GRACE :: Lung Cancer



Dr West

Direct Comparison of 2 EGFR Inhibitors Shows There Are Clinically Significant Differences


At ASCO 2014, I provided the commentary after a key presentation demonstrated that the second generation EGFR tyrosine kinase inhibitor (TKI) Gilotrif (or Giotrif in some parts of the world) (afatinib) as first line therapy compared to standard chemotherapy in EGFR mutation-positive patients gave a significant benefit in overall survival (OS) that hadn’t been seen when other first generation EGFR TKIs, namely Iressa (gefitinib) or Tarceva (erlotinib) were compared to chemotherapy in EGFR mutation-positive patients. The question was whether this difference meant that Gilotrif is a significantly better EGFR TKI than Iressa or Tarceva. I noted that while these results were provocative, trials with Iressa and Tarceva were far smaller and in most cases were stopped early due to early results showing that the EGFR TKI was clearly superior in short term measures like progression-free survival (PFS) and response rate.  Accordingly, we couldn’t say anything definitive about the efficacy of one EGFR TKI vs. another by making inferences of each compared with an increasingly irrelevant comparator. If trial after trial showed that the EGFR TKI was clearly better than chemotherapy, we can’t draw meaningful conclusions of one being better based on how much stronger one looked than another against an inferior option. Instead,  the only reliable way to compare two EGFR TKIs would be to directly compare two EGFR TKIs in a randomized trial with the same eligible population.  In fact, such a trial, called LUX-Lung-7, had already been not only conceived but enrolled, randomizing EGFR mutation positive patients in Asia, Europe, Canada, and Australia to either Iressa or Gilotrif. We just needed to see how it turned out. Continue reading


Are There Clinically Significant Differences Among the 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.


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




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.


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




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.


Should Avastin be Added to EGFR TKI Therapy for EGFR Mutation-Positive NSCLC?

GRACE Cancer Video Library - Lung



Dr. Jack West, medical oncologist, reviews evidence in favor of adding Avastin (bevacizumab) to the EGFR inhibitor Tarceva (erlotinib) for patients with lung cancer that harbors an activating EGFR mutation.

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The historical standard of care over the last several years for patients with advanced non-small cell lung cancer, whose tumor has an activating EGFR mutation, has been single-agent oral EGFR tyrosine-kinase inhibitor therapy. That is a pill like Iressa (gefitinib), or Tarceva (erlotinib), or Gilotrif (afatinib), and these agents are associated with long responses that typically will last 9, or 12, or sometimes more months, but unfortunately, in almost every case, will demonstrate progression after some period of time — and we would always like that to be longer.

One of the big questions that we’ve wanted to know is, if we could add something to this therapy and do better than that — and one of the key questions has been about adding an anti-angiogenic agent, something that blocks the tumor’s blood supply, which is a drug like Avastin (bevacizumab), which is used in other cancer settings, and in some cases, for lung cancer, in combination with chemotherapy. In lab-based studies there is evidence that adding a blood supply blocker, an anti-angiogenic agent, to one of these EGFR inhibitors can more effectively suppress cancer cells, and for longer, but we haven’t seen clear evidence that this is beneficial for patients in the real world. In fact, there have been a couple of large studies that have asked the question about adding Avastin to a drug like Tarceva — these trials, however, have only been in broad populations that are called molecularly unselected, not looking specifically at patients with an EGFR mutation or any other feature, but just really taking all comers.

One of the key studies is called BeTa, and this was a study where all the patients had receive first-line chemotherapy, and were getting, now, a second-line treatment, after progression, and they were either getting Tarceva alone, or the combination of Tarceva with Avastin.


The study, overall, did not show a significant improvement in survival, but when they looked at the different subgroups of patients, based on various clinical characteristics, you can see that a couple of subgroups of patients did particularly well with the combination.


Specifically, when they looked at patients who were Asian or Pacific Islander, or never-smokers — those patients really seemed to skew more toward greater benefit with the combination of Avastin and Tarceva.


They also looked at a small subgroup of patients, whom they had tumor tissue on and were known to have an EGFR mutation, and those patients also trended clearly toward a better effect with the combination of Avastin and Tarceva.

So, that’s provocative, but that’s just one study. What’s interesting as well, though, is that a remarkably similar study was done where patients received either Tarceva alone, or Tarceva and Avastin, as a maintenance therapy. So, they had not progressed, but they had already received first-line therapy, and then went on to get Tarceva, or Tarceva and Avastin.


This study also showed no significant improvement in the overall population — this was, again, a molecularly unselected population, but when they looked at the different subgroups, based on their clinical characteristics, it was the same subgroups who got the benefit, in terms of overall survival, from the combination.


So, again, it is the Asian and Pacific Islander patients, and the never-smokers — the two groups who we know are most enriched for having an EGFR mutation. So, this is really a bit more compelling evidence that, maybe, there’s really something there.

The question was asked more directly in a study done in Japan and just published in Lancet Oncology not too long ago.


This trial had about 150 patients, all with an activating EGFR mutation, who were randomized to receive Tarceva, or Tarceva and Avastin, as a first-line therapy. The study was designed to look for a significant improvement in progression-free survival, the time before at least half the patients had demonstrated significant progression of their cancer, on this combination that they started with, or the single agent.


What they found was a significant improvement in progression-free survival in the patients who received the combination. In fact, the difference in median time to progression, the time when half the patients in each group had progressed, was over six months longer in the patients who got the combination.


When we look at overall survival — most of the patients are still alive, so it’s too early to really say much, but the trend is in the direction of favoring the patients who received the combination.

The other side of the coin, beyond efficacy, is tolerability, and the combination was associated with more side effects, as you’d expect — although, there were no treatment-related deaths with the combination. In the Japanese experience, there were more patients who had significant problems and needed to come off of the drugs, specifically Avastin, than we’ve typically seen with this combination in other studies. 40% or so of the patients had to discontinue the Avastin because of side effects, usually high blood pressure, or leaking protein into the urine, something called proteinuria; whether that is because these patients just had been on these agents for longer than they usually are in other studies, or there is something about the Japanese patients, or EGFR patients, who were more susceptible, we don’t know. But, at the end of the day, it was still a tolerable regimen, and more of the patients did well and did not progress for much longer when they received the combination.

So where does this leave us? We have a more than six month improvement in the median time to progression with the combination, but this is only one study, done in Japan, and sometimes we see differences in studies done in one part of the world, versus another. Overall, I would say that, to me, these data are quite compelling, and it’s enough to lead me to favor the combination for my patients if an insurer will cover the Avastin, which is not, at this point, a clear standard of care. To many investigators and general oncologists, the combination is not yet their preferred regimen — they would like to see more evidence, larger studies, and ideally, work from other parts of the world to corroborate what we saw out of Japan. In fact, there are studies being done, one in Europe and one in North America, that are asking the same question, so we’ll hope to get more information soon, but this is certainly a very promising lead, and enough to lead me to favor the combination for my patients who have an EGFR mutation.

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