Charu Aggarwal, MD: Hello and welcome to an episode of Leading Thoughts Lung Cancer. I'm Dr. Charu Agrawal. I'm an associate professor for lung cancer excellence at the University of Pennsylvania's Abramson Cancer Center. I'm joined here by two of my wonderful colleagues and we'll discuss something a little bit uncommon today. We'll talk about EGFR uncommon mutations, but before we do that, let me introduce our faculty. Jack?
Jack West, MD: Hi, I'm Dr. Jack West. I'm a thoracic oncologist, medical oncologist, associate professor at the City of Hope Cancer Center in the Los Angeles area. Happy to be joining you.
Dr. Aggarwal: Welcome Jack. And Devika?
Devika Das, MD: I'm excited to be here today. I'm Devika Das and I'm a thoracic medical oncologist and a clinical associate professor of medicine at the University of Alabama at Birmingham.
Dr. Aggarwal: Great. So, we now are utilizing targeted therapy for a substantial proportion of our patients with lung cancer. Thirty percent of our patients in first line, if identified, are eligible, and the majority of these patients have sensitizing EGFR mutations in either exon 19 or L858R. But sometimes, and this is rare, but sometimes we do find patients with uncommon alterations such as those in exon 18, which are usually G719X mutations. Or we can have exon 21 mutations such as the L861Q mutations. And it's important to recognize these mutations because there is limited data on efficacy of tyrosine kinase inhibitors (TKIs) in general. While we expect response rates of about 60 to 80% in your common sensitizing mutations, the data with existing first to third generation TKIs suggests that the overall response rate is variable depending on the kind of unusual mutation, and can vary from 20% to 70% depending on which agent is being used.
Most recently, at least in the US, we have an FDA approval of afatinib that was based on post hoc analysis of three large trials. These were the LUX lung trials looking at the use of afatinib that included both sensitizing and uncommon mutations. And when the data was pulled to look for uncommon mutations, we found that there was an overall response rate of about 71% with a median progression-free survival (PFS) of about 11 months for these patients with uncommon EGFR mutations. If you look at that paper carefully, even within that broad umbrella, there were certain subsets of patients that did better and some did worse, depending on where the mutation was located and if it was a compound mutation or not. In the US, afatinib is a preferred agent for use based on that approval. No other drug actually has an approval in this setting.
Osimertinib, which is our favored drug in the sensitizing mutation setting, has been studied in two perspectives. One was actually a prospective clinical trial that was published in the Journal of Clinical Oncology. This was predominantly conducted in Korea and they reported that for these patients with uncommon EGFR mutations, use of osimertinib as a single agent led to an overall response rate of 50%. Small study, but it was prospective about 36 patients. And most recently a study was published called the Unicorn Study published in Journal of Thoracic Oncology where a European cohort was retrospectively evaluated, treated with osimertinib, uncommon mutations where they found an overall response rate of about 61%.
Why do I bring this up? I bring this up for two reasons. One, I've recently been asked by colleagues as well as have seen cases referred to me where patients with uncommon EGFR mutations are often treated similarly to those patients with sensitizing mutations.
So it's sort of like this knowledge gap of should we be treating these patients differently? And the second question really being, if we are indeed to treat them differently, what is your preferred agent? Given the fact that if we were to choose a second-generation agent, we may not have significant intracranial penetration and CNS metastases, of course, are an issue in these patients as well.
So I guess I'll start with you, Jack, and firstly ask, when you see these reports, have you had colleagues reach out to you and say, what is this mutation? Or is the usual consult like, I'm just going to choose osimertinib because it's an EGFR mutation because I don't really think there's differential activity. What are you finding in your clinic?
Dr. West: I generally see more of the latter. I think one of the key questions is, if there is an uncommon mutation, how often is it appreciated? Sometimes it is. Sometimes people may not know what they don't know and just focus on EGFR and say, I know what to do for this.
Now the reality, and you alluded to this, is that it's not grossly inappropriate treatment to give osimertinib anyway. And in fact, sometimes on Twitter or other settings, panel discussions, we might discuss what you would do. And even among many of the experts, I think there's plenty of debate about afatinib versus osimertinib. I'd have to say that my imperfect and cross trial analysis type meta-analysis is that I think that afatinib looks just a shade more active perhaps, but I wouldn't want to put too fine a point on it, and it doesn't have the same intracranial efficacy. At least we don't have great data on this in this setting, but I would infer that osimertinib has better intracranial activity and the tolerability is also an issue.
So I think that many people who eat, sleep, live and breathe this may be aware of the same data and often come down on the side of yes, but osimertinib is better tolerated and good enough. And I think that's not wrong. I recall one patient who was 82, and I knew all the data, and I just thought this is someone in whom it's really hard for me to embrace afatinib, even if I do think it's marginally more efficacious. But I think you know, you also allude to a problem. We talk about precision medicine and then we aggregate all these heterogeneous populations, they're not superimposable. And the more granular we get, I think the more knowledge we're going to have. Now it's going to take a lot of pooling of data to really discern those patterns. But up until mostly now we've just said, “EGFR? Give an EGFR inhibitor” and you're good. And so I think that this just highlights that we can only get better as we look at precision medicine with more granularity.
