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First-Line Shifts in Driver-Mutation Subsets According to FLAURA

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Maximilian Hochmair, MD, Otto Wagner Spital; Suresh Senan, MRCP, FRCR, PhD, VU University Medical Center; Leora Horn, MD, MSc, FRCPC, Vanderbilt University Medical Center; Thomas E. Stinchcombe, MD, Duke University Health System
Published: Monday, Dec 17, 2018



Transcript: 

Mark A. Socinski, MD: We’ve seen a shift based on the FLAURA data to accepting the third-generation drug osimertinib as the first-line standard, at least compared with other first-generation drugs. We’ve had a couple of trials looking at the second generation versus the first generation, and I’m not convinced of activity relative to the toxicity of those second generationals.

It’s hard to beat the FLAURA data at this point. Osimertinib is the first choice in this setting. That raises the issue of what you do after osimertinib. We saw some data at this meeting from Suresh Ramalingham regarding these resistance mechanisms to osimertinib; it was pretty depressing.

Maximilian Hochmair, MD: I’m not convinced that osimertinib should be used in the first-line setting; it’s discussed in our country heavily. Are you a sequencer or a nonsequencer? This data looked very fine, but we saw 75% of our patients develop T790M [amino acid position 790].

Mark A. Socinski, MD: That’s high, yes.

Maximilian Hochmair, MD: It was interesting to see what is coming with osimertinib, as well as after it; there’s a progression to see how it reacts as a systemic therapy. In 60% of our patients, we didn’t find anything like what Suresh Ramalingham presented in his data. In some patients we found metastases and BRAF mutation. They were not druggable targets.

The majority of the patients will receive chemotherapy after osimertinib resistance; this is a bit disappointing. In the beginning of last year, everybody said osimertinib was first line for sure. Now it’s a bit of a discussion, and the sequencing is being mentioned again, which I’m happy about.

Mark A. Socinski, MD: Maybe I misspoke. Maybe others don’t accept FLAURA as the standard. I’m going to ask my 2 colleagues from the United States.

Thomas E. Stinchcombe, MD: Osimertinib is unequivocally the standard; it had a higher progression-free survival [PFS], duration of response, lower-grade (3/4) toxicity, and fewer nervous system [CNS] metastases. We’ve learned from the FLAURA data about biopsy, liquid biopsy, and transition; only about 40% to 50% of patients transitioned.

Mark A. Socinski, MD: I like sequencing, but my concern is, we know there’s a drop-off in patients getting effective therapy.

Leora Horn, MD, MSc, FRCPC: I agree. Osimertinib is the standard. If the OS data come out negative or worse, that gives pause—but it’s definitely the standard.

Mark A. Socinski, MD: What did emerge from the presentation after osimertinib was not a story like T790M, where we had a dominant second mutation. There’s nothing there; you go to chemotherapy. This brings up IMpower150; is that your preferred chemotherapy regimen?

Maximilian Hochmair, MD: I have no other option, and the majority of patients would receive chemotherapy. We don’t have the fourth-generation tyrosine kinase inhibitor available for C7s or 9-7X. This is the point I will try to make for more sequencing, but I don’t know the answer at the moment. The IMpower150 treatment for those patients is the best. The regimen, with this OS overall survival data from your study, looks great: The majority of the patients are still alive after 2 years, even though there are not as many patients. It’s clear we should offer these regimens to this population of patients.

Mark A. Socinski, MD: I would just give you a preview. We submitted an abstract to the European Society of Medical Oncology Asia, with an updated OS in the sensitizing mutations; it’s pretty impressive data in terms of the hazard ration for OS in this population. Stay tuned, and we’ll get more results.

Leora Horn, MD, MSc, FRCPC: There are 2 clean studies that are not the IMpower150, which included a subset. There’s a trial with nivolumab [Opdivo] and pembrolizumab [Keytruda]. The difference is, there’s no bevacizumab [Avastin].

Mark A. Socinski, MD: Right. These patients also were excluded from Keynote 189. It’s hard for me to endorse the Keynote 189 regimen for this reason. Our data suggest that it is a VEGF effect in addition to the immunotherapy alone compared with the control arm, which didn’t distinguish itself. You can replace bevacizumab with atezolizumab, but you don’t receive the added benefit without using the VEGF and PD-L1 [programmed death-ligand 1] inhibitor together. That’s the take-home message.

