WIN 2016
New targets in personalised therapy for patients with lung cancer
Prof Bruce Johnson - Dana-Farber Cancer Institute, Bethesda, USA
To be able to come to the WIN symposium, to be able to go over some of our information on precision medicine in lung cancer. One of the things that happened, I was involved in the initial discovery of the first oncogenic driver that could be effectively targeted in lung cancer, that is the EGFR mutation. That took place twelve years ago. Since 2004 we have been able to continue to identify additional genomic changes in lung cancer that we can effectively target with different pharmaceutical agents.
Could you tell me more about EGFR’s role in cancer therapy?
In 2004 when it was discovered it was part of Discovery Laboratories, that is people were doing sequencing in specific laboratories and then making the association between dramatic responses to inhibitors of the epidermal growth factor receptor tyrosine kinase inhibitors, and at that time it was including gefitinib and erlotinib. Subsequently it became a diagnostic test that became available in commercial laboratories around the world. Then after five years prospective clinical trials demonstrated that patients could have a dramatic prolongation in the time it took for their tumours to grow, that is progression free survival wherein six different trials around the world when inhibitors to the epidermal growth factor receptor were given as oral pills they were able to double the length of time that the medication worked compared to conventional chemotherapy.
Not only did it work better in terms of how long it took for the tumour to grow but also the side effects are dramatically reduced where patients could be taking these medications for many, many months and sometimes even up to years and tolerate the agents relatively well.
How do you see the ongoing discussions at WIN becoming part of standard care?
One of the things that we’re going to be talking about at this symposium, both by myself as well as some of my colleagues, is the ongoing perfection and modification of existing agents directed against different targets. For instance, Bill Sellers from Novartis talked about improving the pharmacologic properties of the agents directed against ABL, the translocated gene in chronic myelogenous leukaemia. One of the things we’ve seen in lung cancer with the ALK rearrangements is the development of more potent and more specific inhibitors. The first agent that was effective for the ALK rearranged tumours that we find in lung cancer was a drug called crizotinib. That’s an agent that’s effective against the ALK rearranged tumours and it’s also effective against a number of other different targets in lung cancer and other tumours. Therefore it has a broad array of anti-tumour activity but it’s not as specific or as potent as some of the other newer medications. Crizotinib caused responses in the majority of patients with lung cancer that had ALK rearranged tumours, however, the duration of time that it worked in patients who had not received an ALK inhibitor was about ten months. By developing agents that are more than tenfold potent and have higher specificity, and there are two different agents that have now been approved called ceritinib and alectinib, and by having agents that are tenfold more potent and more specific the length of time the agents work has gone from about ten to twenty months, you see a doubling of the progression free survival. We anticipate that going forward we’re going to see ongoing work of making agents that become increasingly potent and increasingly specific so that the duration of time with which they work is longer and it avoids the development of some of the resistance over that period of time.
What are your thoughts on the importance of patient advocacy here at WIN?
One of the things that we agree with here at the WIN symposium of involving the patient advocates is the importance of them informing us about how well the therapies are involved. Secondly, what they perceive is how they can participate in the research. One of our patient advocates was a person who had lung cancer and he had the ALK rearrangement that I just mentioned about those drugs. One of the things that has happened, and I’m a person that sees and treats people with lung cancer, is the willingness of our patients to participate in the trials. And not only participate in the trials but also take the time and effort to undergo additional biopsies to find out not only why the medication is working but also why it quits working. One of the things that has informed us is that with the targeted agents there are a limited number of reasons why the drugs quit working. Once you define why they quit working you can either design therapies for patients with that mechanism of resistance or you can design drugs to prevent them from ever happening.
One of the examples that has taken place that we learned from doing repeat biopsies on our patients given targeted therapies was with the mutations in the epidermal growth factor receptor. About 60% of the patients who developed resistance to the epidermal growth factor tyrosine kinase inhibitors develop a specific type of mutation called a gatekeeper mutation. The one in the epidermal growth factor receptor is T790M, that takes place in about 60% of the patients. By identifying this a pyrimidine based irreversible inhibitor was synthesised and reported in Nature about seven years ago. From that backbone a number of different agents were synthesised and multiple ones have now gone into trial. In the patients who had developed acquired resistance mediated by the T790M the patients respond about 60% of the time and it works for about ten months but some people it can work for a number of years. So by doing these biopsies that our patients had willingly participated in we’ve been able to define the mechanism of resistance and then develop the next generation of inhibitors.
Do you have a take home message?
One of the things that the conference has is that it’s focussing on some of the common adult epithelial tumours. We’ve seen a lot of presentations on colorectal cancer, we’ve seen a number of presentations on lung cancer. The thing I would like to see is more information on how we’re learning from what’s going on in the other tumours that should be informing what’s going on with lung cancer, stomach cancer, lung cancer. So, for instance, stomach cancer in Asia is more common than colorectal cancer so it would be nice for us to begin informing ourselves worldwide of what’s going on that can teach us things about what’s going on in the Western populations.
One of the things about coming to the WIN symposium is it focusses on a broad array of tumours but all on precision medicine and the lessons that we learn from the different tumours are important to understand going across the tumours so that we don’t need to repeat the research that’s informing others but yet also to learn about how each of the tumours is different.
