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Dr West

Divergent Paths for Tagrisso (Osimertinib) and Rociletinib for EGFR T790M Mutation-Positive NSCLC and Acquired Resistance: What Happened, and Where Are We Now?

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For patients with an activating EGFR mutation and who develop “acquired resistance”, the pattern of progression that occurs after a sometimes long period of good initial response to an oral EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib), Iressa (gefitinib), or Gilotrif (afatanib), the evolving story of the treatment options has been a wild ride with several ups and a few downs. Over the last two years, several “third generation EGFR TKIs” with a strong affinity for EGFR activating mutations and, importantly, a different mutation called T790M, which is seen in 50-60% of patients with EGFR mutation-positive acquired resistance, but very low affinity for “wild type” (normal, non-mutated) EGFR molecules (which mediate the common, problematic side effects with EGFR TKIs, such as rash and diarrhea).  Given the very different paths that the two leading entrants – Astrazeneca’s Tagrisso (osimertinib, also previously known as AZD9291 and transiently as merelitinib) and Clovis’s rociletinib (also known as CO-1686) – it’s high time to review what has happened to get to where we are now.

The annual ASCO meeting in 2014 included very prominent presentations about these agents (Tagrisso and rociletinib, respectively), at that point still in early trials with several dozen patients each, that showed both agents had marked activity against the subset of patients with acquired resistance whose tumors test positive for T790M. At that time, AZD9291, which ultimately became osimertinib and then branded as Tagrisso, was a half-step ahead in terms of a slightly larger number of patients tested, but both agents were very promising for a population in which alternative treatment options other than standard chemotherapy. Though some concerns were raised about hyperglycemia (high blood sugar levels) in patients on CO-1686, my view at the time was that in people facing the threat of an advanced cancer, taking pills or even possibly insulin to manage blood sugar levels wasn’t likely to be a major issue if it worked effectively. Like many other lung cancer specialists and general oncologists alike, my perspective was that access to either agent would be a welcome opportunity for patients eligible for an accessible clinical trial. 

These two agents have been widely studied in a range of global trials as they continued their footrace over the next 12-18 months. In August, 2015, the remarkably early results with these two agents was featured in back to back articles (on Tagrisso and rociletinib, respectively in the prestigious New England Journal of Medicine.

But since that time, the paths of those two agents have diverged remarkably.  Tagrisso became FDA-approved in November, 2015 after continuing to demonstrate a response rate of significant tumor shrinkage in about 55-60% of T790M-positive recipients and up to 90% experiencing “disease control” that includes less significant shrinkage and stable disease. Importantly, these responses tend to last for many months to a year or longer, and this longitudinal treatment has been associated with a very low risk of significant side effects, with most patients experiencing either no issues or a rash and diarrhea that is so minimal that, in my experience, they haven’t felt warrants a hint of complaint.  The value of offering Tagrisso for T790M-positive acquired resistance has really changed the standard of care for EGFR mutation-positive patients with progression, making it instantly critical to seek and hope to find a T790M mutation, with a valuable subsequent treatment option to pursue before moving on to other options routinely offered for advanced NSCLC.

The path of rociletinib has been very dramatic over the past 6-7 months, but unfortunately it has been in a downward trajectory. Though provocative work over the past year has shown that this agent could work well in patients with T790M detected even in plasma, perhaps obviating the need for repeat tissue biopsies, the side effect profile with further use made it arguably a less attractive option than Tagrisso.  In my own experience, the constellation of nausea, diminished appetite, and diarrhea could create a cascade of weakness and misery that required aggressive dose reductions in a significant minority of patients and an occasional patient expressing dramatically “if this is what I need to do to have my cancer respond, I’d rather die” (though other patients certainly tolerate it better). But the biggest hit came in November, 2015, when the FDA reported that it was planning to delay a decision on potential approval of rociletinib after updated information revealed that the response rate reported to rociletinib of 59% was actually an “unconfirmed” response rate that dropped to about half that rate when looking only at confirmed responses (though the latest published update pegs response rate at 45%). The fortunes for rociletinib, along with Clovis’s stock price, dropped like a rock.

