Jeffrey Weber, MD, PhD
As you look back 20 years to 1999, there were very few agents in the melanoma therapy armamentarium. There had been an adjuvant approval for interferon at high doses back in 1995 and an approval in 1998 for high dose interleukin-2; both agents were toxic.
The earliest trials of the PD-1 antibodies pembrolizumab (Keytruda) and nivolumab (Opdivo) quickly showed that even low doses elicited responses. The antibodies weren’t particularly toxic, either. Preclinical data suggested additivity, if not synergy, of PD-1 and CTLA-4 antibodies, so the next logical step was to add PD-1 antibodies to CTLA-4 antibodies. A trial of ipilimumab with nivolumab followed these early results.
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Patients with large burdens of disease responded quickly and had long durations of responses, showing the regimen to be active and seemingly more efficacious than either single-agent. The phase II and phase III CheckMate 069 (NCT01927419) and CheckMate 067 (NCT01844505) studies later demonstrated a high response rate (RR)—more than 50% for the combination—which meant that we had advanced a long way in 10 years.
We had gone from a 15% or 20% RR with single-agent ipilimumab to a 35% to 45% RR with the PD-1 antibodies. Now, we were seeing a 55% RR with the doublet regimen of ipilimumab and nivolumab. CheckMate 069 led to the approval of the combination therapy.
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