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New Standard for Treating Stage 4 EGFR+ NSCLC

Panelists: Benjamin P. Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Hossein Borghaei, DO, MS, Fox Chase Cancer Center; Roy S. Herbst, MD, PhD, Yale Cancer Center; Suresh S. Ramalingam, MD, Emory University School of Medicine; Naiyer A. Rizvi, MD, Columbia University Medical Center; Thomas E. Stinchcombe, MD, Duke Cancer Institute
Published: Wednesday, Feb 28, 2018



Transcript: 

Benjamin P. Levy, MD: Alright, so let’s move on and talk about a different disease biology with EGFR-mutated lung cancer. EGFR mutations are anywhere from 15% to 40% of our patients, depending on the clinical phenotype. We know these mutations predict sensitivity to first- and second-generation TKIs. Erlotinib, gefitinib, and afatinib have all outperformed chemotherapy in the frontline for EGFR-mutated lung cancer. But we’ve got, yet again, some practice-alternating data that have emerged over the past 5 or 6 months that are going to change our calculus in the way we approach this disease. Suresh, you’ve been intimately involved in and led in many of these efforts with osimertinib. Do you want to talk to us and walk us through the FLAURA data and the clinical implications of that?

Suresh S. Ramalingam, MD: The FLAURA results were just published in the New England Journal of Medicine recently. This study was done to compare osimertinib to the standard, first-generation TKIs—erlotinib and gefitinib—in the frontline setting. We all know that osimertinib is already approved in the second-line, acquired-resistant setting for patients with T790 mutation. What’s unique about osimertinib is it’s a mutation-selective inhibitor that has a very high effect on mutant receptors compared with a wild-type receptor. So the toxicity tends to be less. It also has better CNS penetration compared with the first- and second-generation drugs.

And more importantly, it blocks not only exon 19 and 21 but also the major resistance mechanism in T790M, which is how patients escape in nearly 50% to 60% of the instances when treated with erlotinib or gefitinib. So, based on all these lines of evidence, FLAURA was conducted, a phase III trial. It’s a head-to-head comparison of osimertinib of 80 mg per day versus either erlotinib or gefitinib. Both arms had placebo controls, and close to 550 patients were enrolled in the trial. It was a global study. The PFS was the primary endpoint, and what we showed was the median PFS was 18.9 months with osimertinib compared with 10.2 months with the TKIs, and the hazard ratio was 0.46. The duration of response was almost 2 points higher—8 months for the control group versus 17 months for patients treated with osimertinib.

We also saw a promising survival trend, even though its data are not mature, with a hazard ratio of 0.63 for overall survival. Now, the statistical significance is not there yet, but our hope is that with continued follow-up and maturity, we’ll see that. We also saw protection of the brain for patients treated with osimertinib in the frontline setting. The hazard ratio with osimertinib in patients with CNS metastases at baseline, versus those who did not have, was very similar, 0.46.

Of course, safety was also more favorable with osimertinib. So, the study showed superiority for PFS for osimertinib compared with other agents in a very statistically significant manner. It showed better brain effect and had fewer side effects. And now it’s in the NCCN guidelines for frontline therapy, and at some point, I anticipate it will get FDA approval. So, I think these data do lead to a new standard of care in the frontline setting based on these things.

Benjamin P. Levy, MD: And to the clinician who says—and I’ve heard this before recently on a second opinion—“Well, I want to start with the first-generation TKI because I know I can use osimertinib second, if they have T790M.” I think people feel like using osimertinib up front, they don’t know what to do, and we’ll talk about what potentially you can do after osimertinib. But your answer to that?

Suresh S. Ramalingam, MD: We’ve looked at all the randomized trials done with first- and second-generation TKIs versus chemotherapy in the frontline setting. And if you follow those patients to see how many of them actually get a second-line therapy—it doesn’t have to be a TKI—that’s somewhere in the order of 55% to 75%. So, that’s a drop-off of 30% to 40% of the patients right there who don’t see another line of therapy. Now, on top of that, only half the patients will develop T790. So, if you use the wait-until-later approach, you might lose the opportunity to treat two-thirds of your patients. And I think it’s hard for me to make the case to my patient that I have a drug that has a median PFS of 19 months, but I’m going to give them a drug that has a lesser efficacy so that when things get worse, I have a backup plan. That’s just a hard argument for me.

Naiyer A. Rizvi, MD: And much less toxic.

Suresh S. Ramalingam, MD: Absolutely.

