Evolving NSCLC Treatment Paradigm - Episode 3
Justin Gainor, MD:The success of targetingEGFR,ALK, andROS1has spurred additional efforts to identify additional oncogenic drivers that can be targeted therapeutically. Over the past several years, there have been several notable examples with very promising clinical data that we’ve seen. Important examples of this includeRETrearrangements,METexon 14 skipping, andNTRKrearrangements. So, takingRETrearrangements as an example:RETrearrangements were first identified in lung cancer in late 2012, early 2013. These were found in about 1% to 2% of patients, and they tended to have characteristic clinical and pathologic characteristics. Like other oncogenic rearrangements,RETrearrangements resulted inRETfusions, and these tended to occur in patients with a light- or never-smoking history.
At the time these were first identified, we didn’t really have selective RET inhibitors in the clinic, and so investigators relied on multikinase inhibitors that targeted multiple kinases, not justRET. And so early on, the response rates that were seen with these multikinase inhibitors were relatively modest compared with other oncogenic drivers in lung cancer. So, we observed response rates in the 20% to 30% range. More recently, there have been 2 selective RET inhibitors that have entered clinical testing, and both have shown high response rates, confirming our initial suspicion thatRETis a bona fide oncogenic driver mutation in nonsmall cell lung cancer.
Like the experience withRET, another emerging oncogenic driver in lung cancer has beenMETexon 14 skipping mutations. Here, the pathophysiology is quite distinct, so exon 14 encodes the CBL-binding region inMET, which is important in that it targets the protein for ubiquitin-mediated proteasomal degradation. In the setting of an absence of exon 14, you get decreased degradation ofMET, which results in increased accumulation ofMETon the cell surface. We found thatMETexon 14 skipping is found in about 3% to 5% of patients. And like other oncogenic drivers, it does appear thatMETexon 14 skipping mutations confer sensitivity to treatment with MET-targeted therapies. So, this does appear to be another driver mutation that may be important to test for moving forward.
Alexander Drilon, MD:Tumor mutational burden on a very simplistic level is a measure of how complex a cancer is, meaning the number of mutations that occur within the tumor. And we found that depending on the assay that you use, you can measure TMB, or tumor mutational burden, by counting the number of what we call nonsynonymous mutationsmeaning if you have many more mutations that count as a high score versus if you have much fewer, that would be an intermediate or a lower score. The TMB-high patients, those have been associated with benefit from immune checkpoint inhibition, and, again, this cutoff varies depending on the test that you use. But it seems like there is an association between cancers that are TMB high that have a greater proclivity for response either to single-agent immune checkpoint blockade or to combination immune checkpoint blockade. And so, it’s 1 of the potential biomarkers that we’re looking at in the immuno-oncology space.
Now, TMB doesn’t always completely coincide with the level of PD-L1 expression on cancers, and so I think the approach that’s favored now is to treat these as overlapping but independent biomarkers. And so, if I have a patient who, for example, may have a PD-L1negative tumor but really has a high TMB score, I would think very carefully about whether or not I might get immunotherapy to that patient, even though the PD-L1 status is negative.
Justin Gainor, MD:As the number of targetable genetic alterations increases, it just becomes infeasible to perform single-gene tests one after the other. It really speaks to the need to comprehensively evaluate the genetic landscape of the tumor and do so while simultaneously using the least amount of tumor tissue available. And to that end, I do think that next-generation sequencing using multiplexed assays is becoming the standard of careif not is already the standard of care at most academic institutions—which really does speak to the need to rapidly assess the genetic landscape of the tumor and do so while preserving tissue for future clinical trials.
Transcript edited for clarity.