Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial

Ari VanderWalde; Shay L. Bellasea; Kari L. Kendra; Nikhil I. Khushalani; Katie M. Campbell; Philip O. Scumpia; Lawrence F. Kuklinski; Frances Collichio; Jeffrey A. Sosman; Alexandra Ikeguchi; Adrienne I. Victor; Thach Giao Truong; Bartosz Chmielowski; David C. Portnoy; Yuanbin Chen; Kim Margolin; Charles Bane; Constantin A. Dasanu; Douglas B. Johnson; Zeynep Eroglu; Sunandana Chandra; Egmidio Medina; Cynthia R. Gonzalez; Ignacio Baselga-Carretero; Agustin Vega-Crespo; Ivan Perez Garcilazo; Elad Sharon; Siwen Hu-Lieskovan; Sapna P. Patel; Kenneth F. Grossmann; James Moon; Michael C. Wu; Antoni Ribas

doi:10.1038/s41591-023-02498-y

Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial

Ari VanderWalde^*, Shay L. Bellasea, Kari L. Kendra, Nikhil I. Khushalani, Katie M. Campbell, Philip O. Scumpia, Lawrence F. Kuklinski, Frances Collichio, Jeffrey A. Sosman, Alexandra Ikeguchi, Adrienne I. Victor, Thach Giao Truong, Bartosz Chmielowski, David C. Portnoy, Yuanbin Chen, Kim Margolin, Charles Bane, Constantin A. Dasanu, Douglas B. Johnson, Zeynep ErogluSunandana Chandra, Egmidio Medina, Cynthia R. Gonzalez, Ignacio Baselga-Carretero, Agustin Vega-Crespo, Ivan Perez Garcilazo, Elad Sharon, Siwen Hu-Lieskovan, Sapna P. Patel, Kenneth F. Grossmann, James Moon, Michael C. Wu, Antoni Ribas^*

^*Corresponding author for this work

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

28 Scopus citations

Abstract

In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41–0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19–38%) and 9% (90% CI = 2–25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .

Original language	English (US)
Pages (from-to)	2278-2285
Number of pages	8
Journal	Nature Medicine
Volume	29
Issue number	9
DOIs	https://doi.org/10.1038/s41591-023-02498-y
State	Published - Sep 2023

Funding

We thank the patients and their caregivers, the support of the patient advocates S. Guild and V. Guild, and the support of Bristol Myers Squibb in providing investigational agents for the study. The study was funded by Southwest Oncology Group (SWOG) National Institutes of Health (NIH) and NCI grant nos. LS1616_R01LDRGAPP01, U10CA180888, U10CA180819, U10CA180821 and U10CA18068. Biopsies and their analyses were supported by the Stand Up to Cancer (SU2C) Catalyst-Bristol Myers Squibb-American Association for Cancer Research grant no. CT06-17. A.R. is funded by NIH and NCI grant nos. P01 CA244118 and R35 CA197633, and the Parker Institute for Cancer Immunotherapy, the Ressler Family Fund and support from K. and D. Schultz, T. and D. Jones, K. and J. Witemyre, T. Stutz and J. Isaacson. K.M.C. was supported by the Cancer Research Institute Postdoctoral Fellowship Program, the V Foundation Gil Nickel Melanoma Research Fellowship and the Parker Institute for Cancer Immunotherapy and V Foundation Bridge Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the patients and their caregivers, the support of the patient advocates S. Guild and V. Guild, and the support of Bristol Myers Squibb in providing investigational agents for the study. The study was funded by Southwest Oncology Group (SWOG) National Institutes of Health (NIH) and NCI grant nos. LS1616_R01LDRGAPP01, U10CA180888, U10CA180819, U10CA180821 and U10CA18068. Biopsies and their analyses were supported by the Stand Up to Cancer (SU2C) Catalyst-Bristol Myers Squibb-American Association for Cancer Research grant no. CT06-17. A.R. is funded by NIH and NCI grant nos. P01 CA244118 and R35 CA197633, and the Parker Institute for Cancer Immunotherapy, the Ressler Family Fund and support from K. and D. Schultz, T. and D. Jones, K. and J. Witemyre, T. Stutz and J. Isaacson. K.M.C. was supported by the Cancer Research Institute Postdoctoral Fellowship Program, the V Foundation Gil Nickel Melanoma Research Fellowship and the Parker Institute for Cancer Immunotherapy and V Foundation Bridge Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/s41591-023-02498-y

