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Third Generation EGFR TKIs for Acquired Resistance

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GRACE Cancer Video Library - Lung

GCVL_LU-F12_Third_Generation_EGFR_TKI_Acquired_Resistance

 

Dr. Nathan Pennell, Cleveland Clinic, discusses the concept of acquired resistance and new agents designed to address it, including Rociletinib and Merelitinib.

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So I’d like to talk now about third generation, or mutation-specific inhibitors for epidermal growth factor receptor mutation-positive lung cancer. We know that for EGFR mutation-positive lung cancer, targeted therapy with drugs like Tarceva, Iressa, or Gilotrif are the standard of care based on trials showing they’re better than chemotherapy for improving tumor responses and the time to progression of cancer for many patients, and they can be very effective and sometimes last a long time.

Unfortunately, the majority of patients will eventually go on to develop something called acquired resistance, where the cancer begins to grow despite continued treatment with the drug that worked so well, sometimes for a long time. Something has changed in the cancer that has caused it to be resistant to the drug. When we biopsy these tumors that are progressing, what we find for EGFR mutant patients is that about 50-60% of these tumors have a new mutation, something called T790m, in exon 20. The original mutation is still there, but now it has a new mutation and this has caused the cancer to no longer respond to the Tarceva or the Gilotrif.

The good news is, there’s a whole new class of drugs available that have been specifically designed for this type of cancer, the T790m-positive cancer. These are called mutation-specific inhibitors because they inhibit only the mutant EGFR, and not the normal wild type EGFR that’s spread throughout the rest of your body. So, they tend not to have the same side effects that drugs like Tarceva or Gilotrif would have. They have less of the acne-like rash, less diarrhea; they do have different side effects. For example, one of the best known drugs is called Rociletinib, formerly CO-1686, and while it doesn’t have a rash or much diarrhea, it can raise blood sugar similar to type 2 diabetes which usually can be managed in the same way with oral drugs. The other well known drug is called AZD-9291, and one or both of these drugs is likely to be approved within the next year for T790m-positive EGFR mutant lung cancer.

Both of these have had large trials that have been presented showing that between 50% and 70% of patients with the T790m mutation will have a major response, and the vast majority of patients will have disease control, with a median time, average time, somewhere in the 8-10 month range before progression — some patients significantly longer. These are really nice options for patients who have this specific type of cancer.

Unfortunately, patients will need to have a new biopsy of their cancer at the time of developing acquired resistance, although they are trying to develop blood tests which are hopefully going to eventually replace needing a new procedure to biopsy your cancer. In 2015, for patients who develop acquired resistance, I would recommend a biopsy of the progressing cancer, and if they have T790m, enroll them on one of the clinical trials with either Rociletinib, AZD-9291, or one of the many other third generation EGFR inhibitors that are farther back in development.


GRACE Video

Are There Clinically Significant Differences Among the Third Generation EGFR Inhibitors?

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WCLC_2015_16_Clinically_Significant_Differences_Third_Generation_EGFR_Inhibitors

 

Drs. Ben Solomon, Leora Horn, & Jack West compare the clinical data with the third generation EGFR TKIs so active in acquired resistance and consider whether there are significant differences between them.

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Dr. West:  We now have two, hopefully very soon, commercially available third-generation EGFR inhibitors, osimertinib, and also rociletinib. These agents really seem pretty comparable in efficacy — some differences in toxicity. What do you see as potentially clinically significant differences? If you had both available, how would you approach a patient with T790m mutation-positive acquired resistance?

Dr. Horn:  So yeah, I was going to say their similarities are in the T790m-positive patents — there are some differences in the negative patients.

Dr. West:  We’ll cover that too.

Dr. Horn:  But, I do think that — I’m going to use their numbers because they’re easier to remember than names, 9291 (osimertinib) is a little better tolerated, in my experience, than 1686 (rociletinib), the Clovis drug. I think that, for patients who are going to be on the Clovis drug, we’re going to have to be very diligent about monitoring their blood sugars because the hyperglycemia is a real toxicity that can be quite significant. Now, 9291 did have more rash, but, for these patents, they’re used to be dealing with a rash, they’ve had rashes for years because they’re been on erlotinib, gefitinib, afatinib, and even the rash of 9291 is less severe than the first and second generation agents.

Dr. West:  Clearly, these agents will do well with their marketed names, given how hard they are to differentiate based on their names now! Ben, what do you think here?

Dr. Solomon:  Yeah, look, I agree. I think they’re both very active, they both have response rates of about 50-60% in patients that have progressed on Iressa or Tarceva, but they are different in their toxicities, and rash and diarrhea with the AZD9291 compound, which we believe to be called osimertinib, today, is generally manageable and, for patients, quite similar to the rash they might have experienced, and diarrhea they might have experienced before, or even milder; whereas, hyperglycemia is a completely new toxicity and I think, again, patients need to be vigilant about this toxicity, and doctors need to know how to manage this toxicity with the use of Metformin and monitoring of blood glucose, so it can be a little bit trickier.

Dr. West:  I must say that, about a year and a half ago, when these data were first presented, I thought that managing hyperglycemia with some Metformin seemed pretty trivial for cancer patients who have an effective treatment against cancer — but when there’s an alternative that doesn’t have that, and, in some of my patents I’ve had challenging nausea and anorexia, you know, just diminished appetite, weight loss, fatigue — my experience has been that it’s not a trivial challenge, at least in a subset of patients. That said, they’re both a real advance.


