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Does the Specific EGFR Mutation (Including “Rare” Mutations) Matter When Choosing an Oral EGFR Inhibitor?

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Drs. Leora Horn, Ben Solomon, & Jack West discuss the open question of whether there are clinically significant differences among leading EGFR tyrosine kinases based on the specific EGFR mutation to be treated.

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Dr. West:  What about rare mutations? They’ve really been excluded from a lot of things, but we got a little bit of information at this meeting, the World Conference on Lung Cancer, and there was a publication by James Yang in Lancet Oncology that looked at aggregate results from three different studies with afatinib (Gilotrif), that suggested that at least some of these rare mutations could have a good response to afatinib. What are your thoughts — do you really view all of these rare mutations as one basket, or do you hone it further and treat accordingly, and if you do feel that there are patients who benefit from EGFR inhibitors, is it preferentially afatinib because of these results, or any of them? Leora, what do you think?

Dr. Horn:  So, I thought that James Yang paper was very nice, but I think my bias is that, probably, those rare mutations, would have responded to the first generation inhibitors, as well. We have our database that we’re collecting this data — the DIRECT database, and we’ve got about 3,000 individual mutation patient information in there, so that’s my go-to place when I get information that I’m not sure what to make of a mutation, and I think we’re going to see more and more rare mutations as next generation sequencing is adopted in more places around the world, and we may not always know what to do with that information, and sometimes it may be trial and error.

Dr. Solomon:  Yeah, so I actually have to say your mycancergenome.org is my go-to place, as well, to find out about rare mutations, and I think for patients, and even doctors, who get an EGFR mutation result with a rare mutation, it’s hard to keep track of all these mutations, and at this meeting, for instance, we learned that the group of mutations we call G719X, which includes three different mutations — two of those mutations seem to respond, and one of those, the G719C, doesn’t seem to respond, and so I would encourage people who are uncertain about the significance of mutations to go to mycancergenome.org and make query of the DIRECT database.

Dr. West:  To me, that was one of the themes, both from the Yang paper, and from several of the still relatively small data presentations on rare mutations, is that, de novo T790m mutations, that is, the ones that appear from the time of diagnosis, are associated with a poor outcome, but some of the others, Exon 18, and some Exon 20 insertions, could respond well to these therapies, and it would be a mistake to: A., lump all of these together, because they’re not, we’re missing things, and B., to completely discount the possibility that an EFGR inhibitor could help them.


GRACE Video

First Line Treatment of EGFR Mutation-Positive NSCLC

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GCVL_LU_First_Line_Treatment_EGFR_Mutation-Positive_NSCLC

 

MSKCC medical oncologist Dr. Greg Riely reviews the optimal first line treatment of patients with an EGFR mutation-positive advanced lung cancer.

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When we identify a patient with an EGFR mutant form of lung cancer, we know that there’s a mutation in their tumor. That helps us figure out the first line of treatment — the initial therapy for patients. Now, some of the initial work identifying drugs for patients with EGFR mutant lung cancer focused on patients who had had multiple prior therapies, but over the last five years we’ve had a luxury of big, randomized clinical trials where we take hundreds of patients and randomize half of them to treatment with chemotherapy, and half of them to treatment with EGFR tyrosine-kinase inhibitors — drugs like erlotinib, gefitinib and afatinib.

When we look at those trial results, we see really remarkable improvements in the chance of the tumor shrinking, so that it’s much more likely that with these oral treatments for lung cancer, like erlotinib, gefitinib, or afatinib, that the tumors will shrink — much more likely than with chemotherapy. Importantly, it’s also shown that, from these trials, that we see much longer time until the cancer grows. So, taking a pill leads to longer disease control than we see with IV chemotherapies.


GRACE Video

Should EGFR TKI Therapy be Continued Beyond Progression?

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GCVL_LU_EGFR_TKI_Therapy_Continued_Beyond_Progression

 

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.


GRACE Video

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

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GCVL_LU_Acquired_Resistance_Patterns_EGFR_TKIs_Mutation-Positive_NSCLC

 

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.


GRACE Video

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

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GCVL_LU_Distinctions_Oral_EGFR_Inhibitors_Mutation-Positive_NSCLC

 

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.


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