Cite this

VanderWalde, A., Bellasea, S. L., Kendra, K. L., Khushalani, N. I., Campbell, K. M., Scumpia, P. O., Kuklinski, L. F., Collichio, F., Sosman, J. A., Ikeguchi, A., Victor, A. I., Truong, T. G., Chmielowski, B., Portnoy, D. C., Chen, Y., Margolin, K., Bane, C., Dasanu, C. A., Johnson, D. B., ... Ribas, A. (2023). Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial. Nature Medicine, 29(9), 2278-2285. https://doi.org/10.1038/s41591-023-02498-y

@article{07ae608c52934f18a6fff15b7dd9007e,

title = "Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial",

abstract = "In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41–0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19–38%) and 9% (90% CI = 2–25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .",

author = "Ari VanderWalde and Bellasea, {Shay L.} and Kendra, {Kari L.} and Khushalani, {Nikhil I.} and Campbell, {Katie M.} and Scumpia, {Philip O.} and Kuklinski, {Lawrence F.} and Frances Collichio and Sosman, {Jeffrey A.} and Alexandra Ikeguchi and Victor, {Adrienne I.} and Truong, {Thach Giao} and Bartosz Chmielowski and Portnoy, {David C.} and Yuanbin Chen and Kim Margolin and Charles Bane and Dasanu, {Constantin A.} and Johnson, {Douglas B.} and Zeynep Eroglu and Sunandana Chandra and Egmidio Medina and Gonzalez, {Cynthia R.} and Ignacio Baselga-Carretero and Agustin Vega-Crespo and Garcilazo, {Ivan Perez} and Elad Sharon and Siwen Hu-Lieskovan and Patel, {Sapna P.} and Grossmann, {Kenneth F.} and James Moon and Wu, {Michael C.} and Antoni Ribas",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = sep,

doi = "10.1038/s41591-023-02498-y",

language = "English (US)",

volume = "29",

pages = "2278--2285",

journal = "Nature Medicine",

issn = "1078-8956",

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VanderWalde, A, Bellasea, SL, Kendra, KL, Khushalani, NI, Campbell, KM, Scumpia, PO, Kuklinski, LF, Collichio, F, Sosman, JA, Ikeguchi, A, Victor, AI, Truong, TG, Chmielowski, B, Portnoy, DC, Chen, Y, Margolin, K, Bane, C, Dasanu, CA, Johnson, DB, Eroglu, Z, Chandra, S, Medina, E, Gonzalez, CR, Baselga-Carretero, I, Vega-Crespo, A, Garcilazo, IP, Sharon, E, Hu-Lieskovan, S, Patel, SP, Grossmann, KF, Moon, J, Wu, MC & Ribas, A 2023, 'Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial', Nature Medicine, vol. 29, no. 9, pp. 2278-2285. https://doi.org/10.1038/s41591-023-02498-y

TY - JOUR

T1 - Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma

T2 - a randomized phase 2 trial

AU - VanderWalde, Ari

AU - Bellasea, Shay L.

AU - Kendra, Kari L.

AU - Khushalani, Nikhil I.

AU - Campbell, Katie M.

AU - Scumpia, Philip O.

AU - Kuklinski, Lawrence F.

AU - Collichio, Frances

AU - Sosman, Jeffrey A.

AU - Ikeguchi, Alexandra

AU - Victor, Adrienne I.

AU - Truong, Thach Giao

AU - Chmielowski, Bartosz

AU - Portnoy, David C.

AU - Chen, Yuanbin

AU - Margolin, Kim

AU - Bane, Charles

AU - Dasanu, Constantin A.

AU - Johnson, Douglas B.

AU - Eroglu, Zeynep

AU - Chandra, Sunandana

AU - Medina, Egmidio

AU - Gonzalez, Cynthia R.

AU - Baselga-Carretero, Ignacio

AU - Vega-Crespo, Agustin

AU - Garcilazo, Ivan Perez

AU - Sharon, Elad

AU - Hu-Lieskovan, Siwen

AU - Patel, Sapna P.

AU - Grossmann, Kenneth F.

AU - Moon, James

AU - Wu, Michael C.

AU - Ribas, Antoni

PY - 2023/9

Y1 - 2023/9

N2 - In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41–0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19–38%) and 9% (90% CI = 2–25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .

AB - In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41–0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19–38%) and 9% (90% CI = 2–25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .

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ER -

Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial

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