Roy S. Herbst, MD, PhD: It’s the flu season now, and if you come in with a bad flu, will they say, “Well, I’ll save the Tamiflu until later and transmit up now”? No, you use your best antiviral right away. And I think that’s the case here. That said, we do have to figure out what to do as these patients are living longer and then they become refractory. But I think this drug is less toxic, more efficacious, and works in the brain a little bit better, so one should use it.

Transcript Edited for Clarity

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Transcript: 

Benjamin P. Levy, MD: Alright, so let’s move on and talk about a different disease biology with EGFR-mutated lung cancer. EGFR mutations are anywhere from 15% to 40% of our patients, depending on the clinical phenotype. We know these mutations predict sensitivity to first- and second-generation TKIs. Erlotinib, gefitinib, and afatinib have all outperformed chemotherapy in the frontline for EGFR-mutated lung cancer. But we’ve got, yet again, some practice-alternating data that have emerged over the past 5 or 6 months that are going to change our calculus in the way we approach this disease. Suresh, you’ve been intimately involved in and led in many of these efforts with osimertinib. Do you want to talk to us and walk us through the FLAURA data and the clinical implications of that?

Suresh S. Ramalingam, MD: The FLAURA results were just published in the New England Journal of Medicine recently. This study was done to compare osimertinib to the standard, first-generation TKIs—erlotinib and gefitinib—in the frontline setting. We all know that osimertinib is already approved in the second-line, acquired-resistant setting for patients with T790 mutation. What’s unique about osimertinib is it’s a mutation-selective inhibitor that has a very high effect on mutant receptors compared with a wild-type receptor. So the toxicity tends to be less. It also has better CNS penetration compared with the first- and second-generation drugs.

And more importantly, it blocks not only exon 19 and 21 but also the major resistance mechanism in T790M, which is how patients escape in nearly 50% to 60% of the instances when treated with erlotinib or gefitinib. So, based on all these lines of evidence, FLAURA was conducted, a phase III trial. It’s a head-to-head comparison of osimertinib of 80 mg per day versus either erlotinib or gefitinib. Both arms had placebo controls, and close to 550 patients were enrolled in the trial. It was a global study. The PFS was the primary endpoint, and what we showed was the median PFS was 18.9 months with osimertinib compared with 10.2 months with the TKIs, and the hazard ratio was 0.46. The duration of response was almost 2 points higher—8 months for the control group versus 17 months for patients treated with osimertinib.

We also saw a promising survival trend, even though its data are not mature, with a hazard ratio of 0.63 for overall survival. Now, the statistical significance is not there yet, but our hope is that with continued follow-up and maturity, we’ll see that. We also saw protection of the brain for patients treated with osimertinib in the frontline setting. The hazard ratio with osimertinib in patients with CNS metastases at baseline, versus those who did not have, was very similar, 0.46.

Of course, safety was also more favorable with osimertinib. So, the study showed superiority for PFS for osimertinib compared with other agents in a very statistically significant manner. It showed better brain effect and had fewer side effects. And now it’s in the NCCN guidelines for frontline therapy, and at some point, I anticipate it will get FDA approval. So, I think these data do lead to a new standard of care in the frontline setting based on these things.

Benjamin P. Levy, MD: And to the clinician who says—and I’ve heard this before recently on a second opinion—“Well, I want to start with the first-generation TKI because I know I can use osimertinib second, if they have T790M.” I think people feel like using osimertinib up front, they don’t know what to do, and we’ll talk about what potentially you can do after osimertinib. But your answer to that?

Suresh S. Ramalingam, MD: We’ve looked at all the randomized trials done with first- and second-generation TKIs versus chemotherapy in the frontline setting. And if you follow those patients to see how many of them actually get a second-line therapy—it doesn’t have to be a TKI—that’s somewhere in the order of 55% to 75%. So, that’s a drop-off of 30% to 40% of the patients right there who don’t see another line of therapy. Now, on top of that, only half the patients will develop T790. So, if you use the wait-until-later approach, you might lose the opportunity to treat two-thirds of your patients. And I think it’s hard for me to make the case to my patient that I have a drug that has a median PFS of 19 months, but I’m going to give them a drug that has a lesser efficacy so that when things get worse, I have a backup plan. That’s just a hard argument for me.

Naiyer A. Rizvi, MD: And much less toxic.

Suresh S. Ramalingam, MD: Absolutely.

Roy S. Herbst, MD, PhD: It’s the flu season now, and if you come in with a bad flu, will they say, “Well, I’ll save the Tamiflu until later and transmit up now”? No, you use your best antiviral right away. And I think that’s the case here. That said, we do have to figure out what to do as these patients are living longer and then they become refractory. But I think this drug is less toxic, more efficacious, and works in the brain a little bit better, so one should use it.

Transcript Edited for Clarity
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