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LIBRETTO-001: Targeting RET Fusions in Advanced-Stage NSCLC

Insights From: Suresh Ramalingam, MD, Winship Cancer Institute of Emory University
Published: Friday, Sep 06, 2019




Transcript: 

Suresh Ramalingam, MD: When we look at some of the other targets in non–small cell lung cancer, where we have been studying targeted therapies but have not had a successful outcome, I would put RET fusion gene abnormalities on the top. RET fusions are seen in about 1% to 2% of non–small cell lung cancers, the lung adenocarcinomas in particular. They’re also seen in other cancers like thyroid malignancies.

Initial studies looked at earlier multikinase inhibitors like cabozantinib, vandetanib in patients with RET fusion-positive disease. These agents had response rates of 30% to 40%. The median progression-free survival was not very impressive, in the order of 4 or 5 months. So there was a clear need for better agents in this space. Now we have seen data with 2 possible options in this space. These are the next generation RET inhibitors that are very specific to the tyrosine kinase of the RET fusion gene.

One of these drugs is LOXO-292, and this is an orally administered agent that is being studied in RET positive non–small cell lung cancer patients. The LIBRETTO-001 trial is one of those trials to evaluate the efficacy of LOXO-292 in not only lung cancer patients who have RET fusion but also in other diseases where RET fusions are seen.

We’ve already seen some data with LOXO-292 in RET fusion-positive lung cancer at the World Conference on Lung Cancer in 2018. A cohort of 40 patients were treated, and the response rates were very promising at about 65%. And the waterfall plot indicated that nearly every patient who got this drug had reduction in size of the tumor.

The safety profile was also very impressive. Most of the toxicities are grade 1, very few grade 2 or 3 toxicities. And even the grade 1 toxicities were in the order of nausea, vomiting, fatigue. Some rare patients had liver enzyme elevation. Overall this appeared to be a very well tolerated agent with a high degree of efficacy. At the upcoming World Conference in less than 2 weeks we’ll see more results from the LIBRETTO-001 trial for patients with non–small cell lung cancer.

What I’m hoping is that the promising efficacy we saw in the first cohort of patients will be confirmed. We already know that LOXO-292 has received the breakthrough designation from the FDA in the United States. And our hope is that these results will lead to the approval of this drug and have it available for use in our patients.

Another drug to watch out for in this space is BLU-667, which is also a RET specific kinase inhibitor that has shown promising activity and has also been given the breakthrough status from the FDA. So, we have some really exciting developments for RET-positive patients in the next few weeks to months.

The whole era of using genomic targets to treat lung cancer really came to fruition around late 2007, 2008 with EGFR being the first target. Then we had ALK inhibition, which was first identified in 2007 and treatments were developed in 2009, and FDA approval came shortly thereafter. Since that time, there has been an array of studies looking at various targets that could be treated with targeted therapies. RET, I would describe as something that is part of the second wave of targets for which we have been studying. So at least for the past 6 or 7 years, we’ve had clinical trials looking at RET inhibitors. But I think in the past 2 years with the emergence of data from LOXO-292 and BLU-667, we see a very promising outlook for these patients.

Transcript Edited for Clarity
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Transcript: 

Suresh Ramalingam, MD: When we look at some of the other targets in non–small cell lung cancer, where we have been studying targeted therapies but have not had a successful outcome, I would put RET fusion gene abnormalities on the top. RET fusions are seen in about 1% to 2% of non–small cell lung cancers, the lung adenocarcinomas in particular. They’re also seen in other cancers like thyroid malignancies.

Initial studies looked at earlier multikinase inhibitors like cabozantinib, vandetanib in patients with RET fusion-positive disease. These agents had response rates of 30% to 40%. The median progression-free survival was not very impressive, in the order of 4 or 5 months. So there was a clear need for better agents in this space. Now we have seen data with 2 possible options in this space. These are the next generation RET inhibitors that are very specific to the tyrosine kinase of the RET fusion gene.

One of these drugs is LOXO-292, and this is an orally administered agent that is being studied in RET positive non–small cell lung cancer patients. The LIBRETTO-001 trial is one of those trials to evaluate the efficacy of LOXO-292 in not only lung cancer patients who have RET fusion but also in other diseases where RET fusions are seen.

We’ve already seen some data with LOXO-292 in RET fusion-positive lung cancer at the World Conference on Lung Cancer in 2018. A cohort of 40 patients were treated, and the response rates were very promising at about 65%. And the waterfall plot indicated that nearly every patient who got this drug had reduction in size of the tumor.

The safety profile was also very impressive. Most of the toxicities are grade 1, very few grade 2 or 3 toxicities. And even the grade 1 toxicities were in the order of nausea, vomiting, fatigue. Some rare patients had liver enzyme elevation. Overall this appeared to be a very well tolerated agent with a high degree of efficacy. At the upcoming World Conference in less than 2 weeks we’ll see more results from the LIBRETTO-001 trial for patients with non–small cell lung cancer.

What I’m hoping is that the promising efficacy we saw in the first cohort of patients will be confirmed. We already know that LOXO-292 has received the breakthrough designation from the FDA in the United States. And our hope is that these results will lead to the approval of this drug and have it available for use in our patients.

Another drug to watch out for in this space is BLU-667, which is also a RET specific kinase inhibitor that has shown promising activity and has also been given the breakthrough status from the FDA. So, we have some really exciting developments for RET-positive patients in the next few weeks to months.

The whole era of using genomic targets to treat lung cancer really came to fruition around late 2007, 2008 with EGFR being the first target. Then we had ALK inhibition, which was first identified in 2007 and treatments were developed in 2009, and FDA approval came shortly thereafter. Since that time, there has been an array of studies looking at various targets that could be treated with targeted therapies. RET, I would describe as something that is part of the second wave of targets for which we have been studying. So at least for the past 6 or 7 years, we’ve had clinical trials looking at RET inhibitors. But I think in the past 2 years with the emergence of data from LOXO-292 and BLU-667, we see a very promising outlook for these patients.

Transcript Edited for Clarity
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