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Tumor-Infiltrating Lymphocyte Therapy Gets Positive FDA Feedback for Melanoma

Iovance plans to complete BLA submission for lifileucel by August 2022.

Iovance Biotherapeutics has received positive feedback from the FDA regarding their proposed potency assay and cell co-culture assays for its upcoming Biologics License Application (BLA) for lifileucel (LN-144) for the potential treatment of metastatic melanoma.1

“The favorable feedback received from the FDA on our potency assays and assay matrix brings Iovance a step closer to our submission of a BLA for lifileucel in metastatic melanoma,” Frederick Vogt, PhD, JD, interim president and chief executive officer, Iovance Biotherapeutics, said in a statment. “We look forward to bringing lifileucel to the market quickly to offer [patients with] melanoma a new option following anti–PD-1 therapy.”

The company expects to request a pre-BLA meeting in July 2022 and to complete BLA submission for lifileucel by August 2022.

Lifileucel is being evaluating in the prospective, open-label, multicohort, nonrandomized, multicenter phase 2 IOV-COM-202 trial (NCT03645928) in combination with pembrolizumab (Keytruda) in patients with immune checkpoint inhibitor–naïve advanced melanoma.2

The IOV-COM-202 trial is currently recruiting patients of at least 18 years of age that have received 3 lines or less of prior systemic therapy, have an ECOG performance status of 0 or 1, have at least 1 resectable lesion, and at least 1 measurable lesion following resection for response assessment.

Lifileucel is a tumor-infiltrating lymphocyte (TIL) therapy manufactured at centralized GMP facilities as part of a 22-day process. Patients receive non-myeloablative lymphodepletion chemotherapy with cyclophosphamide and fludarabine before infusion with up to 6 doses of interleukin-2. The first dose of pembrolizumab was given following tumor harvest and the agent was continued every 3 or 6 weeks following lifileucel.

The trial is primarily assessing objective response rate (ORR) according to RECIST v1.1 criteria as well as safety via grade 3 or higher treatment-emergent adverse effects (TEAEs).

The trial has enrolled 7 patients to cohort 1a as of the data cutoff date of April 29, 2021. Patients had a median age of 52.0 years (range, 34-59), 85.7% were female, 71.4% had an ECOG performance status of 0, and 85.7% had stage IV disease. Approximately 29% (28.6%) of patients received 1 prior line of systemic treatment, which could have included chemotherapy (14.3%), targeted therapy in the form of BRAF/MEK inhibition (14.3%), or other (14.3%).

Regarding BRAF mutational status, 14.3% had mutated V600E or V600K, 42.9% had wild-type disease, 14.3% had unknown status, and 28.6% had other status. Moreover, 57.1% of patients had a PD-L1 tumor proportion score of 5% or higher, 28.6% were PD-L1 negative, and 14.3% of patients had this information missing. Just under half, or 42.9%, of patients had elevated lactate dehydrogenase levels. Patients had high tumor burden with a mean sum of diameters of target lesions was 111.4 mm, and 85.7% of patients had more than 3 target and non-target lesions at baseline.

Previous data has demonsrated efficacy of the pembrolizumab/lifileucel combination. Data presented during the 2021 ASCO Annual Meeting showed that at a median follow-up of 8.2 months, the combination yielded an ORR of 85.7%, which included a complete response (CR) rate of 42.9% and a partial response (PR) rate of 42.9%. One patient achieved stable disease with the regimen and disease control rate was 100%.

The safety profile of the combination proved to be consistent with the underlying disease and the known profiles of pembrolizumab, non-myeloablative lymphodepletion, and IL-2. Notably, no unexpected toxicities were reported with pembrolizumab following TIL therapy.

Any-grade toxicities experienced with the combination included thrombocytopenia (100%), chills (85.7%), nausea (85.7%), pyrexia (85.7%), vomiting (85.7%), fatigue (71.4%), febrile neutropenia (71.4%), hypertension (57.1%), neutropenia (57.1%), alopecia (42.9%), cough (42.9%), decreased appetite (42.9%), and peripheral edema (42.9%).

The grade 3 or 4 effects reported with the regimen comprised thrombocytopenia (85.7%), pyrexia (28.6%), fatigue (14.3%), febrile neutropenia (71.4%), hypertension (57.1%), neutropenia (57.1%), and peripheral edema (14.3%).

Updated data on 12 patients in cohort 1A showed that the combination produced an ORR of 67%; this included 3 CRs and 5 PRs. Moreover, 6 of the 8 responders were noted to have continued response to treatment at the time of the last data cutoff, with 5 responders experiencing a duration of response of longer than 1 year.

Iovance has shared plans to open a phase 3 study examining frontline lifileucel in combination with pembrolizumab in patients with immune checkpoint inhibitor–naïve metastatic melanoma in late 2022.

References
  1. Iovance Biotherapeutics announces regulatory and clinical updates for lifileucel in melanoma. News release. Iovance Biotherapeutics, Inc.; April 5, 2022. Accessed April 6, 2022. https://yhoo.it/3v2BYJ4
  2. 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 naïve patients with advanced melanoma. J Clin Oncol. 2021;39(suppl 15):9537. doi:10.1200/JCO.2021.39.15_suppl.9537