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Cabozantinib in RET-Rearranged NSCLC

Panelists: Mary Jo Fidler, MD, Rush; Roy S. Herbst, MD, PhD, Yale ; Geoffrey R. Oxnard, MD, Harvard; Naiyer Rizvi, MD, Columbia; Mark A. Socinski, MD,
Published: Tuesday, Sep 22, 2015


Transcript:

Mark A. Socinski, MD: So, Naiyer, I’m going to ask you. We saw also one of your former colleagues present some data with cabozantinib in yet another molecularly defined population, those with RET translocations.

Naiyer Rizvi, MD: Right. Alex and I started this work a few years back while I was still at Memorial Sloan Kettering, and these RET fusions really are, again, in the 1% club. Unlike the BRAF mutations, they are seen more in never-smokers, similar to the EGFR/ALK patients.

Cabozantinib is one of a few drugs which has RET activity, and we explored the activity in this patient population. What we found was that there really was very high level of activity and durable benefit in patients treated with cabozantinib. I think this is another target that, like as Roy said, is on the top 10 hit list. Roy likes top 10 for some reason. He likes to break it down to top 10.

Mark A. Socinski, MD: He’s the next Letterman of oncology.

Naiyer Rizvi, MD: I think so.

Roy S. Herbst, MD, PhD: Give me five minutes alone at the end.

Naiyer Rizvi, MD: I think it’s a very active drug.

Mark A. Socinski, MD: Roy, thoughts about that?

Roy S. Herbst, MD, PhD: I would agree. Again, we know lung cancer is lung cancer. It’s different in every patient and we’ll talk a bit about immune therapy, which is a catch-all, but it would be nice to be able to divide up the pie as much as we can, and I think this is a drug that can be used in that setting.

Geoffrey R. Oxnard, MD: That being said, it’s a multi-kinase inhibitor, right? It hits a number of targets, and so it’s not an easy drug to take. In fact, I think this trial didn’t prescribe it at the FDA approved dose, but picked a lower dose which might be more tolerable for lung cancer patients.

There are other drugs – sunitinib, sorafenib, alectinib, which may be RET inhibitors, and if we can get that clean drug, that clean RET inhibitor, that might be an opportunity. Until then, we’re dealing with drugs like, vandetanib that hits VEGF, hits RET, and hits a couple of targets and aren’t necessarily the easiest to tolerate.

Roy S. Herbst, MD, PhD: That’s the issue with any kinase inhibitor. What, are there about 500+ kinases? If you look at the phylogenetic tree and how they all branch out, you’re never going to have one that’s completely specific. The antibodies are much more specific. Another approach might be to target with an armed antibody of some sort, but, again, you have to get experience with different agents.

Naiyer Rizvi, MD: So another plug for next-generation sequencing is that we looked at our patient population, that when I was at Memorial Sloan Kettering, who were never-smokers who tested negative for everything by more standard-type panels.

Geoffrey R. Oxnard, MD: Negative for the top 10, right?

Naiyer Rizvi, MD: Negative for the top 10. And we did next-generation sequencing on those samples and found about a quarter of these never-smokers that were more likely to have some sort of druggable target identified. Most of them were actually fusions, so I think that the next-gen panels are better for picking up these fusions than FISH or IHC assays.

Roy S. Herbst, MD, PhD: Were they druggable?

Naiyer Rizvi, MD: Some of them we were able to treat, yes.

Roy S. Herbst, MD, PhD: So I guess if you have a good phase I program with agents or you have a way to repurpose drugs, it might be very good to have that sort of thing available.

Mark A. Socinski, MD: We saw with cabozantinib, the ECOG trial which was done. We’ve been talking about molecularly enriched populations and using targeted therapy at a specific target in which the activity is quite remarkable. But the ECOG data, if I remember correctly, was an EGFR wild-type population.

Geoffrey R. Oxnard, MD: Right. That was erlotinib versus cabozantinib versus the combination in patients wild-type for EGFR, which to me is the question of whether you give focused EGFR inhibitor to EGFR wild-type patients or a multi-kinase inhibitor that’s hitting. They’re focusing on the MEK activity of cabozantinib but also RET, also ROS, also VEGF, a multi-kinase inhibitor. Not surprisingly, the multi-kinase VEGF inhibitor was better than the EGFR inhibitor in wild-type patients.

