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:https://doi.org/10.1056/NEJMoa2210233

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 DijkLindsay 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

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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.

Original language	English
Pages (from-to)	2113-2125
Number of pages	13
Journal	New England journal of medicine
Volume	387
Issue number	23
DOIs	https://doi.org/10.1056/NEJMoa2210233
Publication status	Published - 8 Dec 2022

Keywords

Dermatology
Hematology/Oncology
Skin Cancer
Treatments in Oncology

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https://doi.org/10.1056/NEJMoa2210233

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Rohaan, M. W., Borch, T. H., Van Den Berg, J. H., Met, Ö., Kessels, R., Geukes Foppen, M. H., Stoltenborg Granhøj, J., Nuijen, B., Nijenhuis, C., Jedema, I., Van Zon, M., Scheij, S., Beijnen, J. H., Hansen, M., Voermans, C., Noringriis, I. M., Monberg, T. J., Holmstroem, R. B., Wever, L. D. V., ... Haanen, J. B. A. G. (2022). Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. New England journal of medicine, 387(23), 2113-2125. https://doi.org/10.1056/NEJMoa2210233

@article{431bbc73262b4b96a1265dc0f4bd4905,

title = "Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.",

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.",

keywords = "Dermatology, Hematology/Oncology, Skin Cancer, Treatments in Oncology",

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

note = "Funding Information: Supported by the Dutch Cancer Society , the Netherlands Organization for Health Research and Development , the Dutch Ministry of Health , Stichting Avento , the Antoni van Leeuwenhoek Foundation , Copenhagen University Hospital (Herlev), the Danish Cancer Society , and the Capital Region of Denmark Research Foundation . Publisher Copyright: {\textcopyright} 2022 Massachusetts Medical Society.",

year = "2022",

month = dec,

day = "8",

doi = "https://doi.org/10.1056/NEJMoa2210233",

language = "English",

volume = "387",

pages = "2113--2125",

journal = "New England journal of medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "23",

}

Rohaan, MW, Borch, TH, Van Den Berg, JH, Met, Ö, Kessels, R, Geukes Foppen, MH, Stoltenborg Granhøj, J, Nuijen, B, Nijenhuis, C, Jedema, I, Van Zon, M, Scheij, S, Beijnen, JH, Hansen, M, Voermans, C, Noringriis, IM, Monberg, TJ, Holmstroem, RB, Wever, LDV, Van Dijk, M, Grijpink-Ongering, LG, Valkenet, LHM, Torres Acosta, A, Karger, M, Borgers, JSW, Ten Ham, RMT, Retèl, VP, Van Harten, WH, Lalezari, F, Van Tinteren, H, Van Der Veldt, AAM, Hospers, GAP, Stevense-Den Boer, MAM, Suijkerbuijk, KPM, Aarts, MJB, Piersma, D, Van Den Eertwegh, AJM, De Groot, JWB, Vreugdenhil, G, Kapiteijn, E, Boers-Sonderen, MJ, Fiets, WE, Van Den Berkmortel, FWPJ, Ellebaek, E, Hölmich, LR, Van Akkooi, ACJ, Van Houdt, WJ, Wouters, MWJM, Van Thienen, JV, Blank, CU, Meerveld-Eggink, A, Klobuch, S, Wilgenhof, S, Schumacher, TN, Donia, M, Svane, IM & Haanen, JBAG 2022, 'Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.', New England journal of medicine, vol. 387, no. 23, pp. 2113-2125. https://doi.org/10.1056/NEJMoa2210233

TY - JOUR

T1 - Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.

AU - Rohaan, Maartje W.

AU - Borch, Troels H.

AU - Van Den Berg, Joost H.

AU - Met, Özcan

AU - Kessels, Rob

AU - Geukes Foppen, Marnix H.

AU - Stoltenborg Granhøj, Joachim

AU - Nuijen, Bastiaan

AU - Nijenhuis, Cynthia

AU - Jedema, Inge

AU - Van Zon, Maaike

AU - Scheij, Saskia

AU - Beijnen, Jos H.

AU - Hansen, Marten

AU - Voermans, Carlijn

AU - Noringriis, Inge M.

AU - Monberg, Tine J.

AU - Holmstroem, Rikke B.

AU - Wever, Lidwina D.V.

AU - Van Dijk, Marloes

AU - Grijpink-Ongering, Lindsay G.

AU - Valkenet, Ludy H.M.

AU - Torres Acosta, Alejandro

AU - Karger, Matthias

AU - Borgers, Jessica S.W.

AU - Ten Ham, Renske M.T.

AU - Retèl, Valesca P.

AU - Van Harten, Wim H.

AU - Lalezari, Ferry

AU - Van Tinteren, Harm

AU - Van Der Veldt, Astrid A.M.

AU - Hospers, Geke A.P.

AU - Stevense-Den Boer, Marion A.M.

AU - Suijkerbuijk, Karijn P.M.

AU - Aarts, Maureen J.B.

AU - Piersma, Djura

AU - Van Den Eertwegh, Alfons J.M.

AU - De Groot, Jan Willem B.

AU - Vreugdenhil, Gerard

AU - Kapiteijn, Ellen

AU - Boers-Sonderen, Marye J.

AU - Fiets, W. Edward

AU - Van Den Berkmortel, Franchette W.P.J.

AU - Ellebaek, Eva

AU - Hölmich, Lisbet R.

AU - Van Akkooi, Alexander C.J.

AU - Van Houdt, Winan J.

AU - Wouters, Michel W.J.M.

AU - Van Thienen, Johannes V.

AU - Blank, Christian U.

AU - Meerveld-Eggink, Aafke

AU - Klobuch, Sebastian

AU - Wilgenhof, Sofie

AU - Schumacher, Ton N.

AU - Donia, Marco

AU - Svane, Inge Marie

AU - Haanen, John B.A.G.

N1 - Funding Information: Supported by the Dutch Cancer Society , the Netherlands Organization for Health Research and Development , the Dutch Ministry of Health , Stichting Avento , the Antoni van Leeuwenhoek Foundation , Copenhagen University Hospital (Herlev), the Danish Cancer Society , and the Capital Region of Denmark Research Foundation . Publisher Copyright: © 2022 Massachusetts Medical Society.

PY - 2022/12/8

Y1 - 2022/12/8

N2 - 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.

AB - 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.

KW - Dermatology

KW - Hematology/Oncology

KW - Skin Cancer

KW - Treatments in Oncology

UR - http://www.scopus.com/inward/record.url?scp=85143690227&partnerID=8YFLogxK

U2 - https://doi.org/10.1056/NEJMoa2210233

DO - https://doi.org/10.1056/NEJMoa2210233

M3 - Article

C2 - 36477031

SN - 0028-4793

VL - 387

SP - 2113

EP - 2125

JO - New England journal of medicine

JF - New England journal of medicine

IS - 23

ER -

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma.

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