Lifileucel Shows Long-Term Efficacy in Melanoma

Martin Wermke, MD

A 4-year follow-up study evaluating the tumor infiltrating lymphocyte cell therapy lifileucel (LN-144) in patients with advanced melanoma showed durable efficacy and a 4-year overall survival (OS) rate of 21.9%, according to long-term findings from the phase 2 C-144-01 trial (NCT02360579) presented at the European Society for Medical Oncology (ESMO) Immuno-Oncology Congress 2023.¹

These findings led to an FDA approval for the cellular therapy in this patient population.²

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 (ORR) of 31.4% per independent review committee 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 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 months (95% CI, 4.1-NR) in late responders (n = 9), 26.2 months (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).

Long-Term Survival Benefit

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.

C-144-01 Trial

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 4.³

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 in 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. inhibitor with/without a MEK inhibitor if patients expressed 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 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).

Primary and Secondary End Points

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, 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 was observed in 49.7% of patients, and lactate dehydrogenase (LDH) levels were at or below the upper limit of normal (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 antiD- therapy. The majority of patients with advanced melanoma were heavily pretreated.

Notably, 56.3% of responders to lifileucel had 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.

The incidence of treatment-emergent AEs rapidly decreased within weeks after lifileucel infusion.

The researchers concluded that as responders had lower tumor burden, treating patients with advanced melanoma earlier in their disease course with lifileucel may increase likelihood of benefit from this one time therapy.

REFERENCES:

1. Wermke M, Chesney J, Whitman E, et al. Long-term efficacy and pa erns 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;20(suppl 1):100589. doi: 10.1016/iotech/iotech100589

2. FDA approves first cellular therapy to treat patients with unresectable or metastatic melanoma. News release. FDA. February 16, 2024. Accessed February 16, 2024. http://tinyurl. com/5n7cuszk

3. U.S. Food and Drug Administration updates Prescription Drug User Fee Act (PDUFA) action date for lifileucel for the treatment of advanced melanoma. News release. Iovance Biotherapeutics. September 14, 2023. Accessed January 5, 2043. https://tinyurl.com/2dmnj8dz