Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer

Matthew D. Hellmann; Tavi Nathanson; Hira Rizvi; Benjamin C. Creelan; Francisco Sanchez-Vega; Arun Ahuja; Ai Ni; Jacki B. Novik; Levi M.B. Mangarin; Mohsen Abu-Akeel; Cailian Liu; Jennifer L. Sauter; Natasha Rekhtman; Eliza Chang; Margaret K. Callahan; Jamie E. Chaft; Martin H. Voss; Megan Tenet; Xuemei Li; Kelly Covello; Andrea Renninger; Patrik Vitazka; William J. Geese; Hossein Borghaei; Charles M. Rudin; Scott Antonia; Charles Swanton; Jeff Hammerbacher; Taha Merghoub; Nicholas McGranahan; Alexandra Snyder; Jedd D. Wolchok

doi:10.1016/j.ccell.2018.03.018

Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer

Matthew D. Hellmann, Tavi Nathanson, Hira Rizvi, Benjamin C. Creelan, Francisco Sanchez-Vega, Arun Ahuja, Ai Ni, Jacki B. Novik, Levi M.B. Mangarin, Mohsen Abu-Akeel, Cailian Liu, Jennifer L. Sauter, Natasha Rekhtman, Eliza Chang, Margaret K. Callahan, Jamie E. Chaft, Martin H. Voss, Megan Tenet, Xuemei Li, Kelly CovelloAndrea Renninger, Patrik Vitazka, William J. Geese, Hossein Borghaei, Charles M. Rudin, Scott Antonia, Charles Swanton, Jeff Hammerbacher, Taha Merghoub, Nicholas McGranahan, Alexandra Snyder, Jedd D. Wolchok

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

773 Scopus citations

Abstract

Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC. Hellmann et al. examine non-small-cell lung cancers treated with combined PD-1 and CTLA-4 blockade using whole-exome sequencing and find that high tumor mutation burden is the strongest feature associated with improved objective response, durable benefit, and progression-free survival in multivariable analysis.

Original language	English
Pages (from-to)	843-852.e4
Journal	Cancer Cell
Volume	33
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2018.03.018
State	Published - May 14 2018

Keywords

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Carcinoma, Non-Small-Cell Lung/drug therapy
Exome Sequencing/methods
Female
Humans
Immunotherapy
Ipilimumab/therapeutic use
Lung Neoplasms/drug therapy
Male
Middle Aged
Mutation
Nivolumab/therapeutic use
Progression-Free Survival

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2018.03.018

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Hellmann, M. D., Nathanson, T., Rizvi, H., Creelan, B. C., Sanchez-Vega, F., Ahuja, A., Ni, A., Novik, J. B., Mangarin, L. M. B., Abu-Akeel, M., Liu, C., Sauter, J. L., Rekhtman, N., Chang, E., Callahan, M. K., Chaft, J. E., Voss, M. H., Tenet, M., Li, X., ... Wolchok, J. D. (2018). Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Cancer Cell, 33(5), 843-852.e4. https://doi.org/10.1016/j.ccell.2018.03.018

@article{731094ab558a4777941201bf942438d3,

title = "Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer",

abstract = "Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC. Hellmann et al. examine non-small-cell lung cancers treated with combined PD-1 and CTLA-4 blockade using whole-exome sequencing and find that high tumor mutation burden is the strongest feature associated with improved objective response, durable benefit, and progression-free survival in multivariable analysis.",

keywords = "Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Carcinoma, Non-Small-Cell Lung/drug therapy, Exome Sequencing/methods, Female, Humans, Immunotherapy, Ipilimumab/therapeutic use, Lung Neoplasms/drug therapy, Male, Middle Aged, Mutation, Nivolumab/therapeutic use, Progression-Free Survival",

