Melanoma has been at the very centre of the cancer immunotherapy revolution over the past decade and a half. The CTLA-4 inhibitor Yervoy (ipilimumab), which gained approval in 2011, was the first agent to demonstrate a survival improvement in a phase 3 trial for metastatic melanoma. It was also the first immune checkpoint inhibitor to gain approval, and it kick-started a whole new era in cancer therapy, based on jamming the cancer’s immunosuppressive signals to enable patients’ T-cells to attack cancer cells.

The first PD-1 inhibitors followed shortly afterwards, and these proved even more active. Combinations proved even more potent again: patients on Yervoy and Opdivo (nivolumab, a PD-1 inhibitor) had median overall survival of 72 months on the CheckMate-067 trial which Bristol Myers Squibb conducted – 49% of patients treated were still alive after six and a half years, and 77% of them were no longer on treatment. The same company recently gained approval for another combination, Opdualag (relatlimab, a LAG-3 inhibitor, and the PD-1 inhibitor nivolumab), which offers similar levels of efficacy but causes less side effects. In parallel, small molecule kinase inhibitors have also proven active, in melanomas with mutations in the BRAF proto-oncogene, which leads to a cellular growth switch being turned permanently on.

Despite these advances, many patients eventually relapse, and work is ongoing to address the problem. The first tumor infiltrating lymphocyte therapy gained approval earlier this year, and others are in development. The first individualised cancer vaccine is also nearing approval. The hope is that these new therapies will help at least some relapsed patients to achieve further long-lasting remissions.

Companies & organisations mentioned in this episode:
Amgen, Biontech, Array Biopharma, Bristol Myers Squibb, Daiichi Sankyo, Evaxion Biotech, Iovance Biotherapeutics, Merck, Moderna Therapeutics, National Cancer Institute, Obsidian Therapeutics, Pfizer, Plexxikon & Regeneron Pharmaceuticals.

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