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Other Targeted Approaches in NSCLC: NTRK or RET Fusions

Panelists: Benjamin P. Levy, MD, Sibley Memorial Hospital; Sanjay Popat, PhD, FRCP, Imperial College London; Solange Peters, MD, PhD, Centre Hospitalier Universitaire Vaudois; David Planchard, MD, PhD, Institut Gustave Roussy; Suresh S. Ramalingam, MD, Winship Cancer Institute
Published: Thursday, Oct 18, 2018



Transcript:

Benjamin P. Levy, MD:
Let’s move on to NTRK fusions, quite a story for not just lung cancer, but also all solid tumor malignancies. There was a tissue-agonistic trial enrolling patients from age 4 months all the way into the mid-70s—that would have been unheard of 10 years ago—giving a targeted therapy to patients who harbor these NTRK fusions. Solange, you want to talk a little bit about these data and how they impact practice?

Solange Peters, MD, PhD: It’s interesting because when you speak about NTRK, there are 3 NTRK fusions that I usually describe. But they might be very different from one another, right? We have some, first of all, diagnostic challenges there. There is a development of antibodies trying to fixate on the major ones, particularly in lung cancer, and it’s still an unsatisfactory field of diagnostic assessment. We still have to use our techniques of sequencing, even if you might still miss some fusions. That means we have a change in diagnosis here. We see here that one of these NTRK inhibitors, like you said, was tested across disease and across ages. We just don’t do that so much anymore. BRAF is a good example. You shouldn’t do that, but it worked well. It looked like regardless of the disease, larotrectinib was working quite well.

I think lung cancer with NTRK alterations might be the next player in this potential frontline TKI [tyrosine kinase inhibitor] administration, but we need some more data. Very importantly, it’s not the only drug we have. We’ll also have at the ESMO [European Society for Medical Oncology] meeting the entrectinib data. There will be other players in this field, but we started with ALK. We challenged the diagnostic capability. Remember with ALK that immunohistochemistry, FISH [fluorescence in situ hybridization], and NGS [next-generation sequencing] challenged the diagnostic capability we had. And then, we will probably have this series of drugs that offer good opportunities. We have to be sure that it’s better than platinum-based chemotherapy. All these things are important.

One thing is also important for NTRK-altered lung cancer: that we still have a poor idea or a very vague idea of the demographics of these patients. We don’t really have these age-defining paradigms. Even gender and smoking are still unclear in these patients. I think we have to learn quite a lot with registries and real life data for these patients. It’s nice. It’s like we’re starting the ALK story with something that is new.

Benjamin P. Levy, MD: It’s very unique. I haven’t identified an NTRK fusion yet. We haven’t been looking for them, but it is quite a story. I think that will begin to be told further, and hopefully we’ll have more data. But that response rate is quite competitive.

Solange Peters, MD, PhD: Right, absolutely.

Benjamin P. Levy, MD: It’s going to be tough to beat. Let’s move on to the last gene arrangement, RET fusions. We’ve had some very promising data presented at ASCO [American Society of Clinical Oncology] with the LOXO-292 drug. Sanjay, do you want to talk about the role of this drug specifically for RET fusions?

Sanjay Popat, PhD, FRCP: The RET aberrations are another fusion that we see in lung cancer. They’re not frequent at all, occurring at about 1% prevalence or less depending on the dataset that you look at. They are challenging to identify, depending on the technology that you use. We know that RET is dysregulating many cancer types, and since we have a number of RET inhibitors already licensed for thyroid cancer, it makes a lot of sense to pick them off the shelf and try them on our RET-altered patients. But actually, we’ve been quite disappointed with the efficacy we’ve seen with the traditional RET-active drugs, cabozantinib and vandetanib. There are some drugs that we potentially use in day-to-day life that also have RET activity. Alectinib has some RET activity and nintedanib has some RET activity as well, but there were no really meaningful responses that we’ve seen with those, apart from a few case reports.

