Geoffrey R. Oxnard, MD: For over 10 years, we have been trying to find genomic targets that create treatment options instead of chemotherapy for our lung cancer patients. That started with EGFR mutations over 10 years ago, and has evolved to include less common variants like ALK rearrangements, ROS rearrangements, and BRAF mutations. We know now that if we can find a genomic target, we can offer the potential for a durable response with a pill therapy with few side effects, and this is a really compelling alternative to chemotherapy. It controls brain metastases and improves quality of lives; this is the pursuit of genomic targets that creates treatment options.
We now have FDA-approved targeted therapies for quite a number of targets. We have a range of EGFR inhibitors, some for initial treatment and some for resistance; a range of ALK inhibitors for initial treatment for resistance; and FDA-approved treatments for ROS rearrangements, BRAF mutations, and now PD-L1 immunohistochemistry, an additional molecular target. It means that we have all of these targets, and we need to test routinely for our lung cancer patients to create treatment options that are different than chemotherapy with its established toxicities and challenges.
Beyond those standard-of-care targets, there are additional clear genomic drivers that create off-label treatment options or clinical trial options. These include KRAS mutations, which are well described but have no immediately available therapy, but there are many trials under development. MET splice mutations seem almost as common as ALK rearrangements, and there are many available MET inhibitors. HER2 insertion mutations are clearly drivers. They occur in young individuals and in nonsmokers, but we don’t have great drugs to target HER2, though we have drugs coming along. For RET rearrangements, there are established RET inhibitors and new, exciting RET inhibitors coming. So, there always are going to be the targets where we have approved therapies, and then those additional targets where, if you dig deep, you can try to find off-label or clinical trial options for your lung cancer patients.
Sandip Patel, MD: I think most lung cancer patients who are never-smokers have a different biology to their cancer than those patients who are historically smokers. And so, for any subtype of non—small cell lung cancer—whether it’s adenocarcinoma, squamous, or even never-smokers with the rare small cell lung cancer—I would recommend comprehensive genetic profiling. Among squamous cell non–small cell lung cancers, anywhere from 10% to 15% of patients may have a driver EGFR mutation that you can treat with targeted therapy as opposed to chemotherapy.
Additionally, BRAF inhibitors and HER2 inhibitors may be a factor in about 5% of patients who are never-smokers with squamous histology. And so, I think, broadly, patients who have never smoked and have any form of lung cancer should undergo comprehensive screening for various genomic aberrations, including, at the very least, EGFR, HER2, BRAF, ALK, and ROS1.
Typically, for our patients at UC San Diego Morris Cancer Center, patients will undergo tumor-based tissue sequencing with a next-generation platform—often testing at least 300, 350, or 400 genes. Now, with the availability of clinical exome, we often do this kind of testing in patients with a very specific scenario. For example, a patient who has never smoked and has undergone 300- 400-gene panel testing, who still doesn’t have a known driver mutation—those are patients we may think about for whole exome-based sequencing strategy. Additionally, we’ll often utilize cell-free DNA approaches. This is the so-called liquid biopsy that looks at DNA from cancer in the blood. This is particularly helpful in patients who have difficult-to-reach tumors in terms of biopsy, or patients who are on targeted therapy such as EGFR inhibitors who develop resistance, unfortunately. We’re looking for a specific resistance mechanism such as T790M.
Geoffrey R. Oxnard, MD: My general take on lung cancer is that if you find a driver, that is the driver of that patient’s cancer for the duration, right? A KRAS mutation, an EGFR mutation, these don’t vanish, they don’t change. And so, the chase is figuring out when the right moment is to find that driver and to make sure that your patients get effective genomic testing. I have patients where I test and I test again. Not because I’m looking for a change in their driver, but because sometimes I don’t trust that my prior testing was complete enough or thorough enough, and I want to ensure that for those patients who are motivated—nonsmokers who are younger—that I turn over every stone to get them a genotype that creates treatment options for them.
I will say that if you’ve treated an EGFR-mutant lung cancer, we know that dependencies can evolve and it can acquire new targets. Some common ones, like T790M, and some rare ones, like we’ve seen with acquired REC rearrangements. We know that the genomic makeup of a cancer can evolve under the pressure of targeted therapy, and that can create new treatment strategies to overcome resistance.
Transcript Edited for Clarity