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Should EGFR TKI Therapy be Continued Beyond Progression?

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Dr. Greg Riely, medical oncologist from MSKCC, discusses the controversial question of whether patients should continue on an oral EGFR tyrosine kinase inhibitor after progression.

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After patents develop resistance to EGFR tyrosine-kinase inhibitors, such as erlotinib, gefitinib or afatinib, we eventually have to make a change in systemic therapy, and if we’ve gone through our first generation or second generation of EGFR tyrosine-kinase inhibitors, and even potentially after third generation EGFR tyrosine-kinase inhibitors, we have the option of using chemotherapy. Chemotherapy is very effective for patients with EGFR mutant lung cancer, and I think it’s definitely something that patients shouldn’t fear because it does have great activity and we can make it quite tolerable for patients to receive these chemotherapies. 

One critical question comes up, as to whether we should continue EGFR tyrosine-kinase inhibitors after development of resistance when we’re starting chemotherapy. Kind of an obvious statement is that, if the patient has developed resistance, and many of my patients ask me this question — “if I develop resistance, why should I continue an EGFR tyrosine-kinase inhibitor?” I think it’s a good question. When we started thinking about this with our patients, long ago, we did what the standard thing was, which is we stop EGFR tyrosine-kinase inhibitors and move on to chemotherapy. When we look back at some data where we had patients stop EGFR tyrosine-kinase inhibitor, prior to enrolling in a clinical trial, the general washout, this period of the time off-drug, that we call it, was about two weeks, and in that time, we saw about 20% of patients have a significant worsening of their disease course — and when I say significant worsening of their disease course, their symptoms got so bad that they were hospitalized, and some of them even died after stopping EGFR tyrosine-kinase inhibitors.

Now, I say that not to frighten people, but to point out that, often, in patients with EGFR mutant lung cancer, there is still some benefit for continuation of EGFR TKI, and there may be a role for continuing with chemotherapy. Importantly, this has been studied in a randomized fashion, so patients with EGFR mutant lung cancer with resistance to first-generation EGFR tyrosine-kinase inhibitors, were randomized to chemotherapy with an EGFR tyrosine-kinase inhibitor, and there wasn’t a difference in the outcome. So, it wasn’t clear in an overall patient population that it mattered if you continued. So, this data really indicates that it’s okay not to continue EGFR tyrosine-kinase inhibitors. I think the one area that I might disagree is maybe in the initial switch from an EGFR tyrosine-kinase inhibitor to the chemotherapy — it would be reasonable to overlap those so that you’re getting the benefits of the chemotherapy and we’re seeing shrinkage of the chemotherapy before you pull back on the EGFR tyrosine-kinase inhibitor.


The Potential Value of Repeat Biopsies in Acquired Resistance

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MSKCC medical oncologist Dr. Greg Riely explains the growing value of a repeat biopsy after the development of acquired resistance in patients with an EGFR mutation.

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So, after initial therapy with EGFR tyrosine-kinase inhibitors, patients often develop — always, really, develop progressive disease, known as resistance, where the tumor has become resistant to therapy. How we manage patients and how we treat their disease, after development of resistance, is a complicated area. One way we can learn a little bit more about a patient’s tumor, and help to refine our decision making, is to do a biopsy of a site of progressive disease.

What we learn from a biopsy really is two-fold. The first, and easiest part, is the pathologist looks at it under the microscope and says, “is this still non-small cell lung cancer, or is this changed?” A relatively rare phenomenon is transformation of non-small cell lung cancer into small cell lung cancer — it happens maybe one to three percent of the time, but it’s a relevant thing to find, and we would adjust chemotherapy as a consequence of this.

Another thing to look for when we biopsy a site of resistance is acquisition of new mutations. One of the most common new mutations identified, it happens in about two-thirds of patients, is a secondary mutation called T790M. The important thing about identifying T790M is that we can now, in clinical trials, and hopefully in the future, with FDA approved drugs, target that T790M mutation with a new drug; we have two new drugs that are being developed now, one is called rociletinib and one is called mereletinib — these are specifically designed to target T790M. Now, importantly, any given biopsy has a chance of finding a mutation that’s present, and it also has a chance of missing it — whether that’s because we biopsied a site that didn’t have that mutation or, for whatever reason, our testing didn’t identify the T790M mutation. I think it’s important to know that as a caveat before going in to re-biopsy, but I do think that biopsying tumors at the time of resistance to EGFR tyrosine-kinase inhibitors does help devise the next best therapy for a patient.


Patterns of Acquired Resistance to EGFR TKIs in EGFR Mutation-Positive NSCLC

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Medical oncologist Dr. Greg Riely, MSKCC, summarizes the development of acquired resistance after a good initial response to EGFR inhibitor therapy and the clinical patterns of progression commonly seen.

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For patients with EGFR mutant lung cancer, we generally recommend initial therapy with an EGFR tyrosine-kinase inhibitor — so, that’s gefitinib, erlotinib, or afatinib. We generally see significant tumor shrinkage with these drugs, but after time, patients eventually develop resistance to these therapies. The time until resistance really can vary dramatically, from three months, to even a few years down the road, but eventually patients do develop resistance. 