Mary Jo Fidler, MD: But they weren’t able to correlate with MET expression because they look for that by immunohistochemistry.

Geoffrey R. Oxnard, MD: Partly because it’s not just a MET inhibitor. It has activity in a number of ways.

Mark A. Socinski, MD: So let me ask the panel this. If you’re in community practice and you’re seeing, obviously a general community oncology practice, and a fair amount of that nowadays is lung cancer because of the incidence of the disease, what are the things physician should be testing for? What’s your list of actionable genotypes in this disease at this point?

Geoffrey R. Oxnard, MD: I test EGFR, ALK, ROS first run, in a week before starting therapy, and then I will have next-generation sequencing that gets me the other potentially targetable things which include HER2, BRAF, RET, and a variety of others.

Mark A. Socinski, MD: Any difference?

Naiyer Rizvi, MD: No, I agree.

Roy S. Herbst, MD, PhD: Yeah, it’s the same. The one thing we have in our initial panel is also KRAS, and I’m not going to pretend that we can target KRAS any better than anyone else.

Mark A. Socinski, MD: Well, you can, just not successfully, right?

Roy S. Herbst, MD, PhD: Right. But there are clinical trials and we have a Stand Up for Cancer group that several of us are involved with that actually is looking at that. It’s nice to know for clinical trials, but, in practice, I would say you have to really get that EGFR, your ALK, your ROS1 and you need it quickly. You need it within a week to 10 days. I think the CAP guidelines are 10 days and you really need to find a way to make that happen.

Mark A. Socinski, MD: I think it’s almost time to update the CAP guidelines.

Geoffrey R. Oxnard, MD: What I like about KRAS assay is if you find KRAS, you can stop looking.

Mark A. Socinski, MD: It’s a show stopper.

Roy S. Herbst, MD, PhD: And it’s usually the one easiest to do and comes back first.

Mark A. Socinski, MD: And it’s close to a third of the population depending on where you are.

Roy S. Herbst, MD, PhD: Absolutely.

Naiyer Rizvi, MD: And, again, this is on adenocarcinoma that we’re doing this.
Transcript Edited for Clarity
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Transcript:

Mark A. Socinski, MD: So, Naiyer, I’m going to ask you. We saw also one of your former colleagues present some data with cabozantinib in yet another molecularly defined population, those with RET translocations.

Naiyer Rizvi, MD: Right. Alex and I started this work a few years back while I was still at Memorial Sloan Kettering, and these RET fusions really are, again, in the 1% club. Unlike the BRAF mutations, they are seen more in never-smokers, similar to the EGFR/ALK patients.

Cabozantinib is one of a few drugs which has RET activity, and we explored the activity in this patient population. What we found was that there really was very high level of activity and durable benefit in patients treated with cabozantinib. I think this is another target that, like as Roy said, is on the top 10 hit list. Roy likes top 10 for some reason. He likes to break it down to top 10.

Mark A. Socinski, MD: He’s the next Letterman of oncology.

Naiyer Rizvi, MD: I think so.

Roy S. Herbst, MD, PhD: Give me five minutes alone at the end.

Naiyer Rizvi, MD: I think it’s a very active drug.

Mark A. Socinski, MD: Roy, thoughts about that?

Roy S. Herbst, MD, PhD: I would agree. Again, we know lung cancer is lung cancer. It’s different in every patient and we’ll talk a bit about immune therapy, which is a catch-all, but it would be nice to be able to divide up the pie as much as we can, and I think this is a drug that can be used in that setting.

Geoffrey R. Oxnard, MD: That being said, it’s a multi-kinase inhibitor, right? It hits a number of targets, and so it’s not an easy drug to take. In fact, I think this trial didn’t prescribe it at the FDA approved dose, but picked a lower dose which might be more tolerable for lung cancer patients.

There are other drugs – sunitinib, sorafenib, alectinib, which may be RET inhibitors, and if we can get that clean drug, that clean RET inhibitor, that might be an opportunity. Until then, we’re dealing with drugs like, vandetanib that hits VEGF, hits RET, and hits a couple of targets and aren’t necessarily the easiest to tolerate.

