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GRACE :: Lung Cancer

erlotinib

Not all EGFR Activating Mutations are Created Equal: Time to Stop Pooling Them Together

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It’s been a decade since EGFR gene mutations were first identified as highly correlated with a high probability of response to EGFR tyrosine kinase inhibitors (TKIs) like Iressa (gefitinib) and Tarceva (erlotinib), and more recently Gilotrif (afatinib).   We’ve learned that there are an array of EGFR mutations, and that the two most common ones, an exon 19 deletion or an L858R substitution on exon 21 (an exon is a specific expressed portion of a gene), each somewhere around 40-45% of  the EGFR mutations seen, are actually the ones consistently associated with a dramatic and often long-lasting response to EGFR TKIs. In contrast, the other 10-12% of EGFR mutations, most commonly on exon 18 or exon 20, are a heterogeneous group with a less clear benefit from EGFR TKIs.  

For about the last 5 years, the lung cancer community has reached a pretty clear consensus that the exon 19 deletions and exon 21, L858R substitutions represent so-called “activating mutations”, and patients with these specific mutations in their tumors are the ones that have, in trial after trial, been shown to have a markedly higher response rate (RR) and longer progression-free survival (PFS) with EGFR TKIs than with standard chemotherapy.  Over that time, they have been pooled together and largely presumed to be very comparable. More recent research presented at ASCO 2014, however, rekindles questions that go back many years and cast doubt on whether we should really pool these two mutations together. 

Back in 2006, two different publications came out — one from Boston’s Dana Farber Cancer Institute (on the top of the figure below), and another from New York’s Memorial Sloan-Kettering Cancer Center (bottom of figure below) — each independently reported that while both mutations were associated with very good responses to Iressa or Tarceva, the exon 19 patients seemed to do better, potentially in terms of both PFS and overall survival (OS).  

Exon 19 vs. Exon 21 2006

(click on image to enlarge)

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

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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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Does Adding Avastin to Tarceva Help EGFR Positive Lung Cancer Patients?

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Drs. Nasser Hanna, Melissa Johnson and Jack West discuss results of a phase 2 trial presented at ASCO 2014 that studied if adding Avastin (bevicizumab) to Tarceva helped EGFR positive lung cancer patients increase progression-free survival. June 2014.

Primary endpoint: PFS by independent review


Should We Add Avastin (Bevacizumab) to Tarceva (Erlotinib) for EGFR Mutation-Positive NSCLC?

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I recently had the honor of providing the expert commentary at the ASCO 2014 conference on three high impact lung cancer presentations, all on the subject of treatment options for molecularly defined populations (EGFR and ALK). I’ll review the findings from these three abstracts and my perspective on each of these, starting with a very provocative presentation by Dr. Kato from Japan that attempted to ask the question of whether we should add Avastin (bevacizumab) to Tarceva (erlotinib) as first line therapy for EGFR mutation-positive advanced NSCLC.

There have been a few large trials that directly tested the combination of Tarceva/Avastin vs. Tarceva alone — one as second line treatment (called BeTa), and one as maintenance therapy (called ATLAS).  These have failed to demonstrate a significant benefit for the combination, but they were in molecularly unselected patients, meaning that they were a broad population and not just patients with a specific molecular feature like an activating EGFR mutation.  However, both of these trials provided hints that the combination appeared to be especially effective for specific patients, most likely those with an EGFR mutation. For instance, the BeTa trial showed that two particular clinically defined subsets demonstrated an overwhelming benefit for the combination over Tarceva alone — Asian or Pacific Islander, and never-smokers.  Of course, these are also two subgroups known to be highly enriched for having an activating an EGFR mutation.  The subgroup analysis also showed that the small subgroup with an EGFR mutation also did far better with the combination, corroborating our presumption about why the Asian/Pacific Islander and never-smoker groups did so well.

BeTa Trial Subsets

 

   

  Moreover, the same clinically defined subgroups — Asian or Pacific Islander, as well as never-smokers — were also the two standout subgroups that appeared to benefit most in the ATLAS trial. The subgroup analysis from that trial did not include an analysis by EGFR mutation, but I suspect it would have shown the same effect as seen in the BeTa trial. 

ATLAS trial subsets

 

 

Dr. Kato and colleagues looked specifically at the potential benefit of adding Avastin at 15 mg/kg IV once every three weeks to daily Tarceva at 150 mg daily as first line systemic therapy for advanced NSCLC patients with a prospectively identified EGFR mutation. They randomized 154 patients, of whom 152 received treatment, and demonstrated a rather remarkably improvement in median progression-free survival (PFS) of more than 6 months, increasing from a median of 9.7 months for Tarceva alone to 16.0 months with the Tarceva/Avastin combination. Though the response rate was not significantly different, about 2/3 of patients showing significant tumor shrinkage (called an objective response) in both groups, the disease control rate, which is the combination of patients who demonstrate tumor shrinkage with those who demonstrate at least stable disease, was different, favoring the combination, at 99% of patients on the combination showing tumor shrinkage or stable disease, vs. 88% for those receiving Tarceva alone.

Also quite interesting was the difference between the two common types of activating mutation.  Specifically, both subtypes of activating EGFR mutation — exon 19 deletion and L858R on exon 21 — demonstrated a major improvement in PFS with the combination compared with Tarceva alone. But the patients with an exon 19 deletion had a longer PFS compared with the exon 21 patients, whichever treatment they received.   The improvement in PFS was especially remarkable in exon 19 deletion patients, who actually demonstrated an improvement of nearly 8 months in median PFS, which was a full 18 months with the combination!

PFS by mutation subtype

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Is It Necessary for Early Stage Lung Cancer Patients to Get Molecular Testing for Their Tumors?

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If you were diagnosed with early stage lung cancer, should you receive molecular testing on your tumor in order to get targeted therapy? Dr. Joel Neal of Stanford University Medical Center discusses the reasons for and against it. February 2014.


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