Current Practices and Future Directions for Treatment of EGFR-Mutated Lung Cancer - Episode 3

Potential Challenges of Molecular Testing in NSCLC

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A panel of experts in the management of lung cancer share key insights into challenges associated with retesting for driver mutations, tumor heterogeneity, and potential differences between biopsy and surgical sample test results.

Neal Navani, MRCP, MSc, PhD: Christian, perhaps I can direct the next question to you. You’ve had a patient on adjuvant osimertinib. You have now detected that their disease appears to be progressing. What’s the role of retesting, in your view, at that point?

Christian Grohé, MD: We have not yet seen the data from the liquid biopsy analysis of the ADAURA study, which is going to be presented soon. We could discuss having liquid biopsies sequentially or serially taken in patients on TKI [tyrosine kinase inhibitor] treatment in the adjuvant setting within the 3-year timeframe we have to observe. Overall, this is crucial, as we have learned from the osimertinib resistance data. Obviously, the pattern of resistance is completely different in osimertinib compared to a first- or second-generation TKI. We have to learn about off- and on-target resistance patterns; there are certain patterns we have to understand to have the best systemic therapy afterward. This is a learning curve for all of us.

I strongly suggest, based on the pattern of progression, oligometastatic or multisite metastatic disease progression, that we obtain new tissue samples. Additionally, in the best of all worlds, we would like to have liquid biopsies to see if there’s still clonal circulation of the original EGFR clone we identified prior to treatment. This is something we have to learn. And clearly we have to address the question of how to register all these data in a registry where we can obtain and monitor them, because it is going to be a large data set to follow. We need pilots who could drive us through that, the whole situation, to keep all that information updated. That is going to be complex, at least at the larger centers that care for patients with lung cancer.

Neal Navani, MRCP, MSc, PhD: I think we have seen that there is a real appetite for testing now for patients in the early stage of the disease. I could ask you one last question, if I may. We have talked about reflex testing of a biopsy sample and a surgical sample. Do you anticipate any discordance at all between results we might get? For example, would there be a difference in an EGFR mutation status between the biopsy and the surgical sample?

Christian Grohé, MD: As Solange has pointed out, very often we have small samples that are, for instance, taken from an EBUS [endobronchial ultrasound] function, or a small sample that does not qualify for a whole array of an NGS [next-generation sequencing] signature. Overall, this is a question of how you optimize your standard of care procedures in the bronchoscopy ward. This is clearly a question of how you address that issue in the future; you do so by saying. “We need that kind of material before we can make a decision.” I think there is more room to obtain better results and to have a discussion with our pathologists. They offer you the opportunity to say, “Well, this is not enough for all testing, please provide more material or we have to wait for the surgery.” This is a question of discussions with the pathologist to obtain better specimens from the bronchoscopy ward, which is possible.

Neal Navani, MRCP, MSc, PhD: Thank you. Solange, what about issues regarding heterogeneity? Do you see this as a problem for a clinical practice? Do you think there is going to be discordance between CT-guided biopsy results and the surgical specimen?

Solange Peters, MD, PhD: I think we should be careful to not put any obstacles in the way of installing reflex testing. Regarding heterogeneity, when it’s about driver oncogenes, is not much of a concern. There will always be an exception, a mixed histology in very rare cases, but generally, a driver is a driver. If you have a decent biopsy with little necrosis and viable cells, you will find the driver because you have a malignant phenotype. I would say no, the heterogeneity is not a concern when it is oncogene addiction. Of course, we do not speak about IO [immunotherapy] and PD-L1 and all these dynamic biomarkers. But as soon as you are in the initial diagnosis stage, or maybe just after neoadjuvant chemotherapy, if a driver is present, a driver will still be visible and able to be found. I would say heterogeneity should not be a matter of concern in that specific setting.

Neal Navani, MRCP, MSc, PhD: That is great and very clear. Thank you, Solange.

Transcript Edited for Clarity