Tumour-infiltrating lymphocytes improve progression-free survival in previously treated advanced melanoma patients
To date, there remains a great unmet need for additional effective treatment options for patients with stage IIIC/IV advanced melanoma. Tumour-infiltrating lymphocytes (TILs) therapy recently demonstrated to significantly improve the progression-free survival compared to ipilimumab in patients with previously treated advanced melanoma. Interestingly, the vast majority of patients in this study were anti-PD-1 refractory, making TILs a potentially new treatment option for this challenging patient population.
Immune checkpoint inhibitors and targeted therapies have dramatically improved the outcome of patients with advanced melanoma. Nowadays, a treatment with anti-PD-1 antibodies has become one of the preferred first-line treatment options in the advanced, unresectable setting, whereas adjuvant anti-PD1 for one year is standard of care for patients with stage III melanoma. Nevertheless, approximately half of the patients still dies from their melanoma within five years from the diagnosis of stage IV disease, underscoring the need for additional effective treatment options. In recent years, evidence has emerged on the clinical potential of administering tumour-infiltrating lymphocytes (TIL) in this setting. Subsequent phase I/II trials have shown encouraging results, even in heavily pre-treated patients but the role of TIL treatment in the current treatment landscape for patients with advanced melanoma remains undefined.
In the presented multicentre, open-label phase III trial, patients with unresectable stage IIIC-IV melanoma (7th edition), ≥18 and ≤ 75 years, were randomised (1:1) to TIL therapy or ipilimumab (3 mg/kg Q3W, max 4 doses). Patients were required to have progression of disease after maximum one line of systemic treatment (which could not be ipilimumab). Patients were stratified according to BRAFV600 mutation status, treatment line and centre. Patients randomised to TIL underwent resection of a melanoma lesion (2-3 cm) for the ex vivo outgrowth and expansion of tumour resident T cells. The actual infusion with ≥5x109 of TILs was preceded by non-myeloablative, lymphodepleting chemotherapy consisting of cyclophosphamide + fludarabine, followed by high-dose interleukin-2. The primary endpoint of the trial was progression-free survival (PFS) per RECIST 1.1, with overall and complete response rate (ORR, CR), overall survival (OS) and safety as secondary objectives.
Of the 168 patients enrolled in the M14TIL trial, 86% were refractory to anti-PD-1 treatment. Most patients (82%) had a WHO performance status of 0 and an LDH level below the upper limit of normal (80%). After a median follow-up of 33.0 months, the median PFS was reported at 7.2 months for patients treated with TILs, as compared to 3.1 months in the ipilimumab arm. As such, patients randomised to TIL therapy had a 50% reduction in disease progression or death as compared to standard-of-care treatment (HR[95%CI]: 0.50[0.35-0.72], p< 0.001). The six-month PFS rate was 52.7% for TIL vs. 21.4% with ipilimumab. The ORR reached 48.8% with the TIL therapy as compared to 21.4% for ipilimumab, with corresponding CR rates of 20.2% and 7.1%, respectively. The median OS with the TIL therapy was 25.8 months vs. 18.9 months for ipilimumab (HR[95%CI]: 0.83[0.54-1.27], p= 0.39). Grade ≥3 treatment-related adverse events were reported in all patients receiving TIL and in 57% of those receiving ipilimumab. However, side-effects to the TIL therapy were generally well manageable and most of them had resolved by the time the patients left the hospital after their infusion. Finally, health-related quality of life scores were higher in patients treated with TIL.
This multicentre, phase III trial is the first randomised trial investigating T-cell therapy in solid tumours. The study compared TIL therapy to ipilimumab as a new second line standard of care in patients with metastatic melanoma. TILs significantly improved PFS compared to ipilimumab in patients with advanced melanoma refractory to anti-PD-1 therapy. No new safety issues were observed. These findings raise hope for improved treatment and potential cure for patients with a wide range of metastatic solid tumours.
Haanen J, et al. Treatment with tumor-infiltrating lymphocytes (TIL) versus ipilimumab for advanced melanoma: Results from a multicenter, randomized phase III trial. Presented at ESMO 2022; Abstract LBA3.