Based on the findings, investigators are considering registration with the FDA and EMA.
This article was originally published on our sister site, Cancer Network.
A tumor-infiltrating lymphocyte (TIL) therapy manufactured at various centers in the Netherlands Cancer Institute demonstrated a 50% reduction in the risk of progression or death compared with ipilimumab (Yervoy) for patients with stage IIIC/IV unresectable, treatment-refractory melanoma, according to findings from the randomized phase 3 M14TIL trial (NCT02278887) presented at 2022 European Society for Medical Oncology (ESMO) Congress.
After a median follow-up of 33.0 months, median progression-free survival (PFS) with the TIL therapy was 7.2 months (95% CI, 4.2-13.1) compared with 3.1 months for ipilimumab (95% CI, 3.0-4.3), which was statistically significant (HR, 0.50; 95% CI, 0.35-0.72; P < .001). The 6-month PFS rate was 52.7% with the TIL therapy compared with 21.4% for ipilimumab.
“This is the first multicenter, randomized, controlled trial studying a T-cell therapy in solid cancer, in this case comparing TIL to ipilimumab as more or less a second-line treatment for metastatic melanoma. TIL significantly improved PFS,” lead investigator John Haanen, MD, PhD, Netherlands Cancer Institute in Amsterdam, said in a press conference at the meeting.
In the open-label study, which was initiated in 2014, 168 patients were randomized to receive TILs (n = 84) or ipilimumab (n = 84). Most patients were refractory to a prior anti-PD-1 therapy (86%). Patients were evenly stratified by BRAF status, treatment line, and treatment center. LDH was 2 times or below the upper limit of normal, and all patients had a WHO performance status between 0 and 1.
For those in the TIL arm, the adoptive cell therapy was manufactured from a resected lesion of 2 to 3 cm in size. TILs were collected from the resected tissue and then expanded ex vivo using anti-CD3, feeder cells, and interleuken-2 (IL-2) until they reached at least 5 × 109 cells per infusion.
“The patients undergo surgery and the [TILs are grown] in the time needed for patients to recover from that, because we need a metastatic lesion to grow the TIL. If it is a subcutaneous nodule, it is easy, but if it is a lung nodule, it can be a bigger surgery. The time to grow the cells takes 5 to 6 weeks,” he said. “The total period of treatment consists of 8 weeks, more or less.”
Prior to infusion of the autologous T-cell product, patients received lymphodepleting cyclophosphamide for 2 days at 60 mg/kg/day and 5 days of fludarabine at 25 mg/m2/day. High-dose IL-2 (600,000 IU/kg/dose) was administered every 8 hours following infusion with the TILs to support proliferation. Hospitalization was required throughout this process. In the ipilimumab arm, the CTLA-4 inhibitor was administered at 3 mg/kg every 3 weeks for up to 4 doses.
The overall response rate was 48.8% with the TIL therapy (95% CI, 38%-60%) compared with 21.4% for ipilimumab (95% CI, 13%-32%). The complete response rate was 20.2% for patients treated with the TIL therapy (95% CI, 12%-30%) compared with 7.1% for ipilimumab (95% CI, 3%-15%). An additional 19.1% of patients experienced stable disease in the TIL arm compared with 17.9% in the ipilimumab group, bringing the clinical benefit rates to 67.9% and 39.3% in each arm, respectively.
The median OS was 25.8 months with TILs (95% CI, 18.2-not reached) vs 18.9 months with ipilimumab (95% CI, 13.8-32.6); however, these data were not yet statistically significant with follow-up ongoing (HR, 0.83; 95% CI, 0.54-1.27; P = .39).
Grade 3 or greater treatment-related adverse events were experienced by all patients in the TIL arm compared with 57% of patients in the ipilimumab group. Most of these events were related to IL-2 and the conditioning regimen, Haanen noted.
“There were no new safety concerns with TIL beyond what is known for this treatment. All of these toxicities are driven by the lymphodepleting regimen and the high-dose IL-2. Most of these side effects were already completely gone by the time the patients were released from the hospital and there were no long-term sequelae in patients treated with TILs,” he said. “There was also better health-related quality of life scores in patients treated with TIL.”
The study was conducted in collaboration with the Ministry of Health, Welfare, and Sport in the Netherlands. With this collaboration, it was agreed that if the study was positive, the treatment would become a standard of care in the Netherlands by January 2023, according to Haanen. Beyond that, EMA and FDA registration would be required, he said, which they are currently considering.
“If it gets EMA approval, the next question is how to roll it out,” he said. “At this point, you could involve pharma to do this or train other centers on the protocol to do point-of-care productions.”
For more coverage of ESMO 2022, click here.