author = "Hellmann, {Matthew D.} and Tavi Nathanson and Hira Rizvi and Creelan, {Benjamin C.} and Francisco Sanchez-Vega and Arun Ahuja and Ai Ni and Novik, {Jacki B.} and Mangarin, {Levi M.B.} and Mohsen Abu-Akeel and Cailian Liu and Sauter, {Jennifer L.} and Natasha Rekhtman and Eliza Chang and Callahan, {Margaret K.} and Chaft, {Jamie E.} and Voss, {Martin H.} and Megan Tenet and Xuemei Li and Kelly Covello and Andrea Renninger and Patrik Vitazka and Geese, {William J.} and Hossein Borghaei and Rudin, {Charles M.} and Scott Antonia and Charles Swanton and Jeff Hammerbacher and Taha Merghoub and Nicholas McGranahan and Alexandra Snyder and Wolchok, {Jedd D.}",

year = "2018",

month = may,

day = "14",

doi = "10.1016/j.ccell.2018.03.018",

language = "English",

volume = "33",

pages = "843--852.e4",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "5",

}

Hellmann, MD, Nathanson, T, Rizvi, H, Creelan, BC, Sanchez-Vega, F, Ahuja, A, Ni, A, Novik, JB, Mangarin, LMB, Abu-Akeel, M, Liu, C, Sauter, JL, Rekhtman, N, Chang, E, Callahan, MK, Chaft, JE, Voss, MH, Tenet, M, Li, X, Covello, K, Renninger, A, Vitazka, P, Geese, WJ, Borghaei, H, Rudin, CM, Antonia, S, Swanton, C, Hammerbacher, J, Merghoub, T, McGranahan, N, Snyder, A & Wolchok, JD 2018, 'Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer', Cancer Cell, vol. 33, no. 5, pp. 843-852.e4. https://doi.org/10.1016/j.ccell.2018.03.018

TY - JOUR

T1 - Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer

AU - Hellmann, Matthew D.

AU - Nathanson, Tavi

AU - Rizvi, Hira

AU - Creelan, Benjamin C.

AU - Sanchez-Vega, Francisco

AU - Ahuja, Arun

AU - Ni, Ai

AU - Novik, Jacki B.

AU - Mangarin, Levi M.B.

AU - Abu-Akeel, Mohsen

AU - Liu, Cailian

AU - Sauter, Jennifer L.

AU - Rekhtman, Natasha

AU - Chang, Eliza

AU - Callahan, Margaret K.

AU - Chaft, Jamie E.

AU - Voss, Martin H.

AU - Tenet, Megan

AU - Li, Xuemei

AU - Covello, Kelly

AU - Renninger, Andrea

AU - Vitazka, Patrik

AU - Geese, William J.

AU - Borghaei, Hossein

AU - Rudin, Charles M.

AU - Antonia, Scott

AU - Swanton, Charles

AU - Hammerbacher, Jeff

AU - Merghoub, Taha

AU - McGranahan, Nicholas

AU - Snyder, Alexandra

AU - Wolchok, Jedd D.

PY - 2018/5/14

Y1 - 2018/5/14

N2 - Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC. Hellmann et al. examine non-small-cell lung cancers treated with combined PD-1 and CTLA-4 blockade using whole-exome sequencing and find that high tumor mutation burden is the strongest feature associated with improved objective response, durable benefit, and progression-free survival in multivariable analysis.

AB - Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC. Hellmann et al. examine non-small-cell lung cancers treated with combined PD-1 and CTLA-4 blockade using whole-exome sequencing and find that high tumor mutation burden is the strongest feature associated with improved objective response, durable benefit, and progression-free survival in multivariable analysis.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Carcinoma, Non-Small-Cell Lung/drug therapy

KW - Exome Sequencing/methods

KW - Female

KW - Humans

KW - Immunotherapy

KW - Ipilimumab/therapeutic use

KW - Lung Neoplasms/drug therapy

KW - Male

KW - Middle Aged

KW - Mutation

KW - Nivolumab/therapeutic use

KW - Progression-Free Survival

UR - http://www.scopus.com/inward/record.url?scp=85045237409&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2018.03.018

DO - 10.1016/j.ccell.2018.03.018

M3 - Article

C2 - 29657128

SN - 1535-6108

VL - 33

SP - 843-852.e4

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer

Abstract

Keywords

UN SDGs

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