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Dr West

Lung FAQ: What treatment should I receive now that my NSCLC with an EGFR mutation is progressing after responding for a year?

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The response of cancers with a specific driver mutation , such as an EGFR mutation or ALK rearrangement, to a targeted inhibitor of that target, is often dramatic and long-lasting, but it is also almost always limited in duration, typically lasting several months or a few years.  Beyond that point, we tend to see a subset of the cancer cells become resistant progress, perhaps manifested as one or several  new lesions or growth of one area against a background of most of the remainder of the cancer still being well-controlled.  

In other cases, the progression is more multifocal, sometimes very slow, and sometimes more rapid.  What is the best treatment for patients whose cancer is now progression in this setting of “acquired resistance” after an initial good response to an EGFR tyrosine kinase inhibitor (TKI) or ALK inhibitor?

The short answer is that there is no consensus, so the best we can offer is a thoughtful perspective as someone with both experience in treating many such patients and a knowledge of the current data, which are limited.  And in assessing an optimal treatment approach, I would contend that it really depends on the features of the particular case. Is this someone who demonstrated a very long response interval of at least 8-12 months, or a relatively short period before progression was demonstrated?  Is the pattern of progression very limited, such as just one or a few lesions growing, or much more diffuse? Is the progression very indolent, such as just a few millimeters of change between scans done 2-3 months apart, or faster than that? And is the person with progression experiencing symptoms or not?  And how we’ll are they tolerating the targeted therapy?

It’s worth noting that a minority of people with acquired resistance to an EGFR inhibitor (and likely also with an ALK rearrangement, though this hasn’t been reported specifically) will demonstrate faster progression once the EGFR inhibitor is discontinued, leading to a conclusion that “bad brakes are better than no brakes”…even though someone is experiencing progression, they may experience faster progression if someone discontinues that targeted therapy than if they continue on it.  

The key questions, then, are:

1) Should someone make a change at all?

2) If a new treatment is needed, what should it be?

3) If a new treatment is started, should the person discontinue the targeted therapy or continue it?

Tackling the first question, one point is that asymptomatic, slow progression need not necessitate a change in treatment.  Many patients can continue to demonstrate slow progression and a disease burden far less than they started with prior to targeted therapy, so as long as patients are monitored with regular clinic visits and scans (I personally would do scans every 6-12 weeks or so, with clinic visits interspersed in between in some cases to ensure the person is still feeling well), I consider this not only appropriate but arguably optimal.  You are very unlikely to burn bridges and stretch out the subsequent remaining treatment options over a longer period.

If there’s enough progression to warrant an intervention, what should it be? In those with progression in one lesion (e.g., a new lung or bone lesion, or progression in the brain only, with good disease control outside of the brain), some patients can do very well for months or even years with just a local therapy such as radiation or surgery directed to the progressing lesion and ongoing targeted therapy for the rest of the disease (no real change after the local treatment).  This is particularly appealing for those with slow progression who are tolerating the targeted therapy well and progressing after a longer interval.  

For those with more multifocal progression, initiation of a systemic therapy is warranted.  While there are clinical trials directed towards reversing the resistance and focusing on continuing the targeted therapy as the main intervention, the most common approach is to start the best treatment that would be given as if the person didn’t have a driver mutation.  In most cases of advanced NSCLC, that’s going to be a doublet chemotherapy with or without the anti-angiogenic agent Avastin (bevacizumab).  There haven’t been meaningful studies to confirm this, but that is the recommendation that is pretty close to a consensus among experts, especially since most patients with acquired resistance have as good a performance status as they did before they started any treatment, if not better.

This leaves the question of whether to continue the targeted therapy with the new treatment, a question for which there is almost no real evidence.  There are no prospective trials, though these are now being done.  Though years ago I was not a fan of concurrent chemo and concurrent EGFR TKI therapy, that was in a setting of treating a broad range of patients, most of whom don’t have a driver mutation.  In the setting of treating patients with a driver mutation associated with a very good response to that therapy, I believe that integrating a new chemotherapy-based treatment is appropriate and likely advisable for patients with slower progression of their disease, and who are tolerating that therapy well.  It’s also still reasonable to discontinue the targeted therapy and consider “re-treatment” with the targeted therapy after an interval off of it, as this is occasionally (though not frequently) associated with a response due to re-sensitization, or at least several months of non-progresison.

This is an area in which thoughtful oncologists might well have different recommendations, as there are few studies to guide our plans.  Fortunately, this is an area of keen interest, and we can realistically hope to have more information in the next few years to help guide our recommendations.

