Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma

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

doi:10.1056/NEJMoa2210233

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma

N Engl J Med. 2022 Dec 8;387(23):2113-2125. doi: 10.1056/NEJMoa2210233.

Authors

Maartje W Rohaan¹, Troels H Borch¹, Joost H van den Berg¹, Özcan Met¹, Rob Kessels¹, Marnix H Geukes Foppen¹, Joachim Stoltenborg Granhøj¹, Bastiaan Nuijen¹, Cynthia Nijenhuis¹, Inge Jedema¹, Maaike van Zon¹, Saskia Scheij¹, Jos H Beijnen¹, Marten Hansen¹, Carlijn Voermans¹, Inge M Noringriis¹, Tine J Monberg¹, Rikke B Holmstroem¹, Lidwina D V Wever¹, Marloes van Dijk¹, Lindsay G Grijpink-Ongering¹, Ludy H M Valkenet¹, Alejandro Torres Acosta¹, Matthias Karger¹, Jessica S W Borgers¹, Renske M T Ten Ham¹, Valesca P Retèl¹, Wim H van Harten¹, Ferry Lalezari¹, Harm van Tinteren¹, Astrid A M van der Veldt¹, Geke A P Hospers¹, Marion A M Stevense-den Boer¹, Karijn P M Suijkerbuijk¹, Maureen J B Aarts¹, Djura Piersma¹, Alfons J M van den Eertwegh¹, Jan-Willem B de Groot¹, Gerard Vreugdenhil¹, Ellen Kapiteijn¹, Marye J Boers-Sonderen¹, W Edward Fiets¹, Franchette W P J van den Berkmortel¹, Eva Ellebaek¹, Lisbet R Hölmich¹, Alexander C J van Akkooi¹, Winan J van Houdt¹, Michel W J M Wouters¹, Johannes V van Thienen¹, Christian U Blank¹, Aafke Meerveld-Eggink¹, Sebastian Klobuch¹, Sofie Wilgenhof¹, Ton N Schumacher¹, Marco Donia¹, Inge Marie Svane¹, John B A G Haanen¹

Affiliation

¹ From the Division of Medical Oncology (M.W.R., M.H.G.F., M.K., J.S.W.B., J.V.T., C.U.B., A.M.-E., S.K., S.W., J.B.A.G.H.), the BioTherapeutics Unit, Hospital Pharmacy (J.H. van den Berg, C.N., M.Z., S.S.), the Divisions of Pharmacy and Pharmacology (B.N., J.H. Beijnen), Molecular Oncology and Immunology (I.J., T.N.S., J.B.A.G.H.), Biometrics (R.K., L.D.V.W., M. van Dijk, L.G.G.-O., L.H.M.V., A.T.A., H.T.), Psychosocial Research and Epidemiology (R.M.T.H., V.P.R., W.H.H.), Radiology (F.L.), and Surgical Oncology (A.C.J.A., W.J.H., M.W.J.M.W.), Netherlands Cancer Institute, the Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory (M.H., C.V.), and the Department of Medical Oncology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam (A.J.M.E.), Amsterdam, the Department of Healthcare Innovation and Evaluation, Julius Center for Health Sciences and Primary Care (R.M.T.H.), the Department of Medical Oncology, University Medical Center Utrecht, Utrecht University (K.P.M.S.), Trial and Data Center, Princess Maxima Center for Pediatric Oncology (H.T.), and Oncode Institute (T.N.S.), Utrecht, the Department of Health Technology and Services Research, University of Twente (V.P.R.), and the Department of Medical Oncology, Medical Spectrum Twente (D.P.), Enschede, the Department of Medical Oncology, Erasmus Medical Center, Rotterdam (A.A.M.V.), the Department of Medical Oncology, University Medical Center Groningen, Groningen (G.A.P.H.), the Department of Medical Oncology, Amphia Hospital, Breda (M.A.M.S.-B.), the Department of Medical Oncology, Maastricht University Medical Center, Maastricht (M.J.B.A.), the Department of Medical Oncology, Isala, Zwolle (J.-W.B.G.), the Department of Medical Oncology, Máxima Medical Center, Eindhoven (G.V.), the Departments of Medical Oncology (E.K.), Biomedical Data Sciences (M.W.J.M.W.), Hematology (T.N.S.), and Clinical Oncology (J.B.A.G.H.), Leiden University Medical Center, Leiden, the Department of Medical Oncology, Radboud University Medical Center, Nijmegen (M.J.B.-S.), the Department of Medical Oncology, Medical Center Leeuwarden, Leeuwarden (W.E.F.), and the Department of Medical Oncology, Zuyderland Medical Center, Sittard-Geleen (F.W.P.J.B.) - all in the Netherlands; the Department of Oncology, National Center for Cancer Immune Therapy (T.H.B., Ö.M., J.S.G., I.M.N., T.J.M., R.B.H., E.E., M. Donia, I.M.S.), and the Department of Plastic Surgery (L.R.H.), Copenhagen University Hospital, Herlev, Denmark; and Melanoma Institute Australia, the Faculty of Medicine and Health, University of Sydney, and Royal Prince Alfred Hospital - all in Sydney (A.C.J.A.).

PMID: 36477031
DOI: 10.1056/NEJMoa2210233

Abstract

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.).

Publication types

Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Cell- and Tissue-Based Therapy
Humans
Immunotherapy, Adoptive*
Ipilimumab / adverse effects
Lymphocytes, Tumor-Infiltrating*
Melanoma* / drug therapy

Substances

Ipilimumab

Associated data

ClinicalTrials.gov/NCT02278887