In a Dutch-Danish phase III trial reported in The New England Journal of Medicine, Rohaan et al found that tumor-infiltrating lymphocyte (TIL) therapy prolonged progression-free survival vs ipilimumab in patients with advanced melanoma. 

Study Details

The open-label trial included 168 patients (intention-to-teat [ITT] population) with unresectable stage IIIC or IV melanoma at Netherlands Cancer Institute or the National Center for Cancer Immune Therapy, Copenhagen University Hospital. They were randomly assigned between September 2014 and March 2022 to receive TIL therapy (n = 84) or ipilimumab at 3 mg/kg every 3 weeks for four doses (n = 84). Patients in the TIL group underwent metastasectomy for retrieval and expansion of TILs followed by nonmyeloablative lymphodepleting chemotherapy with cyclophosphamide and fludarabine; a single infusion of at least 5 × 10⁹ TILs was administered, followed by high-dose interleukin-2. Stage IV disease was present in 98% of patients in both groups. Among the 168 patients, 86% had disease refractory to anti–PD-1 therapy. The primary outcome measure was progression-free survival in the ITT population.

Progression-Free Survival

At data cutoff in June 2022, median follow-up was 33.0 months. Median progression-free survival was 7.2 months (95% confidence interval [CI] = 4.2–13.1 months) in the TIL group vs 3.1 months (95% CI = 3.0–4.3 months) in the ipilimumab group (hazard ratio [HR] = 0.50, 95% CI = 0.35–0.72, P < .001). Rates at 6 months were 52.7% (95% CI = 42.9%–64.7%) vs 21.4% (95% CI = 14.2%–32.2%).

Objective response on Response Evaluation Criteria in Solid Tumors version 1.1 was observed in 49% vs 21% of patients, with complete response in 20% vs 7%. Stable disease was achieved in an additional 16% vs 15% of patients; clinical benefit rates were 68% vs 39%.

Median overall survival was 25.8 months (95% CI = 18.2 months to not reached) in the TIL group vs 18.9 months (95% CI = 13.8–32.6 months) in the ipilimumab group (HR = 0.83, 95% CI = 0.54–1.27). Rates at 2 years were 54.3% (95% CI = 43.9%–67.2%) vs 44.1% (95% CI = 33.6%–57.8%).  

Adverse Events

Among 80 patients in the TIL group who received TIL therapy and 82 patients in the ipilimumab group who received at least one dose, treatment-related grade ≥ 3 adverse events occurred in 100% vs 57%. Events in the TIL group were dominated by chemotherapy-associated myelosuppression—eg, decreased neutrophils in 100% of patients, decreased platelets in 89%, and febrile neutropenia in 86%. The most common adverse events related to TIL/interleukin-2 were febrile neutropenia (74%), hypophosphatemia (60%), and fever (45%); the most common related to ipilimumab were colitis (20%), diarrhea (15%), and elevated alanine aminotransferase (10%).

Treatment-related serious adverse events occurred in 15% vs 27% of patients. In the TIL group, capillary leak syndrome of any grade related to interleukin-2 occurred in 30% of patients. Autoimmune toxic effects leading to skin hypopigmentation occurred in 11% of patients; uveitis occurred in 8% and hearing impairment was seen in 4%. Adverse events led to death in one patient in the TIL group, due to arterial thromboembolism considered unrelated to treatment.

The investigators concluded, “In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab.”

John B.A.G. Haanen, MD, PhD, of Netherlands Cancer Institute, Amsterdam, and Inge Marie Svane, MD, PhD, of Copenhagen University Hospital, Herlev, are the corresponding authors for The New England Journal of Medicine article.

Disclosure: The study was funded by the Dutch Cancer Society, Danish Cancer Society, and others. For full disclosures of the study authors, visit nejm.org.