The Impact of <i>EGFR</i> TKI on Nonsquamous NSCLC

Benjamin Levy, MD: EGFR mutations have been emblematic of precision medicine in lung cancer. And also, precision medicine in all solid-tumor cancers. To be able to identify genetic alteration and then wed that genetic alteration to an oral targeted therapy has been changed a lot for our patients. The field within EGFR has evolved rapidly. We started out with first-generation and second-generation TKIs [tyrosine kinase inhibitors]—serlotinib, gefitinib, and afatinib were first. And we saw that these drugs, when you compare them with chemotherapy in patients with advanced-stage disease with EGFR mutations, these patients did better in terms of response rates and progression-free survivals, but perhaps most underrepresented in the literature is that they did better in terms of quality of life, which is so important for patients.

More recently we’ve had next-generation, or third-generation, TKIs. Osimertinib is that drug, a drug that was originally pitched as more of T790M drug, which is a resistant mutation but also now noted to have exquisite activity for sensitizing mutations. And of course now the FLAURA data comparing osimertinib with first-generation TKI for advanced adenocarcinoma patients with EGFR mutations has shown an improvement in progression-free survival, and in a trend toward overall survival that we very rarely see. So a lot of changes here. But I think for now it’s identifying an EGFR mutation helps drive decision making, and certainly I think osimertinib now has become the real preferred agent for these patients.

Now that we can identify genetic alterations within lung cancer, we are starting to use tyrosine kinase inhibitors first. And I think we should always use our first drug. We should always use our best drug first. And oftentimes our best drug has been tyrosine kinase inhibitors. This not only applies for EGFR but it of course applies for ALK, potentially BRAF and ROS as well. So it speaks, or underscores, the importance of comprehensive genomic profiling. There are a lot of questions, however. After you use the TKI, what do you do next?

And I think this is contingent, or the answer is contingent, on what specific genotype you’re talking about. If you’re talking about EGFR, for patients who are on osimertinib who then subsequently develop progression, we’re still trying to learn what the next-best option is. Is it chemotherapy? Is it another targeted drug? And this will be highly contingent on the mechanisms of resistance we identify, which we’re still trying to understand.

For ALK mutations, the same rules apply. We have a great first-line agent with alectinib. What to do after alectinib, we’re still trying to learn. All these drugs have moved so rapidly to the first line, so trying to understand what to do next has been a bit of a challenge and an unanswered question, but it’s a good challenge to have.

I would say that we’re still learning. I think tyrosine kinase inhibitors are probably going for most genotypes to move as the preferred first-line agent. They already have for EGFR and ALK. What to do afterward often depends on many different things—tumor biology. Off a trial, I would say chemotherapy for some of these patients is the best way to go, specifically for EGFR mutations. For ALK mutations, I think we have a better understanding of some sequencing. So patients who were on alectinib perhaps should get lorlatinib next or brigatinib next—we’re learning this[MB1] . But chemotherapy at some point is going to be a part of their equation. We hope that will change over time. But all these patients with specific genotypes who go on tyrosine kinase inhibitors at some point will most likely need some type of chemotherapy regimen.

The experience I’ve had with these tyrosine kinase inhibitors has mirrored what the data have shown, which is that these patients have dramatic improvements in tumor burden, so they have tumor shrinkage. They have the ability to live longer than with chemotherapy. They sometimes can totally overt the need for radiation to their brain because these drugs cross the blood-brain barrier. I would say, most important, the thing that we don’t talk about that much is quality of life. I mean, for these patients, there’s a big difference in both the conversation of what goes down over time in a patient who’s getting a pill versus a patient who’s getting IV [intravenous] chemotherapy. Not that chemotherapy is a bad word, but certainly there’s a better tolerance and better efficacy with these oral agents that are a little more precise.

Video not provided (times on segment grid are wrong). [MB1]Can't confirm that this is what he said.

It’s been a welcome change over the past 10 years with lung cancer to have all these new drugs to give. I would make the argument that I think these drugs are probably the best and that the best drugs should be used first. And I think all of us as lung cancer physicians will tell you how exciting it is to tell a patient that they have a particular gene that we can give a targeted therapy for versus chemotherapy. My experience has been very similar to what we’ve seen in the data. Patients’ better quality of life, more tumor shrinkage, and a chance you know to have a little more longevity when you compare it with before having these tyrosine kinase inhibitors.