Tailspin

 Since then, clinical trials with rociletinib have continued on, and the FDA has continued its review process for the drug. The Oncology Drug Advisory Committee (ODAC) to the FDA, eviewing the evidence in April, came back with a 12-1 vote against approval until results from a randomized trial of rociletinib vs. chemotherapy be completed and demonstrate a clear benefit for rociletinib.  Then, in early May, Clovis announced very suddenly that the FDA, which almost always followed ODAC’s thoughtful recommendations, had notified the company that the FDA would not be offering an approval until further data supported its use. In that same press release, Clovis announced that it was terminating all trials with rociletinib (and was laying off 35% of its employees).

One important issue that the potential approval of rociletinib raised was the question of whether it should be compared to osimertinib or not. Technically, rociletinib didn’t need to be better than its predecessor to the market in the same space, but it is hard to determine what value there is in offering an agent with seemingly less activity and worse side effects than an agent we already have available. This issue of a strong incumbent will be a critical factor for other would-be challengers, further behind in development, which enter a world with Tagrisso as an entrenched, effective therapy in this setting, so how might other agents fit in?

A key relevant question here is how similar or dissimilar these agents truly are. One might well assume that there is a great deal of “cross-resistance” to drugs in the same family, as we see minimal activity of one first or second generation EGFR TKI after another (such as trying Tarceva after Iressa, or Gilotrif after Tarceva), just as you wouldn’t expect to have many people wildly excited about having a Pepsi after drinking a two liter bottle of Coke. But in fact, Dr. Lecia Sequist and colleagues from Massachusetts General Hospital recently reported that they have seen several cases of tumor shrinkage or prolonged stable disease on Tagrisso – including in the brain as well as other parts of the body — in patients who had demonstrated clear progression on rociletinib previously. As someone who had patients progressing on rociletinib in clinical trials, I followed this lead and have treated several of my patients with Tagrisso and also seen several very encouraging responses after progression on rociletinib. This is an important finding for patients in this setting who may benefit.

These advances are very significant, but we must still acknowledge the work that still needs to be done. Third generation EGFR TKIs may prove to offer meaningful benefits to the 40-50% of patients with T790M-negative acquired resistance, or we may need to search for better options elsewhere. It will also represent a great breakthrough if we can do repeat biopsies to check for T790M or other mutations in circulating plasma of patients rather than be required to pursue invasive biopsies at several time points over the course of treatment.  Though we probably can’t predict future developments much better than we might have predicted the drama in this space over the past two years, I can predict that it will be eventful and that we will only have a better understanding of and treatments for EGFR mutation-positive NSCLC in the future.

What do you think of these developments?


13 Responses to Divergent Paths for Tagrisso (Osimertinib) and Rociletinib for EGFR T790M Mutation-Positive NSCLC and Acquired Resistance: What Happened, and Where Are We Now?

  • lhsiao says:

    Dear Dr West, I really appreciated your article above. I am currently in Clovis Tiger I trial, taking Rocelitinib due to Stage IV non-small cell lung cancer (adenocarcinoma) that is EGFR positive. After about 7 months, my disease is stable and I have no significant side effects. I read your article above. I am thinking about switching to Osimertimib. However I also read that Osimertimib has a small side effect of interstitial lung disease (3.3%). I am 42 y/o. Is this a significant side effect and is it still worth it for me to switch to Osimertimib?

  • Dr West
    Dr West says:

    There is a small but real risk of pneumonitis, which is a significant side effect if you get it — but only a very small minority of patients do.. I think the benefit outweighs risk if someone needs a new treatment, but not necessarily if the current treatment is working.

    Good luck.

    -Dr. West

  • ntebyanian says:

    Dear Dr. West,

    My mother was placed on Tagrisso as first line agent because of some evidence of possible leptomeningeal disease on MRI after WBR and some evidence that Tagrisso at 160 worked for a few patients with it. She is being followed at the NIH. She now has a possibility of very early interstitial lung disease —maybe. She had increase in her right pleural effusion and cxr showed some hazziness in both lungs. She has no cough and no fever and normal pulse ox and did better after the fluid was removed. Is the lung toxicity of Tagrisso acute or can it be subtle and chronic? She is doing quite well on it otherwise and I am a bit concerned about taking her off of Tagrisso. She is exon 19 EGFR positive, T790 M negative with some bone mets and with many mets in the brain at diagnosis. We are currently awaiting recommendations from her local oncologist and NIH .

