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Treatment of NSCLC With RET Fusions

Panelists: Joshua Bauml, MD, University of Pennsylvania; D. Ross Camidge, MD, University of Colorado School of Medicine; Robert Doebele, MD, PhD, University of Colorado School of Medicine; Benjamin Levy, MD, Johns Hopkins Sidney Kimmel Cancer Center; Zofia Piotrowska, MD, Harvard Medical School
Published: Thursday, Aug 29, 2019



Transcript:

Benjamin Levy, MD: Let’s finish up here with yet another rare genotype, but good drugs that seem to be moving the bar with RET rearrangements. Zofia, do you want to walk us through both LOXO-292 and some of the data we saw today in abstract 9008 with BLU-667.

Zofia Piotrowska, MD: Yes. I think the list of targets is getting long and the list of drugs is getting even longer, but it is really important to find these because, again, another target. RET fusions seem to make up about 2% of lung cancers, and another target with good drugs. RET fusions have been known to have some modest responses to the multikinase inhibitors like cabozantinib and vandetanib. But we know that those come along with a lot of toxicities because of the multikinase activity. I think it’s been really exciting to see similar themes, the development of really specific drugs that target RET and spare some of these other kinases. Both LOXO-292 and BLU-667 have shown really promising activity against RET fusions across a variety of different fusion partners, which has been exciting.

Both have high-level response rates in the roughly 60% range, still relatively small numbers but these numbers are across the board. And importantly we’re seeing CNS [central nervous system] responses for these patients. Not just systemic but brain responses for these patients. And overall I think good safety profiles for both drugs, when we know that when have highly selective drugs, the toxicity profiles are more favorable.

So today in Dr Justin Gainor, MD’s presentation we saw that there were some toxicities, some LFT [liver function test] abnormalities, some constipation, a little bit of hypertension, neutropenia, but overall all mild and manageable, and the rates of dose reductions and discontinuation due to toxicities were very low. I think that what we look to next with these drugs is to start to move these into the first-line setting. Because again, when we see such activity in later lines of therapy, moving them to the frontline is probably going to be best way to deliver the best drugs first.

Benjamin Levy, MD: I look forward to having these drugs approved. This is such a great option for our patients. In the context of what we have for them now, 2 really good drugs, highly active with very few adverse effects, manageable at least adverse effects. We’ve come a long way. Who would have thought 10 years ago we would have all of these targets identified with multiple drugs for each target? I went into lung cancer 12 years ago because it was easy. There were 4 drugs. And much to my chagrin but much to the benefit of patients, we’ve really moved the bar. Many of you have been part of moving that bar. I want to thank you guys for doing that and also thank you for being on this panel with me to discuss this.

This has been a terrific discussion. Before we conclude, however, I’d like to ask each of our panelists for some final parting thoughts regarding today’s discussion. Josh?

Joshua Bauml, MD: I think that it’s really exiting, the world of targeted therapies is expanding as we’ve been discussing. I think it’s really important that every single patient with nonsquamous non–small cell lung cancer certainly, at least, undergoes comprehensive next-generation sequencing to make sure that they have access to these drugs.

Benjamin Levy, MD: Ross?

D. Ross Camidge, MD: I think as we get these drugs we’re starting to realize what level of activity we need to see to make them a first-line option. We’re comparing them to either a chemotherapy standard or we have to figure out whether an appropriate comparator is chemoimmunotherapy, and then we have to ask ourselves the assumptions we’re making that we can translate that general data to that molecular subgroup.

Benjamin Levy, MD: Bob?

Robert Doebele, MD, PhD: I want to reemphasize the testing. This discussion around which drugs to use in which order becomes completely moot if we’re not actually testing all of our patients and giving them the right therapies. We’ve seen really phenomenal progression-free survival and overall survival times for these patients. I think we have to test all of our patients. Then the other exciting thing is that we’re really being able to understand and learn from our patients with biopsies and ctDNA [circulating tumor DNA] how they become resistant, and actually use that to their advantage in terms of developing new strategies that we can sequence.

Benjamin Levy, MD: Zofia, you drew the short straw, you go last.

Zofia Piotrowska, MD: I would say that maybe a word of caution about acting on PD-L1 [programmed death-ligand 1] before; again, going back to the testing, but before the molecular testing comes back. And I think that we have a lot more to learn about the optimal way to sequence immunotherapy and TKIs [tyrosine kinase inhibitors], particularly for the patients with the onco-driven cancers. But I think the early signals are that using immunotherapy first can have ramifications for later lines of therapy. I think caution in jumping to immunotherapy before all the information is in hand.

