The ASCO Wall 2016
There has been much frustration on many fronts at the number of trials that do not see a relationship between PD-L1 expression and response. Some do, but many don’t. This has lead to quite a few investigators suggesting that the IHC assay may not be as useful as originally hoped, for predicting response to checkpoint blockade or selecting patients for therapy.
While we often do see a trend for more responders with higher levels of expression, the main issue is that PD-L1-negative patients can also see some responses, albeit at a lower rate.
There are many factors that can affect the measurement:
- Fresh vs. archival tissue
- Heterogeneity within the tumour
- Tumour cells (TC) vs. immune cells (IC)
- Different antibodies used for each assay
- The dynamic nature of the tumour microenvironment – does timing of the biopsy matter?
- Human error – a pathologist has to eyeball the IHC readouts and decide the level of staining intensity
And so on. These are just a few examples of the factors that can potentially affect the results, making it quite a challenging test to undertake. There is also time – does the level of expression vary temporally depending on which prior therapies are administered?
It would be easy to be disheartened by this, but fear not!
There were some impressive new data presented at ASCO that were not only intriguing, but also show us a way forward on how a multi-factorial approach could be used in different tumour types. By this I mean we might end up with different tests used in conjunction for several different cancers in order to a) predict responders and non-responders and b) better select patients for appropriate regimens or clinical trials.
It’s not going to be as easy as one size (or test) fits all. Sometimes a more more sophisticated approach will be needed. New data at ASCO gave us hints on what’s to come in this direction.
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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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