27th - 28th Jun 2016
Prof Schilsky speaks with ecancertv at WIN 2016 about changing understandings of cancer aetiology and treatment.
He discusses the growing application of immunotherapy, including checkpoint inhibitors, but cautions against a rush to adopt combination therapy without considering the adaptability and resistance development of tumour cells.
Prof Schilsky also comments on the SHIVA trial, as discussed by Dr Kurzrock, and the need for consistent communication and sharing of standards between clinics to advance personalised cancer care.
WIN 2016 highlights: Changing understandings of cancer
Prof Richard Schilsky - Chief Medical Officer of the American Society of Oncology (ASCO)
This year’s conference, like most of the WIN symposia, really has brought out some of the most innovative speakers, the most innovative science. There’s always something new at the WIN symposium that I hadn’t heard somewhere before. This year we had a fabulous talk by Andrea Califano who always gives a terrific talk but building on the systems biology approach that he has been developing to identify master regulators, switches in molecular pathways that, if targeted, have the potential to be much more effective as targets than the traditional single gene, single protein targets that we’ve been using up until now.
I thought the concept that was presented of viral mimicry was also fascinating, the concept being that we are programmed through evolution to have immune systems that are very effective in fighting viruses because viruses are infections that babies get so if you don’t have a good immune system to fight off a viral infection you’re not going to survive childhood. Cancer is a disease that mostly older people get and so the immune system is not as well prepared to fight off cancer but if you can somehow make your cancer look like it’s a cell that’s been infected by a virus then all of a sudden the immune system potentially becomes much more effective in targeting those cancer cells. So I thought that was a really interesting talk.
What aspects of immunotherapy interest you?
The remarkable things about immunotherapy, as we’ve now seen it unfold, are that it seems to work in just about every cancer type and there’s always a proportion of patients who have a long-term remission. So our challenge is to elevate that proportion of patients who have the long-term remission and we are beginning to learn now which patients are the most susceptible to immunotherapy. There are various biomarkers that have been in development that seem to be able to identify patients who are most susceptible but the one that’s becoming very compelling is a measure of the total mutational burden in the tumour. Again, the concept being that the more mutations the more abnormal proteins are produced by those mutant genes and those abnormal proteins then become recognisable by the immune system so that if you take the brakes off the immune system with a drug like an immune checkpoint inhibitor then the immune system can really seek out and destroy the cancer cells very efficiently. So it’s a very interesting time.
Do you agree that combinations should become first line therapy?
We’ve certainly heard that repetitively throughout the meeting so far, that the great excitement about precision medicine is that when you have a specific target that you know is a driver gene in the tumour and you have a good inhibitor of that target, clearly patients can get very immediate and very profound clinical responses. The problem, of course, that we’ve all come to recognise is that the tumours have a remarkable ability to become resistant and so those responses are not very long lasting. So the concept that has been developed in all medical therapeutics from tuberculosis to Hodgkin’s disease to HIV is combination treatment - hit the offending agent, whether it’s a tumour cell or a virus, with as many as drugs that hit as many vulnerabilities as possible. One of the big challenges, of course, is the tolerability to the patient of receiving those drugs. The good news is many cancer drugs are far less toxic than the chemotherapy drugs of years gone by so it’s going to be possible, again there’s not going to be a single, double or triple drug combination that’s going to work in every person; there may be unique combinations for each person. But this is where WIN is really taking a global leadership role in developing triple therapy for lung cancer with the SPRING trial that’s now in development for patients with advanced non-small cell lung cancer where we already now have a pharmaceutical company sponsor who is going to provide three drugs to support that study. So that study will certainly go forward. Then similar concepts being applied now in other settings within the WIN consortium. So we’re clearly in the forefront there.
How do you feel these could best be put into practice?
We had a session yesterday afternoon where we were having a debate, really, between two very well established investigators as to whether the clinical trial designs that we’ve relied on for many years, like prospective randomised clinical trials, still have a place in this modern era of targeted therapy for cancer. Christophe Le Tourneau presented an update of his analysis of the SHIVA trial, which various people have interpreted in various ways, and I personally think that the fact that the SHIVA trial did not demonstrate a benefit for patients receiving the matched therapy is not an indictment of the field of precision medicine, it only is an illustration of how complicated it is and that we need to continue to do research.
Razelle Kurzrock pointed out some of the flaws in the SHIVA trial and also pointed out, rightfully so, that it’s going to be very difficult to continue to advance precision medicine solely by doing prospective randomised trials. They take a long time to set up, they take a long time to complete, the field is moving very quickly and we need different kinds of clinical trial designs to be able to move the field forward. The one thing that we can’t do, I don’t think, is just move to widespread adoption of precision medicine. We heard, following the formal debate, many comments from people in the audience yesterday some of whom just said we’re ready to just move straight in to giving everybody a precision medicine approach without any proof that that necessarily is of value and, importantly, without any mechanism to capture and record the outcomes of those patients so all the rest of us can learn from those experiences. I think that’s going to be critical going forward.
What else at WIN 2016 are you looking forward to?
I’m looking forward, actually, to the session immediately following lunch today in which I will be participating which will be a round table discussion among many experts in the field focussing on what do we really need to do to continue to accelerate the development of precision medicine approaches. There are many things we need to do, personally I think one of the most important ones is to develop a common approach to annotation of all the genomic variants that are found in patients’ tumours. The tumours are remarkably heterogeneous and complex; we oftentimes don’t understand the biological or clinical significance of the abnormalities found in the tumours and we can’t act on those abnormalities if we don’t know what they mean. We need a common approach with common standards, common vocabulary, common definitions to be able to collectively provide the annotation that’s necessary to really apply precision medicine to its full potential.
So there are issues with communication?
Absolutely, it’s been very much that way and different laboratories report their results in different formats, different content, they have different bioinformatics pipelines, they have different strategies that they use for calling out what’s a variant. Most importantly, many of the variants that are discovered in patients’ tumours are not currently understandable in terms of the so-called variants of unknown significance. The only way we’re going to move from having a variant of unknown significance to a variant whose significance is known is to capture that information in a standardised format so everybody knows what we’re talking about and then capture information about what happens to the patient and what their outcomes are so we can understand what are the consequences of that variant being present.
Do you have a summary message?
As I said at the beginning, the WIN symposium is one of my favourite meetings. I go to lots of meetings, we all go to lots of meetings and we hear some of the most cutting edge science at WIN delivered by people who are working, who are the leaders in the field. There’s ample time for networking and discussion and we’ll continue to see this very forward looking view of precision medicine being described at the WIN symposia going forward.