. There is a need for newer treatments with clinical benefit. Lifileucel, an adoptive cell therapy harnessing the power of tumor-infiltrating lymphocytes (TILs), is emerging as a promising option. We have known of the benefits of TIL therapy for many years. The current trial of lifileucel offers these benefits to a greater group of patients.

In the 33-month follow-up of the global phase II open-label C-144-01 trial, one infusion of lifileucel led to long-lasting responses in patients experiencing disease progression on or after anti–PD-1 therapy. The best outcomes seemed to be in patients who experienced rapid disease progression on checkpoint inhibitors, James M. Larkin, MD, PhD, of The Royal Marsden Hospital NHS Foundation Trust in London, reported at the 2021 ASCO Annual Meeting.¹ The study was simultaneously published in the Journal of Clinical Oncology.²

The best outcomes [with lifileucel] seemed to be in patients who experienced rapid disease progression on checkpoint inhibitors.

— James M. Larkin, MD, PhD

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“The median duration of response was not reached after a median follow-up of 33 months,” Dr. Larkin reported. “A shorter duration of prior anti–PD-1/L1 therapy seems to maximize the duration of response; thus, all newly diagnosed patients should be closely monitored for disease progression on anti–PD-1 therapy. Review of patients who responded indicates that perhaps early intervention at the time of initial disease progression may maximize benefit.”

The study’s senior investigator, Omid Hamid, MD, Chief of Research/Immuno-Oncology at The Angeles Clinic & Research Institute, a Cedars Sinai Affiliate, and Co-Director, Cutaneous Malignancy Program, Cedars-Sinai Cancer Center, emphasized the need for therapies beyond checkpoint inhibition. “Lifileucel has shown its benefit in this population,” he said, and improvements in manufacturing are widening its availability. “The success of lifileucel in metastatic melanoma emphasizes the importance of adoptive T-cell therapy. The current process makes TILs available to a greater population, given its central production process and quick turnaround.”

Omid Hamid, MD

Global Phase II C-144-01 Trial

Lifileucel is an autologous TIL-based therapy that uses tumor-tissue T cells capable of recognizing tumor antigens that can be expanded ex vivo and given back to the patient. It is produced from harvested tumor in a streamlined 22-day centralized manufacturing process and then infused (along with high-dose interleukin-2 [IL-2]) into the patient after nonmyelosuppressive lymphodepletion. Patients in the study received a mean number of 27 billion TILs.

The study included 165 patients with unresectable or metastatic melanoma who had received at least one prior systemic therapy; this included a PD-1–blocking antibody and, if the patient had BRAF V600–mutated disease, a BRAF inhibitor with or without a MEK inhibitor. Dr. Larkin presented results for Cohort 2, which included 66 patients who had received a mean of 3.3 prior therapies and had a high tumor burden at baseline.

Key Findings

The investigator-assessed objective response rate was 36.4%, including complete responses in 4.5% (three patients). At 33 months, the median duration of response was not reached (range, 3–38 months). More than 80% of patients had a reduction in tumor burden, and another 18% had a further tumor reduction after the April 2020 data cutoff, Dr. Larkin reported.

Target lesion reductions were seen across the range of total TIL cell doses and CD4+/CD8+ TIL ratios. The objective response rate was not predicted by any patient or clinical characteristic analyzed.

“Among responders, 79% had received prior ipilimumab, and 46% had received prior anti–PD-1 and anti–CTLA-4 combinations. Responses have continued to deepen over time; of note, most responses were seen at the time of the first scan. One partial response converted to a complete response 24 months after treatment with lifileucel,” Dr. Larkin said.

Dr. Hamid further noted: “A response rate of 36.5% is similar to that with anti–PD-1/CTLA-4 combinations in the second line but is even more striking when you realize that 79% of responders had received prior ipilimumab. Also, the majority of responders had PD-L1–negative disease and, more important, were primary refractory to checkpoint inhibition. The median duration of response has not been reached, and 70% of responders remain relapse-free at 12 months.”

“Although, in the study, the cumulative duration of prior anti–PD-1/L1 therapy was not associated with response rate, it was associated with the duration of response,” Dr. Larkin noted. For duration of therapy ≤ median (5.06 months) vs > median, the hazard ratio was 0.218 (confidence interval = 0.056–0.854), suggestive of statistical significance. According to the multivariate model, he added, “for each 6-month decrease in exposure to prior anti–PD-1/L1, the median duration of response to lifileucel was nearly doubled.”

In addition, the baseline level of lactate dehydrogenase (LDH) seemed to impact the duration of response. Those with LDH levels lower than or equal to the upper limit of normal were found to have a better duration of response (hazard ratio = 0.39).

More to Come

“Although early, promising data have been shown for the combination of lifileucel plus pembrolizumab in patients with checkpoint-naive melanoma,” Dr. Hamid added, referring to a phase II study, also reported at ASCO.³ In this study, treatment led to a disease control rate of 100%, an overall response rate of 85.7%, and a complete response rate of 42.9%. All responding patients remained in remission at cutoff, with the longest duration of response being 16.8 months.

Dr. Hamid commented: “Lifileucel should find a place as a second- or third-line therapy for patients with melanoma…. We await further clarity on the appropriate patients based on biomarker work.” 

DISCLOSURE: Dr. Larkin has received honoraria from Achilles Therapeutics, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Imugene, Incyte, iOnctura, Ipsen, Kymab, Merck Serono, MSD, Nektar, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Secarna, and Vitaccess; has served as a consultant or advisor to Achilles Therapeutics, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Imugen, Incyte, iOnctura, Ipsen, Kymab, Merck Serono, MSD, Nektar, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, Secarna, and Vitaccess; has received institutional research funding from Achilles Therapeutics, Aveo, Bristol Myers Squibb, Covance, Immunocore, MSD, Nektar, Novartis, Pfizer, and Roche; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Boston Biomedical, Bristol Myers Squibb, GSK, Incyte, Merck Serono, Novartis, Pfizer, Pierre Fabre, and Roche/Genentech. Dr. Hamid has received honoraria from Bristol Myers Squibb, Novartis, Pfizer, and Sanofi/Regeneron; has served as a consultant or advisor to Aduro, Akeso Biopharma, Amgen, BeiGene, BioAtla, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Idera, Immunocore, Incyte, Janssen, Merck, NextCure, Novartis, Pfizer, Regeneron, Roche, Sanofi, Seattle Genetics, Tempus, and Zelluna; has participated in a speakers bureau for Bristol Myers Squibb, Novartis, Pfizer, and Sanofi/Regeneron; and has received institutional research funding from Aduro Biotech, Akeso Biopharma, Amgen, Arcus Biosciences, BioAtla, Bristol Myers Squibb, CytomX Therapeutics, Exelixis, Genentech, GlaxoSmithKline, Idera, Immunocore, Incyte, Iovance Biotherapeutics, Merck, Merck Serono, Moderna Therapeutics, NextCure, Novartis, Pfizer, Regeneron, Roche, Sanofi, Seattle Genetics, Torque, and Zelluna.

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: Evaluation of impact of prior anti–PD-1 therapy. 2021 ASCO Annual Meeting. Abstract 9505. Presented June 4, 2021.

2. Sarnaik AM, Hamid O, Khushalani NI, et al: Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. May 12, 2021 (early release online).

3. Thomas SS, In GK, Doger B, et al: Safety and efficacy of lifileucel (LN-144), an autologous, tumor infiltrating lymphocyte cell therapy, in combination with pembrolizumab for immune checkpoint inhibitor naive patients with advanced melanoma. 2021 ASCO Annual Meeting. Abstract 9537. Presented June 4, 2021.