Lifileucel Recommendations in Solid Tumors Deliver Comprehensive Guidance

Recommendations on adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) that address the newly approved therapy lifileucel (Amtagvi) explore safe administration practices and optimal patient selection based on individual characteristics.¹

"Lifileucel is the first cell therapy approved for any solid tumor, so this is an exciting time. We’ve seen the promise of chimeric antigen receptor T-cell therapy and other therapies for hematologic cancers, but we’ve yet to see that promise come to solid tumors, [and] lifileucel is a huge step in that direction,” Allison Betof Warner, MD, PhD, stated.

Betof Warner is a medical oncologist with the Cutaneous Oncology Program and an assistant professor in the Department of Medicine, Division of Medical Oncology, at Stanford Medicine in California. She also serves as director of melanoma medical oncology and of solid tumor cellular therapy and is codirector of the Pigmented Lesion and Melanoma Program.

Not only are logistics addressed in the guidelines, but so is immediate decision-making about the safety of proceeding for particular patients, Betof Warner explained.

The sections of the guidelines, complete with detailed charts, included is charge considerations, patient selection considerations and preoperative assessments, a pre-nonmyeloablative lymphodepletion checklist, a cheat sheet for management of TIL regimen and potential complications, steps in TIL cell therapy and patient journey, and operational considerations for TIL cell therapy.¹

“We’ve tried to address most of the issues that we had when treating patients in the past to help others learn from our collective experience,” Betof Warner said about the new guidelines. The guidelines were based on 2 studies—the phase 2, multicenter C-144-01 trial (NCT02360579) and a randomized, open-label, phase 3 trial (NCT02278887) conducted by the Netherlands Cancer Institute^2,3—as well as accumulated data from the National Cancer Institute.⁴

Using these data resources, “the TIL Cell Therapy Working Group,
which is an international group of experts, created recommendations on how to safely implement this therapy at centers that have not yet done it,” Betof Warner said.

In the C-144-01 trial, 153 patients with advanced melanoma who progressed after immune checkpoint inhibitors and targeted therapy were evaluated. Patients received lifileucel therapy and had a median of 3 lines of prior therapy.

There were 8 patients who had a complete response and 40 patients with partial responses. The objective response rate was 31.4% (95%
CI, 24.1%-39.4%) and the median overall survival (OS) and progression-free survival (PFS) were 13.9 and 4.1 months, respectively. Results from a median study follow-up at 27.6 months showed that the median duration of response was not met; however, 41.7% of responses were maintained at 18 months or less.

In the trial, patients received 1×10⁹–150×10⁹ TIL cells that met the manufacturing product specification and demonstrated a favorable safety profile. The grade 3 and 4 adverse events (AEs) that were observed in 30% of patients were thrombocytopenia (76.9%), anemia (50.0%), and febrile neutropenia (41.7%).

The Netherlands Cancer Institute Study

In the trial conducted by the Netherlands Cancer Institute, 168 patients were randomly assigned to receive either TIL therapy (n = 84) or ipilimumab (Yervoy) (n = 84). Most patients (86%) were refractory to anti–PD-1 treatment.

At the median follow-up of 33 months, the median PFS was 7.2 months in the TIL arm (95% CI, 4.2-13.1) and 3.1 in the ipilimumab arm with an HR of 0.50% (95% CI, 0.35%-0.72%; P = .001).

The overall response rate was 49% (95% CI, 38%-60%) for the TIL arm and 21% for the ipilimumab arm (95% CI, 13%-32%), and complete responses were 20% (95% CI, 12%-30%) and 7% (95% CI, 3%-15%), respectively. The median OS was 25.8 months in the TIL arm (95% CI, 18.2-not reached) and 18.9 in the ipilimumab arm (95% CI, 13.8-2.6) with an HR of 0.83% (95% CI, 0.54%-1.27%; P = .39).

Enrolled patients had unresectable stage IIIC-IV melanoma; were aged 18 to 75 years; and were stratified by BRAF V600 mutation status, line of treatment, and center. Patients received infusion of 5 (or greater) ×10⁹ TIL, which was preceded by nonmyeloablative, lymphodepleting
chemotherapy with cyclophosphamide plus fludarabine and followed by high-dose interleukin-2.

Regarding safety data from the trial, 100% of patients in the TIL arm experienced grade 3 and 4 AEs compared with 57% of patients in the ipilimumab arm. The study’s primary end point was
PFS per RECIST 1.1, and secondary end points were overall and complete response rates, OS, and safety.

Lifileucel

Lifileucel is a treatment that has been in development at the National Cancer Institute since the late 1980s, Betof Warner explained. “It’s just over the last 5 years or so that lifileucel has become a reality as a commercial therapy broadly applicable to patients,” she said. Immune
checkpoint inhibitors and targeted therapies have made a difference for patients with advanced melanoma, improving outcomes. However, approximately half of patients don’t experience long-lasting benefits, and there has been a need for more options. Adoptive cell therapy with TIL is 1 such treatment that demonstrates promising response rates of 36% to 70% in patients with advanced melanoma.³

Clinical trials looking to expand on the efficacy and safety of adoptive cell therapy with TIL therapy include trials evaluating LYL845 (NCT05573035), which expands cells to create greater activity against cancers; this is currently available for lung and colorectal cancer. Trials evaluating IOV-4001 (NCT05361174), which uses an engineered TIL to improve treatment 3 efficacy, and OBX-115 (NCT05470283 and NCT06060613), which hopes to eliminate the need for administering interleukin-2, are also being explored and are currently available for enrollment. “Please consider referring patients early, because they will have much better outcomes and a safer treatment course,” Betof Warner said.

“One of the huge promises of adoptive cell therapy across the board is that it offers a 1-time treatment option to patients [and] has the potential for durable responses in that 1-time therapy treatment,” Betof Warner stated.

REFERENCES:
1. Betof Warner A, Hamid O, Komanduri K, et al. Expert consensus guidelines on management and
best practices for tumor-infiltrating lymphocyte cell therapy. J Immunother Cancer. 2024;12(2):e008735. doi:10.1136/jitc-2023-008735
2. Chesney J, Lewis KD, Kluger H, et al. 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. J Immunother Cancer. 2022;10(12): e005755. doi:10.1136/jitc-2022-005755
3. Haanen JBAG, Rohaan M, Borch TH, et al. Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: results from a multicenter, randomized phase III trial. Ann Oncol. 2022;33(suppl 7):S1406. doi:10.1016/j.annonc.2022.08.036
4. Lifileucel. National Cancer Institute. Updated March 26, 2024. Accessed April 8, 2024.