The melanoma oral abstracts session at ASCO 2014 was packed as a full house in the Arie Crown lecture theatre listened to the latest on new immuno-oncology therapies that are leading a revolution in melanoma treatment.
In the Clinical Science Symposium on PD-1 blockade and in the oral session at ASCO 2013 we heard how PD-1 antibodies nivolumab, MK-3475 (now pembrolizumab) and the PD-L1 antibody MPDL3280A had high response rates, long durations of response with favourable toxicity. This led to melanoma suddenly becoming one of the hottest areas of cancer drug development.
Global incidence of stage III melanoma continues to rise, with a high 5 year relapse rate (89% in stage IIIc), so there remains a need for more effective treatment options. It’s particularly sad to see so many young people end up with metastatic melanoma from over-exposure to tanning beds or too much sun! After going to several melanoma sessions, I don’t go out as much in the mid-day sun here in Florida.
So what did latest data show at ASCO 2014? Is pembrolizumab better than nivolumab? Will combinations be more effective than single agent therapies alone and will toxicities impact the risk:benefit profile?
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In her ASCO Gastrointestinal Cancer symposium (ASCO GI) keynote presentation earlier this year, Elizabeth M. Jaffee MD described the future of immunotherapy as being in combinations.
Overcoming or delaying resistance mechanisms or hitting multiple targets to greater effect will be achieved through combinations of drugs rather than single agent therapy. Combination strategies are the accepted future, whether drug companies like it or not.
In her keynote, Dr Jaffee also likened the revolution in immunotherapy to the same excitement the Beatles brought to music or the same magnitude of technology advances made by Apple. We agree completely.
Thought leaders at ASCO expressed similar sentiments. Steven O’Day (UCLA) said,
“This is truly a brave new world of immunotherapy. I think the message is that the revolution is here, it’s ongoing, and it’s bursting out of melanoma into solid tumors.”
Interestingly, no immunotherapy data was considered to be of worthy of presentation in the plenary session at ASCO this year for the second year running, a decision that may reflect either an unwillingness to showcase early data, however good it may appear to be, or the influence of politics on the selection committee.
One potential combination is to target more than one checkpoint pathway to see if you can obtain a synergistic response. This is the rational for combining the monoclonal antibody ipilimumab and nivolumab. Ipilimumab (Yervoy) targets the CTLA-4 checkpoint protein that prevents dendritic cells from priming T cells to recognize tumors while nivolumab targets the PD-1 checkpoint protein that prevents T cells from attacking cancer cells. Yervoy is an FDA approved therapy for the treatment of metastatic melanoma.
Data published last year in The New England Journal of Medicine by Wolchok et al, showed that combining ‘ipi’ with ‘nivo’ gave more frequent and deeper responses in melanoma, but at the expense of much greater toxicity. Some 53% of patients receiving concurrent treatment had a grade 3-4 adverse event (see Table S-1B in the article).
Does it make sense to combine two immune pathway modulating agents? Does the enormous potential for synergy outweigh the additional toxicity?
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