GRACE Video

Are There Clinically Significant Differences Among the First and Second Generation EGFR TKIs (Iressa, Tarceva, Gilotrif)?

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WCLC_2015_13_Clinically_Significant_Differences_First_Second_Generation_EGFR_TKIs

 

Drs. Ben Solomon, Leora Horn, & Jack West review whether the data and clinical experience suggest any clinically significant differences among the first and second generation EGFR TKIs (Iressa, Tarceva, Gilotrif/Giotrif).

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Dr. West:  What’s your sense of whether there are clinically significant differences among the first or second generation EGFR tyrosine-kinase inhibitors — that is, Iressa, Tarceva, Gilotrif. Are these agents that you consider to be really interchangeable, does it matter what actual mutation the patient has, or do you think it’s really completely a dealer’s choice? Ben, why don’t I start with you?

Dr. Solomon:  Yeah sure, so there’s certainly differences at the clinical level — the second generation inhibitors, afatinib and dacomitinib, do have a lot more toxicity. They’re very potent inhibitors of both mutant and wild type, or normal, EGF Receptors — so skin, nail toxicities, diarrhea, are more common with those drugs than with Iressa or Tarceva. In terms of the question of efficacy, I think we’re all waiting to hear the results of a head to head study; it’s very difficult to compare different phase three studies, but there is some interesting data that has been presented with afatinib from, actually, a couple of different studies, which, admittedly, was a subgroup analysis, which suggested that in the subgroup of patients that had exon 19 deletions, as opposed to the group that had LA58r mutations, there was a survival benefit. But, it’s not clear whether that same difference might have been seen in the other studies with the other drugs, as well, if it was looked for in sufficient numbers. So, to my mind, it’s an open question about whether there’s increased efficacy. I guess the other point Leora alluded to — occasionally, you do see responses to afatinib in patients who have progressed on Iressa or Tarceva, which may suggest some differences in efficacy.

Dr. West:  What are your thoughts on whether there are clinically meaningful differences between them, and whether there is a significant difference between the main activating mutations for all EGFR TKIs, or for afatinib.

Dr. Horn:  So, I completely agree with Ben that the toxicities are clinically meaningful and different between the different agents. LUX-Lung 7 is close to accrual, and so, hopefully —

Dr. West:  That’s a trial directly comparing afatinib to gefitinib (Iressa) in EGFR mutation-positive patients, first-line.

Dr. Horn:  And it’s primarily in Asia because gefitinib, up until a few weeks ago, was not available here.

Dr. West:  I just learned that it’s actually half Asian and half European, which will be helpful to know because we do struggle with the question of whether the results out of Asia are completely generalizable to non-Asian populations. So, I think we’re going to be getting the results of that in the first half, hopefully, of 2016, at least some of the results, and, so, that will hopefully, provide — shed some light on this controversial question.


GRACE Video

Should Third Generation EGFR Inhibitors Be Used Before First Generation EGFR TKIs or After Progression?

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WCLC_2015_19_Third_Generation_EGFR_Inhibitors_Before_First_Generation_EGFR_TKIs

 

Drs. Leora Horn, Ben Solomon, & Jack West consider whether third generation EGFR TKIs, so active in patients with acquired resistance, might be best used prior to development of acquired resistance.

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Dr. West:  So let’s turn to the question of — you have agents like these third-generation EGFR inhibitors that have impressive activity in patients with acquired resistance after a prior, say, first-generation EGFR inhibitor like Iressa (gefitinib), Tarceva (erlotinib), or the second-generation inhibitor Gilotrif (afatinib). Those agents really have activity that seems limited to the first line setting, not much activity in acquired resistance. There’s going to be a temptation to move these later agents into the first line setting with the thought that maybe you can postpone, for much longer, acquired resistance — there’s certainly trials looking at this, but before we have the result of those trials, is that going to be something that you’re going to be tempted to do or recommend?

Dr. Horn:  Not unless I have a patient who maybe has a germline T790m mutation, so T790m at the time of diagnosis. I think that those trials need to come out and we need to see what the combined progression-free survival is, just of third-generation on its own, compared to progression-free survival with a first, followed by a third, and without that data, I’m not tempted to change my practice at this time.

Dr. West:  Ben, what do you think?

Dr. Solomon:  Yeah, I’m with Leora. I think they’re really important trials, the trials with both compounds in the first line, compared with first-generation inhibitors — and I guess the rationale is that you might be able to prevent and delay the emergence of resistance by targeting T790 right from the beginning, but we know resistance develops to these third-generation inhibitors. As well, they’re new mutations that prevent the third-generation inhibitors from binding to the EGFR, and it might be that you may not be able to rescue and make the tumor re-respond to another EGFR inhibitor later on down the track, so I don’t think we can presuppose the answer to these trials, but I think they’re important, and certainly, if the time that you can control the disease by using a third-generation inhibitor first is longer than you can by using a first-generation inhibitor, followed by a third-generation inhibitor, it’s going to change the way we all practice.

Dr. West:  Well, that’s a good point though, that these are all looking at progression-free survival as the primary endpoint, but that’s not really the key issue — it’s not whether a first-generation agent is less than a third-generation agent, as much as first-generation, followed by the third-generation, versus starting with the third-generation, because your goal isn’t just to get them to this coming Christmas, but have patients live many Christmases in the future, and, so, I think that, to me, seeing if it changes overall survival, or really, looking further beyond just one line of therapy is an important issue.


GRACE Video

Should EGFR TKI Therapy be Continued Beyond Progression?

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GRACE Cancer Video Library - Lung

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.


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