Rolling BLA Initiated by FDA for Lifileucel in Patients With Advanced Melanoma


A biologics license application for lifileucel has been initiated by the FDA following positive findings of the phase 2 C-144-01 trial in advanced melanoma.

A rolling submission of the biologics license application (BLA) for lifileucel (LN-144) was initiated to the FDA for patients with advanced melanoma who have progressed on/after prior anti-PD-1/PD-L1 therapy, and if BRAFmutation-positive, also prior BRAF or BRAF/MEK inhibitor therapy.1

The basis of the BLA comes from findings of the phase 2 C-144-01 trial (NCT02360579) which assessed the efficacy and safety of the tumor-infiltrating lymphocyte therapy lifileucel in this patient population.2

In cohort 4 (n = 87) of the multicenter, phase 2 study, lifileucel demonstrated an objective response rate (ORR) of 29% (95% CI, 19.5%-39.4%) per independent review committee (IRC) assessment and RECIST v1.1 criteria.2Three patients who responded to treatment achieved complete responses (CRs) and another 22 experienced partial responses (PRs). Further, at a median follow-up of 23.5 months, the median duration of response (DOR) in this cohort was 10.4 months.

“Initiating our rolling BLA submission for lifileucel is a significant step towards our goal to deliver the first individualized, one-time cell therapy for melanoma patients with significant unmet need. In parallel, we are executing our on-boarding and personnel training at authorized treatment centers, education and awareness initiatives, internal capacity planning, and launch readiness activities to prepare for commercialization,” said Frederick Vogt, PhD, JD, interim president and chief executive officer of Iovance, in a press release. “The FDA is supportive of our regulatory approach, and we look forward to continuing this collaboration throughout the submission and review process.”

The C-144-01trial is an open-label, multi-cohort study exploring lifileucel in adult patients with advanced melanoma. The study enrolled patients with unresectable or metastatic melanoma who had been treated with at least 1 prior systemic therapy, including an anti–PD-1 therapy and if BRAF mutation positive, BRAF/MEK inhibitors.3,4

Enrollment was open to patients aged 18 years and older with radiographic confirmation of progression, at least 1 resectable tumor lesion for TIL generation and at least one target lesion for response assessment, and an ECOG performance status of 0 to 1.

Patients were enrolled into 4 cohorts where cohort 1 examined patients treated with non-cryopreserved TIL product, generation, cohort 2 looked at patients treated with cryopreserved second-generation TIL product, cohort 3 looked at re-treatment with TIL therapy, and cohort 4 looked at patients treated with cryopreserved second-generation TIL product.

Those enrolled were predominantly male (59%) and had an ECOG score of 0 (56%). The median age of patients was 55 years (range, 20-79) and approximately a quarter of patients (26%) had BRAF V600E or V600K mutations with 68% being wild-type. Positive PD-L1 expression (tumor proportion score ≥5%) was observed in 35% of patients and LDH levels were above the ULN in 59% of patients. The mean number of lesions was 6, representing a high tumor burden and liver and/or brain metastases were reported in 42% of patients at baseline.

Further, the mean number of prior therapies was 3.3 (range, 1-9), 99% of patients had progression on anti–PD-1/PD-L1 therapy, and 77% had progressive disease on anti–CTLA-4.

In the trial, patients received a nonmyeloablative lymphodepletion regimen consisting of cyclophosphamide at a dose of 60 mg/kg once a day for 2 days followed by fludarabine at dose of 25 mg/m2 once a day for 5 days. Lifileucel was administered as a single infusion at about 24 hours from the last dose of fludarabine. Also, a short course of bolus interleukin-2 at 600,000 IU/kg was given to patients every 8 to 12 hours for up to 6 doses, starting within 3 to 24 hours of completing the infusion.

The primary objective of the trial was investigator-assessed objective response rate using RECIST v1.1 criteria with secondary end points consisting of DOR, overall survival, and safety.

Data from cohort 4 of the trial showed positive results, including an ORR of 29%, were supported by findings from cohort 2 (n = 66). Here, lifileucel elicited an ORR of 35% (95% CI, 23.5%-47.6%) per IRC. There were 5 patients who achieved CR and 18 with PRs. At a median follow-up of 36.6 months, the median DOR was not yet reached.

When patients were pooled from cohorts 2 and 4 (n = 153), lifileucel showed an ORR of 31% (95% CI, 24.1%-39.4%), and at a median follow-up of 27.6 months, the median DOR was also not yet reached.

Findings also revealed that patients in cohort 4 had higher disease burden at baseline compared with those in cohort 2. In cohort 4, a substantially higher proportion of patients (64.4%) had elevated lactate dehydrogenase levels at baseline vs cohort 2 (40.9%), and more baseline tumor lesions at 83.9% vs 65.2%, respectively.

In cohort 2, patients had about half of the cumulative duration of PD-1 therapy prior to lifileucel compared with patients in cohort 4. There was also a reduced duration of previous PD-1 therapy that was linked with an increase in DOR with lifileucel.

When evaluating safety, both cohorts had patients with treatment-emergent adverse effects which were noted to align with the underlying disease and the known safety profiles of nonmyeloablative lymphodepletion and IL-2. The safety findings were consistent between cohorts 4 and 2.

Additional data from the C-144-01 trial are expected to be presented at a medical conference later this year.

“Lifileucel represents hope and a new treatment for thousands of people with advanced melanoma who have very limited options after they progress on available standard of care,” said Kyleigh LiPira, chief executive officer of the Melanoma Research Foundation, in the press release. “Cell immunotherapies are revolutionizing cancer treatment, and we are excited about the potential for the first FDA-approved TIL cell therapy for the treatment of melanoma, which helps us take another step towards finding a cure.”

  1. Iovance Biotherapeutics initiates biologics license application (BLA) submission for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics, Inc. August 25, 2022. Accessed August 26, 2022.
  2. Iovance Biotherapeutics announces positive clinical data for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics, Inc. May 26, 2022. Accessed August 26, 2022.
  3. Study of lifileucel (LN-144), autologous tumor infiltrating lymphocytes, in the treatment of patients with metastatic melanoma (LN-144). Updated March 25, 2021. Accessed August 26, 2022.
  4. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39(24):2656-2666. doi:10.1200/JCO.21.00612
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