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Dr Pennell

Are Tarceva and Iressa Equally Effective in Patients with Epidermal Growth Factor Receptor Mutations?

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Hi all! I had to take a month off in July as I was forgetting what my family looked like, but am now refreshed and ready to talk (write, really) about more interesting topics in the field of lung cancer. I just returned from the World Conference on Lung Cancer in San Francisco, where Drs. West, Sanborn, and I enjoyed some great foo… I mean, learned a great deal about what is happening in the world of lung cancer.

Of course, much of the truly practice changing research was presented only a couple of months ago at the ASCO meeting in Orlando, but there was certainly enough going on to keep us busy. Today, I thought I would comment on a presentation by Dr. David Jackman from the Dana Farber Cancer Institute in Boston, who is predominantly interested in non-small cell lung cancer containing activating mutations in the EGFR gene. Most who follow posts on this site already know a lot about this topic, but to sum it up: about 10-15% of North American and European NSCLC patients harbor specific EGFR mutations which confer exquisite sensitivity to EGFR inhibitors such as Iressa (gefitinib) and Tarceva (erlotinib).

Dr. Jackman and his group have put together an international database of clinical information from 223 patients with NSCLC who have been treated with EGFR inhibitors as part of five clinical trials over the last decade, along with information about which had EGFR mutations and which did not. These trials, all small single-arm trials, comprise patients from the United States, Europe, and Asia, and some of the patients have been treated with Iressa and some with Tarceva. By grouping these patients in one database, Dr. Jackman is able to draw conclusions about the efficacy of these drugs in different subgroups of patients. For example, he can compare how patients with exon 19 deletion mutations do compared to patients with exon 21 mutations, or how patients in Asia compare to Western patients, or even how patients do with Iressa compared to Tarceva.

Let me be clear that this type of research has clear limitations. This is not a randomized trial in which patients with one of these characteristics is directly compared to others, so most of the time you cannot draw definitive conclusions about outcome differences between groups in this way. But it does provide intriguing and valuable ideas about these comparisons, which can then be verified in a prospective (going forward) study.

One of the concepts that has been bandied about for some time is that patients with exon 21 EGFR mutations (45% of the total) do not seem to benefit for quite as long a time from EGFR inhibitors like Tarceva as do patients with exon 19 mutations (also about 45%). This has sort of become an accepted fact, based upon the outcomes from some of these small studies that were included in the Jackman database. And indeed, in his database Dr. Jackman showed that the patients treated with EGFR TKIs seemed to have a longer time to disease progression (14.6 months vs 9.7 months; p = .02) and overall survival (30.8 vs 14.8 months, p < .001) when they had exon 19 versus exam 21 mutations. However, when he looked at the Japanese EGFR mutant patients treated with Iressa, there appeared to be no difference in survival between patients with the two different mutations (they did equally well).

Unfortunately, there was only one North American trial that used Iressa, but again there did not seem to be any differences in survival between mutation types (albeit that this trial by Dr. Sequist in Boston had very small numbers to use for the comparison).

So what can we conclude from this discrepancy? One possibility is that the numbers are too small to conclude anything, and the Japanese trial is simply a statistical outlier. Another is that the mutations have different levels of predicting benefit in Asian patients, since the Western studies had too few Asian-ethnicity patients for a good comparison. But an intriguing idea is that perhaps Iressa and Tarceva are not truly equivalent drugs, as has been speculated given similar outcomes overall. It is possible that Iressa better inhibits the EGFR molecule in exon 21 mutant tumors than does Tarceva, and perhaps we should be using Iressa in the mutant population preferentially (ignoring for the moment that Iressa is not available in he United States right now).

Europe has recently approved the use of Iressa in EGFR mutant NSCLC patients in first-line, and hopefully as this is more broadly adopted we can answer this question definitively. It would also be nice to see the mutation subtype breakdown from the IPASS study, where Iressa was shown to dramatically prolong progression free survival when used in first-line treatment of EGFR mutant patients compared to patients getting traditional chemotherapy. For now, I will continue to use the tool I have available (Tarceva) in my mutation+ patients, but I think we should watch this very closely going forward to be sure we are giving our patients the most effective drugs available.


6 Responses to Are Tarceva and Iressa Equally Effective in Patients with Epidermal Growth Factor Receptor Mutations?

  • JimC Forum Moderator
    JimC says:

    Dr. Pennell,

    Welcome back, and thank you for another very interesting and informative post. It seems that specific mutation testing will become more prevalent and will lead to more individualized and effective treatments.

    And since my wife has the exon 19 deletion, I choose to believe that Dr. Jackman’s exon 19 vs. exon 21 statistics are significant!

    Jim

  • Dr West
    Dr West says:

    I was at Dr. Jackman’s presentation but really think that the observation that certain mutations may do better with Iressa instead of Tarceva is provocative, but I think it’s based on far too little evidence to really sway me that there is a meaningful difference between these two EGFR tyrosine kinase inhibitors in the mutation-positive patients. The lab-based work suggests that it requires much less of either EGFR inhibitor to inhibit a cancer cell with an EGFR mutation than a cancer cell with normal EGFR (EGFR “wild type”). Since standard dosing of Iressa at 250 mg daily gives far less biological effect than a standard dose of Tarceva, my sense has been that either is more than enough for the EGFR mutation patients but that the higher effective dosing of Tarceva leads to more effectiveness in those patients without a mutation. Admittedly, that’s a theory.

    The reality is that the clear majority of work in Asian patients has been with Iressa, while the majority of work in Western populations has been with Tarceva. I don’t think we’ve got enough good data yet to make comparisons of the two drugs that really are comparing the same thing in similar populations. I would have no difficulty extrapolating all of the Iressa work to Tarceva, except I’d anticipate more rash and perhaps diarrhea side effects because of the higher effective dosing of EGFR inhibitory activity.

    -Dr. West

  • tanny says:

    Quick question (from an older article), but Dr. Pennell mentioned:

    “And indeed, in his database Dr. Jackman showed that the patients treated with EGFR TKIs seemed to have a longer time to disease progression (14.6 months vs 9.7 months; p = .02) and overall survival (30.8 vs 14.8 months, p < .001) when they had exon 19 versus exam 21 mutations. However, when he looked at the Japanese EGFR mutant patients treated with Iressa, there appeared to be no difference in survival between patients with the two different mutations (they did equally well).”

    I’ve been searching for commentaries or journal articles or even the presentation by Dr. Jackman, but I was wondering if anyone recalls what exactly were the OS numbers for the Japanese EGFR mutant patients treated with Iressa? For instance, were they both closer to 14.8 months, or 30.8 months, regardless of exon 19 or 21?

    And was this generalization based on one particular Japanese study or multiple studies involving the Japanese? I know that this presentation should be taken with a grain of salt, but I couldn’t help but wonder. Thanks!

  • Dr West
    Dr West says:

    I don’t have that info. Dr. Pennell may know. I will try to reach Dr. Jackman and find out what I can.

  • Dr Pennell
    Dr Pennell says:

    Hmm, I do know that the median survival of Asian patients on Iressa is around 2 years, but I don’t know the specific breakdown from the Jackman database. The database was compiled from multiple trials.

  • tanny says:

    Thanks Dr. West and Dr. Pennell.

    And is it just me, or does it seem like the majority of studies & journal articles show that EGFR mutational positive patients have the Exon 19 mutation far more commonly than the Exon 21 mutation? It almost seems like 2:1 or 60% (exon 19) vs 30% (exon 21), as opposed to 1:1 (45% and 45%).

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