FDA Approval Sought for Lifileucel in Unresectable or Metastatic Melanoma

Frederick Vogt, PhD, JD

Iovance Biotherapeutics has submitted a rolling biologics license application (BLA) to the FDA seeking the approval of the tumor infiltrating lymphocyte (TIL) therapy lifileucel (LN-44) for the treatment of patients with advanced unresectable or metastatic melanoma who progressed on or after prior anti–PD-1/L1 therapy and targeted therapy.¹

The BLA is supported by data from 153 patients with advanced melanoma enrolled in cohort 2 (n = 66) and cohort 4 (n = 87) of the phase 2 C-144-01 trial (NCT02360579).²

At a median follow-up of 36.5 months, findings showed that these patients experienced an overall response rate (ORR) of 31.4% (95% CI, 24.1%-39.4%) per independent review committee assessment by RECIST v1.1 criteria. Nine patients achieved a complete response (CR) and 39 had a partial response (PR). The median time from lifileucel infusion to best response was 1.5 months, and 7 patients who initially had a PR improved to a CR in the approximate 10 months following the initial analysis of the data.

“Completing our BLA submission for lifileucel is a critical step forward in our journey to deliver the first individualized, one-time cell therapy for a solid tumor. I would like to acknowledge the patients and physicians who participated in the C-144-01 clinical trial and the FDA review team for their commitment and support, as well as our internal team for their tremendous effort in completing the first BLA submission for Iovance,” Frederick Vogt, PhD, JD, interim president and chief executive officer of Iovance Biotherapeutics, stated in a news release.¹

“Our preparations for commercialization remain on track to support a launch later this year. We look forward to continued collaboration with the FDA as they review this new class of treatment for advanced melanoma patients with limited options.”

In April 2022, the FDA delivered positive feedback regarding the company’s proposed matrix of potency assays for the BLA seeking the approval of lifileucel in the treatment of patients with metastatic melanoma.³ In August 2022, Iovance submitted a rolling BLA for lifileucel to the regulatory agency.⁴

However, in November 2022, the company announced it received FDA feedback regarding supplemental assay validation information and comparability data for lifileucel, and it planned to complete the rolling submission in the first quarter of 2023.⁵

“Melanoma Research Alliance [MRA] congratulates Iovance for completing the BLA submission and moving closer toward making TIL therapy an option for people with advanced melanoma who have progressed following prior treatments,” Marc Hurlbert, PhD, chief executive officer of the MRA, stated in a news release.¹ “We hope for an FDA approval as quickly as possible for patients with significant unmet need who have no approved treatment options.”

C-144-01 enrolled patients at least 18 years of age with unresectable or metastatic melanoma who must have progressed on at least 1 prior systemic therapy that included a PD-1 inhibitor.⁶ Patients with a BRAF V600 mutation must also have received a prior BRAF inhibitor with or without a MEK inhibitor. Other key inclusion criteria included at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and a life expectancy of at least 3 months.

Key exclusion criteria receipt of an organ allograft or prior cell transfer therapy; melanoma of uveal/ocular origin; symptomatic and/or untreated brain metastases; or chronic systemic steroid therapy.

Enrolled patients underwent nonmyeloablative lymphodepletion with cyclophosphamide at 60 mg/kg once daily for 2 days followed by fludarabine at 25 mg/m² once daily for 5 days.⁷ Lifileucel was thawed and administered as a single infusion at 1 x 10⁹ to 150 × 10⁹ cells approximately 24 hours from the last dose of fludarabine. A short course of bolus interleukin-2 (IL-2) at 600,000 IU/kg was infused every 8 to 12 hours for up to 6 doses, starting within 3 to 24 hours after lifileucel infusion.

Investigator-assessed ORR served as the trial’s primary end point. Secondary end points included duration of response (DOR), disease control rate, overall survival (OS), and safety.

In cohorts 2 and 4, the median of 3 prior lines of therapy (range, 1-9), including anti–PD-1 therapy in 100% of patients with a median of 2 lines (range, 1-7).² Other prior therapies included anti–CTLA-4 therapy (81.7%), and prior combination anti–PD-1 and anti–CTLA-4 therapy (53.6%).

Baseline disease characteristics were generally similar between the 2 cohorts, although those in cohort 4 had both a higher disease burden with more than 3 lesions (83.9% in cohort 4 vs 65.2% in cohort 2) and a higher proportion of patients with elevated lactate dehydrogenase (64.4% in cohort 4 vs 40.9% in cohort 2).

Additional updated data from cohorts 2 and 4 showed that the median DOR was not yet reached (NR), and 41.7% of responses lasted for at least 24 months (47.8% in cohort 2 and 36.0% in cohort 4). The median OS was NR (95% CI, 30.4 months–NR) in patients who experienced a response at first assessment at 6 weeks. All patients achieved a median OS of 13.9 months (95% CI, 10.6-17.8).

Furthermore, responses were observed across all subgroups, including patients with immune checkpoint inhibitor primary–resistant disease and those who received prior anti–CTLA-4 therapy and/or targeted therapies.

Regarding safety, treatment-emergent adverse effects (TEAEs) were consistent with the underlying disease and known AE profiles of nonmyeloablative lymphodepletion and IL-2. Rates of TEAEs decreased within the first 2 weeks following lifileucel infusion.

References

1. Iovance Biotherapeutics completes biologics license application (BLA) submission for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics. March 24, 2023. Accessed March 27, 2023. https://ir.iovance.com/news-releases/3/2023
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 March 27, 2023. https://ir.iovance.com/news-releases/11/2022
3. Iovance Biotherapeutics announces regulatory and clinical updates for lifileucel in melanoma. News release. Iovance Biotherapeutics. April 5, 2022. Accessed March 27, 2023. https://ir.iovance.com/news-releases/4/2022
4. Iovance Biotherapeutics initiates biologics license application (BLA) submission for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics. August 25, 2022. Accessed March 27, 2023. https://ir.iovance.com/news-releases/8/2022
5. Iovance Biotherapeutics provides update on biologics license application submission for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics. November 18, 2022. Accessed March 27, 2023. https://ir.iovance.com/news-releases/11/2022
6. Study of lifileucel (LN-144), autologous tumor infiltrating lymphocytes, in the treatment of patients with metastatic melanoma (LN-144). ClinicalTrials.gov. Updated March 25, 2021. Accessed March 27, 2023. https://www.clinicaltrials.gov/ct2/show/NCT02360579
7. 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