How that resistance manifests is really important for deciding how to deal with the consequences of resistance. So, if we see resistance develop in a  handful of sites and it’s very slow growth, we may actually just monitor that disease progression, acknowledging that the disease is beginning to become resistant, but recognizing that we don’t want to make changes in therapy too quickly. Importantly, if there is a single site of resistance, and if it’s a site that may cause symptoms or a site that is causing symptoms, such as a painful boney metastasis, it’s a very reasonable approach to target just that site that’s developing resistance, so that we can continue controlling the rest of the body with the oral medication, and then control the single-site progression — for instance, if a lung nodule has popped up that wasn’t there before, and is growing, it would be reasonable to consider radiation therapy for that lung nodule, or even, in some cases, surgical resection of that lung nodule to remove that resistant nodule, and observe how patients do afterward.

In a retrospective series from my institution, we took a handful of patients who had been treated this way — where, after a single site of resistance developed, we did radiation or surgery, for that site of resistance, and we found that the time until we had to make a change in their systemic therapy, i.e., drop the EGFR tyrosine-kinase inhibitor, or add chemotherapy, was over a year for most patients. And so, as a consequence, I think we spared a change in therapy for a year, and we generally helped patients. 

Now, of course, this needs to be studied more, but I think this is a reasonable strategy for patents with single-site resistance.


Are There Distinctions Among Currently Available Oral EGFR Inhibitors for EGFR Mutation-Positive NSCLC?

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Dr. Greg Riely, medical oncologist from MSKCC, considers the evidence on whether there are clinically significant differences among the currently available first and second generation oral EGFR inhibitors for patients with an EGFR mutation.

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For patients who are diagnosed with EGFR mutant lung cancer, there’s a choice of initial therapies. There are three FDA approved EGFR tyrosine-kinase inhibitors — these are gefitinib (with the trade name Iressa), erlotinib (with the trade name Tarceva), or afatinib (with the trade name Gilotrif). These three drugs have been developed over the course of the past 15 years or so, and they have a great deal of similarity in that all of them target wild-type, or regular EGFR, the EGFR protein that’s found throughout your body, and they all have different doses — I think that’s probably the difference that we see among them, is largely related to dose. If we look at clinical trial data, and to talk with physicians who have given all three drugs, I think the general consensus is that, at their recommended dose, the FDA approved dose, that the side effect profile, particularly with regard to rash and diarrhea, is probably the lowest with gefitinib, rash and diarrhea is a bit higher with erlotinib, and finally, with afatinib, it’s the highest.

Now, for a given patient, this is largely irrelevant, given that we adjust doses to make it so the patient has a tolerable side effect profile, so that if we’ve given erlotinib at the FDA approved dose and found that it causes too much rash, we generally back down the dose. Similarly for afatinib, we will reduce the dose of afatinib to make the rash and diarrhea more tolerable. 

So, when taken together, picking the right EGFR tyrosine-kinase inhibitor, or picking the one that works for a given patient, is a lot about what the physician is comfortable with, and finding the right dose for that patient. 

Now, importantly, I’ll contrast these first or second-generation EGFR tyrosine-kinase inhibitors like gefitinib, erlotinib, and afatinib, with the newer tyrosine-kinase inhibitors like rociletinib, or mereletinib, the so-called third-generation, or T790M specific drugs — these have a very different profile of activity, and we still have yet to learn as much as we need to know about their side effect profile.


Differences Among Specific EGFR Mutations

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Medical oncologist Dr. Greg Riely, MSKCC, discusses evidence for whether there are clinically significant differences among specific EGFR mutations that should lead to differences in management.

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Within the overview of EGFR mutations, there’s several different types — the two most common are EGFR exon 19 deletion and EGFR L858r; together, these represent more than 80% of EGFR mutations. In addition to these two common types, there are some uncommon types, but some of these are related to responsiveness to EGFR tyrosine-kinase inhibitors, so rarer ones like G719A, L861, these are rare, but we have pretty good evidence that they lead to response to drugs, just as those patients who have L858r or exon 19 deletion.

There are patients who have exon 20 insertions — in general, EGFR exon 20 insertions are associated with resistance to EGFR tyrosine-kinase inhibitors like erlotinib, gefitinib and afatinib, and so, as a consequence, that’s not our first line therapy for those patients with EGFR exon 20 insertions.

Going back to the two most common EGFR mutations, exon 19 deletion and EGFR L858r, since these are the most common ones, we have more data on patient outcomes for these two mutations. When we look at a broad variety of data, typically with afatinib, we see that afatinib may actually be more effective for those patients with EGFR exon 19 deletions than it is for patients with EGFR L858r.

There has been similar data reported for patients treated with gefitinib and erlotinib as well. Though the data is not quite as clear cut, it does seem that those drugs also work a bit better for patients with EGFR exon 19 deletions.

Now what the consequence of those differences is, is quite controversial. I think that, in general, I still recommend treatment with an EGFR tyrosine-kinase inhibitor — and I don’t prefer one or the other, for patients with EGFR exon 19 deletions, EGFR L858r, as well as the rarer ones like G719A or L861Q.


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