In the phase 2 C-144-01 trial, patients had durable responses to treatment with the tumor-infiltrating lymphocyte lifileucel after more than 28 months of follow-up.
After more than 28 months of follow-up, the tumor-infiltrating lymphocyte (TIL) therapy lifileucel (LN-144) showed a positive objective response rate (ORR) with the median duration of response (DOR) not yet reached in pretreated patients with advanced melanoma who had received immune checkpoint inhibition, according to findings from a cohort of the phase 2 C-144-01 trial (NCT02360579) presented at the 2021 American Association for Cancer Research (AACR) Annual Meeting.1
“It is clear based on these data that lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma represents a viable therapeutic option warranting further investigation,” said Jason A. Chesney, MD, PhD, who presented the findings during the AACR meeting. Chesney is the chief of the Division of Medical Oncology and Hematology and director of the James Graham Bron Cancer Center, University of Louisville in Kentucky.
Currently, few treatment options exist for patients with advanced melanoma who are refractory to or develop resistance to an immune checkpoint inhibitor, including retreatment with immunotherapy or chemotherapy, and neither has a significant impact on response or survival.
Previously, autologous TIL therapy has had the most efficacy in melanomas and has demonstrated antitumor efficacy and durable complete responses (CRs) in patients with heavily pretreated metastatic melanoma.2
The C-144-01 trial was a global, open-label, multicohort, multicenter study of the centrally manufactured and cryopreserved autologous TIL therapy lifileucel in patients with unresectable or metastatic melanoma who have progressed on immune checkpoint inhibitors and BRAF/MEK inhibitors if the patient is BRAF-mutant.1
Patients were eligible if they had 1 tumor lesion (about 1.5 cm in diameter) resectable for TIL generation, at least 1 tumor lesion for assessment of response, aged 18 years old or older, and had an ECOG performance status of 0 or 1.
The study consisted of 4 cohorts, 3 of which are now closed to enrollment. Cohort 1 included treatment of 30 patients with a first-generation non-cryopreserved TIL therapy, cohort 2 included 66 patients who were treated with a second-generation cryopreserved TIL therapy, and 75 patients were included in the pivotal cohort and received treatment with a cryopreserved second-generation TIL product. The ongoing third cohort includes 10 patients who will receive re-treatment with a TIL therapy. During the AACR meeting, Chesney focused on findings from the second cohort.
Primary end point for the second cohort was investigator-assessed ORR by RECIST 1.1; the secondary end points included safety and other efficacy assessments.
At baseline, the 66 patients had a median age of 55 (range, 20-79) 59% were male, 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 median 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%.
Patients in the cohort also had a high tumor burden at baseline, Chesney pointed out, with a mean target lesion size of 10.6 cm in diameter (range, 1.1-34.3), 77% had more than 3 target and non-target lesions, and 42% had liver and/or brain lesions.
The process of manufacturing lifileucel consisted of tumor tissue procurement across various resection sites, and the tissue was then sent to the central manufacturing facility where the tissue was fragmented and the TILs were isolated and cultured ex vivo before being expanded, reinvigorated, harvested, and cryopreserved—a process which took 22 days to complete. The cryopreserved products were then shipped back to the treatment center where the patients received a nonmyeloablative lymphodepletion regimen of cyclophosphamide 60 mg/kg for 2 days followed by fludarabine 25 mg/m2 for 5 days. Then, lifileucel was infused followed by administration of up to 6 doses of a interleukin-2 (IL-2) at 600,000 U/kg every 8 to 12 hours for 2 to 4 days.
Lifileucel was successfully manufactured regardless of the organ site of the resected tumor, Chesney noted.
The median study follow-up was 28.1 months, at which point the ORR was 36.4%, which consisted of CRs in 4.5% and partial responses in 31.8%. Additionally, 43.9% had stable disease for a disease control rate of 80.3%. The median DOR was not reached (range, 2.2-35.2+ months).
Responses were observed in patients regardless of BRAF mutational status or tumor PD-L1 expression and were also seen in patients with various lactate dehydrogenase levels, baseline tumor burdens, the presence of liver and/or brain metastases, and in patients who previously received anti–CTLA-4 therapy or BRAF/MEK inhibition.
The response and disease control rates were consistent with that of prior reports from the cohort presented at the 2020 American Society of Clinical Oncology Annual Meeting.3 However, with extended follow-up, 17.7% of patients had further reduction in target lesion size since the prior data cutoff period. A total of 81% of evaluable patients had a reduction in their tumor burden.1
Of the 24 responders, 79% had previously received ipilimumab (Yervoy) and 4% had a partial response converted to a CR after 2 years following infusion with lifileucel; 49% of responders were still on the study at data cutoff.
Chesney noted that the target lesion sum diameter reduction was seen across the range of total TIL doses and that the investigators believed that the target lesion sum diameter reductions were seen across the range of TIL CD4-positive and CD8-positive cell doses.
At least 1 treatment-emergent adverse event (TEAE) was observed in all 66 patients and were of grade 3/4 in severity in 97%. Two patients experienced a grade 5 event due to intra-abdominal hemorrhage that was possibly due to TIL therapy in one patient and acute respiratory failure not related to TIL therapy in the second patient.
“The adverse event profile is manageable and consistent with the underlying advanced disease and known profiles of the nonmyeloablative lymphodepletion regimen and high-dose IL-2,” Chesney commented.
The most common any-grade TEAEs 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%).
No new safety risks were identified with the longer follow-up. Additionally, the number of TEAEs reduced over time.
“The decreasing frequency of adverse events over time supports the risk/benefit proposition of one-time therapy of lifileucel for these patients,” Chesney said.
1. Chesney JA, Larkin JMG, Kirkwood JM, et al. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up. Presented at: 2021 American Association for Cancer Research Annual Meeting; April 10-15, 2021; Virtual. Abstract CT008.
2. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550-4557. doi:10.1158/1078-0432.CCR-11-0116
3. Sarnaik A, Khushalani NI, Chesney JA, et al. Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies. J Clin Oncol. 2020;38(suppl 15):10006. doi:10.1200/JCO.2020.38.15_suppl.10006