clinical topic updates
Emerging Targets to Consider Including in a Larger Molecular Testing Panel
There are several targeted therapies that are approved by the US Food and Drug Administration (FDA) for patients with specific oncogenic alterations in non–small cell lung cancer (NSCLC). There are also agents for other specific genetic abnormalities on the horizon.
Vice Chair, Clinical Research
“Since we now have FDA-approved therapies for MET exon 14 mutations and for RET gene rearrangements, we should be trying to identify these alterations in all of our patients with NSCLC. Additionally, targets for other specific genetic abnormalities are on the horizon.”
Patients with NSCLC often have EGFR gene mutations or the ALK fusion oncogene, and, generally, these are alterations that will persist, staying with these patients throughout their disease course. FDA-approved therapies are available to treat patients with these oncogenic drivers. Additional alterations may be present at the time of diagnosis, along with the more common alterations, and EGFR mutations with MET amplification is an example. And then, frequently, resistance mutations will emerge at some point after the initial success with targeted therapy in a patient with a single actionable driver.
When considering the newer and emerging targetable drivers in metastatic NSCLC, it is useful to divide them into the following 2 categories: those with recent FDA approvals and those that we anticipate being able to target clinically in the near future. Regarding the first category, 2 therapies were approved in 2020 (ie, capmatinib and tepotinib) for mutations that lead to splicing abnormalities in the MET gene (ie, MET exon 14 mutations). These mutations result in overactive MET signaling, so targeting those alterations is a reasonable approach. Similarly, we saw the approval of agents targeting the RET gene rearrangements (ie, selpercatinib and pralsetinib). Since we now have FDA-approved therapies for MET exon 14 mutations and for RET gene rearrangements, we should be trying to identify these alterations in all of our patients with NSCLC.
Additionally, targets for other specific genetic abnormalities are on the horizon, and we anticipate being able to treat our patients with NSCLC with these targets in the clinic in the near future. These include KRAS G12C mutations, EGFR exon 20 insertions, and HER2/ERBB2 mutations.
KRAS is the most common oncogenic driver in patients with NSCLC. There are different point mutations that occur in KRAS, and the most common is the KRAS G12C mutation. There are a number of drugs (eg, sotorasib and adagrasib) that are currently in development that have been shown to lead to responses in patients with KRAS G12C–mutant NSCLC, and we hope for and await the FDA approvals of newer agents in the coming year.
Further, agents such as mobocertinib and amivantamab are in development for patients with EGFR exon 20 insertions. These insertions have generally been thought to be resistant to the available EGFR tyrosine kinase inhibitors and, collectively, they occur in approximately 1% to 2% of patients with NSCLC. Overall response rates of approximately 40% have been reported with mobocertinib and amivantamab in previously treated patients with NSCLC with EGFR exon 20 insertions.
Finally, HER2 mutations occur in approximately 1% to 2% of patients with NSCLC, and we have seen promising data with antibody-drug conjugates suggesting that these are targetable oncogenic drivers in NSCLC. Thus, drugs such as trastuzumab and deruxtecan have a potential role in HER2-mutant disease, and we may have FDA approvals in the coming year for this group of patients.
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