Lifileucel Melanoma BLA Delayed Until 2022

Maria Fardis, PhD, MBA

An anticipated biologics license application (BLA) for the tumor-infiltrating lymphocyte (TIL) therapy lifileucel (LN-144) will be delayed until 2022, according to Iovance Biotherapeutics, the company developing the therapy. The delay is due in part to regulatory feedback from the FDA regarding a lack of validation for the company's potency assays.

“TIL is a first-in-class, one-time administration cell therapy and the first potential BLA for a cell therapy in solid tumors,” Maria Fardis, PhD, MBA, president and chief executive officer, Iovance, said in a statement. “As such, TIL product is complex by nature and alignment with FDA on a potency assay is an important step toward BLA submission.

Lifileucel consists of autologous TILs that are harvested from tumor resections. The TILs are then expanded ex vivo and administered once enough cells have been reached. Prior to administration, patients received lymphodepleting chemotherapy and following infusion of the TILs up to 6 doses of high-dose IL-2, to support immune expansion and proliferation.

Iovance received a Regenerative Medicine Advanced Therapy (RMAT) designation from the FDA for the therapy in 2018, based on earlier data. The RMAT designation is intended for cell and gene therapies that address serious or life-threatening diseases and is based on promising preliminary evidence. "With a RMAT designation for lifileucel, FDA recognizes the unmet need for patients with metastatic melanoma who progress after anti-PD-1 therapy,” Fardis added.

In updated findings from cohort 2 of the phase 2 C-144-01 trial, which were presented during the virtual 2021 AACR Annual Meeting, lifileucel elicited an objective response rate of 36.4% with a median duration of response that was not yet reached at 28.1 months for patients with advanced melanoma. Patients had received multiple therapies prior to entering the study, including PD-1 inhibitors and targeted therapies, if appropriate.

The open-label C-144-01 trial consists of 4 cohorts, 3 of which are now closed to enrollment. Cohort 2, which was presented at AACR, included 66 patients with unresectable or metastatic melanoma. In this cohort of the study, the cells were cryopreserved in between manufacturing and administration.

At baseline, the 66 patients had a median age of 55 (range, 20-79), 56% had an ECOG performance status of 0, 68% had BRAF wild-type disease, and 35% were PD-L1–positive (tumor proportion score ≥5). The mean number of prior therapies was 3.3 (range, 1-9), which included anti–PD-1/PD-L1 therapy in all patients, anti–CTLA-4 therapy in 80%, and BRAF/MEK inhibition in 23%. The mean target lesion size was 10.6 cm in diameter (range, 1.1-34.3). Additionally, 77% had more than 3 target and non-target lesions and 42% had liver and/or brain lesions.

At the 28.1-month median follow-up for cohort 2, 4.5% of patients experienced a complete response and 31.8% had a partial response. Additionally, 43.9% had stable disease for a disease control rate of 80.3%.

No new safety risks were identified at the AACR assessment, and the number of treatment-emergent adverse events (TEAE) reduced over time. The most common TEAEs of any grade were thrombocytopenia (89.4%), chills (80.3%), anemia (68.2%), pyrexia (59.1%), neutropenia (56.1%), and febrile neutropenia (54.5%).

The most common grade 3/4 TEAEs were thrombocytopenia (81.8%), anemia (56.1%), febrile neutropenia (54.5%), and neutropenia (39.4%). Two patients experienced a grade 5 event due to intra-abdominal hemorrhage that was possibly due to TIL therapy in 1 patient and acute respiratory failure not related to TIL therapy in the second patient.