Overcoming EGFR Inhibitor Resistance in Non-T790M-Positive NSCLC

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Roy S. Herbst, MD, PhD: The other area where I think next-generation EGFR TKIs might have some headway would be in adjuvant therapy, in people where you’ve treated all the disease you know of but you’re using them for long periods of time. You can imagine a drug like the AZD9291 [osimertinib], for example, might be a very good drug to use in that setting.

The other thing I wanted to bring up is that at least half the resistance is not due to T790M. While these agents do have a little bit of activity in that setting, it’s always hard to determine how much is true activity versus just retreating for a patient who has been off of the EGFR inhibitor for a period of time.

I’ve been impressed from some of the work that came out of Memorial Sloan Kettering. We were involved at Yale and Vanderbilt with Dr. William Pao and his group looking at cetuximab plus afatinib, that combination. That’s a combination where we know there is activity, both in preclinical studies and in the clinic, against non-T790M resistance. Actually, SWOG 1403 just started enrolling patients, and this is a trial that’s actually looking at that combination, cetuximab/afatinib versus afatinib for first-line treatment. It’s another question of EGFR-mutant disease. Another question, will that give us a longer PFS and survival?

Mark A. Socinski, MD: I think it brings up a point. The standard of care in this population is repeat biopsies and repeat testing over time to determine what the mechanism of resistance is.

Roy S. Herbst, MD, PhD: Right, let the science drive the therapy. The nice thing is that every one of our centers and probably most of the people who are watching have the ability to get a biopsy, whether it be tissue or now the liquid biopsy, which wasn’t the case a while back.

Naiyer Rizvi, MD: I have a question for the group. I saw a patient just yesterday, and she was biopsied and was waiting for the results of her tests. Her question very astutely was, “If I’m negative, is it reasonable for you to biopsy another lesion and see if I’m positive?” She turned out to be positive so it didn’t matter.

Mark A. Socinski, MD: Is this positive for T790M?

Naiyer Rizvi, MD: T790M — I think that’s another question I would have for the group.

Mark A. Socinski, MD: I was going to ask Geoff. One of the things that I was relatively impressed with was the activity of rociletinib in the T790M-negative patients. I think the response rate was 37% or something like that. I’ve heard a couple of people say, well, if it works to a lesser degree if you’re negative and it works better if you’re positive, why do you test? Why not just give everyone a trial of it?

Naiyer Rizvi, MD: I don’t think the T790M-negative responses were as durable. Those responses were not that durable.

Geoffrey R. Oxnard, MD: All these trials have enriched for T790M patients, patients who were T790M-positive with a local assay but not with a central assay. It’s a murky question of how do you call positivity. I’ve certainly seen those patients who just get the drug and zip right through it and progress. Those patients are real and you’re not helping them out by giving them the wrong drug. I think we can sort out this biomarker.

In the patient who’s biopsy-negative, I do sometimes see plasma-positive, and then I see that the biopsy, if it’s retested with a more sensitive assay, becomes positive. So there does have to be some persistence to find it, so it’s a little bit of a moving target. But there are some patients who don’t benefit and we want to find those people, too.

Mark A. Socinski, MD: Right! The group at Massachusetts General across town from you presented data, I think it’s recently published, looking at serial biopsies over time. There’s differential expression, whether that’s clonal heterogeneity or whatever that’s about, it happens.

Geoffrey R. Oxnard, MD: And does the status change because your biopsy just misses stuff?

Mark A. Socinski, MD: Right. Exactly.

Geoffrey R. Oxnard, MD: Or the biology actually changes.

Transcript Edited for Clarity

Mark A. Socinski, MD: Right, so interesting.