Nuances in Treating Advanced Lung Adenocarcinoma - Episode 9

Treatment of Metastatic EGFR-Positive NSCLC


Mark A. Socinski, MD: All right, let’s switch gears. We have been talking about the latest wave. I would say that the previous wave, at least from a phase III point of view, was almost within 10 years of the initial reports of EGFR mutations, which were in 2004. We had a number of different trials that looked into EGFR mutants, comparing chemotherapy to one of the TKIs. And it established a new standard of care in this setting. Initially, at least in the United States for the longest time—some of us go back to gefitinib days—we only had erlotinib.

We had erlotinib, and then in the span of a couple of years, we got afatinib, and then we had gefitinib come back after this absence for over a decade or so. So, I guess one of the questions I want to start off with is—we’ve seen some recent data from LUX-Lung 7 that are, to date, the only comparison we have in the public domain that compares a second-generation agent, afatinib, to a first-generation agent, gefitinib—what are your views? Is afatinib a better drug?

Ross Camidge, MD, PhD: I probably have to eat my hat, since I didn’t think that the study was going to be positive. But let’s explore what a positive study is. So, when you look at the PFS curves, they really stay pretty similar. What happened is that there’s a little longer tail on the afatinib arm, and so what’s positive is the hazard ratio. The median didn’t shift. And what I think that’s telling you is that there is a slightly broader spectrum of action in afatinib. We know it hits other HER family members, so it could be a mechanism of acquired resistance that you’re suppressing. Does this mean this is the solution for everybody? The answer is probably no. Certainly, we know the toxicity is greater. That study has not changed my practice. So, if you have an EGFR mutation in the absence of the FLAURA data, in my practice, you’re still going to start on erlotinib.

Mark A. Socinski, MD: Mark, you’re not starting with erlotinib?

Mark G. Kris, MD: I think Ross is alluding to it, that it depends on goals of care. For a small benefit and more toxicity, is it right for that patient? For certain patients it’s right, and for many patients it’s not. And that’s how the decision is made. I think the data are there that it’s a little bit better, but it’s not a lot better, and it’s got more toxicity, absolutely. By the way, there is a lot more flexibility with the dose. I think all of our targeted therapies, with rare exception, have been dosed in wild-type patients, for the phase I setting, at least. There’s a lot more flexibility there. However, it’s more toxic, and it’s not right for every patient. I think we’re in agreement here, by and large.

Mark A. Socinski, MD: Yes.

Ross Camidge, MD, PhD: So, you know that there’s going to be a study at ASCO of dacomitinib versus gefitinib. That’s a late-breaking abstract, so we’re going to see another second-generation versus first-generation drug and see if there’s a similar story.

Mark A. Socinski, MD: Let me ask the panel, if you have an exon 19 deletion mutation next week in your clinic…David, what are you going to use?

David R. Spigel, MD: It’s funny, because our pathways like us to use afatinib, but I use erlotinib.

Mark A. Socinski, MD: Ross?

Ross Camidge, MD, PhD: Erlotinib.

Mark G. Kris, MD: Afatinib and bevacizumab.

Mark A. Socinski, MD: That’s the next question. Jared?

Jared Weiss, MD: Gefitinib.

Mark A. Socinski, MD: All right. And what about exon 21 L858R? Any difference?

Ross Camidge, MD, PhD: Same treatment.

Jared Weiss, MD: Well, we agree on the same answer, at least.

Mark A. Socinski, MD: That’s the one thing in LUX-Lung 7 that impressed me the most: In the exon 21 population, the response rate was around 70% versus 45%. I was impressed with that.

Mark G. Kris, MD: The chemotherapy was better in those arms. I don’t think anybody is going to go back and give chemotherapy to these patients upfront. So, I think we’re all in agreement, we would give whatever we’d give to the exon 19 population to the exon 21 population.

Mark A. Socinski, MD: Right. So, getting back to Mark’s comment. We saw in a Japanese trial a very positive impact on PFS of adding bevacizumab to erlotinib. It has been published. I think we’ve seen no difference in survival as of this point.

David R. Spigel, MD: I think that’s correct.

Ross Camidge, MD, PhD: Yes, those are the only data I’ve seen.

Mark A. Socinski, MD: Right. Mark, what are your thoughts on that data? Is this something you do?

Mark G. Kris, MD: I do it in every patient where bevacizumab would be safe, yes, because you should give your best drugs upfront—the greatest duration of benefit. Nothing for a patient has greater meaning, usually, than that first disease-free interval.

Mark A. Socinski, MD: Getting back to your goals of care, they might say, “But doctor, do I really have to come in every 3 weeks and get an IV put in and get an expensive drug that I have a high co-pay on?”

Mark G. Kris, MD: Again, I know all of us make choices with that patient in mind. For some people, it’s not right. You could see somebody who loves to sing, and they wouldn’t like the hoarseness side effect, and that might not be a good drug for them. That’s what happens. But I would recommend it to them, unless there’s a reason not to do it.

Mark A. Socinski, MD: Jared, what are your thoughts?

Jared Weiss, MD: I think that’s a reasonable way to think about it, but I think about it a little bit differently in the absence of a survival advantage. What I love the most about the oral TKIs is the demedicalization of the patient’s life. So, to your point about coming to the infusion room every 3 weeks—you combine drugs with greater efficacy than doublet chemotherapy for that population. The patient’s going to have fewer cancer-related symptoms and fewer side effects than with cytotoxic doublet chemotherapy, although it’s not side effect free. And then there’s the oral aspect. All of these come together to create a more normal life, and I really hesitate to take that away from the patient in the absence of a clear survival advantage. I think it’s a reasonable thing to think of for a motivated patient, but it’s not something that I reach for commonly in my practice.

Mark G. Kris, MD: But I challenge you to ask your patient next time, “If you know your cancer will come back 6 months faster by doing this, is it worth it to you to come?”

Jared Weiss, MD: It’s a very fair question. The counterchallenge would be if you directly told the patient, “You will derive no survival advantage from this.” And we’re in an era where for the majority of patients, we now have second-line TKIs. Do you really still want to do it? We’d both probably get some surprising answers from our patients, and it leads to personalization and involving patients in decision making.

Ross Camidge, MD, PhD: The other question is, the patient could ask, “Dr Kris, can you tell me where I am on this PFS curve? With which one of these am I on the tail?” And you don’t know for that individual patient.

Mark G. Kris, MD: That one, you never know.

Jared Weiss, MD: These are philosophical differences in looking at the same data, and different patients will choose different therapies if we counsel them properly.

Transcript Edited for Clarity