Clinical trialPhase 3Melanoma (skin cancer)

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma

N Engl J Med · 2022168 patients

Rohaan MW, Borch TH, van den Berg JH, Met Ö, Kessels R, Geukes Foppen MH, et al. N Engl J Med. 2022. 387:2113-2125

Study type: Clinical trial
Study name: TIL (NKI/CCIT M14TIL)
Phase: Phase 3
Design: Multicentre, randomised, open-label (1:1) trial in the Netherlands and Denmark
Sample size: 168 patients
Source: N Engl J Med · 2022
Trial registration: NCT02278887

In plain words

In this approach, immune cells found in a tumour removed by surgery are multiplied in the laboratory into billions of cells and then given back to the patient. In patients most of whom had not responded to standard immunotherapy, this approach led to a response in nearly half of them. It is a demanding treatment that needs chemotherapy beforehand, a hospital stay and a specialist centre.

Key results

7.2 vs 3.1 months

Median progression-free survival

HR 0.50; 95% CI 0.35 to 0.72; P<0.001

49% vs 21%

Objective response

25.8 vs 18.9 months

Median overall survival

Drugs in this study:Cyclophosphamide (Endoxan)Ipilimumab (Yervoy)

Dose and schedule cards

TIL cell therapy (lifileucel; AMTAGVI)

Unresectable or metastatic melanoma after anti-PD-1 therapy and, with a BRAF V600 mutation, after a BRAF inhibitor with or without a MEK inhibitor; selected patients with good performance statusCycle length: OnceOn the page “Melanoma (skin cancer)” · Unresectable or metastatic melanoma: later lines

Unresectable or metastatic melanoma after anti-PD-1 therapy and, with a BRAF V600 mutation, after a BRAF inhibitor with or without a MEK inhibitor; selected patients with good performance status

Drug	Dose	Route	Schedule
Lymphodepletion
Cyclophosphamide (with mesna)	60 mg/kg	IV	Daily, 2 days
Fludarabine	25 mg/m²	IV	Daily, 5 days (after cyclophosphamide)
Cell infusion
Lifileucel (autologous TIL)	7.5×10⁹ to 72×10⁹ viable cells (single dose)	IV	24 hours to 4 days after the last fludarabine dose
After infusion
Interleukin-2 (aldesleukin)	600,000 IU/kg	IV	Every 8 to 12 hours, up to 6 doses; starting 3 to 24 hours after the infusion

Cycle length: Once
Duration: One-time treatment

Per the FDA label. Administer in a hospital with access to intensive care. Premedication: acetaminophen and an H1 antihistamine about 30 to 60 minutes before the infusion; avoid prophylactic systemic corticosteroids. Boxed warning: treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment; filgrastim from day 1 after the infusion until the ANC is above 1000/µL on 3 consecutive days; antimicrobial prophylaxis per institutional protocol. In the phase 3 trial, hospital-manufactured TIL was given after lymphodepletion with cyclophosphamide (2 days) and fludarabine (5 days), together with high-dose interleukin-2.

On the page “Melanoma (skin cancer)” · Unresectable or metastatic melanoma: later lines

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Tumour-infiltrating lymphocytes (TIL)

Resection of a metastatic lesion for TIL production; then non-myeloablative IV lymphodepleting chemotherapy (cyclophosphamide for 2 days, then fludarabine for 5 days), infusion of at least 5×10⁹ TIL cells, followed by high-dose interleukin-2 (84 patients). The exact doses of cyclophosphamide, fludarabine and interleukin-2 are not stated in the abstract or the trial registry (the FDA-approved regimen for lifileucel is given on the melanoma page).

2Ipilimumab

Ipilimumab 3 mg/kg IV, 4 cycles (84 patients).

Source of the regimen details: Abstract of the paper (ipilimumab 3 mg/kg; at least 5×10⁹ TIL cells) and ClinicalTrials.gov NCT02278887 (2 days of cyclophosphamide, 5 days of fludarabine; 4 cycles of ipilimumab). The exact doses of the lymphodepleting drugs and interleukin-2 are not stated in these sources.

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 to 75 years with unresectable stage IIIC or IV cutaneous melanoma (per the abstract), with a resectable metastatic lesion large enough (2 to 3 cm or more in total) for TIL production and other measurable disease, ECOG 0 or 1 and at most one prior line of systemic therapy (other than ipilimumab) for advanced disease; ocular or mucosal melanoma and adjuvant ipilimumab within the past 6 months were excluded (ClinicalTrials.gov). 86% of patients had anti-PD-1-refractory disease.

Endpoints

Primary outcome: progression-free survival. Secondary: objective response, overall survival and safety.

Safety and side effects

Grade 3 or higher treatment-related adverse events occurred in all patients in the TIL group (mainly myelosuppression from lymphodepleting chemotherapy) and in 57% of the ipilimumab group. This treatment requires hospital admission and specialist centres.

Clinical significance and place in guidelines

This was the first phase 3 trial to show the superiority of a cell therapy in a solid tumour. Hospital-produced TIL has become available in some European countries (such as the Netherlands). In the US, a different commercial TIL product (lifileucel) received FDA accelerated approval in 2024 based on a separate single-arm study.

Limitations

Open-label design; the comparator was ipilimumab, which is no longer an optimal standard second-line treatment; only patients with a tumour resectable for TIL production and good general condition were eligible; access and cost are limiting.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.