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LIBRETTO-001 Regimen Overview

Insights From: Jacob Sands, MD, Dana-Farber Cancer Institute; Benjamin Besse, MD, PhD, Institut d'Oncologie Thoracique; Alexander Drilon, MD, Memorial Sloan Kettering Center; Marcia Brose, MD, PhD, Perelman School of Medicine
Published: Wednesday, Nov 20, 2019


Transcript:

Alexander Drilon, MD:
We’ve tried to develop effective targeted therapies for RET-dependent cancers for several years. However, these older agents, such as cabozantinib and vandetanib, are what we call multikinase inhibitors, or “dirtier drugs,” which hit many different targets apart from RET. In contrast, selpercatinib is a selective RET inhibitor that very meaningfully hits RET but avoids these other targets that can result in adverse effects in patients.

This selective RET inhibitor is currently in a phase I/II registrational trial, called LIBRETTO-001, that’s designed to identify the activity and elucidate the safety of the drug across different cancers with dependency on RET, including RET-fusion-positive lung cancers, RET-fusion-positive papillary thyroid cancers, and RET-mutant medullary thyroid cancers.

There is a large safety data set for selpercatinib that exceeds 530 patients, and the drug is very well tolerated. Most of the adverse effects were grade 1 and 2 and manageable, and these included diarrhea, hypertension, and LFT [liver function test] abnormalities. I think the best integrated measure of how safe the drug is, is the treatment discontinuation rate, which was less than 2% for any drug-related toxicity, making this drug very amendable to long-term dosing.

In terms of activity in RET-fusion-positive lung cancers, we recently presented the registrational data set for the primary analysis set of RET-fusion-positive lung cancers that previously had a platinum doublet. In those patients the objective response rate was 68%.

We also looked at patients who were treatment-naïve, probably a situation where we more want to use this drug compared with patients who had chemotherapy before, and the objective response rate was 85%. So very impressive results.

The median duration of response with selpercatinib was in excess of 20 months, and the median progression-free survival was in excess of 18 months. And this really highlights that we can achieve very durable disease control in patients who have RET-fusion-positive lung cancers.

Jacob Sands, MD: We now have data from more selective RET inhibitors. So namely BLU-667 and LOXO-292, now called selpercatinib. These are highly selective drugs for RET, which really minimizes the toxicity profile, and we’re seeing that in the results of the trials that have been presented. By being highly selective as well, we’re also seeing greater efficacy in these drugs and with more durable responses to these therapies. This is really a significant advance compared with their prior multikinase inhibitors, which, as I mentioned, have really hit multiple targets, and therefore we end up seeing higher toxicity on those drugs.

Marcia Brose, MD, PhD: The RET inhibitors that are currently in development are different from the current kinase inhibitors because, while they all target RET, they target RET to a different degree, and more importantly, they lack targeting of additional kinases. In the beginning we used to think that it was good if people had VEGF receptor inhibition because it could give them 2 targets—both the RET and the VEGF receptor inhibitor action. What we know now is that they don’t target RET as well. So the benefit of the new agents is that they really specifically target the mutation that’s in the cancer cell without causing a lot of toxicity, which comes from the nonspecific targeting of other pathways. And that’s really the game changer in the 2 agents that I’m aware of that are currently in development.

When we started to actually target RET directly, our efficacy went way up. So we were actually getting responses in 70%, 80%, 90% of patients. This is almost double what we had seen previously in other kinase inhibitors. Similarly, when you look at grade 3 toxicity for instance, with the RET inhibitors, we see it almost never. Whereas with the other inhibitors we see it quite frequently—not to say that those agents aren’t manageable and that we can’t, you know, make this a tolerable agent. And certainly compared with nothing, these were game changers in their time. But the ability to get double the results with such a low-toxicity profile, primarily mostly a few grade 1s, a few grade 2s, and almost never a grade 3. That really is a whole new level as far as a good toxicity profile and really is a benefit to those patients.


Transcript Edited for Clarity
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Transcript:

Alexander Drilon, MD:
We’ve tried to develop effective targeted therapies for RET-dependent cancers for several years. However, these older agents, such as cabozantinib and vandetanib, are what we call multikinase inhibitors, or “dirtier drugs,” which hit many different targets apart from RET. In contrast, selpercatinib is a selective RET inhibitor that very meaningfully hits RET but avoids these other targets that can result in adverse effects in patients.

This selective RET inhibitor is currently in a phase I/II registrational trial, called LIBRETTO-001, that’s designed to identify the activity and elucidate the safety of the drug across different cancers with dependency on RET, including RET-fusion-positive lung cancers, RET-fusion-positive papillary thyroid cancers, and RET-mutant medullary thyroid cancers.

There is a large safety data set for selpercatinib that exceeds 530 patients, and the drug is very well tolerated. Most of the adverse effects were grade 1 and 2 and manageable, and these included diarrhea, hypertension, and LFT [liver function test] abnormalities. I think the best integrated measure of how safe the drug is, is the treatment discontinuation rate, which was less than 2% for any drug-related toxicity, making this drug very amendable to long-term dosing.

In terms of activity in RET-fusion-positive lung cancers, we recently presented the registrational data set for the primary analysis set of RET-fusion-positive lung cancers that previously had a platinum doublet. In those patients the objective response rate was 68%.

We also looked at patients who were treatment-naïve, probably a situation where we more want to use this drug compared with patients who had chemotherapy before, and the objective response rate was 85%. So very impressive results.

The median duration of response with selpercatinib was in excess of 20 months, and the median progression-free survival was in excess of 18 months. And this really highlights that we can achieve very durable disease control in patients who have RET-fusion-positive lung cancers.

Jacob Sands, MD: We now have data from more selective RET inhibitors. So namely BLU-667 and LOXO-292, now called selpercatinib. These are highly selective drugs for RET, which really minimizes the toxicity profile, and we’re seeing that in the results of the trials that have been presented. By being highly selective as well, we’re also seeing greater efficacy in these drugs and with more durable responses to these therapies. This is really a significant advance compared with their prior multikinase inhibitors, which, as I mentioned, have really hit multiple targets, and therefore we end up seeing higher toxicity on those drugs.

Marcia Brose, MD, PhD: The RET inhibitors that are currently in development are different from the current kinase inhibitors because, while they all target RET, they target RET to a different degree, and more importantly, they lack targeting of additional kinases. In the beginning we used to think that it was good if people had VEGF receptor inhibition because it could give them 2 targets—both the RET and the VEGF receptor inhibitor action. What we know now is that they don’t target RET as well. So the benefit of the new agents is that they really specifically target the mutation that’s in the cancer cell without causing a lot of toxicity, which comes from the nonspecific targeting of other pathways. And that’s really the game changer in the 2 agents that I’m aware of that are currently in development.

When we started to actually target RET directly, our efficacy went way up. So we were actually getting responses in 70%, 80%, 90% of patients. This is almost double what we had seen previously in other kinase inhibitors. Similarly, when you look at grade 3 toxicity for instance, with the RET inhibitors, we see it almost never. Whereas with the other inhibitors we see it quite frequently—not to say that those agents aren’t manageable and that we can’t, you know, make this a tolerable agent. And certainly compared with nothing, these were game changers in their time. But the ability to get double the results with such a low-toxicity profile, primarily mostly a few grade 1s, a few grade 2s, and almost never a grade 3. That really is a whole new level as far as a good toxicity profile and really is a benefit to those patients.


Transcript Edited for Clarity
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