Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma

Christian U Blank; Minke W Lucas; Richard A Scolyer; Bart A van de Wiel; Alexander M Menzies; Marta Lopez-Yurda; Lotte L Hoeijmakers; Robyn P M Saw; Judith M Lijnsvelt; Nigel G Maher; Saskia M Pulleman; Maria Gonzalez; Alejandro Torres Acosta; Winan J van Houdt; Serigne N Lo; Anke M J Kuijpers; Andrew Spillane; W Martin C Klop; Thomas E Pennington; Charlotte L Zuur; Kerwin F Shannon; Beatrijs A Seinstra; Robert V Rawson; John B A G Haanen; Sydney Ch'ng; Kishan A T Naipal; Jonathan Stretch; Johannes V van Thienen; Michael A Rtshiladze; Sofie Wilgenhof; Rony Kapoor; Aafke Meerveld-Eggink; Lindsay G Grijpink-Ongering; Alexander C J van Akkooi; Irene L M Reijers; David E Gyorki; Dirk J Grünhagen; Frank M Speetjens; Sonja B Vliek; Joanna Placzke; Lavinia Spain; Robert C Stassen; Mona Amini-Adle; Céleste Lebbé; Mark B Faries; Caroline Robert; Paolo A Ascierto; Rozemarijn van Rijn; Franchette W P J van den Berkmortel; Djura Piersma; Andre van der Westhuizen; Gerard Vreugdenhil; Maureen J B Aarts; Marion A M Stevense-den Boer; Victoria Atkinson; Muhammad Khattak; Miles C Andrews; Alfons J M van den Eertwegh; Marye J Boers-Sonderen; Geke A P Hospers; Matteo S Carlino; Jan-Willem B de Groot; Ellen Kapiteijn; Karijn P M Suijkerbuijk; Piotr Rutkowski; Shahneen Sandhu; Astrid A M van der Veldt; Georgina V Long

doi:10.1056/NEJMoa2402604

Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma

Christian U Blank
, Minke W Lucas
, Richard A Scolyer
, Bart A van de Wiel
, Alexander M Menzies
, Marta Lopez-Yurda
, Lotte L Hoeijmakers
, Robyn P M Saw
, Judith M Lijnsvelt
, Nigel G Maher
, Saskia M Pulleman
, Maria Gonzalez
, Alejandro Torres Acosta
, Winan J van Houdt
, Serigne N Lo
, Anke M J Kuijpers
, Andrew Spillane
, W Martin C Klop
, Thomas E Pennington
, Charlotte L Zuur

Kerwin F Shannon, Beatrijs A Seinstra, Robert V Rawson, John B A G Haanen, Sydney Ch'ng, Kishan A T Naipal, Jonathan Stretch, Johannes V van Thienen, Michael A Rtshiladze, Sofie Wilgenhof, Rony Kapoor, Aafke Meerveld-Eggink, Lindsay G Grijpink-Ongering, Alexander C J van Akkooi, Irene L M Reijers, David E Gyorki, Dirk J Grünhagen, Frank M Speetjens, Sonja B Vliek, Joanna Placzke, Lavinia Spain, Robert C Stassen, Mona Amini-Adle, Céleste Lebbé, Mark B Faries, Caroline Robert, Paolo A Ascierto, Rozemarijn van Rijn, Franchette W P J van den Berkmortel, Djura Piersma, Andre van der Westhuizen, Gerard Vreugdenhil, Maureen J B Aarts, Marion A M Stevense-den Boer, Victoria Atkinson, Muhammad Khattak, Miles C Andrews, Alfons J M van den Eertwegh, Marye J Boers-Sonderen, Geke A P Hospers, Matteo S Carlino, Jan-Willem B de Groot, Ellen Kapiteijn, Karijn P M Suijkerbuijk, Piotr Rutkowski, Shahneen Sandhu, Astrid A M van der Veldt, Georgina V Long

Personalized Cancer Treatment (PCT)

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Abstract

BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy.

METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival.

RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group.

CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

Original language	English
Pages (from-to)	1696-1708
Number of pages	13
Journal	The New England journal of medicine
Volume	391
Issue number	18
Early online date	2-Jun-2024
DOIs	https://doi.org/10.1056/NEJMoa2402604
Publication status	Published - 7-Nov-2024

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Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III MelanomaFinal publisher's version, 620 KBLicence: Taverne

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Blank, C. U., Lucas, M. W., Scolyer, R. A., van de Wiel, B. A., Menzies, A. M., Lopez-Yurda, M., Hoeijmakers, L. L., Saw, R. P. M., Lijnsvelt, J. M., Maher, N. G., Pulleman, S. M., Gonzalez, M., Torres Acosta, A., van Houdt, W. J., Lo, S. N., Kuijpers, A. M. J., Spillane, A., Klop, W. M. C., Pennington, T. E., ... Long, G. V. (2024). Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma. The New England journal of medicine, 391(18), 1696-1708. https://doi.org/10.1056/NEJMoa2402604

@article{a76cf375c6304c2da8aa0b33ae2c9620,

title = "Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma",

abstract = "BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy.METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival.RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7\% (99.9\% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2\% (99.9\% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9\% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9\% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0\% of the patients had a major pathological response, 8.0\% had a partial response, 26.4\% had a nonresponse (>50\% residual viable tumor), and 2.4\% had progression; in 4.2\%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1\% among patients in the neoadjuvant group who had a major pathological response, 76.1\% among those who had a partial response, and 57.0\% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7\% of the patients in the neoadjuvant group and in 14.7\% in the adjuvant group.CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).",

author = "Blank, \{Christian U\} and Lucas, \{Minke W\} and Scolyer, \{Richard A\} and \{van de Wiel\}, \{Bart A\} and Menzies, \{Alexander M\} and Marta Lopez-Yurda and Hoeijmakers, \{Lotte L\} and Saw, \{Robyn P M\} and Lijnsvelt, \{Judith M\} and Maher, \{Nigel G\} and Pulleman, \{Saskia M\} and Maria Gonzalez and \{Torres Acosta\}, Alejandro and \{van Houdt\}, \{Winan J\} and Lo, \{Serigne N\} and Kuijpers, \{Anke M J\} and Andrew Spillane and Klop, \{W Martin C\} and Pennington, \{Thomas E\} and Zuur, \{Charlotte L\} and Shannon, \{Kerwin F\} and Seinstra, \{Beatrijs A\} and Rawson, \{Robert V\} and Haanen, \{John B A G\} and Sydney Ch'ng and Naipal, \{Kishan A T\} and Jonathan Stretch and \{van Thienen\}, \{Johannes V\} and Rtshiladze, \{Michael A\} and Sofie Wilgenhof and Rony Kapoor and Aafke Meerveld-Eggink and Grijpink-Ongering, \{Lindsay G\} and \{van Akkooi\}, \{Alexander C J\} and Reijers, \{Irene L M\} and Gyorki, \{David E\} and Gr{\"u}nhagen, \{Dirk J\} and Speetjens, \{Frank M\} and Vliek, \{Sonja B\} and Joanna Placzke and Lavinia Spain and Stassen, \{Robert C\} and Mona Amini-Adle and C{\'e}leste Lebb{\'e} and Faries, \{Mark B\} and Caroline Robert and Ascierto, \{Paolo A\} and \{van Rijn\}, Rozemarijn and \{van den Berkmortel\}, \{Franchette W P J\} and Djura Piersma and \{van der Westhuizen\}, Andre and Gerard Vreugdenhil and Aarts, \{Maureen J B\} and \{Stevense-den Boer\}, \{Marion A M\} and Victoria Atkinson and Muhammad Khattak and Andrews, \{Miles C\} and \{van den Eertwegh\}, \{Alfons J M\} and Boers-Sonderen, \{Marye J\} and Hospers, \{Geke A P\} and Carlino, \{Matteo S\} and \{de Groot\}, \{Jan-Willem B\} and Ellen Kapiteijn and Suijkerbuijk, \{Karijn P M\} and Piotr Rutkowski and Shahneen Sandhu and \{van der Veldt\}, \{Astrid A M\} and Long, \{Georgina V\}",

