Lifileucel Demonstrates Long-Term Efficacy and Survival Benefit in Advanced, Pretreated Melanoma

The autologous tumor infiltrating lymphocyte (TIL) cell therapy lifileucel (LN-144) demonstrated clinically meaningful antitumor activity alongside early, durable responses in patients with advanced melanoma following progression on checkpoint inhibitors, supporting its use as a viable potential treatment option in this population, according to long-term findings from the phase 2 C-144-01 trial (NCT02360579) presented at the 2023 ESMO Immuno-Oncology Congress.¹

After 4 years of follow-up, patients from cohorts 2 and 4 of the study (n = 153) experienced a substantial reduction in tumor burden from baseline, with an objective response rate of 31.4% per independent review committee (IRC) assessment. The median time to best response for those who achieved a partial response or better was 1.5 months (range, 1.3-30.4). The longest duration of IRC-assessed response was ongoing at 55.8 months. Moreover, 4 patients converted to a complete response more than 1 year after treatment with lifileucel.

Additionally, the median duration of response (DOR) for all responders (n = 48) was not reached (NR; 95% CI, 8.3-NR). Further breakdown of DOR according to patterns of response showed that the median DOR was NR in early responders (n = 39; 95% CI, 6.1-NR), 19.8 (95% CI, 4.1-NR) in late responders (n = 9), 26.2 (95% CI, 4.1-NR) in responders without a deepened response (n = 32), and NR (95% CI, 8.3-NR) in responders with deepened responses (n = 16).

Assessment of long-term survival benefit revealed that the median overall survival (OS) was 13.9 months (95% CI, 10.6-17.8) among all patients, with a 4-year OS rate of 47.3 (95% CI, 32.5%-60.7%). Four-year OS rates according to patterns of response were 48.3% in early responders (95% CI, 31.9%-62.9%), 41.7% (95% CI, 10.9%-70.8%) in late responders, 37.2% (95% CI, 21.0%-53.5%) in responders without a deepened response, and 68.2% (95% CI, 39.5%-85.4) in responders with deepened responses.

“We consider these responses to be promising overall, in that they showed favorable long-term survival outcomes, durable responses, and long-term safety [with lifileucel],” lead study author Martin Wermke, MD, head of the Early Clinical Trial Unit of the National Center for Tumor Diseases Dresden at the University Hospital Carl Gustav Carus in Dresden, Germany, stated in an oral presentation of the data. "[As] responders are more likely to have lower tumor burden, it might be good to move this agent into earlier treatment lines or combine it with [another] regimen.”

A substantial portion of patients with advanced melanoma will develop resistance to immune checkpoint inhibitors, indicating a need for effective therapeutics post-progression. Moreover, there is a lack of extensive follow-up data in this setting. Autologous TIL cell therapy has emerged as a promising approach for this population. The one-time autologous TIL lifileucel has demonstrated enduring clinical benefits in patients with advanced melanoma who progressed on or after anti–PD-1/L1 therapy.

To further investigate lifileucel in this population, investigators designed the prospective, open-label, multicohort, multicenter C-144-01 trial. Previously reported findings from the study showed that the agent produced an IRC-assessed ORR of 31.4% (95% CI, 24.1%-39.4%) at a median follow-up of 36.5 months in a combined population of patients enrolled in cohorts 2 and 4.²

The current analysis included updated findings on treatment outcomes and patterns of response to lifileucel in cohorts 2 and 4.¹ Patients in cohort 2 were enrolled onto the study between April 2017 and January 2019; those in cohort 4 were enrolled between February 2019 and December 2019. Eligibility criteria, manufacturing, and treatment were the same for both cohorts. The data cutoff for the current analysis was June 30, 2023, and the median study follow-up was 48.1 months.

“This 4-year analysis represents the longest follow-up to date of patients treated with lifileucel TIL cell therapy in the post-immune checkpoint inhibitor setting for advanced melanoma,” Wermke noted during the presentation.

The study enrolled patients 18 years of age or older with unresectable or metastatic melanoma progressed on or after 1 or more prior lines of systemic therapy. This includes a PD-1 inhibitor and a BRAF inhibitor with/without a MEK inhibitor if patients express a BRAF V600 mutation. Patients were also required to have 1 or more resectable tumor lesions at least 1.5 cm in diameter for the manufacturing of cryopreserved lifileucel, and 1 or more target tumor lesions for RECIST 1.1 response assessment.

