Targeted Therapies in Advanced NSCLC - Episode 2
Transcript:Mark A. Socinski, MD: Since 2009, when the IPASS trial was published, we’ve seen advanced nonsquamous—mainly adenocarcinoma of the lung—transform into a genotypic disease. What I mean by that is that it’s not enough to say that a patient has adenocarcinoma of the lung. We need to know the genetic makeup of that cancer. It is akin to breast cancer, an adenocarcinoma of the breast.
An oncologist would not make a therapeutic recommendation without knowing estrogen and progesterone receptor status, as well as HER2 status. Those define therapeutic paradigms that are followed for the benefit of the patient. In adenocarcinoma of the lung, our current guidelines say that all patients must be tested for EGFR mutations and ALK translocations. And the reason is because the standard of care has changed in those subsets to targeted oral agents rather than standard chemotherapy.
The list beyond EGFR and ALK that I think are critical, are testing for ROS1—we have very good data with crizotinib in that setting—BRAF mutations, RET alterations, and MET alterations, either amplification or exon 14 skip mutations, which are a variety of abnormalities in MET that make that an oncogenic driver.
This list is going to continue to grow, but I think that oncologists today need to think beyond EGFR and ALK to ROS1, RET, MET alterations, and BRAF alterations, because we have effective therapeutics, for those patients, that may actually be better than standard chemotherapy—although we don’t have proof of that at this time.
Gregory J. Riely, MD: Whenever you go to an oncology conference, you probably walk away learning about a new mutation that you wish you were testing for because of some interesting data that says you can target it with some drug that’s approved in some other indication. The only way we can identify all these mutations in our patients, in an efficient way, is with next-generation sequencing.
Even in my own institution, we’ve had a big evolution in how we test patients. A number of years ago, we started just testing for EGFR mutations. We recognize that KRAS mutations were important, so we tried to do an analysis that combined EGFR and KRAS. And then over time, we saw BRAF was important, so we added that on. And then we learned about ALK and ROS, and we had to do FISH testing for those two things.
We did mutation testing, and then we did FISH testing, and it kept our pathologists quite busy. And probably the most important thing, is we ran out of tissue. So we did mutation testing for a handful of things, and then we went to do ALK-FISH testing. We got that done. Then we went to do ROS; there was no tissue left, so we couldn’t test for some of the key things that we really cared about that we thought would help our patients.
Moving forward, we went to a next-generation sequencing panel. Next-generation sequencing is an amazing platform that allows people to sequence hundreds of genes on a very small biopsy specimen. When we diagnose a patient with lung cancer, the most we can get is one or two core needle biopsies. When we go to test for mutations, we run out of tissue on that. But, if we use next-generation sequencing, we can identify mutations in hundreds of genes, and get those results.
The biggest challenge with next-generation sequencing, is understanding the results. You have hundreds of genes, and you find mutations in things that you’ve never heard of, and you don’t always know exactly what to do with that. Some next-generation sequencing providers will provide interpretation of the results, and sometimes the interpretation is a bit more open to disagreement than I would like.
I think that there are a number of things that we can target based on prospective phase II evidence showing that a drug works. If we draw our line there, next-generation sequencing is extraordinarily valuable for identifying all of those mutations and making the best opportunity for your patient. If we go on to some of the more esoteric mutations, for which we often hear everolimus is recommended, that’s probably not the best approach.
So, I think next-generation sequencing is the way of the future and it’s the platform that allows us to integrate any new mutations that we identify and get those fast results that we need to treat our patients.
Alice T. Shaw, MD, PhD: There are a number of different ways that we can diagnose oncogenic mutations or rearrangements in our patients. Early on for EGFR mutations, we were using sequencing—sometimes PCR-based sequencing methods. And that has been a very good and reliable method.
These days, we still are using sequencing, oftentimes next-generation sequencing, to identify EGFR mutations. Rearrangements are a little bit more difficult for us in terms of detection, and there are a number of different assays that we can use for detecting ALK rearrangement, for example.
The first FDA approved test for ALK rearrangement, is FISH, which is fluorescence in situ hybridization. It’s a break-apart FISH assay that has become adopted fairly widely around the world as a very standard test for ALK rearrangement. But it is a tricky assay—one that requires a lot of experience and expertise. I’ve seen both false positive and false negative calls with ALK-FISH, so it is a trickier assay.
Fortunately, we have a second FDA approved assay now for ALK rearrangement, and that is immunohistochemistry, or IHC. So that’s a Ventana ALK IHC system that’s now approved for use, and can also be used to detect ALK rearrangement. And we find ALK IHC to be very reliable. It’s looking specifically for expression of the ALK protein, which only occurs in the setting of a chromosomal rearrangement. And I think most people will find that ALK immunohistochemistry will end up being more reliable and cost-effective than ALK-FISH.
The third method I’ll mention for ALK rearrangement detection is next-generation sequencing. We’ve been using that more and more as well. So that’s also a good method to detect the presence of rearrangement. And the advantage of that is that we actually get sequencing data so we know what the ALK fusion partner is as well. So, I would say there are a number of different platforms that we can use for each of the different oncogenic drivers, and these are rapidly evolving; it’s kind of a moving target for these diagnostics.
Transcript Edited for Clarity