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T790M Mutations: Understanding Resistance to EGFR Tyrosine Kinase Inhibitor Therapy

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A few months ago, I had a patient in my clinic who is a lifelong never-smoker with an adenocarcinoma.  I had her tumor checked for molecular markers, which revealed that she had both an activating EGFR mutation (exon 19 deletion) and a T790M mutation associated with resistance (see Dr. Pennell’s excellent summary for an introduction to EGFR mutations).   Not sure what to expect from an EGFR tyrosine kinase inhibitor like Tarceva (erlotinib), I started her on chemo first, which she responded to for a while, and then put her on a Tarceva-based trial for second line.  Though her cancer-related symptoms of cough and non-exertional chest pain improved significantly within just a few weeks, her scan actually showed a mixed response: dramatic improvement of her chest disease, but modest progression with new bone lesions.

We now have a little more information to help guide our expectations in this setting. A new publication in the Journal of Clinical Oncology from Su and colleagues from Taiwan provides several valuable new insights on T790M, the mutation that has been identified as the most common cause of acquired resistance to an EGFR tyrosine kinase inhibitor (TKI) after an initial good response in patients with an EGFR activating mutation The investigators looked for both activating mutations and T790M mutations in Taiwanese patients, predominantly (about 75%) never-smokers and >90% with an adenocarcinoma, both before (107 patients) and after EGFR TKI therapy (87 patients) using three different methods: typical DNA sequencing, MALDI-TOF, and next generation sequencing.  For those who are really curious, extremely scientifically gifted, or very bored, this last link provides a good explanation of sequencing techniques, but this is really getting outside of the scope of what we need to know here; basically, direct gene sequencing is the usual mutation detection technique, MALDI-TOF is a less commonly used novel approach, and next generation sequencing is the “gold standard” that really clarifies who has what.

What they found was that MALDI-TOF was far more sensitive at picking up mutations than direct sequencing, with the former correlating very well with next generation sequencing.  While this was true for activating mutations in the EGFR TKI-naive patients (mutations detected in 37% vs. 44% of patients with direct sequencing vs. MALDI-TOF, respectively), this was especially true for T790M, detected in 3% vs. 25% of patients by direct sequencing vs. MALDI-TOF, respectively.  In the EGFR TKI treated population (who may have been selected for high probability of having a response to an EGFR TKI, or have been enriched for being already known to have a mutation before going on an EGFR TKI), EGFR activating mutation frequency before they started EGFR TKI therapy was 55% with direct sequencing and 77% with MALDI-TOF; T790M was detected in 3% and 32% of these patients with these two techniques.  Finally, in the 12 patients who had tissue testing for EGFR activating and T790M resistance mutation after they completed EGFR TKI therapy, direct sequencing detected activating mutations in 9 patients (75%) and a T790M mutation in 4 patients (33%), while MALDI-TOF detected an EGFR activating mutation in all 12 patients (100%) and a T90M mutation in 10 patients (83%).

As you would expect, these molecular markers were correlated with outcomes on an EGFR TKI (shown for MALDI-TOF as the more sensitive technique).  Specifically, those who had an activating EGFR mutation and no resistance mutation had the longest progression-free survival (PFS), followed by those who had both an activating EGFR mutation but also a T790M resistance mutation, and then patients with no activating or resistance mutation having the least impressive PFS:

t790m-su-pfs

 

 

 

 

 

 

(click on image to enlarge)

 

In contrast, there were no differences in outcomes by overall survival, nor were there differences in the response rate based on initial T790M status.

Where do these results leave us? We’re limited by the fact that the MALDI-TOF technique of mutation detection is not readily available (I don’t know of any commercial lab that uses it), but the findings indicate that the particular technique matters greatly in detecting both activating mutations and T790M mutations associated with resistance, presumably because a fraction of patients will have a smaller proportion of cancer cells with the mutation in question, and the techniques vary in their sensitivity at small numbers of copies of the mutated genes.  These results demonstrate that patients T790M mutations are not rare prior to the start of EGFR TKI therapy (though they may be difficult to detect with the more commonly available techniques) and are associated with a shorter PFS than we see in patients with an activating EGFR mutation and no T790M mutation; in the small numbers reported here, the clear majority have a T790M mutation after having received EGFR TKI therapy for a while.

It’s also important to note, however, that this work was done on a relatively small Taiwanese population with a low incidence of smoking, almost entirely looking at adenocarcinomas, and an overall group in which the general majority of patients have an EGFR activating mutation.  For this reason, I think we need to be cautious in presuming that everything we learn here is likely to follow the same patterns in North America or Europe.

Still, the results provide some new information and indicate that patients with an initial T790M mutation can still respond to an EGFR TKI, but that we might expect that they won’t respond for long.   In my patient’s case, I presume that the cancer in her chest has more activating mutation than T790M, the bone involvement is resistant because of the prevalence of T790M in the cancer cells of her progressing skeletal metastases.  A short response, to be sure, but understandable. One more piece of the puzzle.


13 Responses to T790M Mutations: Understanding Resistance to EGFR Tyrosine Kinase Inhibitor Therapy

  • graceabchen says:

    Dr. West: Thank you for presenting this information. You stated “ In contrast, there were no differences in outcomes by overall survival, nor were there differences in the response rate based on initial T790M status.” However, looking at the PES plot, one would think that the blue line (the one without T790M detected) would do better, because over 10% of this group are still progression free at 55th month while the other two groups have the longest PES at 16th month. Did Su’s paper discuss the response rate and overall survival time? If yes, please add the details. Thanks, AB

  • Laya D. says:

    Thanks Dr. West.

