Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study

Abstract

BackgroundPatients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma.MethodsEligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1).ResultsThe Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD <median had greater likelihood of response than those with either (OR=2.08) or both (OR=4.42) risk factors. The most common grade 3/4 treatment-emergent adverse events (≥30%) were thrombocytopenia (76.9%), anemia (50.0%), and febrile neutropenia (41.7%).ConclusionsInvestigational lifileucel demonstrated clinically meaningful activity in heavily pretreated patients with advanced melanoma and high tumor burden. Durable responses and a favorable safety profile support the potential benefit of one-time lifileucel TIL cell therapy in patients with limited treatment options in ICI-refractory disease.

A twenty year perspective on melanoma therapy

“…Recent efforts to scale this approach with private sector investment have permitted clinical trials to be conducted by a significantly larger number of treatment centers. And, the same durable response rates, if not modestly higher, have been observed even among patients who have received and failed to response to immune checkpoint antibody therapy and BRAF inhibitor-based treatment (for those with BRAF-V600 mutations; Chesney et al, 2022). It is expected that this approach will receive FDA approval, permitted its more widespread use, though still somewhat limited to centers with the ability to manage highdose IL-2 toxicity.…”

Cell Immunotherapy against Melanoma: Clinical Trials Review

“…CR and PR were observed in 5% and 26% of patients, among those who responded to the treatment. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively [26].…”

Tumor-Infiltrating Lymphocyte and Other Cell Therapies for Metastatic Melanoma

“…Recently, a phase II study was published showing results of lifileucel in patients with advanced melanoma after several lines of therapy, including checkpoint inhibition and targeted therapies if BRAF mutated. 41 In this study, 153 sequentially enrolled patients, 66 from a previously reported cohort 42,43 with a longer follow-up and 87 newly reported patients, were pooled for analysis with a median of 3.0 lines of prior therapies. Of these, 81.7% had received both anti-PD-1 and anti-CTLA-4.…”

“…Moreover, another question that remains is whether TIL therapy would be as effective after pretreatment with anti–PD-1/anti–CTLA-4 combination therapy. Recently, a phase II study was published showing results of lifileucel in patients with advanced melanoma after several lines of therapy, including checkpoint inhibition and targeted therapies if BRAF mutated 41 . In this study, 153 sequentially enrolled patients, 66 from a previously reported cohort 42,43 with a longer follow-up and 87 newly reported patients, were pooled for analysis with a median of 3.0 lines of prior therapies.…”