GRACE :: Lung Cancer

Exon 21

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.

Does Gilotrif Help EGFR Positive Lung Cancer Patients?


An analysis of two large studies of EGFR lung cancer patients tried to determine if Gilotrif helped patients live longer.

Combined OS analysis: mutation categories

Gilotrif (Afatinib) Reports Survival Benefit for EGFR Mutation-Positive Advanced NSCLC: Is it a Superior EGFR Inhibitor?


One of the high profile presentations in the lung cancer track at ASCO 2014 was from Dr. James Yang of a pooled analysis of the LUX-Lung 3 and LUX-Lung 6 trials, each comparing Gilotrif (afatinib) to standard chemotherapy as first line treatment of EGFR mutation-positive advanced NSCLC, which for the first time demonstrated an actual survival benefit not seen in similarly designed trials with Iressa (gefitinib) or Tarceva (erlotinib). We should expect to see a huge marketing campaign built on this result, implying that Gilotrif is now the leading choice of oral EGFR inhibitors that would be considered for EGFR mutation-positive patients. But is this a fair claim?

The LUX-Lung 3 trial compared Gilotrif to cisplatin/Alimta (pemetrexed) in a global trial, while LUX-Lung 6 compared Gilotrif to cisplatin/gemcitabine in an Asian trial, each with over 300 EGFR mutation-positive patients. Both showed a highly significant improvement in response rate and progression-free survival that largely reproduced the same results seen in several preceding trials with Iressa (gefitinib) or Tarceva (erlotinib) vs. other chemo regimens over the past few years.  However, all of the preceding trials have failed to demonstrate a difference in overall survival (OS) from the EGFR tyrosine kinase inhibitor (TKI).  This has been presumed to have been because the vast majority of patients receiving initial chemotherapy have crossed over to an EGFR TKI at progression, with the presumption that these patients then demonstrate the same kind of dramatic and long-lasting response that we hope to see in EGFR mutation-positive patients starting on an EGFR TKI as initial treatment. In other words, we might presume that it doesn’t matter if you receive an EGFR TKI as first or subsequent treatment if you have an EGFR mutation, as long as you get it, so this “crossover” effect should negate any survival benefit from an EGFR TKI given as first line therapy.

The LUX-Lung trials did not demonstrate a significant improvement as individual studies, and in fact, the LUX-Lung 6 trial didn’t even show an improvement in median OS for the Gilotrif arm over chemotherapy. Overall, when we look at the absolute results of the two trials, at least in terms of median OS, we see that they did very comparably to preceding trials with other EGFR TKIs — in fact, the best median OS was seen in a Japanese trial with Iressa.

Is OS superior to other EGFR TKIs

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Top 10 Key Presentations at ASCO 2014: Join Us for Discussion at Upcoming #LCSM Chat 5/22


Top10ListEvery year, many of the most important developments in cancer care are presented at ASCO. This year, we’ve got what I think is a very important year in lung cancer, with several practice-changing results/. Impressively, this is a year in which the most important trials include some focusing on first line treatment of patients with an EGFR mutation, some on acquired resistance in EGFR mutation-positive patients, some work on MET as a target, a couple on patients with squamous NSCLC or general NSCLC that includes squamous and non-squamous NSCLC, one striking finding in stage III resected NSCLC, and even a couple of most immediately practice-changing results in small cell lung cancer.

I’ll clarify that, working within the limit of a top 10 list , I couldn’t include some notable but negative trials, particularly those for which we’ve already learned of their negativity in press releases. And while immunotherapies continue to demonstrate their promise, the presentations at ASCO this year really just reinforce what we’ve already seen.  Because they don’t break significant new ground, this isn’t a year when immunotherapy trials are in the top 10 — though I expect at leasat one or two among next year’s top 10 list.

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New FDA Indication for First Line Tarceva in EGFR Mutation-Positive NSCLC May Be Good for Roche but BAD for Patients: Here’s Why


Earlier this week, the FDA approved the oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) Tarceva (erlotinib) for the approximately 10% of advanced NSCLC patients with an activating EGFR mutation in North America and Europe (approximately 30% in Asia).   While that’s generally a good thing, and it’s in keeping with the evidence very strongly supporting erlotinib or another EGFR TKI as the optimal systemic therapy for patients with an activating EGFR mutation, the indication was paired with a positive result on a specific mutation test marketed by Roche called cobas and used in the EURTAC trial of Tarceva vs. chemo that was conducted in Europe on patients with an activating EGFR mutation on the Roche test that was approved to be paired with the first line Tarceva indication.

I’m concerned that this development may well be detrimental for patients, even if it’s a shrewd move for Roche.  Why? Because there is already a clear consensus that EGFR TKI therapy is the preferred treatment for patients with an activating EGFR mutation, and the evidence supporting it is so overwhelmingly compelling that it’s uncommon to have erlotinib refused by payers as the treatment of choice in EGFR TKI-naive patients, even before the official FDA approval.  Moreover, over the past 9 years since activating EGFR mutations were first identified, a wide range of different tests to detect them have been used.  We know that the excellent responses with EGFR TKIs are seen primarily in patients with the more common exon 19 and exon 21 mutations, which are the ones specifically detected with the cobas test from Roche, but many other testing platforms can do this quite well and have been used for years and years now to identify patients who are great candidates for early EGFR TKI therapy.  

By linking the indication for first line Tarceva in EGFR mutation-positive patients with a positive result on the cobas test, Roche may well have enforced a monopoly on molecular testing, but there is no reason to think that their test is meaningfully better than many other options.  To me, this move seems as crass and transparently commercial at the expense of good science and care as seeking an FDA approval that erlotinib needs to be taken daily with a venti Starbucks latte if Starbucks had wrangled their way into a strategic partnership and got written into the EURTAC protocol.  My fear is that many people who have had EGFR mutation testing done by other reputable sources will now have their opportunity to receive first line Tarceva jeopardized based on the linked approval of the indication with the test.  Some people may require additional biopsies and incur treatment delays, increased risks, and added costs just because Roche finagled an opportunistic rider on the science.

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