EGFR TKIs for Relapsed/Refractory NSCLC

Jared Weiss, MD:Progression is in the eye of the beholder. Formally in oncology, progression is defined as 20% growth of cancer along a messed-up system called RECIST. In clinical practice, particularly with theEGFRTKIs, this becomes much more subjective. There are a number of factors that you want to look at that could be summarized as: is the cancer threatening to hurt your patient? So, you’re looking at the locations of the spread. Central lesions pressing on a major airway or a major vessel are much more scary than peripheral lesions that are likely to be asymptomatic if they grow.

You’re looking at whether it’s symptomatic or asymptomatic, and NCCN actually specifically recognizes that factor. And, in my practice, I’m also looking at the pace of growth. Very slow-growing cancer is unlikely to hurt my patient very soon, whereas rapidly progressive disease needs to be actioned. These things are integrated together into an assessment of how likely is this cancer to hurt the patient now versus not. If you have a cancer that you’re not very scared about—slow-growing, peripheral lesions—there’s absolutely nothing wrong with carefully following that cancer on scans and treating past progression. In contrast, if you have rapidly growing symptomatic central lesions, then you really need to change what you’re doing.

I will continue TKI past progression if I’m not scared that the progression is going to hurt the patient. More specifically, if the lesions are not central, they are not rapidly growing, and if they are not symptomatic, I will continue past progression in the absence of these characteristics. One twist to this is if it’s just one or two spots, particularly if they’re small, particularly if they’re peripheral, that I think are threatening the patient. An alternative approach is to do radiation to those spots, followed by re-initiation of the TKI. The idea is you have some resistance change just in one or two spots. If they’re amenable to surgery or radiation with low morbidity, you ablate or remove those spots, and then you can continue as well on TKIs.

Repeat molecular testing only became useful with the availability of osimertinib. Prior to the availability of osimertinib, there really was no purpose to repeat testing in standard clinical practice. If you can’t do something with a result, why make the patient go through a biopsy with its discomforts and its risks? We’re really only doing that as part of research endeavors. There were some patients who were altruistic and helped us to understand the biology that did lead to the existence of these third-generation TKIs. And further, once those trials became available at institutions that had them or patients that could travel, we were starting to test patients to get them on those trials.

Osimertinib has been extensively studied. At this point, we know that it is less toxic than the first-generation TKIs. It’s a very well-tolerated drug with less rash, less diarrhea. Listening to patients in clinic in who have been on it, they globally feel better than on chemotherapy or even on first-generationEGFRTKIs. We know from a variety of studies that they all show a response rate in T790M-positive patients of roughly two-thirds, with the majority of the remaining patients having stable disease. Much more recently, we have a press release, no hard data, comparing osimertinib to cytotoxic doublet at the second-line therapy for patients who’ve progressed on first-line TKI. And, all we know from that press release is that PFS was superior with the targeted therapy, a result that I think most of us expected.

The use of this data in practice is actually very simple. When your newer agent is more effective, less toxic, and more convenient to the patient, the oral agent de-medicalizes the life of the patient. It’s very easy to know to switch to that agent over cytotoxic chemotherapy. And so, what this data changed in clinical practice is: number 1) it has now become mandatory at the time of acquired resistance to anEGFRTKI to get some kind of repeat molecular testing specifically looking for T790M; and number 2) if you find that, you treat with osimertinib, not with cytotoxic chemotherapy.

Weiss case 1:

A 65-year-old man with stage IV NSCLC.

• Tissue biopsy showed EGFR+ adenocarcinoma
• The patient was enrolled in a clinical trial of erlotinib vs erlotinib/bevacizumab
• He was treated with erlotinib for 10 months before developing asymptomatic progression, with slowly growing lesions.
• He was continued on erlotinib for 3 more months; His next scan showed rapid progression.
• Repeat bronchoscopy and mutation testing showed an acquired EGFR T790M mutation
• Patient was subsequently switched to osimertinib