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A new phase II study finds that blockade of CTLA-4 with continuation of PD-1 blockade can reverse primary resistance to PD-1 blockade therapy in some patients
A new phase II trial recently published on Nature Medicine shows that blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade can reverse primary resistance to PD-1 blockade therapy in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against PD-L1 and whose tumors progressed.
All 91 enrolled patients had advanced melanoma with primary resistance to anti-PD-1 or anti-PD-L1 inhibitors; they were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone to test whether CTLA-4 blockade, alone or in combination with continued PD-1 blockade, could reverse resistance to previous anti-PD-1 sequentially or concomitantly. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab and objective response rates were 28% and 9%, respectively, with grade 3 or higher treatment-related adverse events occurring in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The unusual randomization in a 3:1 fashion was chosen to ensure adequate power for the main translational objective, which was designed to assess differences in CD8 T cell infiltration between biopsies of patients with response or no response to therapy in the combination therapy group. Despite this, the change in intratumoral CD8 T cell density observed in the analysis did not reach statistical significance. As authors conclude, «The study demonstrates that combined therapy with nivolumab and ipilimumab yields superior progression free survival and objective response rate compared to single-agent ipilimumab in patients with advanced melanoma with primary resistance to anti-PD-1 or anti-PD-L1 therapy. On the basis of these results, the combination of nivolumab and ipilimumab should be considered the preferred regimen over ipilimumab alone to treat patients with advanced melanoma not responding to previous anti-PD-1, although patients and physicians should consider the corresponding increase in toxicity».