    Thanks

  • Dr West
    Dr West says:

    I’m very sorry to hear about your mother’s diagnosis and recent issues.

    Pneumonitis tends to come on early when it occurs, but this is an uncommon to rare side effect in a new drug that we just don’t have a lot of experience with yet. It will make sense to make a very careful judgment among everyone involved with your mother’s care about the risk vs. benefit of continuing on it.

    Good luck.

    -Dr. West

  • apple81 says:

    Hello Dr West,
    Thank you for your continued education! My mother is a 72 yo non-smoker who developed stage 4 non-small cell lung cancer (pneumonic form; no mets outside of the lung) 1 year ago. She was EGFR positive, so was on Tarceva for the past 12 months. Unfortunately, she has now developed Tarceva resistance, and has also developed a large pleural effusion.

    My questions are regarding the next steps. We’re hoping she tests positive for the T790 Mutation.
    Do you recommend the tissue biopsy and/or ‘liquid biopsy’/blood test for the T790 Mutaion? Also what are your thoughts testing for the T790 Mutation in the pleural fluid (apparently it’s difficult to do a lung biopsy because of the pleural effusion)?

    Even if the tissue and/or liquid biopsy or pleural fluid are negative for the T790 Mutation, because of the chance of having a false negative (sampling error in the biopsy or thoracentesis, and lack of systemic metastases so the ‘liquid biopsy’ may be falsely negative) what do you think about at least trying a course of Tagrisso before starting on chemo? If not, then I imagine chemo would be the next recommendation, correct? Any new chemo recommendations?

    Thank you!
    Eric

  • Dr West
    Dr West says:

    Tagrisso will not be covered if the tests are negative for T790M, so it’s not feasible to expect to just try it.

    It’s perfectly reasonable to start with a liquid biopsy test of plasma. If it’s positive, you can move to Tagrisso, but if it’s negative, you can do a tissue biopsy. It’s also often possible to do a test from cancer cells in the pleural fluid. Sometimes the fluid doesn’t have any or many cancer cells, but sometimes it may just be a question of working with the right pathology lab.

    If negative, chemo would be the leading option (and no new chemo recommendations — sorry).

    Good luck.

    -Dr. West

  • apple81 says:

    Hello Dr. West,
    Thank you for your, as always, sage advice. I’m sorry that my second ‘draft’ reply didn’t go through, and I forgot to mention in my first reply that my mom has a new large pleural effusion (which apparently makes the tissue biopsy difficult).

    An expedited T790 mutation is becoming an issue, because my mother’s cancer has gone from unnoticeable 2 months ago to now having innumerable nodules in her Left lower and upper lobe, as well as a large left pleural effusion, and also because she is now becoming symptomatic with a significant cough and dyspnea with exertion.

    It sounds like the liquid biopsy takes a few weeks to get a result, and then, because of her lack of metastases outside of the lung, she could have a false-negative result. I didn’t realize the tissue biopsy couldn’t be done if the large pleural effusion is present, so a thoracentesis was recommmended. However, it sounds like the thoracentesis has about a 60% chance of having enough tumor cells in it to be tested.

    I didn’t envision it would be some timely and complicated to find out if she has the T790 mutation, so I just wanted to check to see if you had any recommendations in terms of the best and quickest way to get the T790 mutation result in this situation?

    Thank you again!

    Eric

  • apple81 says:

    Hello again,
    Thank you for your guidance with the T790 mutation testing. My mother’s pleural effusion made the lung biopsy difficult to do and apparently the lung nodules were too small to biopsy (although there are a Lot of them), so her pleural fluid was tested. Apparently the pleural fluid had cancer cells in it, and they were negative for the T790 mutation. We’re waiting to hear whether the MET amplification is present in cancer cells also from the pleural fuid (if there are, then she could possibly go in to a clinical trial at Mass General in Boston).

    For a 73 yo otherwise healthy woman non-smoker with stage IV NSC lung cancer (no mets outside of the lung) with EGFR mutation that has developed resistance to erlotinib after 12 months, are there any clinical trials (preferably in Seattle/Portland or the Bay Area) that you would recommend she go in to now as opposed to starting on chemo?

    Thank you!