Roy S. Herbst, MD, PhD: That’s the issue with any kinase inhibitor. What, are there about 500+ kinases? If you look at the phylogenetic tree and how they all branch out, you’re never going to have one that’s completely specific. The antibodies are much more specific. Another approach might be to target with an armed antibody of some sort, but, again, you have to get experience with different agents.

Naiyer Rizvi, MD: So another plug for next-generation sequencing is that we looked at our patient population, that when I was at Memorial Sloan Kettering, who were never-smokers who tested negative for everything by more standard-type panels.

Geoffrey R. Oxnard, MD: Negative for the top 10, right?

Naiyer Rizvi, MD: Negative for the top 10. And we did next-generation sequencing on those samples and found about a quarter of these never-smokers that were more likely to have some sort of druggable target identified. Most of them were actually fusions, so I think that the next-gen panels are better for picking up these fusions than FISH or IHC assays.

Roy S. Herbst, MD, PhD: Were they druggable?

Naiyer Rizvi, MD: Some of them we were able to treat, yes.

Roy S. Herbst, MD, PhD: So I guess if you have a good phase I program with agents or you have a way to repurpose drugs, it might be very good to have that sort of thing available.

Mark A. Socinski, MD: We saw with cabozantinib, the ECOG trial which was done. We’ve been talking about molecularly enriched populations and using targeted therapy at a specific target in which the activity is quite remarkable. But the ECOG data, if I remember correctly, was an EGFR wild-type population.

Geoffrey R. Oxnard, MD: Right. That was erlotinib versus cabozantinib versus the combination in patients wild-type for EGFR, which to me is the question of whether you give focused EGFR inhibitor to EGFR wild-type patients or a multi-kinase inhibitor that’s hitting. They’re focusing on the MEK activity of cabozantinib but also RET, also ROS, also VEGF, a multi-kinase inhibitor. Not surprisingly, the multi-kinase VEGF inhibitor was better than the EGFR inhibitor in wild-type patients.

Mary Jo Fidler, MD: But they weren’t able to correlate with MET expression because they look for that by immunohistochemistry.

Geoffrey R. Oxnard, MD: Partly because it’s not just a MET inhibitor. It has activity in a number of ways.

Mark A. Socinski, MD: So let me ask the panel this. If you’re in community practice and you’re seeing, obviously a general community oncology practice, and a fair amount of that nowadays is lung cancer because of the incidence of the disease, what are the things physician should be testing for? What’s your list of actionable genotypes in this disease at this point?

Geoffrey R. Oxnard, MD: I test EGFR, ALK, ROS first run, in a week before starting therapy, and then I will have next-generation sequencing that gets me the other potentially targetable things which include HER2, BRAF, RET, and a variety of others.

Mark A. Socinski, MD: Any difference?

Naiyer Rizvi, MD: No, I agree.

Roy S. Herbst, MD, PhD: Yeah, it’s the same. The one thing we have in our initial panel is also KRAS, and I’m not going to pretend that we can target KRAS any better than anyone else.

Mark A. Socinski, MD: Well, you can, just not successfully, right?

Roy S. Herbst, MD, PhD: Right. But there are clinical trials and we have a Stand Up for Cancer group that several of us are involved with that actually is looking at that. It’s nice to know for clinical trials, but, in practice, I would say you have to really get that EGFR, your ALK, your ROS1 and you need it quickly. You need it within a week to 10 days. I think the CAP guidelines are 10 days and you really need to find a way to make that happen.

Mark A. Socinski, MD: I think it’s almost time to update the CAP guidelines.

Geoffrey R. Oxnard, MD: What I like about KRAS assay is if you find KRAS, you can stop looking.

Mark A. Socinski, MD: It’s a show stopper.

Roy S. Herbst, MD, PhD: And it’s usually the one easiest to do and comes back first.

Mark A. Socinski, MD: And it’s close to a third of the population depending on where you are.

Roy S. Herbst, MD, PhD: Absolutely.

Naiyer Rizvi, MD: And, again, this is on adenocarcinoma that we’re doing this.
Transcript Edited for Clarity
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