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Advances in RET Inhibition in NSCLC

Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Maximilian Hochmair, MD, Otto Wagner Spital; Suresh Senan, MRCP, FRCR, PhD, VU University Medical Center; Leora Horn, MD, MSc, FRCPC, Vanderbilt University Medical Center; Thomas E. Stinchcombe, MD, Duke University Health System
Published: Tuesday, Nov 20, 2018



Transcript:

Benjamin P. Levy, MD:
Let’s discuss the last mutation, RET fusions, and some of the wonderful data vis-à-vis that was discussed at ASCO [American Society of Clinical Oncology] this year. Lyudmila, do you want to talk about that data, the role of testing RET fusion, and LOXO-292?

Lyudmila A. Bazhenova, MD: RET fusions can be found in lung cancer. It’s probably going to be below BRAF [kinase B-Raf], above NTRK [tropomyosin receptor kinase], and at the level of MET [skipping mutation]. It’s in about 1% to 2% of patients with lung cancer.
In lung cancer, the majority of RET oncogenic drivers of fusion, contrary to thyroid cancer, were mostly point mutations. The most common fusion in RET, regarding lung cancer, is KIF5B [kinesin family member 5B]. We have tried targeting RET in lung cancer for quite some time using a multitargeted, so-called “dirty RET inhibitor,” and the efficacy of those compounds was okay: about 18% to 20% if you consider various documents.

Maybe the reason why we are not seeing better RET activity in those patients is because we can’t elevate the dose because we are inhibiting either kinases such as VEGF [vascular endothelial growth factor] and c-KIT [tyrosine-protein kinase] that lead to increased toxicity.
When LOXO-292 was developed, it was designed specifically for RET kinase inhibitors, which means it does not inhibit anything else. The first time the data on LOXO-292 [were] presented at ASCO by Dr. Alexander Drilon, it produced the best waterfall plot I’ve ever seen.

Benjamin P. Levy, MD: Lots of water.

Lyudmila A. Bazhenova, MD:
It’s all water. There is nothing above the 0 line, so every single patient had a decrease of a disease in a tumor. The response rate presented at ASCO was about 70% to 75%; they specifically singled the non–small cell lung cancer [NSCLC] patients, and the response rate in that population was 77%. Responses were durable: The median duration of response [had] not been reached at the time of [the] ASCO presentation, and some responses were not confirmed at the time of ASCO presentations.
Here at World Lung [IASLC], there’s going to be a presentation specifically on non–small cell lung cancer patients treated with LOXO-292, and it basically looks as good as it looked in ASCO 2018.


Transcript Edited for Clarity

 

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Transcript:

Benjamin P. Levy, MD:
Let’s discuss the last mutation, RET fusions, and some of the wonderful data vis-à-vis that was discussed at ASCO [American Society of Clinical Oncology] this year. Lyudmila, do you want to talk about that data, the role of testing RET fusion, and LOXO-292?

Lyudmila A. Bazhenova, MD: RET fusions can be found in lung cancer. It’s probably going to be below BRAF [kinase B-Raf], above NTRK [tropomyosin receptor kinase], and at the level of MET [skipping mutation]. It’s in about 1% to 2% of patients with lung cancer.
In lung cancer, the majority of RET oncogenic drivers of fusion, contrary to thyroid cancer, were mostly point mutations. The most common fusion in RET, regarding lung cancer, is KIF5B [kinesin family member 5B]. We have tried targeting RET in lung cancer for quite some time using a multitargeted, so-called “dirty RET inhibitor,” and the efficacy of those compounds was okay: about 18% to 20% if you consider various documents.

Maybe the reason why we are not seeing better RET activity in those patients is because we can’t elevate the dose because we are inhibiting either kinases such as VEGF [vascular endothelial growth factor] and c-KIT [tyrosine-protein kinase] that lead to increased toxicity.
When LOXO-292 was developed, it was designed specifically for RET kinase inhibitors, which means it does not inhibit anything else. The first time the data on LOXO-292 [were] presented at ASCO by Dr. Alexander Drilon, it produced the best waterfall plot I’ve ever seen.

Benjamin P. Levy, MD: Lots of water.

Lyudmila A. Bazhenova, MD:
It’s all water. There is nothing above the 0 line, so every single patient had a decrease of a disease in a tumor. The response rate presented at ASCO was about 70% to 75%; they specifically singled the non–small cell lung cancer [NSCLC] patients, and the response rate in that population was 77%. Responses were durable: The median duration of response [had] not been reached at the time of [the] ASCO presentation, and some responses were not confirmed at the time of ASCO presentations.
Here at World Lung [IASLC], there’s going to be a presentation specifically on non–small cell lung cancer patients treated with LOXO-292, and it basically looks as good as it looked in ASCO 2018.


Transcript Edited for Clarity

 
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