We’ve noticed for a while now that trials involving immunotherapies have not just standard adverse events reported, but also immune related adverse events (irAEs). We saw these articulately in combination trials at ASCO earlier this month.
Most of these have involved colitis, hepatitis, pneumonitis and such like. If the signs and symptoms are picked up early through careful monitoring and education, these can be more easily managed and controlled.
What about auto-immune diseases?
Is there a risk of auto-immune disease with long term use usage of checkpoint blockade, especially in situations where patients may be treated until progression, which could be a long time if the patient is one of the lucky ones who get a durable complete response?
In today’s post we take a look at these issues. To learn more, subscribers can log in.
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?
To learn more about these insights, log-in for our analysis of the data on nivolumab in renal cell carcinoma (RCC) presented at ASCO 2014.