Transcript Edited for Clarity 

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Transcript: 

Mark A. Socinski, MD: We’ve seen a shift based on the FLAURA data to accepting the third-generation drug osimertinib as the first-line standard, at least compared with other first-generation drugs. We’ve had a couple of trials looking at the second generation versus the first generation, and I’m not convinced of activity relative to the toxicity of those second generationals.

It’s hard to beat the FLAURA data at this point. Osimertinib is the first choice in this setting. That raises the issue of what you do after osimertinib. We saw some data at this meeting from Suresh Ramalingham regarding these resistance mechanisms to osimertinib; it was pretty depressing.

Maximilian Hochmair, MD: I’m not convinced that osimertinib should be used in the first-line setting; it’s discussed in our country heavily. Are you a sequencer or a nonsequencer? This data looked very fine, but we saw 75% of our patients develop T790M [amino acid position 790].

Mark A. Socinski, MD: That’s high, yes.

Maximilian Hochmair, MD: It was interesting to see what is coming with osimertinib, as well as after it; there’s a progression to see how it reacts as a systemic therapy. In 60% of our patients, we didn’t find anything like what Suresh Ramalingham presented in his data. In some patients we found metastases and BRAF mutation. They were not druggable targets.

The majority of the patients will receive chemotherapy after osimertinib resistance; this is a bit disappointing. In the beginning of last year, everybody said osimertinib was first line for sure. Now it’s a bit of a discussion, and the sequencing is being mentioned again, which I’m happy about.

Mark A. Socinski, MD: Maybe I misspoke. Maybe others don’t accept FLAURA as the standard. I’m going to ask my 2 colleagues from the United States.

Thomas E. Stinchcombe, MD: Osimertinib is unequivocally the standard; it had a higher progression-free survival [PFS], duration of response, lower-grade (3/4) toxicity, and fewer nervous system [CNS] metastases. We’ve learned from the FLAURA data about biopsy, liquid biopsy, and transition; only about 40% to 50% of patients transitioned.

Mark A. Socinski, MD: I like sequencing, but my concern is, we know there’s a drop-off in patients getting effective therapy.

Leora Horn, MD, MSc, FRCPC: I agree. Osimertinib is the standard. If the OS data come out negative or worse, that gives pause—but it’s definitely the standard.

Mark A. Socinski, MD: What did emerge from the presentation after osimertinib was not a story like T790M, where we had a dominant second mutation. There’s nothing there; you go to chemotherapy. This brings up IMpower150; is that your preferred chemotherapy regimen?

Maximilian Hochmair, MD: I have no other option, and the majority of patients would receive chemotherapy. We don’t have the fourth-generation tyrosine kinase inhibitor available for C7s or 9-7X. This is the point I will try to make for more sequencing, but I don’t know the answer at the moment. The IMpower150 treatment for those patients is the best. The regimen, with this OS overall survival data from your study, looks great: The majority of the patients are still alive after 2 years, even though there are not as many patients. It’s clear we should offer these regimens to this population of patients.

Mark A. Socinski, MD: I would just give you a preview. We submitted an abstract to the European Society of Medical Oncology Asia, with an updated OS in the sensitizing mutations; it’s pretty impressive data in terms of the hazard ration for OS in this population. Stay tuned, and we’ll get more results.

Leora Horn, MD, MSc, FRCPC: There are 2 clean studies that are not the IMpower150, which included a subset. There’s a trial with nivolumab [Opdivo] and pembrolizumab [Keytruda]. The difference is, there’s no bevacizumab [Avastin].

Mark A. Socinski, MD: Right. These patients also were excluded from Keynote 189. It’s hard for me to endorse the Keynote 189 regimen for this reason. Our data suggest that it is a VEGF effect in addition to the immunotherapy alone compared with the control arm, which didn’t distinguish itself. You can replace bevacizumab with atezolizumab, but you don’t receive the added benefit without using the VEGF and PD-L1 [programmed death-ligand 1] inhibitor together. That’s the take-home message.

Transcript Edited for Clarity 
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