Stay tuned for our LIVE OncLive News Network coverage straight from the #ASH18 conference floor! 

Select Topic:
Browse by Series:

Promising EGFR Inhibitors in Development for NSCLC

Panelists: Benjamin P. Levy, MD, Sibley Memorial Hospital; Shirish M. Gadgeel, MD, University of Michigan; Lyudmila A. Bazhenova, MD, UCSD Morris Cancer Center; Anne S. Tsao, MD, MD Anderson Cancer Center; Mohammad Jahanzeb, MD, FACP, University of Miami, Miller School of Medicine
Published: Wednesday, Oct 24, 2018



Transcript: 

Benjamin P. Levy, MD: There’s a disparity of approaches for treating or interrogating post osimertinib for mutation in addition to chemotherapy options, which shows the various competing standards that exist. We’re just trying to learn what to do. So we’ve talked about osimertinib and the emerging TKIs [tyrosine kinase inhibitors] that we’ve learned about in the past 6 to 12 months, specifically at ASCO [American Society of Clinical Oncology Annual Meeting] this year and subsequently published in the JCO [Journal of Clinical Oncology] concurrently with the ARCHER data and the dacomitinib.

Shirish M. Gadgeel, MD: The results of the study reflect how quickly the field is moving. We have a trial wherein we have a survival improvement of comparing one TKI to another, which is one of the first studies to demonstrate a survival improvement in the field of thoracic oncology; however, this may not necessarily change the standard of care. The ARCHER 1050, a study presented at ASCO last year, was the first to randomize patients who were EGFR mutation positive—the sensitive mutations—either exon del19 or L858R—exon 21 mutation to either dacomitinib at 45 mg daily or gefitinib at 250 mg daily. At last year’s ASCO, what was demonstrated was the significant improvement in progression-free survival, which was the primary endpoint with a hazard ration of 0.59, which translated into a median progression-free survival with dacomitinib of about 14.7 or approximately 15 months and 9 months with gefitinib. It was impressive improvement in progression-free survival.

The 2 important things to note about this study are (1) that the study specifically excluded patients with brain metastases. Based on several series, the percentage of patients who have brain metastases at baseline can vary from 25% to 38%—that’s a substantial proportion of EGFR mutation–positive patients who were not enrolled on the study. The second issue is the toxicity: Patients may experience both rash and diarrhea, both of which may lead to a significant portion of patients’ requiring a dose reduction from 45 mg to 30 mg and requiring drug discontinuation.

But at this year’s ASCO, the study demonstrated an improvement in overall survival, which was not the primary endpoint. Nonetheless, it was striking that there was a survival improvement in patients who received dacomitinib with a hazard ratio of 0.76. There was a 24% reduction in the risk of dying in patients who received dacomitinib. I do view this data with a little bit of caution when you look at medians—and clearly hazard ratios are more reflective of the benefit.

The median survival with dacomitinib was about 24 months, whereas for gefitinib it was 26 months—which would be considered somewhat less than what we have seen in studies done in comparable time periods, in which we have seen median survivals with the first-generation EGFR inhibitors in the range of about 36 months, or 3 years. It raises the possibility that the standard arm underperformed. Nonetheless, to see a survival advantage was truly impressive.

It may not necessarily change the standard of care, as we now have osimertinib. If these data were presented 3 years ago, one would have described the toxicities observed with this drug and incorporated it into standard practice. But now that we have osimertinib, which has shown an even more impressive progression-free survival and not yet an overall survival advantage, this doesn’t necessarily displace the osimertinib but does raise the possibility. This is pure speculation—that the FLAURA results may also end up with the longer follow-up, showing a survival advantage.

Mohammad Jahanzeb, MD, FACP: Let’s not forget afatinib, LUX-Lung 3 and 6, which had 31- and 33-month overall survival. This is not an unprecedented, shockingly impressive overall survival.

Shirish M. Gadgeel, MD: Correct.

Anne S. Tsao, MD: In the United States, dacomitinib will probably not have much use; however, throughout the rest of the world, dacomitinib will be utilized because of the difference in medical and healthcare costs and the fact that in Asia, dacomitinib is more commonly used and osimertinib is not widely available.

Benjamin P. Levy, MD: The toxicity of the drug, as Shirish highlighted, is probably going to be prohibitive in its routine use in clinical practice. There was a large percentage of patients who were discontinued from treatment on that trial. But let’s give it credit: It is the first phase III trial comparing TKI versus TKI that exhibited OS [overall survival] advantage. It will be interesting to see whether there will be any traction of this in the United States. I agree with Anne—the traction will be global. With osimertinib landing front and center, giving its efficacy and toleration, I have a hard time understanding where this drug is going to land in the United States.

Shirish M. Gadgeel, MD: When we’re discussing osimertinib, the toxicity profile, and the CNS [central nervous system] activity, not only are the data more impressive in FLAURA, but when you combine that with its activity in the CNS, we don’t have any evidence that dacomitinib necessarily would have similar activity in the CNS because they excluded those patients. Considering the toxicity profile, I don’t think this would change the standard of care at the present time.