Tumor samples were obtained from each patient and cultured ex vivo to expand the population of TILs. Following lymphodepletion, patients received infusions of cryopreserved lifileucel followed by interleukin-2 (IL-2).³

The study’s primary end point was ORR. Secondary end points included DOR, disease control rate, progression-free survival, OS, and the incidence of adverse effects (AEs).

Of the 153 patients included on the study, 66 were in cohort 2 and 87 were in cohort 4.¹ The median age in the full analysis set was 56 years (range, 20-79).1 Positive PD-L1 expression (tumor proportion score ≥1%) was observed in 49.7% of patients, and lactate dehydrogenase (LDH) levels were at or below the ULN in 45.8% of patients. Liver and/or brain lesions by IRC were seen in 47.1% of patients, and the median sum of diameters for target lesions was 101.1 mm (range, 13.5-552.9). The percentage of patients with 3 or more baseline lesions at anatomic sites was 71.2% and 75.8% had more than 3 baseline target and nontarget lesions. The median number of prior lines of therapy was 3 (range, 1-9), and 71.2% of patients experienced primary resistance to prior anti–PD-1/L1 therapy. The majority of patients with advanced melanoma were heavily pretreated.

Notably, 56.3% of responders to lifileucel had lactate dehydrogenase (LDH) levels at or below the ULN, and 62.5% had over 3 baseline target and nontarget lesions. The median sum of diameter for target lesions for responders was 68.8 mm (range, 13.5-552.9).

The safety profile of lifileucel was consistent with the known profiles of nonmyeloablative lymphodepletion and IL-2. Notably, the incidence of treatment-emergent adverse effects (AEs) rapidly decreased within 2 weeks after lifileucel infusion. No new late-onset lifileucel-related serious AEs were reported.

The biologics license application seeking the approval of lifileucel in this patient population is currently under priority review by the FDA, with an updated PDUFA date of February 24, 2024.⁴

“These data have been submitted to the FDA, and we eagerly await their decision on whether lifileucel may become the first licensed cellular therapy to be approved for [this tumor type],” Wermke concluded.

Dr Wermke reports the following disclosures: received grants from Roche; received consulting fees from Immatics, Tacalyx, Boehringer; received support for meeting attendance/travel from Pfizer, Bristol-Myers-Squibb, Astra-Zeneca, Amgen, Gemoab, Sanofi, Immatics, Merck Serono, Janssen, Iovance; served on advisory boards for Bristol-Myers Squibb, Novartis, Lilly, Boehringer, ISA, Amgen, Immatics, Bayer, ImCheck; received honoraria from Lilly, Boehringer, SYNLAB, Janssen, Merck Serono, GWT, Amgen, Novartis.

References

1. Wermke M, Chesney J, Whitman E, et al. Long-term efficacy and patterns of response of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced melanoma: a 4-year analysis of the C-144-01 study. Ann Oncol. 2023;34(suppl 2):100589. doi:10.1016/iotech/iotech100589
2. Iovance Biotherapeutics announces updated clinical data for lifileucel in advanced melanoma at Society for Immunotherapy of Cancer (SITC) Annual Meeting. News release. Iovance Biotherapeutics. November 10, 2022. Accessed January 5, 2024. https://www.globenewswire.com/en/news-release/2022/11/10/2553619/0/en/Iovance-Biotherapeutics-Announces-Updated-Clinical-Data-for-Lifileucel-in-Advanced-Melanoma-at-Society-for-Immunotherapy-of-Cancer-SITC-Annual-Meeting.html
3. Study of lifileucel (LN-144), autologous tumor infiltrating lymphocytes, in the treatment of patients with metastatic melanoma (LN-144). ClinicalTrials.gov. Updated July 12, 2023. Accessed January 5, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT02360579
4. U.S. Food and Drug Administration updates Prescription Drug User Fee Act (PDUFA) action date for lifileucel for the treatment of advanced melanoma. Iovance Biotherapeutics. September 14, 2023. Accessed January 5, 2043. https://ir.iovance.com/news-releases/news-release-details/us-food-and-drug-administration-updates-prescription-drug-user