note = "Copyright {\textcopyright} 2024 Massachusetts Medical Society.",

year = "2024",

month = nov,

day = "7",

doi = "10.1056/NEJMoa2402604",

language = "English",

volume = "391",

pages = "1696--1708",

journal = "The New England journal of medicine",

issn = "0028-4793",

publisher = "MASSACHUSETTS MEDICAL SOC",

number = "18",

}

Blank, CU, Lucas, MW, Scolyer, RA, van de Wiel, BA, Menzies, AM, Lopez-Yurda, M, Hoeijmakers, LL, Saw, RPM, Lijnsvelt, JM, Maher, NG, Pulleman, SM, Gonzalez, M, Torres Acosta, A, van Houdt, WJ, Lo, SN, Kuijpers, AMJ, Spillane, A, Klop, WMC, Pennington, TE, Zuur, CL, Shannon, KF, Seinstra, BA, Rawson, RV, Haanen, JBAG, Ch'ng, S, Naipal, KAT, Stretch, J, van Thienen, JV, Rtshiladze, MA, Wilgenhof, S, Kapoor, R, Meerveld-Eggink, A, Grijpink-Ongering, LG, van Akkooi, ACJ, Reijers, ILM, Gyorki, DE, Grünhagen, DJ, Speetjens, FM, Vliek, SB, Placzke, J, Spain, L, Stassen, RC, Amini-Adle, M, Lebbé, C, Faries, MB, Robert, C, Ascierto, PA, van Rijn, R, van den Berkmortel, FWPJ, Piersma, D, van der Westhuizen, A, Vreugdenhil, G, Aarts, MJB, Stevense-den Boer, MAM, Atkinson, V, Khattak, M, Andrews, MC, van den Eertwegh, AJM, Boers-Sonderen, MJ, Hospers, GAP, Carlino, MS, de Groot, J-WB, Kapiteijn, E, Suijkerbuijk, KPM, Rutkowski, P, Sandhu, S, van der Veldt, AAM & Long, GV 2024, 'Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma', The New England journal of medicine, vol. 391, no. 18, pp. 1696-1708. https://doi.org/10.1056/NEJMoa2402604

TY - JOUR

T1 - Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma

AU - Blank, Christian U

AU - Lucas, Minke W

AU - Scolyer, Richard A

AU - van de Wiel, Bart A

AU - Menzies, Alexander M

AU - Lopez-Yurda, Marta

AU - Hoeijmakers, Lotte L

AU - Saw, Robyn P M

AU - Lijnsvelt, Judith M

AU - Maher, Nigel G

AU - Pulleman, Saskia M

AU - Gonzalez, Maria

AU - Torres Acosta, Alejandro

AU - van Houdt, Winan J

AU - Lo, Serigne N

AU - Kuijpers, Anke M J

AU - Spillane, Andrew

AU - Klop, W Martin C

AU - Pennington, Thomas E

AU - Zuur, Charlotte L

AU - Shannon, Kerwin F

AU - Seinstra, Beatrijs A

AU - Rawson, Robert V

AU - Haanen, John B A G

AU - Ch'ng, Sydney

AU - Naipal, Kishan A T

AU - Stretch, Jonathan

AU - van Thienen, Johannes V

AU - Rtshiladze, Michael A

AU - Wilgenhof, Sofie

AU - Kapoor, Rony

AU - Meerveld-Eggink, Aafke

AU - Grijpink-Ongering, Lindsay G

AU - van Akkooi, Alexander C J

AU - Reijers, Irene L M

AU - Gyorki, David E

AU - Grünhagen, Dirk J

AU - Speetjens, Frank M

AU - Vliek, Sonja B

AU - Placzke, Joanna

AU - Spain, Lavinia

AU - Stassen, Robert C

AU - Amini-Adle, Mona

AU - Lebbé, Céleste

AU - Faries, Mark B

AU - Robert, Caroline

AU - Ascierto, Paolo A

AU - van Rijn, Rozemarijn

AU - van den Berkmortel, Franchette W P J

AU - Piersma, Djura

AU - van der Westhuizen, Andre

AU - Vreugdenhil, Gerard

AU - Aarts, Maureen J B

AU - Stevense-den Boer, Marion A M

AU - Atkinson, Victoria

AU - Khattak, Muhammad

AU - Andrews, Miles C

AU - van den Eertwegh, Alfons J M

AU - Boers-Sonderen, Marye J

AU - Hospers, Geke A P

AU - Carlino, Matteo S

AU - de Groot, Jan-Willem B

AU - Kapiteijn, Ellen

AU - Suijkerbuijk, Karijn P M

AU - Rutkowski, Piotr

AU - Sandhu, Shahneen

AU - van der Veldt, Astrid A M

AU - Long, Georgina V

PY - 2024/11/7

Y1 - 2024/11/7

N2 - BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy.METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival.RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group.CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

AB - BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy.METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival.RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group.CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).

U2 - 10.1056/NEJMoa2402604

DO - 10.1056/NEJMoa2402604

M3 - Article

C2 - 38828984

SN - 0028-4793

VL - 391

SP - 1696

EP - 1708

JO - The New England journal of medicine

JF - The New England journal of medicine

IS - 18

ER -

Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma

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