The introduction of new RET inhibitors designed to switch off the RET fusion in lung cancer, such as the LOXO-292 drug and the BLU-667 compound, [is] a real game-changer for this disease. There is nothing worse than finding a patient who has never smoked; you’ve looked through EGFR, ALK, and ROS; and then you finally found a RET fusion, but you try another TKI with very modest efficacy. To see these new data is really quite encouraging because with both of these compounds, we have a large number of patients with really quite meaningful, dramatic responses very early on and very meaningful PFS [progression-free survival] as well. Undoubtedly, both of these agents will lead to some sort of approval in due course and hopefully become standard for this type of disease.

Benjamin P. Levy, MD: Is anyone use the LOXO-292 drug for RET fusions yet? We have a patient who I share with Memorial Sloan Kettering, and I think my clinical experience has mirrored what we saw in the waterfall plots of dramatic responses with meaningful improvement. This is really moving the bar, obviously not just for EGFR and ALK cases, but for these rare mutations where we don’t really have much. This, to me, underscores the importance of comprehensive genomic profiling. We can’t just test for EGFR and ALK. We really have to look for these other drivers that are actionable with well-tolerated TKIs that could potentially outperform chemotherapy in terms of response rate or PFS. I look forward to further data with these genotypes and others that may be forthcoming. David?

David Planchard, MD, PhD: I completely agree. The challenge is to screen that quite quickly in this population. If you don’t do it up front, generally, you never do after. You start chemotherapy, you start immune treatment, and after, you don’t go back to the tumor tissue biopsy. That’s why I really try to push the oncologists to perform this NGS panel up front to have the whole picture of the disease and to have the best adaptation of the treatment.

Otherwise, you will miss these patients, particularly for the RET fusions. I think the most challenging, as you talked about previously, is the NTRK population because we also screen all the patients and we do not find lung NTRK patients. The incidence is probably lower than 1%, and it’s really a rare, rare disease in non–small cell lung cancer. We know that we can find this type of molecular alteration across probably more than 20 different tumor types, but in the lung, it’s probably a rare, rare alteration. That’s why we need to push further to screen this population.

Solange Peters, MD, PhD: We have to be careful that some of our panels or some of our recruitments are potentially not completely ideal in identifying RET fusions. You have to have a critical look at what we really detect and how that could maybe improve it. But it’s so rare that it’s difficult to make real evidence out of it at a glimpse.


Transcript Edited for Clarity
 

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Transcript:

Benjamin P. Levy, MD:
Let’s move on to NTRK fusions, quite a story for not just lung cancer, but also all solid tumor malignancies. There was a tissue-agonistic trial enrolling patients from age 4 months all the way into the mid-70s—that would have been unheard of 10 years ago—giving a targeted therapy to patients who harbor these NTRK fusions. Solange, you want to talk a little bit about these data and how they impact practice?

Solange Peters, MD, PhD: It’s interesting because when you speak about NTRK, there are 3 NTRK fusions that I usually describe. But they might be very different from one another, right? We have some, first of all, diagnostic challenges there. There is a development of antibodies trying to fixate on the major ones, particularly in lung cancer, and it’s still an unsatisfactory field of diagnostic assessment. We still have to use our techniques of sequencing, even if you might still miss some fusions. That means we have a change in diagnosis here. We see here that one of these NTRK inhibitors, like you said, was tested across disease and across ages. We just don’t do that so much anymore. BRAF is a good example. You shouldn’t do that, but it worked well. It looked like regardless of the disease, larotrectinib was working quite well.

I think lung cancer with NTRK alterations might be the next player in this potential frontline TKI [tyrosine kinase inhibitor] administration, but we need some more data. Very importantly, it’s not the only drug we have. We’ll also have at the ESMO [European Society for Medical Oncology] meeting the entrectinib data. There will be other players in this field, but we started with ALK. We challenged the diagnostic capability. Remember with ALK that immunohistochemistry, FISH [fluorescence in situ hybridization], and NGS [next-generation sequencing] challenged the diagnostic capability we had. And then, we will probably have this series of drugs that offer good opportunities. We have to be sure that it’s better than platinum-based chemotherapy. All these things are important.

One thing is also important for NTRK-altered lung cancer: that we still have a poor idea or a very vague idea of the demographics of these patients. We don’t really have these age-defining paradigms. Even gender and smoking are still unclear in these patients. I think we have to learn quite a lot with registries and real life data for these patients. It’s nice. It’s like we’re starting the ALK story with something that is new.

