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Mutation Testing for All Patients With 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: Tuesday, Dec 04, 2018



Transcript: 

Benjamin P. Levy, MD: We’ve talked about EGFR [estimated glomerular filtration rate] and ALK [anaplastic lymphoma kinase] and ROS [reactive oxygen species]. We talked about these rare mutations that do exist. If you test and capture, you can certainly align patients with the right drug. It really underscores the importance of molecular testing, [which is] comprehensive genomic profiling of the tissue.

There’re many questions regarding the optimization of this, and we all have different approaches to receive results. Some of us send it out to a third-party vendor or do it in house. Maybe we can talk, in the last 3 to 5 minutes, about the best practices with molecular testing; the whole concept of tissue stewardship; and how we receive quick results. Then we can talk about the interpretation of data in the context of PD-L1 [programmed death-ligand 1]. Remember, most genotypes, single-agent immunotherapy, even for a high–PD-L1 express, is probably not the correct answer—at least for many of these patients. How do we do this optimally so that we can get answers as needed?

Mohammad Jahanzeb, MD, FACP: I can start. I think that a lot of tissue is wasted on useless immunohistochemical tests. First and foremost, we should talk to our pathologists and say, “Please do not do 8 tests and waste tissue.” Second is to realize that it takes very little tissue to do next-gen sequencing [NGS]. I’ve done it on cellblocks from a pleural infusion and EBUS [endobronchial ultrasound] samples. We should encourage that intervention radiologist to be a little bolder and do a core biopsy; that’s to obtain the tissue and not waste it—that’s something that is very important.

The second most common problem that I see is this anxiety on the part of the family, and the oncologist acquiescing to that anxiety to start chemotherapy right away, when they come. I tell them, “You have had this in your body for a couple of years or more—this is not a medical emergency. It has become an emotional emergency. It’ll take about 3 weeks. I can do the wrong thing next week, because I’ve still got preauthorization for chemotherapy. I can do the wrong thing next week or the right thing in 3 weeks—what would you like?” Then everybody says, “Do the right thing.” I’ve heard from some junior doctors that they don’t have the guts to do that. I would keep preaching this until everybody develops the guts to do the right thing.

Benjamin P. Levy, MD: Patience is a virtue.

Mohammad Jahanzeb, MD, FACP: Yes.

Shirish M. Gadgeel, MD: I would say that at least the 4 molecular markers for which we have now FDA-approved treatments in frontline EGFR, ALK, ROS1 [receptor tyrosine kinase], and BRAF be done. And depending upon how accessible it is, you either just do those 4 tests first. If they are negative, you can start them on systemic therapy and then make every effort possible to get their tumor tested by a reference lab with next-generation sequencing for the other molecular alterations that we talked about that are maybe not that common; wherein that information could be used in the second-line setting. Today we’ve reached a point where at least every patient with and without squamous cells should have molecular next-generation sequence testing done on their tumor at some point. Preferably in [the] frontline. But if not, at least subsequently so that patients are being treated by targeted therapies.

Anne S. Tsao, MD: This is a likely patient to have a mutation, right? Your nonsmokers and young patients, whether they’re squamous or adenocarcinoma we try to pull out all the stops so that they get their tumor tested. What I do with these patients is send plasma testing while we’re waiting for a biopsy and sequencing to be done, because you know the families have to wait a week or two to receive results. And then another 2 to 3 weeks to receive genetic test results. I send that plasma test off in my clinic and receive information, most of the time.

Shirish M. Gadgeel, MD: The test is helpful if you get a positive result. But if you don’t get a positive result, that still doesn’t mean you should not be testing.

Benjamin P. Levy, MD: Absolutely.

Lyudmila A. Bazhenova, MD: Back to your point about junior physicians not feeling comfortable delaying therapy. I saw a paper where that was actually measured. When the physicians were asked, “Would you be willing to delay therapy for molecular testing?”, the patients were asked the same question. And it’s interesting that the majority of patients were willing to delay the therapy, whereas the majority of physicians were not. We are tricking ourselves when we are starting our patients on therapy without knowing the molecular testing.

There was an interesting modelling abstract at ASCO [American Society of Clinical Oncology] by Nathan A. Penell that [looked] at efficacy with a standard patient population of all-comers and the standard incidence of lung cancer, comparing NGS up front versus different combinations of small panel followed by NGS single gene, one-by-one until 4 were complete. And then followed by NGS, which was actually more cost-effective to the insurance company than any other options described.

Benjamin P. Levy, MD: The PD-L1, at least in our institution, is done in 2 days with patients. The NGS takes about 2 to 3 weeks. If you think that a patient has an actionable mutation and their PD-L1 is high, we may wait for the tissue to come back for the specific genotype to be identified—a plasma genotyping. I know we said this before, but single-agent checkpoint inhibitors probably are not the best drugs for many of these patients, specifically for EGFR and ALK-rearranged lung cancer, even if they’re PD-L1 high.