Trasncript Edited for Clarity
 

Slider Left
Slider Right


Transcript: 

Benjamin P. Levy, MD: There’s a disparity of approaches for treating or interrogating post osimertinib for mutation in addition to chemotherapy options, which shows the various competing standards that exist. We’re just trying to learn what to do. So we’ve talked about osimertinib and the emerging TKIs [tyrosine kinase inhibitors] that we’ve learned about in the past 6 to 12 months, specifically at ASCO [American Society of Clinical Oncology Annual Meeting] this year and subsequently published in the JCO [Journal of Clinical Oncology] concurrently with the ARCHER data and the dacomitinib.

Shirish M. Gadgeel, MD: The results of the study reflect how quickly the field is moving. We have a trial wherein we have a survival improvement of comparing one TKI to another, which is one of the first studies to demonstrate a survival improvement in the field of thoracic oncology; however, this may not necessarily change the standard of care. The ARCHER 1050, a study presented at ASCO last year, was the first to randomize patients who were EGFR mutation positive—the sensitive mutations—either exon del19 or L858R—exon 21 mutation to either dacomitinib at 45 mg daily or gefitinib at 250 mg daily. At last year’s ASCO, what was demonstrated was the significant improvement in progression-free survival, which was the primary endpoint with a hazard ration of 0.59, which translated into a median progression-free survival with dacomitinib of about 14.7 or approximately 15 months and 9 months with gefitinib. It was impressive improvement in progression-free survival.

The 2 important things to note about this study are (1) that the study specifically excluded patients with brain metastases. Based on several series, the percentage of patients who have brain metastases at baseline can vary from 25% to 38%—that’s a substantial proportion of EGFR mutation–positive patients who were not enrolled on the study. The second issue is the toxicity: Patients may experience both rash and diarrhea, both of which may lead to a significant portion of patients’ requiring a dose reduction from 45 mg to 30 mg and requiring drug discontinuation.

But at this year’s ASCO, the study demonstrated an improvement in overall survival, which was not the primary endpoint. Nonetheless, it was striking that there was a survival improvement in patients who received dacomitinib with a hazard ratio of 0.76. There was a 24% reduction in the risk of dying in patients who received dacomitinib. I do view this data with a little bit of caution when you look at medians—and clearly hazard ratios are more reflective of the benefit.

The median survival with dacomitinib was about 24 months, whereas for gefitinib it was 26 months—which would be considered somewhat less than what we have seen in studies done in comparable time periods, in which we have seen median survivals with the first-generation EGFR inhibitors in the range of about 36 months, or 3 years. It raises the possibility that the standard arm underperformed. Nonetheless, to see a survival advantage was truly impressive.

It may not necessarily change the standard of care, as we now have osimertinib. If these data were presented 3 years ago, one would have described the toxicities observed with this drug and incorporated it into standard practice. But now that we have osimertinib, which has shown an even more impressive progression-free survival and not yet an overall survival advantage, this doesn’t necessarily displace the osimertinib but does raise the possibility. This is pure speculation—that the FLAURA results may also end up with the longer follow-up, showing a survival advantage.

Mohammad Jahanzeb, MD, FACP: Let’s not forget afatinib, LUX-Lung 3 and 6, which had 31- and 33-month overall survival. This is not an unprecedented, shockingly impressive overall survival.

Shirish M. Gadgeel, MD: Correct.

Anne S. Tsao, MD: In the United States, dacomitinib will probably not have much use; however, throughout the rest of the world, dacomitinib will be utilized because of the difference in medical and healthcare costs and the fact that in Asia, dacomitinib is more commonly used and osimertinib is not widely available.

Benjamin P. Levy, MD: The toxicity of the drug, as Shirish highlighted, is probably going to be prohibitive in its routine use in clinical practice. There was a large percentage of patients who were discontinued from treatment on that trial. But let’s give it credit: It is the first phase III trial comparing TKI versus TKI that exhibited OS [overall survival] advantage. It will be interesting to see whether there will be any traction of this in the United States. I agree with Anne—the traction will be global. With osimertinib landing front and center, giving its efficacy and toleration, I have a hard time understanding where this drug is going to land in the United States.

Shirish M. Gadgeel, MD: When we’re discussing osimertinib, the toxicity profile, and the CNS [central nervous system] activity, not only are the data more impressive in FLAURA, but when you combine that with its activity in the CNS, we don’t have any evidence that dacomitinib necessarily would have similar activity in the CNS because they excluded those patients. Considering the toxicity profile, I don’t think this would change the standard of care at the present time.


Trasncript Edited for Clarity
 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: Oncology Best Practice™ Decision Points in Advanced NSCLC: Assessing Treatment Options Beyond Disease ProgressionNov 30, 20181.0
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
Publication Bottom Border
Border Publication
x