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
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
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 .
UR - http://www.scopus.com/inward/record.url?scp=85168087345&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85168087345&partnerID=8YFLogxK
U2 - 10.1038/s41591-023-02498-y
DO - 10.1038/s41591-023-02498-y
M3 - Article
C2 - 37592104
AN - SCOPUS:85168087345
SN - 1078-8956
VL - 29
SP - 2278
EP - 2285
JO - Nature medicine
JF - Nature medicine
IS - 9
ER -