GRACE :: Lung Cancer

Challenging Cases in Lung Cancer: Acquired Resistance to an EGFR Inhibitor in a Patient with Advanced NSCLC and EGFR Mutation

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It’s been a while since we released another podcast from the recording I did with Drs. Jyoti Patel from Northwestern and Bob Doebele from University of Colorado earlier this year.  In that session, we covered a series of real life scenarios in managing lung cancer that are at the outer limits of what we can say we know and leave us relying more on our best judgment than on evidence. Along with the comments by Drs. Patel and Doebele, we’ve then added responses from a collection of additional great lung cancer experts (Drs. Suresh Ramalingam, Jonathan Goldman, Julie Brahmer, Heather Wakelee, and Karen Reckamp) when presented with the same case.  Here, you can see the convergence of principles but also how we sometimes struggle in our varied recommendations.

Here is a podcast of an important topic that comes up here all too often: What do we do for a patient with advanced NSCLC  and a known EGFR mutation who has responded very well and for a long time to an EGFR tyrosine kinase inhibitor (TKI), but now demonstrates rather slow but clear progression compared to their best response?  Should we continue on the EGFR TKI without any changes for a while? When we decide a change is needed, how do we approach that? Do we stop the EGFR TKI temporarily or for good, or do we continue it and add a chemotherapy-based regimen in addition?  And when we reach a point of clear acquired resistance, how valuable is it to do a repeat biopsy? Is this just an arguably a nice thing to consider or an approach that the experts would clearly pursue?

Below you’ll find the audio and video versions of the podcast, as well as the transcript and figures (in truth, this isn’t a very video-oriented presentation, so you won’t miss much by concentrating on the audio and/or the transcript only):

grace-cases-acquired-resistance-to-EGFR-TKI-audio-podcast

grace-cases-acquired-resistance-to-egfr-tki-transcript

grace-cases-acquired-resistance-to-egfr-tki-figures

Folks interested in this topic may also want to check the podcasts from our discussions/webinar with Dr. Lecia Sequist, of Massachusetts General Hospital, who spoke with us earlier about what we know and are still learning about acquired resistance to EGFR TKIs and also her follow-up discussion of the potential insights we might glean from repeat biopsies in this setting.

Thanks to all of our wonderful participants in these case discussions, and to LUNGevity Foundation for partnering with us in supporting this series.


0 Responses to Challenging Cases in Lung Cancer: Acquired Resistance to an EGFR Inhibitor in a Patient with Advanced NSCLC and EGFR Mutation

  • ts says:

    Both the transcript and figures appear to link to the power point pdf’s of who and questions, no discussion. Guessing a glitch?

  • Dr West says:

    I’m not somewhere where I can fix this right now, but it should be fixable in a couple of hours. Thanks for catching this.

    -Dr. West

  • Dr West says:

    Not a big deal. The figures are just what appeared. I had just mistakenly uploaded the figures file as the transcript one as well. That’s now fixed.

  • graceabchen says:

    Thank all doctors for discussing your practices to deal with the challenging case of acquired resistance to TKI’s for EGFR-positive patients. One fundamental difficulty is that the cause of resistance is still not known. Knowing the cause would be a big step forward not only for prevention and but also for treatment. I would appreciate all of you commenting on this.

  • fortmyr says:

    Dr. West & colleagues, thank you for this very informative post. From what I read (in transcripts), all doctors seemed increasingly interested in doing re-biopsies, the logic being that this might lead nore patients to be able to get on the ‘right’ clinical trial (for them)? Interesting discussion and I guess we’ll hear more about this in years to come as the research in cancer biology is evolving rapidly.

    Myriam

  • ts says:

    Couldn’t help but notice Dr. Doebele mentioned local treatment for liver mets. Any chance we could hear more from him on this?

    Thanks for the post.

    GB- I think a few of the doctors mentioned that patients are open to re-biopsy for that reason – to get a better understanding of the resistance. I’m sure the researchers are hard at work on this. Well, I hope so.

    Myriam – frustratingly, my clinic biopsied the new liver met but only to check that it was the same stuff, and later, to check ALK status. They “don’t do” resistance testing since they don’t offer clinical trials that use that info. I guess practices will change.

