Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden

Michael Schenker; Mauricio Burotto; Martin Richardet; Tudor-Eliade Ciuleanu; Anthony Gonçalves; Neeltje Steeghs; Patrick Schoffski; Paolo A Ascierto; Michele Maio; Iwona Lugowska; Lorena Lupinacci; Alexandra Leary; Jean-Pierre Delord; Julieta Grasselli; David S P Tan; Jennifer Friedmann; Jacqueline Vuky; Marina Tschaika; Somasekhar Konduru; Sai Vikram Vemula; Ruta Slepetis; Georgia Kollia; Misena Pacius; Quyen Duong; Ning Huang; Parul Doshi; Jonathan Baden; Massimo Di Nicola

doi:10.1136/jitc-2024-008872

Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden

Michael Schenker, Mauricio Burotto, Martin Richardet, Tudor-Eliade Ciuleanu, Anthony Gonçalves, Neeltje Steeghs, Patrick Schoffski, Paolo A Ascierto, Michele Maio, Iwona Lugowska, Lorena Lupinacci, Alexandra Leary, Jean-Pierre Delord, Julieta Grasselli, David S P Tan, Jennifer Friedmann, Jacqueline Vuky, Marina Tschaika, Somasekhar Konduru, Sai Vikram VemulaRuta Slepetis, Georgia Kollia, Misena Pacius, Quyen Duong, Ning Huang, Parul Doshi, Jonathan Baden, Massimo Di Nicola

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB).

PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne ® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab.

RESULTS: In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals.

CONCLUSIONS: Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab.

TRIAL REGISTRATION NUMBER: NCT03668119.

Original language	English
Article number	e008872
Journal	Journal for ImmunoTherapy of Cancer
Volume	12
Issue number	8
DOIs	https://doi.org/10.1136/jitc-2024-008872
Publication status	Published - 6 Aug 2024
Externally published	Yes

Keywords

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Female
Humans
Ipilimumab/therapeutic use
Male
Middle Aged
Mutation
Neoplasm Metastasis
Neoplasms/drug therapy
Nivolumab/therapeutic use

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Schenker, M., Burotto, M., Richardet, M., Ciuleanu, T.-E., Gonçalves, A., Steeghs, N., Schoffski, P., Ascierto, P. A., Maio, M., Lugowska, I., Lupinacci, L., Leary, A., Delord, J.-P., Grasselli, J., Tan, D. S. P., Friedmann, J., Vuky, J., Tschaika, M., Konduru, S., ... Di Nicola, M. (2024). Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden. Journal for ImmunoTherapy of Cancer, 12(8), Article e008872. https://doi.org/10.1136/jitc-2024-008872

@article{2c31064ccc4744d8b6e2a08c7ac6af7a,

title = "Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden",

abstract = "BACKGROUND: Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB).PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne {\textregistered} CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab. RESULTS: In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals.CONCLUSIONS: Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab.TRIAL REGISTRATION NUMBER: NCT03668119.",

keywords = "Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Female, Humans, Ipilimumab/therapeutic use, Male, Middle Aged, Mutation, Neoplasm Metastasis, Neoplasms/drug therapy, Nivolumab/therapeutic use",

author = "Michael Schenker and Mauricio Burotto and Martin Richardet and Tudor-Eliade Ciuleanu and Anthony Gon{\c c}alves and Neeltje Steeghs and Patrick Schoffski and Ascierto, {Paolo A} and Michele Maio and Iwona Lugowska and Lorena Lupinacci and Alexandra Leary and Jean-Pierre Delord and Julieta Grasselli and Tan, {David S P} and Jennifer Friedmann and Jacqueline Vuky and Marina Tschaika and Somasekhar Konduru and Vemula, {Sai Vikram} and Ruta Slepetis and Georgia Kollia and Misena Pacius and Quyen Duong and Ning Huang and Parul Doshi and Jonathan Baden and {Di Nicola}, Massimo",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2024",

month = aug,

day = "6",

doi = "10.1136/jitc-2024-008872",

language = "English",

volume = "12",

number = "8",

}

Schenker, M, Burotto, M, Richardet, M, Ciuleanu, T-E, Gonçalves, A, Steeghs, N, Schoffski, P, Ascierto, PA, Maio, M, Lugowska, I, Lupinacci, L, Leary, A, Delord, J-P, Grasselli, J, Tan, DSP, Friedmann, J, Vuky, J, Tschaika, M, Konduru, S, Vemula, SV, Slepetis, R, Kollia, G, Pacius, M, Duong, Q, Huang, N, Doshi, P, Baden, J & Di Nicola, M 2024, 'Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden', Journal for ImmunoTherapy of Cancer, vol. 12, no. 8, e008872. https://doi.org/10.1136/jitc-2024-008872

Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden. / Schenker, Michael; Burotto, Mauricio; Richardet, Martin et al.
In: Journal for ImmunoTherapy of Cancer, Vol. 12, No. 8, e008872, 06.08.2024.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden

AU - Schenker, Michael

AU - Burotto, Mauricio

AU - Richardet, Martin

AU - Ciuleanu, Tudor-Eliade

AU - Gonçalves, Anthony

AU - Steeghs, Neeltje

AU - Schoffski, Patrick

AU - Ascierto, Paolo A

AU - Maio, Michele

AU - Lugowska, Iwona

AU - Lupinacci, Lorena

AU - Leary, Alexandra

AU - Delord, Jean-Pierre

AU - Grasselli, Julieta

AU - Tan, David S P

AU - Friedmann, Jennifer

AU - Vuky, Jacqueline

AU - Tschaika, Marina

AU - Konduru, Somasekhar

AU - Vemula, Sai Vikram

AU - Slepetis, Ruta

AU - Kollia, Georgia

AU - Pacius, Misena

AU - Duong, Quyen

AU - Huang, Ning

AU - Doshi, Parul

AU - Baden, Jonathan

AU - Di Nicola, Massimo

PY - 2024/8/6

Y1 - 2024/8/6

N2 - BACKGROUND: Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB).PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne ® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab. RESULTS: In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals.CONCLUSIONS: Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab.TRIAL REGISTRATION NUMBER: NCT03668119.

AB - BACKGROUND: Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB).PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne ® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab. RESULTS: In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals.CONCLUSIONS: Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab.TRIAL REGISTRATION NUMBER: NCT03668119.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Female

KW - Humans

KW - Ipilimumab/therapeutic use

KW - Male

KW - Middle Aged

KW - Mutation

KW - Neoplasm Metastasis

KW - Neoplasms/drug therapy

KW - Nivolumab/therapeutic use

U2 - 10.1136/jitc-2024-008872

DO - 10.1136/jitc-2024-008872

M3 - Article

C2 - 39107131

VL - 12

JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

IS - 8

M1 - e008872

ER -

Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden

Abstract

Keywords

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