So, this has been extremely informative. Before we end this discussion, I’d like to get some closing thoughts from each of our panelists. Lyudmila, some closing thoughts before we end the program?

Lyudmila A. Bazhenova, MD: Over the last couple years, there has been a transformation in lung cancer where we’re learning more about molecular abnormalities that can be targeted. ALK patients of 34 months PFS [progression-free survival], for example, responded to NTRK [neurotrophic tyrosine kinase] and RET [rearranged during transfection]. It is very gratifying to put patients on those trials. If you don’t look for NTRK mutation, you don’t look for RET mutations. You won’t find it.

Shirish M. Gadgeel, MD: We no longer have a general definition for lung cancer. There are many subsets of lung cancers, and knowing what specific type your patient has is very important in deciding therapy. We have these wonderful tools, but they only work in specific patients. Identifying which type of lung cancer the patient has it very important.

Mohammad Jahanzeb, MD, FACP: I concur. And instead of repeating myself, I’ll add one point that you had highlighted but I think is extremely important: that if we don’t test, you will do lots of unnecessary comprehensive brain radiation, because a lot of the patients who are ALK and EGFR positive have multiple metastases. The majority of them are asymptomatic. If they don’t have edema or some other neurological compromise, we can wait 3 weeks to save them from brain radiation. Why? Because previously these patients at 10 to 12 months’ survival did not live to see the neuropsychiatric sequel in the second and third year. Now nearly everyone lives beyond that point.

Benjamin P. Levy, MD: Good point. Anne?

Anne S. Tsao, MD: All of us would agree that the last year or two have been incredibly exciting for lung cancer. We can now talk to our patients with optimism, because we can do things that we couldn’t in the past. While we haven’t necessarily made the same progress in small cell, squamous cell, and mesothelioma, we’re getting there. There’s definitely cause for excitement and hope.

Benjamin P. Levy, MD: Who would have thought? I went into lung cancer because it was easy. There were only 3 drugs when I went into it. And now I’m playing catchup trying to keep up with all the different targeted therapies and specific genotypes.
Thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us, and we hope you found this Peer Exchange discussion to be useful and informative.

Transcript Edited for Clarity 

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Transcript: 

Benjamin P. Levy, MD: We’ve talked about EGFR [estimated glomerular filtration rate] and ALK [anaplastic lymphoma kinase] and ROS [reactive oxygen species]. We talked about these rare mutations that do exist. If you test and capture, you can certainly align patients with the right drug. It really underscores the importance of molecular testing, [which is] comprehensive genomic profiling of the tissue.

There’re many questions regarding the optimization of this, and we all have different approaches to receive results. Some of us send it out to a third-party vendor or do it in house. Maybe we can talk, in the last 3 to 5 minutes, about the best practices with molecular testing; the whole concept of tissue stewardship; and how we receive quick results. Then we can talk about the interpretation of data in the context of PD-L1 [programmed death-ligand 1]. Remember, most genotypes, single-agent immunotherapy, even for a high–PD-L1 express, is probably not the correct answer—at least for many of these patients. How do we do this optimally so that we can get answers as needed?

Mohammad Jahanzeb, MD, FACP: I can start. I think that a lot of tissue is wasted on useless immunohistochemical tests. First and foremost, we should talk to our pathologists and say, “Please do not do 8 tests and waste tissue.” Second is to realize that it takes very little tissue to do next-gen sequencing [NGS]. I’ve done it on cellblocks from a pleural infusion and EBUS [endobronchial ultrasound] samples. We should encourage that intervention radiologist to be a little bolder and do a core biopsy; that’s to obtain the tissue and not waste it—that’s something that is very important.

The second most common problem that I see is this anxiety on the part of the family, and the oncologist acquiescing to that anxiety to start chemotherapy right away, when they come. I tell them, “You have had this in your body for a couple of years or more—this is not a medical emergency. It has become an emotional emergency. It’ll take about 3 weeks. I can do the wrong thing next week, because I’ve still got preauthorization for chemotherapy. I can do the wrong thing next week or the right thing in 3 weeks—what would you like?” Then everybody says, “Do the right thing.” I’ve heard from some junior doctors that they don’t have the guts to do that. I would keep preaching this until everybody develops the guts to do the right thing.

Benjamin P. Levy, MD: Patience is a virtue.

Mohammad Jahanzeb, MD, FACP: Yes.

