Journal Article

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

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

2023

Overview

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 . Patients with stage 4 or unresectable stage 3 melanoma refractory to first-line anti-programmed death protein 1 (PD-1) or anti-programmed cell death 1 ligand 1 have longer progression-free survival when treated with a combination of anti-cytotoxic T-lymphocyte protein 4 (CTLA-4) and anti-PD-1 versus anti-CTLA-4 alone.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/580 / 692/308/575 / Apoptosis / B7-H1 Antigen / Biomedical and Life Sciences / Biomedicine / Cancer Research / CD8 antigen / Cell death / Cell density / CTLA-4 Antigen / CTLA-4 protein / Cytotoxicity / Humans / Immunotherapy / Infectious Diseases / Ipilimumab - adverse effects / Ipilimumab - therapeutic use / Ligands / Lymphocytes / Lymphocytes T / Melanoma / Melanoma - drug therapy / Metabolic Diseases / Metastases / Metastasis / Molecular Medicine / Monoclonal antibodies / Mortality / Neurosciences / Nivolumab - adverse effects / Nivolumab - therapeutic use / PD-1 protein / PD-L1 protein / Proteins / Statistical analysis / Statistical significance / Survival / Targeted cancer therapy / Toxicity / Tumors