How to Manage TKI Progression: Nuances of Care and Updates on T790M-directed Therapies [Video Transcript]

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In this segment I'm going to be talking about how to manage patients who progress On first or second generation TKI. And I think what we know now is that patients who have advanced adenocarcinoma of the lung were EGFR-positive, they should be offered a first-generation or second-generation TKI with either erlotinib, gefitinib or afatanib, and we've seen unprecedented advances with implementing this strategy: improvements in response rate, improvement in progression-free survival and improvement in quality of life compared to chemotherapy.

Unfortunately however, patients who receive a first or second generation TKI will inevitably develop progression and I think what to do in this scenario is a challenge. I always tell my fellows in my institution: it's an easy decision, what to do upfront for the patient. Choose your TKI of choice and deliver it. But when patients progress, this is where things get a little more murky and challenging. And what I say is what is the overall burden of disease doing that can help guide decision-making.

Decision-making must factor in the pace of disease growth, the presence of lung cancer symptoms, and the potential identification of T790M which makes patient eligible for osimertinib. I really just go through three common clinical scenarios that we see in this setting, and we certainly recently highlighted in the publication of ours and tell you what I would do in each of the scenarios. Clearly there's probably many different scenarios that can happen, but these are the three most common that I see.

The first scenarios of patients on first or second generation TKI and their cancer is growing, and they have symptoms and it's clear that you need to make a different treatment choice for the patient – the TKI is no longer working, and it's clear from the patient's symptoms and it's clear from the scans that this cancer is growing. For those patients I would say the first stop for them is what we call plasma genotyping.

I think we now know that we can identify mutations of a simple blood test in this setting, and if the patient does have a T790M mutation in the blood, they should be delivered the drug osimertinib or Tagrisso. I think what we know about this drug osimertinib is that the response rates are as high as 50-60% in the data in this setting and the PFS is around 9 to 12 months and it certainly has outperformed chemotherapy historically.

If the blood test is done in the T790M is not identified, that doesn't mean you're done. In these patients, I think it's important that we do a tissue biopsy next. The sensitivity of a blood test is only around 60-70%, meaning there will be about 30-40% have false-negative rates, meaning that they still may harbor the T790M mutation in their tissue is just not picked up in the blood.

I would say in this scenario where a patient is progressing – they're developing symptoms – certainly do the blood test. If the blood test is positive, you can deliver the Tagrisso, the osimertinib. If it's negative that patient should get a biopsy. If the biopsy of course shows T790M, you should give osimertinib. If patients don't have an identifiable T790M mutation, certainly there other mutations that may allow them to be plugged into clinical trials like MET mutations, but those patients should receive chemotherapy. I think what we know is that chemotherapy works in this scenario, is of course not as good as the osimertinib, but certainly can improve symptoms and improve overall survival. So that's the first scenario.

The second scenario is a little more challenging and that is when a patient's overall disease burden is relatively stable, but only one site is growing so there's either a site growing in the adrenal gland, a site growing in the brain, and this is what we call oligometastatic progression where the overall disease burden is relatively stable and one site is growing. I think for these patients, treatment decisions must be individualized, but certainly one consideration is local aggressive management of that oligometastatic site that's growing with continuation of the TKI that they're already on. So for instance many of my patients come in and their lung lesions are stable but they have a growing adrenal lesion. We can certainly consider addressing the adrenal lesion with either radiation or surgery and discontinue them on the TKI.

Reasonable data suggest that this can keep the patient on the TKI longer and delay treatment decisions. So I think that again, treatment decisions must be individualized in this setting, but for patients that are driver mutation-positive, -- any driver mutation, for that matter – who develop oligometastatic progression, I think it's important to consider aggressive management, whether it be SRS to the brain with continuation of the TKI or surgery for an adrenal lesion that's growing, I would continue treatment and just ride out the TKI as long as he can until you really need to make a switch.

The third scenario which is perhaps the most challenging is for a patient in which their disease is growing, albeit very slowly, but they're tolerating the TKI. I think there are competing standards and there's no right or wrong here, and I think, once again, treatment decisions must be individualized. I have several patients who have heard about osimertinib or Tagrisso. I know that there's another drug that's available. However, there are scenarios where I will discontinue them on the TKI. They are feeling well, they're tolerating the drug, it's asymptomatic, their cancer is growing, it's growing but it's growing slowly. So you could certainly consider continuing them on the drug that they're on anyway whether it be erlotinib, gefitinib or afatinib, and just continue to follow them closely. A lot of this, again, it depends on the patient's desires and your own comfortability with watching.

These are the three most common scenarios I see. I think there are many nuances to how to manage these patients upon progression. I think the advent, the development, the implementation of osimertinib – this is a wonderful drug for patients that are T790M-positive and certainly highlights the importance and need to identify T790M, first tried in the blood, if you're not finding it in the blood when these patients progress, please do a tissue biopsy because you will find it sometimes when you don't find it in the blood.

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