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Dr. Jack West is a medical oncologist and thoracic oncology specialist who is the Founder and previously served as President & CEO, currently a member of the Board of Directors of the Global Resource for Advancing Cancer Education (GRACE)

 

Why T790M status matters: The new value proposition for repeat biopsies in acquired resistance
Author
Howard (Jack) West, MD

One of the ongoing questions in managing EGFR mutation-positive advanced NSCLC has been whether it should be routine to do repeat biopsies to look for new findings after a patient has developed acquired resistance to an EGFR tyrosine kinase inhibitor (TKI). Here are a few posts in which the topic has been covered:

http://cancergrace.org/lung/2011/04/05/dr-lecia-sequist-on-the-value-of-repeat-biopsies-with-ongoing-treatment-of-lung-cancer/

http://cancergrace.org/lung/2013/05/21/kelly-repeat-biopsy-acquired-resistance-targeted-therapy/

http://cancergrace.org/lung/2012/12/15/repeat-biopsies-vi/

http://cancergrace.org/lung/2013/04/26/riely-repeat-biopsy-acquired-resistance-targeted-therapy/

http://cancergrace.org/lung/2013/06/04/oxnard-repeat-biopsy-acquired-resistance-targeted-therapy/

Overall, many investigators in the field of EGFR have favored this, largely to get a better understanding of the mechanism of acquired resistance and to check for the oft-cited but rarely seen transformation to small cell histology.  For some of these investigators, it has made sense to favor rebiopsy because they may have had clinical trials specifically for patients with a specific mechanism of resistance, such as the T790M mutation on exon 20 that is seen in 60% of patients who develop acquired resistance to an EGFR TKI. But up until very recently, T790M status hasn't been that important to know when it doesn't lead to changes in how you manage patients.  While the lab-based work on the combination of Gilotrif(afatinib) and Erbitux (cetuximab) for acquired resistance to reversible EGFR TKIs like Tarceva (erlotinib) or Iressa (gefitinib) suggested that this combination would be particularly helpful for the subset of patients with a T790M mutation, the actual clinical study of the afatinib/cetuximab combination showed no difference in results between those patients with or without a T790M mutation.  

With no highly compelling answer to the question of "If I don't have a clinical trial depending on it, what can I do with the information likely to be obtained from a repeat biopsy?", this approach has largely remained limited to the research centers that have been focused on the research efforts in this arena; it has not penetrated as a common approach in routine management.  But I think that the results of some of the exciting trials with novel EGFR TKIs AZD9291 and CO1686 just presented at ASCO 2014 will change that.

Dr. Pasi Jänne from Dana Farber Cancer Institute in Boston presented the initial clinical results with AZD9291, a novel EGFR TKI with specific activity against T790M, in patients with an EGFR mutation and acquired resistance.  Over 200 patients were enrolled at a variety of dose levels, and the investigators did not restrict patients based on T790M status. Though responses were not limited to those patients with a T90M mutation, the response rate was three-fold higher -- 64% vs. 22% -- in the T790M-positive population. Moreover, the response rate was essentially the same whether patients had just been on another EGFR TKI right before AZD9291 or had been off of EGFR TKIs for a while. In contrast, the patients who were T790M-negative had a lower response rate of just 11% in those just switching from another EGFR TKI, compared with a 36% response rate in those who had been off of EGFR TKI therapy for a longer interval. This suggests that many of the responses seen in T790M mutation-negative patients were really just a "retreatment effect" that you might see as a very brief benefit from another EGFR TKI as well.   Along the same lines, the time before progression in T790M mutation-positive responding patients was far, far longer than the transient period of usually just a few weeks before progression then occurred in the T790M negative patients.

Dr. Lecia Sequist followed with her presentation on CO1686, another third generation EGFR TKI with lab-based demonstrated activity against the T790M mutation. This work is earlier in development and with smaller numbers than the results presented on AZD9291 by Dr. Jänne, but it demonstrated a similarly encouraging response rate of 58% in a population of patients with acquired resistance to EGFR TKI therapy that only included those with a T790M mutation. 

These two agents represent a major step forward in management of acquired resistance for acquired resistance to EGFR TKIs, and they are both moving forward focusing primarily or exclusively on the 60% of acquired resistance patients with a T790M mutation. As studies with these agents become more widely available very rapidly in the next year, we should expect to see a shift in practice patterns that now make it desirable, if not mandatory, to obtain a repeat biopsy once acquired resistance becomes apparent, in order to determine whether someone has a T790M mutation and is eligible to pursue one of these treatments, initially on a clinically trial and hopefully soon as an FDA-approved treatment.  In the process, we can expect to learn a lot more about what we might see during the evolution of a cancer on EGFR TKI treatment. 

We will also face a new challenge of what to do for the 40% of EGFR mutation-positive patients who develop acquired resistance but don’t have a T790M mutation. Let’s hope we can identify promising clinical research leads for them as well.

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