The treatment landscape changed significantly with the first melanoma clinical trials in 2001, which evaluated the CTLA-4 antibodies ipilimumab (Yervoy) and tremelimumab.
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.
So as of 1999, the outlook was dismal for patients with metastatic disease and the data suggested that fewer than 10% of patients with stage IV disease would survive 5 years.
The treatment landscape changed significantly with the first melanoma clinical trials in 2001, which evaluated the CTLA-4 antibodies ipilimumab (Yervoy) and tremelimumab. It quickly became obvious that these antibodies could induce long-lasting responses in a minority of patients. Even those with stable disease and partial responses appeared to benefit from the antibodies and would live longer.
The data with CTLA-4 antibodies, while showing a significant level of dose-related toxicity, led to multiple trials that directly precipitated ipilimumab’s approval. The MDX-010-020 study (NCT00094653), the pivotal ipilimumab trial, was the first randomized phase III trial ever to show benefit in melanoma.
It was a very significant moment and set the scene for further development of checkpoint inhibition in cancer. I recently saw a photo of the investigators from that study, including myself, from ASCO 2010, where the data were presented. We were all smiles because we were about to hear that the first effective therapy for metastatic melanoma was here.
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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.
However, it wasn’t just nivolumab that looked encouraging; pembrolizumab also showed promise in early studies before its 2014 approval.
We began to apply these new agents to the adjuvant mode, where patients remain at a high risk for relapse after surgery. The BMS-029/EORTC 18071 (NCT00636168) trial suggested a clear benefit in relapse-free survival and overall survival with ipilimumab. The next results of the adjuvant trial, CheckMate 238 (NCT02388906), led to the approval of nivolumab in that setting in 2017.
Targeted therapies were also coming along. In 2002, it was evident that there were major genetic drivers of melanoma growth and metastasis such as the mutated BRAF gene.
Patients with BRAF mutations could have rapid, dramatic responses to BRAF inhibitors, but these responses were typically short in duration. The addition of MEK inhibitors increased the potency of BRAF inhibitors and decreased their toxicity. After the approval of the first 2 BRAF inhibitors, vemurafenib (Zelboraf) and dabrafenib (Tafinlar), along came the BRAF/MEK combinations vemurafenib and cobimetinib (Cotellic), and dabrafenib and trametinib (Mekinist). We now have 3 sets of targeted drugs following the 2018 approval of the third BRAF/MEK doublet, encorafenib (Braftovi) and binimetinib (Mektovi).
As immunotherapies were used in the adjuvant mode, so were targeted agents. The encouraging results of the adjuvant COMBI-AD study (NCT01682083) led to the 2018 approval of adjuvant dabrafenib and trametinib for patients with high-risk resected stage III melanoma. Almost every patient with resected stage III or IV disease is now receiving adjuvant therapy, which is going to change [the way that we approach] melanoma.
Next came the adjuvant CheckMate 915 trial (NCT03068455), which is evaluating the combination of ipilimumab and nivolumab. If it’s positive, every patient with high-risk melanoma with a chance of relapse will receive combination immunotherapy; this will continue to change the landscape of melanoma.
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Jeffrey S. Weber, MD, PhD, is Deputy Director of the NYU Langone Perlmutter Cancer Center.
We have multiple ongoing combination studies, and it’s anyone’s guess what the most effective regimen will be [5 or 10 years from now], but one thing remains clear: The world of melanoma has made a huge amount of progress in the past 20 years.
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.