Second-line treatment with tumor-infiltrating lymphocytes (TILs) improves progression-free survival (PFS) compared with ipilimumab in patients with advanced, non-resectable stage 3-4 melanoma, results from an investigator-driven randomized phase 3 trial show.

Although immune checkpoint inhibitors and targeted therapies have profoundly improved outcomes for patients with (advanced) melanoma, approximately 50% still die from their disease within 5 years following stage IV diagnosis. Thus, there is a great unmet need for novel treatment options in this patient population. Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) is a (elaborative and time-consuming) treatment modality with promising response rates of 36% to 70% in heavily pre-treated patients with advanced melanoma, observed in multiple phase 1/2 trials [2,3].

Dr. John Haanen (Netherlands Cancer Institute) and colleagues performed the first investigator-driven, open-label, randomized-controlled, phase 3 clinical trial (NCT02278887) comparing treatments with TIL and ipilimumab. For the trial, 168 patients with unresectable, stage 3-4 cutaneous melanoma who had progression after one line of systemic treatment (no ipilimumab) were randomized to receive TIL treatment (single infusion of ≥5×109 TILs) or ipilimumab (3 mg/kg every 3 weeks, max 4 doses). About 90% of the patients had received prior anti-PD1 therapy. The primary endpoint of study was progression-free survival (PFS) in the intention-to-treat (ITT) population; secondary endpoints were overall and complete response rate (RR), overall survival (OS), and safety.

The trial met its endpoint: with a median follow-up of 33 months, median PFS was 7.2 months for patients randomized to TIL treatment versus 2.1 months for patients treated with ipilimumab (HR, 0.50; P<0.001). PFS rates at 6 months were 52.7% and 21.4%, respectively. TIL therapy was superior to ipilimumab in all pre-specified subgroups. ORR was 48.8% in TIL-treated patients (20.2% complete response) versus 21.4% in ipilimumab-treated patients (7.1% complete response). Immature OS data showed a trend in favor of TIL treatment; median OS was 25.8 months in TIL-treated patients versus 18.9 months in ipilimumab-treated patients (HR, 0.83; P=0.39). Safety of TIL treatment was manageable, and scores for health-related quality-of-life were significantly higher in TIL-treated patients during the 60 months of follow-up (mean difference at 6 months, 7.7; P<0.01).

“This first randomized phase 3 trial demonstrates that second-line TIL significantly improves PFS compared with ipilimumab in patients with unresectable, advanced melanoma,” Dr. Haanen stated. “Therefore, TIL could become a possible new treatment option for this population.”

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