Is There an Optimal EGFR TKI? Examining the Evidence [Video Transcript]

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In this segment I'll be talking about the role of EGFR mutations in non-small cell lung cancer. I think what we know about EGFR mutations is that they occur in about 15% of all patients with advanced non-small cell lung cancer, adenocarcinoma, but that number is misleading. In patients that are female never smokers, that incidence can go up to 50%. It really speaks volumes about the importance of doing genomic profiling upfront for all our patients, so that we can identify these EGFR mutations, and allow them to receive targeted therapies, rather than chemotherapy.

I think what we know about the EGFR and the EGFR-TKI story in lung cancer is that—similar to other clinical scenarios—we have competing standards, which is not necessarily a bad thing. We have an embarrassment of riches with good options for patients—all pills. Currently there are 3 approved EGFR TKIs for advanced EGFR-positive patients.

There's gefitinib, erlotinib, and afatinib, and I think what we know about these drugs is that, when they compare these drugs to chemotherapy, they improve response rates, they improve progression-free survival, and, importantly and perhaps underrepresented in the literature, they improve quality of life. None of these drugs, when compared head-to-head with chemotherapy in the intention-to-treat population, improve overall survival, but that may be due to the high rate of crossover.

Two angles I want to take with this in terms of how to choose the TKI when patients come in: 1 is the Del 19 story. Of EGFR mutations, there are 2 more common EGFR mutations: the Del 19 and the L858R. In 2 studies—the LUX-LUNG 3 and the LUX-LUNG 6 study—that compared afatinib to either cisplatin + pemetrexed or cisplatin + gemcitabine, while there was no difference in overall survival and intention to treat analysis, in the subset analysis preplanned for the Exon Del 19 patients, there was an overall survival advantage with afatinib. And because of that, I think, for patients that are Del 19, there should be a consideration to offer afatinib. I will say that afatinib tends to be slightly more toxic in terms of GI toxicities and cutaneous toxicities when compared to either gefitinib or erlotinib, but for a very fit patient with a Del 19, I will consider afatinib, and maybe not be hesitant to dose reduce.

The second angle is the head-to-head comparison. Before about a year or 2 ago, we did not have any head-to-head comparison between these TKIs, but there was a study recently—the LUX-LUNG 7—that compared afatinib to gefitinib. The bottom line was that afatinib improved response rates and improved the 2-year progression free survival rate when compared to gefitinib. Because of that, I think the drug is probably more efficacious than gefitinib, though we don't have survival data from that study. That said, I think, as in any therapy, we must factor in toxicities when we're giving these drugs to our patients, and afatinib does tend to have slightly more high rates of AEs. And for older patients, I would generally not give afatinib, no matter what the subtype of EGFR mutation is, and offer them erlotinib.

Two other things to consider: combination strategies. There are multiple combination strategies adding certain drugs to a TKI upfront to see if it can improve outcomes. We have some very compelling data from Japan recently looking at erlotinib vs erlotinib plus bevacizumab for patients who are at an advanced stage and have EGFR mutations.

What we saw from that study, which has now been published, is that the addition of bevacizumab to erlotinib provided a meaningful and robust improvement in progression-free survival and response rate. Because of that, there is a larger study being undertaken right now to see if we can see the same trends. I would say if the trends hold up and—there may even be a survival event advantage reported, although we don't know yet—certainly bevacizumab added to erlotinib may be a strategy to consider.

The more recent data, which have just come out, are looking at gefitinib plus pemetrexed vs gefitinib alone. Similar strategy: adding pemetrexed to gefitinib, comparing it to gefitinib alone for EGFR-positive patients. We saw a similar trend that we do with the bevacizumab: adding an active drug was reasonably well-tolerated and improved PFS. To my knowledge, that study did not show a survival advantage, but nevertheless, I think it highlights the importance of thinking of combination strategies that may work for our patients and are well-tolerated.

The final thing I'll say about EGFR mutated lung cancers: yes, we have 3 TKIs that work very well, but there is a third-generation TKI called osimertinib, which is a drug that is geared towards targeting T790M, but it also certainly hits EGFR mutations as well. I think we think of osimertinib (Tagrisso) as being a drug active when patients progress on first-generation TKI, if they have a T790M mutation.

But what I'll say is there are very compelling data now about how using this drug as a first-line may offer a significant benefit. We don't have data yet to suggest that we should be using this routinely and I certainly don't use osimertinib as a first-line drug, but there are really nice data coming out showing very high response rates and very competitive progression-free survival with this drug. We'll just have to stay tuned to see if it all pans out.

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