    Eric

  • Dr West
    Dr West says:

    I don’t know of anything in particular — you or her doctor may be able to find something searching on clinicaltrials.gov. I must confess, however, that I would consider it far more likely that chemotherapy will be beneficial than to try a clinical trial as the first treatment after Tarceva in a patient with T790M-negative acquired resistance. It isn’t to say that I think a trial would be a bad idea, but I would be less inclined to favor a trial, with the benefits not established and totally unknown, compared to platinum doublet chemotherapy that has a known and well-established survival benefit, than as a later line where there isn’t a competing standard treatment with a well-established benefit.

    Good luck.
    -Dr. West

  • apple81 says:

    Thank you, Dr. West.

    I literally read and re-read every thing that you write to make sure I’m doing everything that I can for my mom! I can’t thank you enough for this service! It’s such an interesting field of medicine that we can have So many choices to choose from, although it’s also stressful for patients (and family members of patients), because trying to predict/guess which medicine will turn out to be effective in future studies can have life or death consequences!

    We’re still waiting for the MET alteration result, but, assuming that it’s negative, it seems we’ve narrowed my mom’s next step down to 3 options:
    1. Platinum Doublet Chemo
    2. Atezolizumab + Platinum Doublet Chemo Phase 3 Trial (although Immunotherapy studies haven’t looked very promising for non-smoking EGFR patients, maybe Immunotherapy in combination with chemo would be more effective?)
    3. Osimertinib + navitoclax Phase 1 Trial (or Osimertnib + Necitumumab Phase 1 Trial)

    You mentioned option 3 in a past post, so I wanted to check to see what you’re latest thoughts were about that option (and also whether you’d heard any preliminary results from the TIGER-3 study?; that study is no longer accepting patients now, but I’m interested to know whether the 3rd generation TKIs are found to be effective even for T790m negative patients).

    Any preferences between those 3 options?

    Thank you!

    Eric

  • Dr West
    Dr West says:

    I haven’t heard anything further about osimertinib combinations or any results from TIGER-3 — in fact, my understanding is that all of the rociletinib clinical research has been shut down.

    My general approach has been to move to chemo-based treatment in patients with an EGFR mutation and T790M-negative acquired resistance. I have yet to learn of any emerging treatment directed against T790M-negative EGFR acquired resistance that has demonstrated efficacy.

    As I’ve written, immunotherapy hasn’t panned out as an effective therapy for most patients with a driver mutation. Yes, a combination could be more effective, but I prioritize treatments with proven benefits, such as chemotherapy, over much more investigational approaches, especially those that have not looked especially promising thus far.

    Good luck.
    -Dr. West

  • jjkk says:

    Dr. West,
    My over 80 year old mother had stage 3b disease with exon 19 deletion, did well on Tarceva for 10months, and then tested positive for t790m mutation in a recurrent supraclavicular LN that reappeared. She was on Tagrisso for 5-6wks and on follow up has rising tumor marker with new pleural effusion and new small lung nodule. Her other lymph nodes and primary lung nodule are stable size. Needless to say we are upset.
    What is the reason for this?
    what are the best options? and how effective should we expect them to be.
    should she stay on Tagrisso?
    Should any other testing for other resistant patterns be done on the pleural fluid?

    thank you for your guidance

  • Dr West
    Dr West says:

    Not every patient has a good response to Tagrisso. The response rate is about 60% in this setting. It is quite possible that only a small amount of the cancer cells are actually positive for T790M. At this point, we don’t know exactly why some patients respond and others don’t.

    I can’t give medical advice to people who are not my patient, which means I can’t ever answer a question of “What should we do?” — that’s what her doctor is for. But I would note that there’s very little evidence of real progression. The rising tumor marker means essentially nothing. Most experts think that’s a very poor way to monitor patients and feel it’s as likely to lead to confusion and poor care than actual insight. The pleural effusion is a rather soft call for progression, as is the small nodule. I think the leading options are to keep the Tagrisso going for another 6-8 weeks to see whether more convincing evidence of progression occurs, or switch to chemo-based treatment. It’s reasonable to check the pleural fluid for cancer cells and potentially send off for detailed molecular testing to look for other mechanisms that MIGHT POSSIBLY give an idea of another treatment approach, but that isn’t a standard approach and doesn’t have any proven benefit. Switching to standard platinum doublet chemotherapy once clear progression on Tagrisso has been determined is a very reasonable approach and would be the leading evidence-based strategy.

    Good luck.
    -Dr. West

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