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Tumor-Infiltrating Lymphocyte Therapy vs Ipilimumab for Advanced Melanoma
Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma.
In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival.
A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression.
In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).
Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced MelanomaN. Engl. J. Med 2022 Dec 08;387(23)2113-2125, MW Rohaan, TH Borch, JH van den Berg, Ö Met, R Kessels, MH Geukes Foppen, J Stoltenborg Granhøj, B Nuijen, C Nijenhuis, I Jedema, M van Zon, S Scheij, JH Beijnen, M Hansen, C Voermans, IM Noringriis, TJ Monberg, RB Holmstroem, LDV Wever, M van Dijk, LG Grijpink-Ongering, LHM Valkenet, A Torres Acosta, M Karger, JSW Borgers, RMT Ten Ham, VP Retèl, WH van Harten, F Lalezari, H van Tinteren, AAM van der Veldt, GAP Hospers, MAM Stevense-den Boer, KPM Suijkerbuijk, MJB Aarts, D Piersma, AJM van den Eertwegh, JB de Groot, G Vreugdenhil, E Kapiteijn, MJ Boers-Sonderen, WE Fiets, FWPJ van den Berkmortel, E Ellebaek, LR Hölmich, ACJ van Akkooi, WJ van Houdt, MWJM Wouters, JV van Thienen, CU Blank, A Meerveld-Eggink, S Klobuch, S Wilgenhof, TN Schumacher, M Donia, IM Svane, JBAG Haanen
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The explosion in treatment options for metastatic melanoma over the past decade has centered on two general lines of attack: targeted therapy for patients who have a specific mutation in the BRAF gene and various forms of immunotherapy aimed towards increasing immune response to the tumor. This trial compared two different types of immunotherapy: ipilimumab, which is an anti-CTLA4 (cytotoxic T-lymphocyte antigen 4) antibody that received FDA approval in March 2011, and adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TILs). TIL therapy involves first extracting TILs from the patient’s own tumor and then expanding the TILs in culture using interleukin-2 (IL-2). The patient’s own TILs are depleted with chemotherapy and then the patient’s expanded TILs are returned to the patient, after which high-dose IL-2 is given. It is unsurprising that this regimen causes significant morbidity; 10% of the patients in the TILs arm of the trial spent time in the ICU, although none of the patients died from the regimen. However, side effects from TIL therapy are somewhat time-limited in that they mostly occur during the use of chemotherapy and high-dose IL-2. Ipilimumab has significant associated morbidity as well, and side effects from that regimen and other forms of immunotherapy may occur over a much longer period of time.
The study found an increased response with TILs compared with ipilimumab, with a 2-year overall survival of 54.3% in the TIL group and 44.1% in the ipilimumab group. The implications and significance of this result are hampered by the fact that, nowadays, ipilimumab is rarely given as single-agent therapy as a first-line agent, although it was the only effective immunotherapy agent approved by either the FDA or European Union authorities at the time this study was conceived around 2014. Ipilimumab is associated with both a lower response rate and an increased number of adverse events compared with pembrolizumab or nivolumab, which are more likely to be used as first-line agents today. For first-line treatment, the study is therefore comparing TIL therapy to a standard that is not currently being used. However, this study enrolled both patients having their initial melanoma treatment and patients who progressed on prior treatment. For patients who had been given either pembrolizumab or nivolumab prior to being enrolled in the trial but progressed on that regimen, the authors found TIL therapy to be an appropriate treatment option.
The study indicates that TIL therapy is effective in some patients with metastatic melanoma, with a 10% improved 2-year survival compared with ipilimumab. Some patients will respond to one regimen but not to another, and it is heartening to have another potential treatment option against melanoma. However, this regimen is far from the final answer, with a 2-year survival of just over 50%. Unfortunately, we still have a long road ahead in terms of fighting this deadly disease.
In this phase III trial, 168 patients with advanced melanoma refractory to anti–PD-1 therapy were randomized to receive tumor-infiltrating lymphocyte (TIL) therapy or ipilimumab 3 mg per kg for four cycles. Median progression-free survival was 7.2 months (objective response rate [ORR] of 49%) with TIL versus 3.1 months (ORR of 21%) with ipilimumab (HR, 0.50). Anti–CTLA-4 therapy with ipilimumab is frequently utilized in patients with PD-1–refractory melanoma who have not received it already, and TIL therapy has the potential to be considered the new standard of care in these patients. However, it is crucial to note that the trial patients had a much better prognosis than usual, with only 20% with elevated lactate dehydrogenase (LDH) levels at baseline — the trial did not permit LDH levels more than two times the upper limit of the normal range and only ECOG 0 to 1 and patients aged up to 75 years (median age was 59) were enrolled.
These eligibility restrictions removed many of the sickest patients with melanoma with large tumor burdens from the trial population and allowed a healthier group of patients who were able to wait the several weeks without treatment required for TIL therapy (given the time needed for surgical harvest and TIL expansion). Nevertheless, for patients with PD-1–refractory advanced melanoma aged under 75 years, with good performance status and near/normal LDH levels, referral to an academic center for TIL therapy should be strongly considered. TIL therapy may potentially become FDA-approved sometime in 2023 as well.