Faster Turnaround Times and Other Advances in Precision Medicine

Alain Mita, MD, is a medical oncologist who has been principal investigator in more than 50 early drug development studies, as well as several Phase II and III studies. Dr. Mita has helped develop several anticancer drugs that have been granted FDA approval. Prior to joining Cedars-Sinai in August 2011, he was associate professor in the Department of Medicine at the University of Texas Health Science Center at San Antonio. His role at Cedars-Sinai as co-director of the Experimental Therapeutics Program at the Samuel Oschin Comprehensive Center is to develop infrastructure for clinical trials and build the pipeline of novel targeted anticancer therapies to increase available treatment options for patients. His major interests in his own research include new treatments for lung cancer and new agents capable of inducing cancer cell death by apoptosis.

How is precision medicine advancing patient treatment?

Precision medicine is one of the major advances in oncology treatment over the last 15 years or so. It all started when we identified driver mutations and the genetically mutated pathways in cancer that lead to cancer growth and spread, and with the identification of drugs that can specifically target these driver mutations and have a major impact on patient survival. 

“The old paradigm that all lung cancers are the same and all colon cancers are the same and all breast cancers are the same is long gone.”

The old paradigm that all lung cancers are the same and all colon cancers are the same and all breast cancers are the same is long gone. We are trying now to really molecularly characterize every patient with cancer and to identify the driver mutations and customize the treatment based on those driver mutations. So again, in the field of lung cancer, we started about 15 years ago when we identified EGFR driver mutations and that led to the approval of the first targeted therapies for lung cancer. Since then we’ve made tremendous progress; currently we manage to identify driver mutations in the majority of lung cancers, which was not the case just a few years ago. A few years ago, in more than half of our lung cancer patients, we couldn’t identify a driver mutation. Now this unknown field of driver mutations is less than 25 percent of the patients.

Even if we identify driver mutations, there are still some mutations for which we do not yet have adequate treatment. But we are trying and that’s where our program comes in. With these experimental drug Phase 1 studies, we are trying to identify treatments for the newer mutations and hopefully, in the not so distant future, we’ll have treatments for every single one of these driver mutations.

What would you say is the greatest challenge physicians face when implementing precision medicine?

I think that nowadays physicians acknowledge the importance of identifying driver mutations. The big challenge is not that the physicians are not aware of this, but it’s a matter of making timely decisions. Just around four or five years ago, we were doing sequential identification of the driver mutations. We were testing for EGFR and if the test was negative, we were testing for ALK and if that was negative, we were going for other mutations—you would have to choose. But for the last four or five years we’ve had the multiplex testing. That has changed the field because we can test for all of these mutations simultaneously and we don’t have the problem of whether we have enough tissue to test for one versus another; we can test for all of them at the same time. There was still the problem that it took about two to three weeks to get the results back. Some patients were sick enough or eager enough to start treatment that they didn’t want to wait for the results and there was the temptation to start on something right away instead of waiting to see what the best treatment was.

Finally, over the last couple of years, with the evolution of technology, these timelines are becoming much shorter. I’ve had the opportunity of working together with some of these newer technologies that can provide results within 24 hours, which is absolutely astonishing and allows the physicians to make timely decisions and to make the best decision.

In what other ways have new technologies improved precision medicine?

One of the other challenges is the sensitivity and specificity of the test. There is no perfect test and we have to make sure with confidence that the result the test brings us is right and not a false negative or a false positive. That was also a problem in the past, but I think that technology is getting better and better.

Another problem was the amount of tissue that was needed for the biopsy because again, in the not-so-distant past, we needed to provide a big piece of tumor to be able to perform all of these tests. Now these tests can be performed on a very small amount of tissue and soon we may be able to do that on one single cell, which is quite remarkable considering where we came from.

Then the last piece of the puzzle is that sometimes we identify driver mutations for which we don’t yet have treatments. The best and most recent example is the KRAS gene. We know that there are different mutant forms of KRAS, and they are not all identical and there are now treatments that can treat certain KRAS mutations but not others. We’ve known about KRAS for more than 30 years and have been trying to target it for the last 30, and yet we have not been able to come up with treatment until last year. That was when we developed the first treatment that targets KRAS, granted it only targets a certain mutation, specifically G12C. But soon I’m pretty confident that other treatments will become available for the other mutants. I hope that in the future we will be able to have targeted therapies for all these identified driver mutations.

“Some of these newer technologies can provide results within 24 hours, which is absolutely astonishing and allows the physicians to make timely decisions and to make the best decision.”

Have there been any other recent advances related to developing treatments?

We are getting better at understanding not only the driver mutation but also the mechanism of resistance because all of these treatments work for a while and then they stop working. We’re now starting to understand why the treatment stops working and we have second- and third-generation treatments that can reverse this resistance. That is becoming critical because if you identify why the treatment fails and you have a backup plan, that will expand the patient’s life by a considerable amount of time. Sometimes now we can even prevent the development of resistance and this is the very exciting direction that I think the field is moving.

Can you explain the difference between first-, second-, and third-generation treatments?

Let’s take one example that is easy to understand. When we identified the activating mutation for EGFR and we came up with the first treatments that were targeting that mutation, erlotinib and gefitinib, those were remarkable drugs and they did result in improved survival compared to chemotherapy. However, resistance to these treatments is unavoidable— it happens 100 percent of the time. By performing additional biopsies and trying to molecularly characterize these resistant tumors, we identified other mutations, for example EGFR T790M. Then we generated a second generation of EGFR inhibitor that can potentially inhibit that T790M mutation and drugs like osimertinib that target the same gene, the EGFR, but they are more precise against certain variants of this mutation and they can work and treat cancers that have become resistant to the first-generation treatment. And now we have third-generation treatments and they are evolving daily; this is true not just for EGFR, but also for other mutations such as ALK and BRAF. It’s the result of relentless clinical research and partnership with industry and perfecting our cancer treatments every year.