  • Dr West says:

    AB,

    I don’t think there’s much to add to what’s been described in Dr. Sequist’s presentation. We know that development of a second mutation like T790M is associated with something in the range of 50% of cases with acquired resistance, and that perhaps 5-10% of patients will have over-expression of c-MET as a potential way to circumvent the inhibition of EGFR. Beyond that, we don’t have more answers right now.

    ts,

    I’m afraid that I don’t have ongoing access to Dr. Doebele, who is mostly concentrating on lab-based work. I’ve actually asked him if he’s interested in participating on the faculty, but he feels to committed to other pursuits. I don’t know that I’ll have another good opportunity to do a follow-up, and I’m even less confident that he’ll haev an evidence based answer. It’s not to say that people wouldn’t ever do it, but the basis for the recommendation is, I believe, mostly that it’s possible, not that there’s good reason to expect it would be very helpful. I think you would have received a more concrete recommendation in favor of it if there were a compelling rationale for it.

    -Dr. West

  • certain spring says:

    Thanks, Dr West, for making available a very interesting set of responses. Re the liver issue, I would be keen to read a post or discussion thread about the latest thinking on the treatment of liver mets, since this is a problem so many people here will face or are facing. Maybe next year!
    ts, since you have a biopsy, would it be worth sending it to a lab that does T790M/C-Met testing?

  • Dr West says:

    certain spring, and others,

    I’m sorry to say that there isn’t any new thinking about liver mets. The clear majority of oncologists don’t feel that local therapy is helpful or appropriate for the vast majority of patients with metastatic lung cancer, and I’m among them. If I were to ask a series of experts about the role of local therapy for liver metastases in the setting of advanced lung cancer, it wouldn’t make for much of a program, because most wouldn’t understand the question and would likely just say, “there is none”. The latest thinking is that they should be treated with systemic therapy. In colon cancer, there is a potential role for treating one or a few liver metastases with local therapy, but that’s just not the case in lung cancer.

    -Dr. West

  • graceabchen says:

    Dr. West, thanks for your response. Is there any clue suggesting that the second mutation grows from the mutated genes already exists before the TKI treatment, or it is induced by the TKI’s?

  • Dr West says:

    It’s possible to see a resistance mutation “de novo”, right at the time of diagnosis in a patient, so that a patient may have both an activating mutation and a resistance mutation even before they start an EGFR TKI. What happens in that case? It’s probably different from case to case depending on how prevalent each of these mutations is within the cancer cells of a patient, and what the actual individual mutations are. I suspect that many of the cases of EGFR mutation positive patients who don’t respond to an EGFR TKI (perhaps 20-40%) fit in that category, even if a resistance mutation isn’t seen.

    I’m seeing a patient now who has an exon 19 activating mutation and an exon 20 resistance mutation, right from the time of diagnosis. She had a great response of her chest disease to Tarceva, but her bone mets have progressed, and I imagine that more of the cancer cells in the bone lesions have the resistance mutation, while perhaps much of her disease in her lungs shows only the activating mutation. But I don’t know for sure.

    It’s more common to have a resistance mutation become acquired over the course that someone is being treated successfully with Tarceva. But even then, it may be that only a minority of the cancer cells have developed it, which may be why you can see a good overall response with “net shrinkage” even as parts of the cancer begin to grow again.

    -Dr. West

  • graceabchen says:

    Dr. West, Is it possible that the TKI can cause the positive-EGFR genes, e.g., those with exon 19 or 21, or the healthy genes to mutate into resistant genes?

  • Dr West says:

    I don’t have more to add than I said yesterday. We don’t have the answers to these questions.

    -Dr. West

  • emilyr says:

    Thanks for another interesting post. If a patient is on tarceva first line and develops resistance and chooses to try chemotherapy next instead of a clincial trial- will this exclude a patient from moving to a clinical trial when the chemo stops working? For example- I noticed in the exclusion criteria for the afatinib and cetiximab trial it says “No intervening systemic therapy between cessation of gefitinib or erlotinib and initiation of the treatment in the study”.

  • Dr West says:

    There are very few trials yet written in this setting, so there aren’t any clear rules or expectations established yet. I suspect that some will have this kind of exclusion but others won’t. There haven’t been enough examples out there yet to get a sense of which approach will be the more common one.

    -Dr. West

  • ts says:

    emilyr,
    I thought the same as you – it turns out that some people in that situation go back on Tarceva for a prescribed length of time in order to re-qualify for the clinical trial. Not sure if that always works, but it has been done.

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