    Laya

  • FaithAndHope79 says:

    Thank you Dr. West.

  • Dr West
    Dr West says:

    AB,
    Among the 76 patients with mutation testing pre-EGFR TKI, the response rate in T790M patients was 56.5%, compared with 72.7% in those without an EGFR mutation. These are in a small number of patients, so the difficulties aren’t close to being statistically significant (and I’d have to say the response rate in patients with a de novo T790M mutation is higher than I’d have expected).

    The overall survival curves are really overlapping and don’t suggest any difference. the median overall survival was actually 21.1 months for those with a T790M mutation and 15.5 months. Though that difference sounds striking, when the numbers are small, median survivals can be very inaccurate, since the median is just a snapshot at a single point in time. The differences aren’t close to statistically significant, and the actual curves look very much overlapping.

    -Dr. West

  • Dan-HP says:

    Dr West – You have probably addresseed this before, so my apologies for asking…. could you provide some background on exactly what is the benchmark for a therapy extending “overall survival”? Does the oncology profession have a uniform defintion or does it vary from trial to trial. It seems like I read about trial ater trial that have some PFS benefit, but no overall survival benefit. However, it does seem like the survival dial is moving just a bit based on (1) if one has a mutuation for which a targeted therapy exists, and/or(2) stringing together multiple therapies. This gets me to wondering if assessment of overall survival is based on the ability a therapy to impact one’s reaching the 5-year mark.

    Thanks much,

    Dan

  • graceabchen says:

    Dr. West:
    Thank you for adding information. Although Su’s paper only considered three groups, there are probably subgroups in the T790M-negative group, such as MET amplification and other mutations. I assume that the 10% who are progression free at the 50th month still have not acquired the resistance. My next question is: If an EGFR+ patient who initially responds well to tarceva but develops progression later, is it necessary that he/she acquires one of these resistant mutations? In other words, is it possible that tarceva simply stops wroking, despite that the mutation (EGFR+) remains the same?
    Thanks, AB

  • Dr West
    Dr West says:

    Dan-HP,

    There is a lot of debate about progression-free vs. overall survival. Seeing a proven improvement in overall survival is our “gold standard” of what we hope to see, but if people cross over to the effective treatment after a trial, or if the effects of the trial treatment are diluted over several lines of subsequent therapy, you are likely to see the effects of an effective therapy wash out because of these subsequent treatments. You certainly can’t assess the value of a treatment on survival if people on both arms get the treatment, and the only question is whether it’s on or after the trial — in that case, you can only speak to whether the timing is important for survival.

    Lung cancer used to be a field in which overall survival was the only factor that mattered, and part of the issue was that there weren’t treatments that could prolong survival after the study treatment. We now have the fortunate position of having people potentially receiving several lines of effective and life-prolonging treatment, and this range of options blunts the survival effect of any one intervention. Because of that, progression-free survival is becoming more accepted as potentially relevant, though we’d always prefer to know with greater certainty that our interventions are adding to the bottom line of overall survival.

    AB,

    We know that there is a sizable minority (around 40%) of patients with an EGFR mutation develop acquired resistance without having evidence of a T790M mutation (about half) or c-MET overexpression (about 10%). However, I don’t think the remaining patients just gradually lose responsiveness to EGFR tyrosine kinase inhibitor therapy for no reason. I think it’s far more likely that there are other molecular markers that we haven’t detected that represent another reason for resistance or a new driver mutation that is now pacing the progression of the cancer.

    -Dr. West

  • Dan-HP says:

    Thank you, Dr. West.

  • steveg says:

    Dr. West,

    Thank you for sharing the info. I read that Tovok from Boehringer Ingelheim is the drug targeting T790M. The drug was in phase III trial back in 2010, but I could not find much info since then. Do you know it is still in trail or on the market already? I am looking for options for my mom who has developed resistance to Tarceva.

    Thanks,
    Steve

  • Dr West
    Dr West says:

    It is not on the market yet, but the results of the phase III trial that could lead to that are anticipated soon, potentially at our upcoming major cancer meeting called ASCO, in early June. If positive, it could lead to the approval of afatinib (Tovok) in the US and elsewhere around the world. Of note, this trial that represents the leading potential for this agent is only in patients with an EGFR mutation, in the first line setting, so not targeted for acquired resistance. It is also not likely to be specifically directed to patients with a T790M mutation.

    -Dr. West

  • steveg says:

    Dr. West,

    Thanks for the reply. I thought Tovok can be used as a second line setting after Tarceva fails, no? I read your other reviews and it seems C-MET related medicines (MetMAb & ARQ197 etc.) could be another options. Unfortunately, most of the C-MET related trials in US exclude patients (my mom included) who have taken Tarceva. Anyway, she is about to start Alimta+Avastin combo, I hope for the best.

    Thanks again.
    Stephen

  • maheddon says:

    Veristrat uses MALDI-TOF mass spectrometry to determine likelihood of response to a TKI. Can they determine T790M status as well?

  • Dr West
    Dr West says:

    I’m pretty sure they can’t/don’t.

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