Transcript:Mark A. Socinski, MD: As Tom said, we like to make this diagnosis. I always paraphrase the old Wide World of Sports, “The thrill of victory and the agony of defeat.” Because a year later, you’re dealing with resistance, you’re dealing with several flavors of progressive disease. Ben, walk us through the kind of thought process of mechanisms of resistance and what we should be thinking and doing.

Benjamin P. Levy, MD: Sure. I think that, similar to how we understand up-front genomic characterization of lung adenocarcinomas for initial treatment decisions, we’ve got a better understanding of mechanisms of resistance for those patients treated with EGFR directed therapies. I think we know now that probably 50% to 60% of patients develop a second site EGFR mutation in T790M. Other mutations have been elucidated—PI3-kinase mutations, MET amplification—and then reported small cell transformation. So I think with this better understanding, it becomes more of a direction that we need to understand what’s going on at progression with either a tissue biopsy or even plasma genotyping, bringing this back into the fold. Interestingly in their EAP, the T790M-directed therapy, osimertinib, did allow T790M to be captured from the plasma to drive the enrollment. The onus is now to really understand this either with tissue biopsy or plasma genotyping. I would argue that the gold standard is still tissue biopsy to understand what’s going on with these patients, because we now have available therapies in clinical trials that are targeting these mechanisms of resistance.

Mark A. Socinski, MD: So, this is a huge paradigm shift for us because we never re-biopsy. We were always happy with the first biopsy. But I think we have to re-biopsy. Blood-based testing is coming, and we all use that. But I believe tissue and blood are complementary. You may not get the answer on blood, so tissue is part of that. We have several patients where they’ve had three, four, five biopsies over time because we know T790M can change over time in this particular setting. We, as of 3 or 4 months ago, now have a drug for this setting. Walk us through that data with osimertinib.

Benjamin P. Levy, MD: There were data recently published in April 2015 in New England Journal of Medicine looking at osimertinib, which is a T790M-directed therapy, third-generation TKI. Patients had received first-generation TKI and had developed a documented T790M mutation. With delivery of this drug, the response rate was in the 60% range, which if we put that in the context of what chemotherapy does in this setting, it doubles it, basically. I think we know chemotherapy in this setting elicits a response rate of around 25% to 30%. The PFS was around 9 to 10 months, which doubles what the PFS is historically in chemotherapy, and with very long durations of response. For those patients that did achieve a response, the duration of response was more than a year. Just as important as the efficacy is the tolerability of this drug. There were very manageable AEs, and because it spares wild-type EGFR, we’re not getting the rash and the diarrhea that we’ve seen with these first-generation TKIs. And unlike the other third-generation TKI, rociletinib, there’s very low risk of hyperglycemia. Overall, I think it completely changed the landscape of what we’re doing in this patient population, completely changed what we need to do with biopsying these patients to identify T790M. It is really a win for the patient because of the efficacy and tolerability as well.

Mark A. Socinski, MD: What’s your experience been, Tom?

Thomas E. Stinchcombe, MD: It is very well tolerated, and we’ve had a number of these third-generations, and they’re a huge advance. Like Ben said, there’s not much rash or diarrhea—the stereotypical EGFR toxicities. And the patients tolerate them very well, in terms of fatigue and other toxicities, and it’s a paradigm shift. There’s no other way to put it, I think, at this point.

Mark A. Socinski, MD: Jared, what’s the message for the community oncologist in this situation? Is it think about re-biopsy, think about retesting in this population?

Jared Weiss, MD: Oh, I think it’s a simple message and even stronger than that. I think at progression, every patient with an EGFR mutation, who’s progressed on one of these first-gen TKIs, should have a repeat biopsy to ascertain the mechanism of resistance.

Mark A. Socinski, MD: Let me explore that a little bit more, because we know that many of these patients with EGFR mutations, even though they may meet RECIST criteria, they have very slow progression, they remain asymptomatic, and the 7-mm nodules go to 9 mm. And the report says: progression of disease, the patient is fine, the patient is perfectly happy on erlotinib. When do you biopsy?

Jared Weiss, MD: So I think you biopsy when you’re going to use it.

Mark A. Socinski, MD: When it’s time to say uncle.

Jared Weiss, MD: I think that’s right. In clinical practice, this underscores the importance of looking at your own scans to understand not just progression, but is anything rapidly progressing? Is anything progressing near a central airway or vessel that scares you? Is the patient symptomatic from the progression in a way that can be explained by scans? And there are two alternative options to switching agents. You can just put a thumb over whatever is bothering you if you think it’s not threatening your patient. Or if you think it is, but it’s an isolated site that’s easily accessible to some form of ablative or resective surgery, you can destroy or remove that spot. We have a trial ongoing doing so with stereotactic radiosurgery.

Mark A. Socinski, MD: Yes. I always like to think, as I look at multiple scans over time, if I do nothing, what’s the patient going to be like in 3 months? Am I putting that patient at risk of either more rapid progression or some visceral crisis, or whatever that it may be? And if I’m nervous about that, I think it’s time to make a switch. But you’ve got to re-biopsy first.

Transcript Edited for Clarity