Benjamin P. Levy, MD: It’s very unique. I haven’t identified an NTRK fusion yet. We haven’t been looking for them, but it is quite a story. I think that will begin to be told further, and hopefully we’ll have more data. But that response rate is quite competitive.

Solange Peters, MD, PhD: Right, absolutely.

Benjamin P. Levy, MD: It’s going to be tough to beat. Let’s move on to the last gene arrangement, RET fusions. We’ve had some very promising data presented at ASCO [American Society of Clinical Oncology] with the LOXO-292 drug. Sanjay, do you want to talk about the role of this drug specifically for RET fusions?

Sanjay Popat, PhD, FRCP: The RET aberrations are another fusion that we see in lung cancer. They’re not frequent at all, occurring at about 1% prevalence or less depending on the dataset that you look at. They are challenging to identify, depending on the technology that you use. We know that RET is dysregulating many cancer types, and since we have a number of RET inhibitors already licensed for thyroid cancer, it makes a lot of sense to pick them off the shelf and try them on our RET-altered patients. But actually, we’ve been quite disappointed with the efficacy we’ve seen with the traditional RET-active drugs, cabozantinib and vandetanib. There are some drugs that we potentially use in day-to-day life that also have RET activity. Alectinib has some RET activity and nintedanib has some RET activity as well, but there were no really meaningful responses that we’ve seen with those, apart from a few case reports.

The introduction of new RET inhibitors designed to switch off the RET fusion in lung cancer, such as the LOXO-292 drug and the BLU-667 compound, [is] a real game-changer for this disease. There is nothing worse than finding a patient who has never smoked; you’ve looked through EGFR, ALK, and ROS; and then you finally found a RET fusion, but you try another TKI with very modest efficacy. To see these new data is really quite encouraging because with both of these compounds, we have a large number of patients with really quite meaningful, dramatic responses very early on and very meaningful PFS [progression-free survival] as well. Undoubtedly, both of these agents will lead to some sort of approval in due course and hopefully become standard for this type of disease.

Benjamin P. Levy, MD: Is anyone use the LOXO-292 drug for RET fusions yet? We have a patient who I share with Memorial Sloan Kettering, and I think my clinical experience has mirrored what we saw in the waterfall plots of dramatic responses with meaningful improvement. This is really moving the bar, obviously not just for EGFR and ALK cases, but for these rare mutations where we don’t really have much. This, to me, underscores the importance of comprehensive genomic profiling. We can’t just test for EGFR and ALK. We really have to look for these other drivers that are actionable with well-tolerated TKIs that could potentially outperform chemotherapy in terms of response rate or PFS. I look forward to further data with these genotypes and others that may be forthcoming. David?

David Planchard, MD, PhD: I completely agree. The challenge is to screen that quite quickly in this population. If you don’t do it up front, generally, you never do after. You start chemotherapy, you start immune treatment, and after, you don’t go back to the tumor tissue biopsy. That’s why I really try to push the oncologists to perform this NGS panel up front to have the whole picture of the disease and to have the best adaptation of the treatment.

Otherwise, you will miss these patients, particularly for the RET fusions. I think the most challenging, as you talked about previously, is the NTRK population because we also screen all the patients and we do not find lung NTRK patients. The incidence is probably lower than 1%, and it’s really a rare, rare disease in non–small cell lung cancer. We know that we can find this type of molecular alteration across probably more than 20 different tumor types, but in the lung, it’s probably a rare, rare alteration. That’s why we need to push further to screen this population.

Solange Peters, MD, PhD: We have to be careful that some of our panels or some of our recruitments are potentially not completely ideal in identifying RET fusions. You have to have a critical look at what we really detect and how that could maybe improve it. But it’s so rare that it’s difficult to make real evidence out of it at a glimpse.


Transcript Edited for Clarity
 
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TitleExpiration DateCME Credits
Community Practice Connections™: Oncology Best Practice™ Decision Points in Advanced NSCLC: Assessing Treatment Options Beyond Disease ProgressionNov 30, 20181.0
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