Benjamin Levy, MD: Great. On behalf of our panel we thank you for joining us and hope you found this OncLive Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity

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Transcript:

Benjamin Levy, MD: Let’s finish up here with yet another rare genotype, but good drugs that seem to be moving the bar with RET rearrangements. Zofia, do you want to walk us through both LOXO-292 and some of the data we saw today in abstract 9008 with BLU-667.

Zofia Piotrowska, MD: Yes. I think the list of targets is getting long and the list of drugs is getting even longer, but it is really important to find these because, again, another target. RET fusions seem to make up about 2% of lung cancers, and another target with good drugs. RET fusions have been known to have some modest responses to the multikinase inhibitors like cabozantinib and vandetanib. But we know that those come along with a lot of toxicities because of the multikinase activity. I think it’s been really exciting to see similar themes, the development of really specific drugs that target RET and spare some of these other kinases. Both LOXO-292 and BLU-667 have shown really promising activity against RET fusions across a variety of different fusion partners, which has been exciting.

Both have high-level response rates in the roughly 60% range, still relatively small numbers but these numbers are across the board. And importantly we’re seeing CNS [central nervous system] responses for these patients. Not just systemic but brain responses for these patients. And overall I think good safety profiles for both drugs, when we know that when have highly selective drugs, the toxicity profiles are more favorable.

So today in Dr Justin Gainor, MD’s presentation we saw that there were some toxicities, some LFT [liver function test] abnormalities, some constipation, a little bit of hypertension, neutropenia, but overall all mild and manageable, and the rates of dose reductions and discontinuation due to toxicities were very low. I think that what we look to next with these drugs is to start to move these into the first-line setting. Because again, when we see such activity in later lines of therapy, moving them to the frontline is probably going to be best way to deliver the best drugs first.

Benjamin Levy, MD: I look forward to having these drugs approved. This is such a great option for our patients. In the context of what we have for them now, 2 really good drugs, highly active with very few adverse effects, manageable at least adverse effects. We’ve come a long way. Who would have thought 10 years ago we would have all of these targets identified with multiple drugs for each target? I went into lung cancer 12 years ago because it was easy. There were 4 drugs. And much to my chagrin but much to the benefit of patients, we’ve really moved the bar. Many of you have been part of moving that bar. I want to thank you guys for doing that and also thank you for being on this panel with me to discuss this.

This has been a terrific discussion. Before we conclude, however, I’d like to ask each of our panelists for some final parting thoughts regarding today’s discussion. Josh?

Joshua Bauml, MD: I think that it’s really exiting, the world of targeted therapies is expanding as we’ve been discussing. I think it’s really important that every single patient with nonsquamous non–small cell lung cancer certainly, at least, undergoes comprehensive next-generation sequencing to make sure that they have access to these drugs.

Benjamin Levy, MD: Ross?

D. Ross Camidge, MD: I think as we get these drugs we’re starting to realize what level of activity we need to see to make them a first-line option. We’re comparing them to either a chemotherapy standard or we have to figure out whether an appropriate comparator is chemoimmunotherapy, and then we have to ask ourselves the assumptions we’re making that we can translate that general data to that molecular subgroup.

Benjamin Levy, MD: Bob?

Robert Doebele, MD, PhD: I want to reemphasize the testing. This discussion around which drugs to use in which order becomes completely moot if we’re not actually testing all of our patients and giving them the right therapies. We’ve seen really phenomenal progression-free survival and overall survival times for these patients. I think we have to test all of our patients. Then the other exciting thing is that we’re really being able to understand and learn from our patients with biopsies and ctDNA [circulating tumor DNA] how they become resistant, and actually use that to their advantage in terms of developing new strategies that we can sequence.

Benjamin Levy, MD: Zofia, you drew the short straw, you go last.

Zofia Piotrowska, MD: I would say that maybe a word of caution about acting on PD-L1 [programmed death-ligand 1] before; again, going back to the testing, but before the molecular testing comes back. And I think that we have a lot more to learn about the optimal way to sequence immunotherapy and TKIs [tyrosine kinase inhibitors], particularly for the patients with the onco-driven cancers. But I think the early signals are that using immunotherapy first can have ramifications for later lines of therapy. I think caution in jumping to immunotherapy before all the information is in hand.

Benjamin Levy, MD: Great. On behalf of our panel we thank you for joining us and hope you found this OncLive Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity
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