As Targeted Treatments Multiply, it's Crucial to Identify the Mutations Driving Lung Cancers


There are a host of treatments available for non-small cell lung cancer (NSCLC) these days, and for patients, perhaps the most crucial step in choosing one is to make sure a pathologist genetically sequences the tumor, so that doctors will know which mutations are driving the cancer.

There are a host of treatments available for non-small cell lung cancer (NSCLC) these days, and for patients, perhaps the most crucial step in choosing one is to make sure a pathologist genetically sequences the tumor, so that doctors will know which mutations are driving the cancer.

This is vital because there is a growing array of targeted drugs, both approved by the Food and Drug Administration (FDA) and experimental, that are capable of honing in on specific gene mutations to stop their detrimental activity. For some patients, these drugs can be more effective than treatments that affect both sick and healthy cells, such as chemotherapies, and can have less bothersome side effects.

There are targeted drugs designed to stop the dangerous activity of a number of rare, cancer-causing mutations, including rearrangements of the ROS1, ALK, RET and TRK genes and mutations of the MET or EGFR genes. The drugs work by quieting proteins, or kinases, made by these defective genes, which sit on the outsides of cancer cells. That’s why many of the novel drugs are described as “kinase inhibitors.” Some of these drugs have the added benefit of being able to treat the central nervous system, meaning that they can cross the blood/brain barrier and fight any spread of the cancer to the brain.

In a recent interview, OncLive, one of CURE’s online sister publications, discussed the state of this field with Alexander Drilon, M.D., a medical oncologist who specializes in treating lung cancer at Memorial Sloan Kettering Cancer Center, in New York.

OncLive met with Drilon at the 18th World Conference on Lung Cancer, held by the International Association for the Study of Lung Cancer Oct. 15-18 in Yokohama, Japan.

Q: There are targeted agents available that can treat ROS1 gene rearrangements, and more are being studied in clinical trials. What should patients know if they’re told they have this type of genetic glitch?

A: We know that ROS1 rearrangements occur in about 1 to 2 percent of NSCLCs and, fortunately, they’re highly (treatable) drivers. Crizotinib (Xalkori) is a ROS1 inhibitor that also inhibits ALK and MET and is approved by the FDA. For the treatment of patients with advanced ROS1-rearranged lung cancer, we’re trying to move the needle forward by looking at better therapies that target ROS1. (These treatments may turn out to be more potent and better able to cross the blood/brain barrier than the therapies already approved).

(The experimental drug) entrectinib is a multikinase inhibitor that has activity against ALK, ROS1 and TRK. (In phase 1 and 2 clinical trials in patients with ROS1-positive NSCLC,) the overall response rate with entrectinib was about 75 percent, with a comparable response rate in the central nervous system and a progression-free survival (PFS) of 19 months. That’s similar to our experience with the efficacy of crizotinib. However … entrectinib was designed to penetrate the blood/brain barrier, and we know that it probably will have better central nervous system efficacy. Beyond that, if you look at the preclinical data comparing crizotinib and entrectinib side by side, entrectinib is much more potent than crizotinib … So, the hope (is that) we’ll see a prolongation in PFS.

What should people know about non-small lung cancers that are driven by MET mutations?

We’ve known about MET as a driver for a long time, and many different drugs have been developed to target (this mutation that’s present in 1 to 4 percent of NSCLCs). These are both antibodies … and TKIs. We’ve learned in the last couple of years that there are specific (MET-related biomarkers) that are probably bona fide drivers of tumors. The first of these is MET exon 14 splicing mutations. The second is highly MET-amplified lung cancers. For both of these, we have data now with several agents, including crizotinib, (the experimental) capmatinib and other TKIs, showing that patients with either alteration can respond very well to targeted therapy.

The second state where we see MET activation playing a substantial role is in acquired resistance (to targeted treatments). We know that, (when patients take) the EGFR TKIs, … we’re seeing MET amplifications emerge as a mechanism of resistance. In fact, with the recent data set with osimertinib, we’re seeing about 30 percent of cases in that one series (develop) MET amplifications on top of the original … mutation. We have clinical trials now looking at combination therapy of an EGFR TKI and a MET TKI, and are seeing responses in patients who have a MET amplification. We’re seeing a trend where you need a higher level of MET amplification to see the most meaningful response rates.

Why is it important for targeted drugs that treat NSCLC to be able cross the blood/brain barrier to reach the central nervous system?

NCSLCs, in general, are tumors that like to metastasize to the central nervous system compartment and cause both parenchymal brain metastases and, in some cases, leptomeningeal disease, which is a bad prognostic feature. (That’s why,) in drug development, we need to focus on the central nervous system penetrance of these agents.

A good lesson … is what we’ve seen with ALK-rearranged lung cancers. The ALEX randomized phase 3 trials were a head-to-head comparison of crizotinib and alectinib (Alecensa). (Alectinib) offers improved central nervous system coverage, and we’re seeing that (it sparks) much more durable disease control, with prolonged PFS compared to crizotinib. This drug is also more potent against a variety of other mutations that may emerge and drive resistance to earlier therapies like crizotinib.

A similar story is with the FLAURA trial data in patients with (EGFR-expressing NSCLC. In one arm, this trial) randomized patients in the firstline setting to erlotinib (Tarceva) or gefitinib (Iressa). (Patients in the other arm took) osimertinib (Tagrisso), which, in addition to coverage for T790M (mutations), offers much more favorable central nervous system coverage. With that (data) readout, we’re seeing a prolongation of PFS.

Why is next-generation sequencing of NSCLC tumors vital?

Next-generation (comprehensive) sequencing (of mutated genes in tumors) will be a vital way we approach molecular profiling for patients with NSCLCs. In the past, when we knew about maybe a few (cancer-driving) genes like EGFR, ALK or ROS1, it was easier to come up with a more focused or targeted approach by doing piecemeal testing for these individual genes. But we’ve found that, now, when you (fail to test all at once for every possible known gene mutation that can cause NSCLC), you can end up wasting much more tissue, because you need more biopsies, which obviously can result in a higher amount of (complications) for patients.

Next-generation sequencing is really one big catch-all test. If you choose the appropriate assay, you’re able to catch mutations, fusions and amplification events. As we know, many of the newer drivers, MET exon 14 splicing alterations, the newer fusions like NTRK, RET, NRG1 and things like MET copy number changes — these are things you’re not able to detect with the older algorithm. It’s important to choose a comprehensive test, because when you put all these rare events together, they make up a substantial proportion of the pie.

Our approach at our institution is that we recognize that there are sick patients who need an answer very quickly, and so we do a rapid phase of profiling (with) a turnaround time of 24 to 48 hours. That’s coupled with liquid biopsies, where you get an answer in five to seven days. The rest of the tumor sample is then sent for comprehensive testing, which can take anywhere from two to six weeks, depending on the assay you choose. But, absolutely, it’s a paradigm that is being adopted more and more, especially in the community setting, where oncologists are sending broader panels for sequencing of the patients’ tumors.

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