For additional information: 

Webinar on Acquired Resistance to EGFR TKIs, by Dr. Lecia Sequist, MGH 

Acquired Resistance Case Discussion by Multiple Cancer Specialists

Local Therapy in Acquired Resistance

Ongoing Treatment Beyond Progression with Targeted Therapy

Retreating After Progression with Targeted Therapy


14 Responses to Lung FAQ: What treatment should I receive now that my NSCLC with an EGFR mutation is progressing after responding for a year?

  • ssflxl says:

    Dr. West

    What a timely post. I had cyberknife to my local spread (thoracic inlet lesion) in my left lung in May, and continue on a slightly higher dose of Tarceva. My repeat PET this week showed that the thoracic inlet is gone, but my primary left anterior tumor is still about 2 cm with SUV of 6.9 (was 6.2 before). As I have oligomet disease, with only 1 met in my paraspinal muscle that was initially removed by radiation , should I now insist on repeat radiation to my primary tumor? My rad onc doesn’t want to radiate the primary – I had it done initially at diagnosis, but did not get the max dose of 60 Gray. However, there is a lot of literature about surgical removal or radiation treatment of both primary and met lesions in oligomet disease, with curative intent (I know it’s not going to be a cure, but at least, it can prolong overall survival). Your opinion and Dr. Loiselle’s opinion would be appreciated. I feel I only have a window period to get repeat radiation if I were to get it.

    thanks

    ssflxl

  • Dr West
    Dr West says:

    When you ask “should I” questions, that’s a red flag of a question we can’t answer. There aren’t any real data here to say that it’s definitely better to radiate or re-irradiate the primary tumor in this setting of residual disease for metastatic cancer, and “no” is still the textbook answer. Is it reasonable? I’d say so, but I think anyone would be on thin ice insisting on radiation when it isn’t the standard of care and really doesn’t have solid evidence, but rather primarily a rationale, in support of doing it. Even the docs who are giving local radiation for oligometastatic disease or “oligoprogression” aren’t suggesting that there is good evidence to support this clearly being the new standard.

    -Dr. West

  • ssflxl says:

    Dr. West

    Thanks for your perspective. I understand where you are coming from. As an oncology patient for the last 2 years, I just want to make an observation about oncology in general. the field is highly driven by standard of care and data. However, as a patient, sometimes we can’t wait for the data because we have a very small window of opportunity to try something before it’s too late. In my case, do something that is more proactive and have an Anticipatory Approach, instead of wait until we see more cancer before we do anything. It’s like jumping out of the plane and you’re told that you can’t open the chute until you see the ground. Well, it’s not whether we will hit the ground but it’s a matter of how fast you will hit it, and by the time you see the ground to open the chute, it’s too late. I am not talking about turning to snake oils and such, but having a rational approach even though there is not great evidence yet. I think that’s why so many people turn to alternative therapies for their illness because at least it gives them hope – although it’s false hope.

    ssflxl

  • Dr West
    Dr West says:

    Your point is very well taken, and I just mean to say that there is a difference between me saying that the rationale is reasonable enough to proceed and sticking my neck out and saying that you should insist on it. Not only is it really not appropriate for me to tell someone here who isn’t my patient what they should do, but I would say that there just isn’t the strength of any evidence to say that one should insist, as if the answer is quite clear. I recognize that absence of proof isn’t proof of absence, but that only gets you far enough to justify a more creative approach, not to mandate it.

    Also, I’ll add that in practice, many and probably most oncologists do plenty of treatments that are outside of the current standards of care for their individual patients, and I don’t think that’s inappropriate. An absolutely huge amount of real life in the cancer clinic doesn’t have enough good evidence to guide us on what to do (or we see it and believe we can do better), and/or we substitute judgment rather than be enslaved by rigid standards. The further you are from being directly involved, the easier it is to sneer condescendingly and talk about what the evidence shows or doesn’t show. But those same people are usually just as inclined to deviate with their own patients as anyone else. It’s just easier to be a purist when it’s an abstract question rather than a real person you’re working with.

    -Dr. West

  • ssflxl says:

    Dr. West

    I understand where oncologists are coming from, although I don’t agree with the “wait until we see cancer” approach, especially when you know for sure that it’s going to be here, not a matter of “if” it’s going to be here. As patients, sometimes all we have is “gut feeling” or rationale, not real proof and we are glad that at least there is no negative evidence. At least, my rationale is not Unreasonable.

    thanks so much

    ssflxl

  • graceabchen says:

    Dr. West: Thank you for providing an updated view on how to deal with progression on TKI. Related to when to switch treatment is the question of re-biopsy. It is required by all clinical trials. Is it usually required for other alternatives, such as local treatments or chemotherapies? More specifically, is biopsy required on every nodule to be treated with cyberknife? Thanks, AB

  • certain spring says:

    Not to get in the way of AB’s question, but just wanted to say thank you for this very useful post, which will help many people in a confusing situation.
    And to ssflxl, I am sorry you are facing this new dilemma and I understand your frustration. Glad to hear however that the radiation has worked for the met.

