Article
作者: Nuijen, Bastiaan ; Stoltenborg Granhøj, Joachim ; van Thienen, Johannes V. ; van den Eertwegh, Alfons J.M. ; Meerveld-Eggink, Aafke ; Retèl, Valesca P. ; van Harten, Wim H. ; Valkenet, Ludy H.M. ; van der Veldt, Astrid A.M. ; Piersma, Djura ; Jedema, Inge ; Schumacher, Ton N. ; Hansen, Marten ; van Zon, Maaike ; Svane, Inge Marie ; Haanen, John B.A.G. ; Fiets, W. Edward ; Noringriis, Inge M. ; van den Berkmortel, Franchette W.P.J. ; Wilgenhof, Sofie ; ten Ham, Renske M.T. ; van Dijk, Marloes ; Torres Acosta, Alejandro ; van Houdt, Winan J. ; Holmstroem, Rikke B. ; Karger, Matthias ; Met, Özcan ; Kessels, Rob ; Voermans, Carlijn ; Nijenhuis, Cynthia ; Hospers, Geke A.P. ; Ellebaek, Eva ; Aarts, Maureen J.B. ; Blank, Christian U. ; Grijpink-Ongering, Lindsay G. ; Borch, Troels H. ; van den Berg, Joost H. ; Stevense-den Boer, Marion A.M. ; van Tinteren, Harm ; Klobuch, Sebastian ; Monberg, Tine J. ; Beijnen, Jos H. ; Lalezari, Ferry ; Suijkerbuijk, Karijn P.M. ; Kapiteijn, Ellen ; Vreugdenhil, Gerard ; de Groot, Jan-Willem B. ; van Akkooi, Alexander C.J. ; Rohaan, Maartje W. ; Donia, Marco ; Boers-Sonderen, Marye J. ; Hölmich, Lisbet R. ; Geukes Foppen, Marnix H. ; Wever, Lidwina D.V. ; Borgers, Jessica S.W. ; Wouters, Michel W.J.M. ; Scheij, Saskia
BACKGROUND: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.
METHODS: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.
RESULTS: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.
CONCLUSIONS: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.).