Osimertinib and Plasma Genotyping

Jared Weiss, MD: The major selection criteria for osimertinib is acquired resistance defined by the T790M molecular change. And, of course, you can’t detect that molecular change unless you test for it. Plasma testing is a rapidly evolving alternative to tissue-based testing. It is not perfect. If you get a test result that is positive, you can use it. In contrast, if you get a negative result, particularly if you don’t see the original EGFR sensitizing mutation on that plasma testing, you need to do a repeat biopsy.

The tests are available now. There are multiple commercially available liquid-based testing platforms that can be used. None have specific FDA approval for testing for T790M at the time of acquired resistance. The closest thing that we have is Roche’s cobas assay, which does have FDA approval for up-front EGFR testing and is capable of finding T790M. That and multiple other commercial platforms are available.

My practice and NCCN basically agree, although I think I’m much more passionate about a theme that they just endorse as one option. In my clinical practice, I am very passionate that whether you’re talking about EGFR or another actionable molecular change, that you always use targeted therapy as long as you possibly can. It is more convenient for the patient. It is less toxic for the patient, and generally in every situation under which we have data, it tends to work better than chemotherapy for the patient.

In my practice, at the time of diagnosis, the patient gets a first-generation TKI. They get that for as long as they can, and so, I may do some treatment past progression. I may do some radiation to spots of isolated progression, but I treat until I think I can’t use that first-generation TKI any longer. And, at that point, I obtain repeat molecular testing looking for T790M. If I don’t find it, the patient gets a cytotoxic doublet. If I do find it, the patient gets osimertinib. In the case of osimertinib, I treat as long as I can on osimertinib. I am comfortable extrapolating the principles that we’ve learned from first-line EGFR treatment and from other targeted therapies to say that I will sometimes use osimertinib past progression, and I will sometimes use radiation to help me get there.

At whatever point I decide that osimertinib is no longer the right option for the patient, that they need something different, I will then write the patient for cytotoxic therapy. Although, when new clinical trials evolve to treat some of these resistance mechanisms of osimertinib, that’s when I’ll start introducing yet another repeat biopsy into my practice.

One important point that may be worth making is that I have not mentioned immunotherapy. I do consider an immunotherapy regimen an option for the EGFR-mutated lung cancer patient, but I don’t consider it an early-line option. We have some data out there suggesting that the efficacy of these agents may be a little bit less for patients who’ve never smoked and for EGFR-mutated populations, granted, very heavily overlapping populations. And so, I don’t throw out the drugs. I will consider them for later lines of therapy, but I’m first going to use up the EGFR access as much as I can, including experimental options. And, time will tell if this is right, but in my practice, I’m moving to a cytotoxic doublet before considering immunotherapy.

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