  • Dr West
    Dr West says:

    Sorry I accidentally overlooked responding to AB’s question in a more timely way — busy week. Repeat biopsies are certainly required by some clinical trials for acquired resistance, but I really don’t think every one requires a repeat biopsy from the time of progression. Most may require tissue to be submitted, but I’d really be surprised if every single trial requires an additional biospy that isn’t considered the standard of care or clearly useful for clinical management right now.

    As for cyberknife, there isn’t a uniform policy about this. There isn’t a clear role for cyberknife on multiple lung nodules. If a radiation oncologist is inclined to consider this, a biopsy may or may not be felt needed to confirm a viable cancer there — but it’s an individual determination, not a uniform rule or policy.

    -Dr. West

  • graceabchen says:

    Dr. West: Thank you for your response. AB

  • Khaldoun says:

    Dear Dr. West
    I have been now on Tarceva 150 mg daily since Jan , my last bone scan results are progression of the metastatic bone disease (Newly developed multiple active bone lesions in the thoracolombar spine , around right shoulder joint ,right 6th rib posteriorly, sternum ,sacrum , left iliac bone and upper shaft of left fumer since prior scan )
    My Oncologist is still holding to Tarceva and I am continuing with 150mg daily dose ,
    I was wondering if such progression is considered as enough to warrant intervention or it is still safe to continue with the current path ?
    Would you consider going for Altima at this stage ?

  • Dr West
    Dr West says:

    This does sound like multifocal progression that is a pretty significant change compared with last scan. In such settings, I usually consider a chemo-based approach if a person hasn’t received it before. Specifically, my approach is to favor the kind of chemo regimen I’d use as first line therapy in that person if they didn’t have a “driver mutation” and targeted therapy given as first line treatment against that.

    -Dr. West

  • hopey5000 says:

    My take. Since there is no established treatment, you’re making an educated guess just like the doctor. First, it makes sense to try to determine the source of resistance. If its for example T790M, it makes sense to look at experimental treatments addressing that. Some studies suggest that a dual approach could be helpful. “Tang, Dual MET EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer, Br J Cancer. 2008 September 16; 99(6): 911, 922.

    Choice os doctor or facility can make more sense here, and a place like Mass Gen where a lot of the initial research was done could be good. You can check recent studies on Google Scholar and see what makes sense. My understanding is that no one drug or combination has shown substantial efficacy, so you are making an educated guess on response possibilities.

  • Lillly says:

    Dear Dr. West,
    My dad (61 yrs old) was diagnosed with stage IV nonsquamous NSCLC over two years ago and he actually still has no symptoms of the actual cancer. He has had the three tumors in his lungs the whole time without them spreading anywhere else, and one actually going completely dormant (not even being mentioned on CT scan results) after the second line. The other two just showed growth on this last scan. The larger of the remaining two is currently 2.5 cm. He’s about to start the third line of chemo. After the first line, tumors started growing back about 2 months later. But after the second line, they were dormant (or “under control” as his doctors say) for over a year. Aside from having a very mild heart attack a few months back (which he says wasn’t even a big deal – he drove himself to the hospital and had a half hour procedure done), he feels better than ever. The chemo will start this Tuesday and doctors opted for Vinorelbin. Would you mind giving your thoughts on this? On the actual drug, and possibility of symptoms staying as good as they are. And whether you would suggest a similar strategy – going with more chemo even when he’s feeling so good without it?

  • Dr West
    Dr West says:

    This post is about a different subject, so in the future, please start a topic in the discussion forum (by hitting the button that says “”Ask Us”).

    I would refer you to the FAQ on options for patients with advanced NSCLC who have progressed after initial chemotherapy:

    http://cancergrace.org/lung/2010/10/04/lung-cancer-faq-2nd-line-nsclc-option/

    As you’ll read there, vinorelbine doesn’t have proven activity in previously treated patients, but it’s often minimally toxic and is sometimes effective for patients who have already received chemo. The most common treatment alternatives we favor in these situations are listed in the link above.

    As for whether to pursue further treatment when someone is feeling well and has already received several lines of therapy, that’s a personal decision that requires careful consideration of whether the benefits of further treatment exceed the risks. I am always wary about treating patients who are without symptoms, since you can only make them feel worse with more treatment.

    Good luck.

    -Dr. West

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