Shirish M. Gadgeel, MD: I would say that at least the 4 molecular markers for which we have now FDA-approved treatments in frontline EGFR, ALK, ROS1 [receptor tyrosine kinase], and BRAF be done. And depending upon how accessible it is, you either just do those 4 tests first. If they are negative, you can start them on systemic therapy and then make every effort possible to get their tumor tested by a reference lab with next-generation sequencing for the other molecular alterations that we talked about that are maybe not that common; wherein that information could be used in the second-line setting. Today we’ve reached a point where at least every patient with and without squamous cells should have molecular next-generation sequence testing done on their tumor at some point. Preferably in [the] frontline. But if not, at least subsequently so that patients are being treated by targeted therapies.

Anne S. Tsao, MD: This is a likely patient to have a mutation, right? Your nonsmokers and young patients, whether they’re squamous or adenocarcinoma we try to pull out all the stops so that they get their tumor tested. What I do with these patients is send plasma testing while we’re waiting for a biopsy and sequencing to be done, because you know the families have to wait a week or two to receive results. And then another 2 to 3 weeks to receive genetic test results. I send that plasma test off in my clinic and receive information, most of the time.

Shirish M. Gadgeel, MD: The test is helpful if you get a positive result. But if you don’t get a positive result, that still doesn’t mean you should not be testing.

Benjamin P. Levy, MD: Absolutely.

Lyudmila A. Bazhenova, MD: Back to your point about junior physicians not feeling comfortable delaying therapy. I saw a paper where that was actually measured. When the physicians were asked, “Would you be willing to delay therapy for molecular testing?”, the patients were asked the same question. And it’s interesting that the majority of patients were willing to delay the therapy, whereas the majority of physicians were not. We are tricking ourselves when we are starting our patients on therapy without knowing the molecular testing.

There was an interesting modelling abstract at ASCO [American Society of Clinical Oncology] by Nathan A. Penell that [looked] at efficacy with a standard patient population of all-comers and the standard incidence of lung cancer, comparing NGS up front versus different combinations of small panel followed by NGS single gene, one-by-one until 4 were complete. And then followed by NGS, which was actually more cost-effective to the insurance company than any other options described.

Benjamin P. Levy, MD: The PD-L1, at least in our institution, is done in 2 days with patients. The NGS takes about 2 to 3 weeks. If you think that a patient has an actionable mutation and their PD-L1 is high, we may wait for the tissue to come back for the specific genotype to be identified—a plasma genotyping. I know we said this before, but single-agent checkpoint inhibitors probably are not the best drugs for many of these patients, specifically for EGFR and ALK-rearranged lung cancer, even if they’re PD-L1 high.

So, this has been extremely informative. Before we end this discussion, I’d like to get some closing thoughts from each of our panelists. Lyudmila, some closing thoughts before we end the program?

Lyudmila A. Bazhenova, MD: Over the last couple years, there has been a transformation in lung cancer where we’re learning more about molecular abnormalities that can be targeted. ALK patients of 34 months PFS [progression-free survival], for example, responded to NTRK [neurotrophic tyrosine kinase] and RET [rearranged during transfection]. It is very gratifying to put patients on those trials. If you don’t look for NTRK mutation, you don’t look for RET mutations. You won’t find it.

Shirish M. Gadgeel, MD: We no longer have a general definition for lung cancer. There are many subsets of lung cancers, and knowing what specific type your patient has is very important in deciding therapy. We have these wonderful tools, but they only work in specific patients. Identifying which type of lung cancer the patient has it very important.

Mohammad Jahanzeb, MD, FACP: I concur. And instead of repeating myself, I’ll add one point that you had highlighted but I think is extremely important: that if we don’t test, you will do lots of unnecessary comprehensive brain radiation, because a lot of the patients who are ALK and EGFR positive have multiple metastases. The majority of them are asymptomatic. If they don’t have edema or some other neurological compromise, we can wait 3 weeks to save them from brain radiation. Why? Because previously these patients at 10 to 12 months’ survival did not live to see the neuropsychiatric sequel in the second and third year. Now nearly everyone lives beyond that point.

Benjamin P. Levy, MD: Good point. Anne?

Anne S. Tsao, MD: All of us would agree that the last year or two have been incredibly exciting for lung cancer. We can now talk to our patients with optimism, because we can do things that we couldn’t in the past. While we haven’t necessarily made the same progress in small cell, squamous cell, and mesothelioma, we’re getting there. There’s definitely cause for excitement and hope.

Benjamin P. Levy, MD: Who would have thought? I went into lung cancer because it was easy. There were only 3 drugs when I went into it. And now I’m playing catchup trying to keep up with all the different targeted therapies and specific genotypes.
Thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us, and we hope you found this Peer Exchange discussion to be useful and informative.

Transcript Edited for Clarity 
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