Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial

Aparna R. Parikh; Annamaria Szabolcs; Jill N. Allen; Jeffrey W. Clark; Jennifer Y. Wo; Michael Raabe; Hannah Thel; David Hoyos; Arnav Mehta; Sanya Arshad; David J. Lieb; Lorraine C. Drapek; Lawrence S. Blaszkowsky; Bruce J. Giantonio; Colin D. Weekes; Andrew X. Zhu; Lipika Goyal; Ryan D. Nipp; Jon S. Dubois; Emily E. Van Seventer; Bronwen E. Foreman; Lauren E. Matlack; Leilana Ly; Jessica A. Meurer; Nir Hacohen; David P. Ryan; Beow Y. Yeap; Ryan B. Corcoran; Benjamin D. Greenbaum; David T. Ting; Theodore S. Hong

doi:10.1038/s43018-021-00269-7

Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial

Aparna R. Parikh, Annamaria Szabolcs, Jill N. Allen, Jeffrey W. Clark, Jennifer Y. Wo, Michael Raabe, Hannah Thel, David Hoyos, Arnav Mehta, Sanya Arshad, David J. Lieb, Lorraine C. Drapek, Lawrence S. Blaszkowsky, Bruce J. Giantonio, Colin D. Weekes, Andrew X. Zhu, Lipika Goyal, Ryan D. Nipp, Jon S. Dubois, Emily E. Van SeventerBronwen E. Foreman, Lauren E. Matlack, Leilana Ly, Jessica A. Meurer, Nir Hacohen, David P. Ryan, Beow Y. Yeap, Ryan B. Corcoran, Benjamin D. Greenbaum, David T. Ting, Theodore S. Hong

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158 Scopus citations

Abstract

Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13–41%) and 20% for PDAC (five of 25; 95% CI, 7–41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19–58%) in CRC and 29% (five of 17; 95% CI, 10–56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers.

Original language	English
Pages (from-to)	1124-1135
Number of pages	12
Journal	Nature Cancer
Volume	2
Issue number	11
DOIs	https://doi.org/10.1038/s43018-021-00269-7
State	Published - Nov 2021
Externally published	Yes

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Parikh, A. R., Szabolcs, A., Allen, J. N., Clark, J. W., Wo, J. Y., Raabe, M., Thel, H., Hoyos, D., Mehta, A., Arshad, S., Lieb, D. J., Drapek, L. C., Blaszkowsky, L. S., Giantonio, B. J., Weekes, C. D., Zhu, A. X., Goyal, L., Nipp, R. D., Dubois, J. S., ... Hong, T. S. (2021). Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial. Nature Cancer, 2(11), 1124-1135. https://doi.org/10.1038/s43018-021-00269-7

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title = "Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial",

abstract = "Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13–41%) and 20% for PDAC (five of 25; 95% CI, 7–41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19–58%) in CRC and 29% (five of 17; 95% CI, 10–56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers.",

author = "Parikh, {Aparna R.} and Annamaria Szabolcs and Allen, {Jill N.} and Clark, {Jeffrey W.} and Wo, {Jennifer Y.} and Michael Raabe and Hannah Thel and David Hoyos and Arnav Mehta and Sanya Arshad and Lieb, {David J.} and Drapek, {Lorraine C.} and Blaszkowsky, {Lawrence S.} and Giantonio, {Bruce J.} and Weekes, {Colin D.} and Zhu, {Andrew X.} and Lipika Goyal and Nipp, {Ryan D.} and Dubois, {Jon S.} and {Van Seventer}, {Emily E.} and Foreman, {Bronwen E.} and Matlack, {Lauren E.} and Leilana Ly and Meurer, {Jessica A.} and Nir Hacohen and Ryan, {David P.} and Yeap, {Beow Y.} and Corcoran, {Ryan B.} and Greenbaum, {Benjamin D.} and Ting, {David T.} and Hong, {Theodore S.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = nov,

doi = "10.1038/s43018-021-00269-7",

language = "English",

volume = "2",

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journal = "Nature Cancer",

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Parikh, AR, Szabolcs, A, Allen, JN, Clark, JW, Wo, JY, Raabe, M, Thel, H, Hoyos, D, Mehta, A, Arshad, S, Lieb, DJ, Drapek, LC, Blaszkowsky, LS, Giantonio, BJ, Weekes, CD, Zhu, AX, Goyal, L, Nipp, RD, Dubois, JS, Van Seventer, EE, Foreman, BE, Matlack, LE, Ly, L, Meurer, JA, Hacohen, N, Ryan, DP, Yeap, BY, Corcoran, RB, Greenbaum, BD, Ting, DT & Hong, TS 2021, 'Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial', Nature Cancer, vol. 2, no. 11, pp. 1124-1135. https://doi.org/10.1038/s43018-021-00269-7

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T1 - Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial

AU - Parikh, Aparna R.

AU - Szabolcs, Annamaria

AU - Allen, Jill N.

AU - Clark, Jeffrey W.

AU - Wo, Jennifer Y.

AU - Raabe, Michael

AU - Thel, Hannah

AU - Hoyos, David

AU - Mehta, Arnav

AU - Arshad, Sanya

AU - Lieb, David J.

AU - Drapek, Lorraine C.

AU - Blaszkowsky, Lawrence S.

AU - Giantonio, Bruce J.

AU - Weekes, Colin D.

AU - Zhu, Andrew X.

AU - Goyal, Lipika

AU - Nipp, Ryan D.

AU - Dubois, Jon S.

AU - Van Seventer, Emily E.

AU - Foreman, Bronwen E.

AU - Matlack, Lauren E.

AU - Ly, Leilana

AU - Meurer, Jessica A.

AU - Hacohen, Nir

AU - Ryan, David P.

AU - Yeap, Beow Y.

AU - Corcoran, Ryan B.

AU - Greenbaum, Benjamin D.

AU - Ting, David T.

AU - Hong, Theodore S.

PY - 2021/11

Y1 - 2021/11

N2 - Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13–41%) and 20% for PDAC (five of 25; 95% CI, 7–41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19–58%) in CRC and 29% (five of 17; 95% CI, 10–56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers.

AB - Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging. We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13–41%) and 20% for PDAC (five of 25; 95% CI, 7–41%). In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19–58%) in CRC and 29% (five of 17; 95% CI, 10–56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control. This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers.

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JO - Nature Cancer

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ER -

Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial

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