Rationales for Repeat Molecular Testing

Jared Weiss, MD: There are really only two rationales for repeat testing at progression. One is if it’s applicable for a clinical trial. So, that might be an altruistic patient who’s happy to help with discovery of biology—I’m grateful to such patients—or in the same vain, if there’s a clinical trial, that can bring action to whatever change you’re looking for. The second, and more broader, applicability is if you can do something with the result. Until the availability of the third-generation EGFR TKI trials, I was actually not testing. I was not obtaining repeat biopsy at the time of progression of first-generation EGFR TKIs. But, now we have an FDA-approved actionable therapy. Osimertinib has FDA approval for T790M-positive EGFR-mutated lung cancer. This T790M change is about 60% of acquired resistance, so it’s very common, and it’s driven my reason to get these biopsies because I can actually do something with them.

For a patient who gets comprehensive molecular testing up front; has viable results showing that it’s not specimen-inadequate, but a good specimen that shows there are driver mutations but nothing actionable; if I see that patient, in consultation at later lines of therapy, I’m not going to repeat the molecular testing. There’s really no purpose. In contrast, if the patient had only limited testing up front, if all that was tested—for example, was EGFR and ALK or EGFR, ALK, and ROS1—something that I see quite commonly in my consultative practice, then I will do repeat testing. But my goal is not so much that I need a new specimen. If there’s tissue left from the original one, I don’t mind using that. What I’m doing is just testing more broadly, looking for what the actual driver is, because there are a number of emerging actionable changes, specifically recommended by NCCN as category 2A or 2B. And there are a number of clinical trials for additional molecular changes that I would consider high-promise, that I can use those results for.

How I use molecular results depends a lot on what the result is. So, let’s talk about a real-world case of a man in his 60s who had gotten 10 months out of first-line EGFR TKI, progressed, and gets repeat testing to determine his mechanism of resistance. If I find nothing useful, I’m going to give him a cytotoxic doublet, assuming that he’s eligible for it and that’s consistent with his priorities. In contrast, 60% of the time I’m going to find T790M mutation. That’s actionable. FDA-approved a third-generation TKI, osimertinib, has about two-thirds chance of response. So, if I find that, I’m going to use that.

There are also other molecular changes that I might find that I might consider trials for. For example, high-level MET amplification can be an alternative resistance mechanism, and we do have a clinical trial for those patients. If I find a change that I don’t have a trial for, I’m going to ask the patient if they’re open to considering traveling. If they are, then I will get on clinicaltrials.gov, I’ll find out where that trial is, I’ll contact the PI at that site, and I’ll try to arrange a consult for that patient. In a similar light, we do sometimes consider FDA-approved drugs being used off-label. Some of these are specifically mentioned by NCCN as a category 2A or 2B option. We would, at that point, bring a clinical pharmacist in on the discussion to talk about safety, to talk about what level of data there are available, and to talk about the drug acquisition.

Weiss case 2:

A 62 year-old neversmoker with stage IV adenocarcinoma

• Mutation testing showed an EGFR exon 19 mutation
• The patient was treated with erlotinib for 1 year; he developed diarrhea and rash which was successfully managed
• After 3 months, his disease showed progression on CT; he remained without symptoms.
• He subsequently developed cough and shortness of breath, correlated to progression of a centrally located lung lesion on his follow up CT scan
• Repeat biopsy and molecular testing of the central lesion showed EGFR T790M-positivity
• He was switched to osimertinib therapy and achieved a partial response
• The patient reported dramatic improvement in his well-being