Dr. Aggarwal: Very well said. And I think I'm seeing more of the latter as well, and I don't know if it's really truly an under-appreciation of the differentiation between different mutations or is it more of just, well, osimertinib should work based on this new data? I don't know. What are you seeing, Devika?
Dr. Das: I think I see a mix of both. I think one of the bigger things is for a lot of our colleagues in non-academic centers, this is a very small part of their patient population. So again, not as common for them as it is for a lot of us in tertiary care centers, so that is something big that I appreciate. I know a lot of our colleagues, the moment they see EGFR on the next gen sequencing and they see all these numbers and letters after – at least in our practice – we get a lot of emails right off the bat. What am I going to do different here? So that is a good thing. I think asking for help if you don't have a large patient population and reaching out to a tertiary care colleague is a great idea in this setting.
I think the reason that a lot of my colleagues do not want to use afatinib, even though you know can look it up and find that afatinib is approved in the US for some of these rare mutations, uncommon mutations, is because of the tolerability.
And I think it's a real issue. They're often looking for ways to justify osimertinib. So even if they can find this one small study – the two that you cited – is often is used as a way to get osimertinib approved in some of these settings because afatinib is absolutely not a tolerable agent in for a lot of people because again, this is a population that is often younger and is working full-time and dealing with the toxicity of afatinib is just not conducive with everyday life. So I think that is a reason we're gravitating more towards osimertinib.
The one thing that I do feel that we could talk a little bit more about and for people to appreciate is exon 20 insertions are very different than all of these mutations that we talked about, and that frontline platinum-based cytotoxic chemotherapy is what would be preferable. I've seen a few patients get on osimertinib with that mutation and we know it doesn't work in that setting. And then we do have FDA approvals in the second-line for those mutations. So I think it is confusing. It's not a big part of their patient panel, and I completely appreciate that. But reaching out and understanding what the differences are I think is incredibly important when you don't see them every day in clinic.
Dr. Aggarwal: That's very well said. I think exon 20 is becoming increasingly actionable. We have certainly new FDA approvals. We now have two approved agents, amivantamab as well as mobocertinib, with several others looking very promising that were presented at several national meetings last year, with perhaps even better intracranial penetration. So those are coming.
Let me ask you this. When you're treating a patient with an EGFR uncommon mutation, how are you really choosing an agent? Is it based on response rate? Is it based on PFS? Devika, you talked a little bit about toxicity, but let's say a patient with an L861Q is going to have a very high response rate with both afatinib and osimertinib, then how you making that decision?
Dr. Das: For me personally, I have started out with afatinib and this has really not been based on what I wanted to do, but sometimes we're in a payer system and have to navigate between different payers. I have had to show that afatinib has caused significant amount of toxicities in certain patients, so I have started out with that. But letting the patients know right away that you are probably going to have a lot of skin and GI toxicities and then make it good documentation of that to then request osimertinib. So I've been able to get those in sort of a second-line setting for intolerability. But that is a challenge in practice because afatinib has this approval – again, not based on great data – there's a lot of payer-based sort of judgment making here and we have to struggle through those hoops to get the right drug.
Dr. Aggarwal: So mainly based on insurance approval and payer. What about you, Jack? Are you using outcome data to make a determination?
Dr. West: Yeah. I think it's really very individualized to the therapeutic index and some patients would really prioritize efficacy, saying “I just want the most efficacious agent. I don't care that much about toxicity.” And I think it's worth bearing in mind that afatinib comes in 20, 30, and 40 milligram tablets. So it's not like we have no agency in modulating that. I mean patients may benefit and do quite fine with afatinib at 30 if 40 is too toxic and that's fine. And for other patients, like the one I mentioned who was older and I think pretty toxicity averse, I chose differently.
So I don't think this is a one size fits all for me. And I don't think there's any clear best answer that anyone's doing anything right or wrong. I think of all, there's many things that we can spar about and argue about who's right or wrong, and this is one where I think there's a huge amount of room for judgment and even for those of us who are the same person looking at the same data, might have a different approach for one patient versus the one we see a week later.
Dr. Aggarwal: Absolutely. And I think that's a very nice way to summarize this episode is that this is a different group of patients. They don't really cleanly fall into any of the categories for which we currently have approvals based on prospective clinical trials. So EGFR sensitizing mutations are completely different class as our exon 20 insertion mutations, which should be recognized and identified because those are actually the patients that may not benefit from osimertinib and have approved agents. But amongst these other uncommon mutations, we do have the opportunity now to either use afatinib. It's important to recognize that that may be associated with some toxicities that can be modulated based on dose adjustments and dose reductions, as well as perhaps it's not the worst idea to use osimertinib based on some emerging, albeit retrospective, data.
This has been a great episode. I'd like to thank both Jack and Devika for your insights. I hope to see you both again in another episode of Leading Thoughts Lung Cancer.
Dr. West: Let's count on it. Take care.
Dr. Das: Thank you.
