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Considering Available Data for Entrectinib

Insights From: David S. Hong, MD, MD Anderson Cancer Center; David Hyman, MD, Memorial Sloan Kettering Cancer Center
Published: Tuesday, Aug 13, 2019



Transcript: 

David Hyman, MD: One of the differences between entrectinib and larotrectinib is the fact that entrectinib is not a purely selective TRK inhibitor but in addition, it inhibits at least 2 other kinases, ALK [anaplastic lymphoma kinase] and ROS1. And that’s responsible for its activity in ROS1 fusion patients but may also result in a slightly different profile of the 2 drugs.

One of the major differences in the entrectinib and larotrectinib development programs has been the inclusion of young children in a larotrectinib development program, who have not been included in the entrectinib program until much more recently. And those data haven’t been shared in a public fashion. So the data that we have in the public domain for entrectinib is primarily from older adolescents and adults.

One of the other differences in the entrectinib program is that it does appear that a much higher rate of patients came into this study with brain metastasis at baseline. That’s something that we really didn’t see in the larotrectinib development program. Although both programs allowed patients with brain metastasis to enroll, there does appear to be a higher rate of that in the entrectinib program.

So accounting for those differences in the 2 study populations, the entrectinib response rate that was reported does appear to be numerically somewhat lower than the larotrectinib response rate. Although certainly these cross-study comparisons have to be done with caution. And the relatively small numbers of patients, especially in the entrectinib program, mean that the confidence intervals around those  response rate point estimates need to be interpreted with caution. Again, there were some differences in the patient population. The other notable feature from an efficacy standpoint in the entrectinib study was that for the duration of response, the amount of time that the responders spent on therapy, the median was under 1 year.

By comparison, in the larotrectinib program, in the most recent data update, at a median follow-up of 18 months, the median duration of response had not yet been reached. We don’t know what the median ultimately will be in the duration of response with larotrectinib, and we don’t know exactly what drives the difference of the duration of response that’s been reported in these clinical trials, whether it has something to do with the drug itself or whether it has to do with the study populations. But we can at least observe those differences and that may be something that is a consideration at the bedside.

David S. Hong, MD: Dr Alex Drilon, who’s a friend of mine, has really been at the forefront of trying to understand how both larotrectinib and entrectinib affect brain metastases. His oral presentation at this ASCO [the American Society of Clinical Oncology annual meeting] showed that larotrectinib in patients with brain metastasis had significant efficacy, approximately 60% response rate. The entrectinib data, which are more mature in the sense that they have more patients—he was also a significant senior author on that abstract—showed approximately 55% response rate, probably equivalent brain penetration.

What was interesting about the larotrectinib data was that in central nervous system GBM [glioblastoma multiforme], the response rates are lower, around 35%, which contrasts with pediatric central nervous diseases such as pontine gliomas, etcetera, which invariably respond. Almost every one of those patients respond. I think what this tells us is that we just don’t have enough mature data to really understand the response rates in adult gliomas or GBM CNS [central nervous system] disease relative to pediatric disease, where there truly is some difference. But we’ll see. We’ll see as the data mature and more patients are enrolled.

Transcript Edited for Clarity
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Transcript: 

David Hyman, MD: One of the differences between entrectinib and larotrectinib is the fact that entrectinib is not a purely selective TRK inhibitor but in addition, it inhibits at least 2 other kinases, ALK [anaplastic lymphoma kinase] and ROS1. And that’s responsible for its activity in ROS1 fusion patients but may also result in a slightly different profile of the 2 drugs.

One of the major differences in the entrectinib and larotrectinib development programs has been the inclusion of young children in a larotrectinib development program, who have not been included in the entrectinib program until much more recently. And those data haven’t been shared in a public fashion. So the data that we have in the public domain for entrectinib is primarily from older adolescents and adults.

One of the other differences in the entrectinib program is that it does appear that a much higher rate of patients came into this study with brain metastasis at baseline. That’s something that we really didn’t see in the larotrectinib development program. Although both programs allowed patients with brain metastasis to enroll, there does appear to be a higher rate of that in the entrectinib program.

So accounting for those differences in the 2 study populations, the entrectinib response rate that was reported does appear to be numerically somewhat lower than the larotrectinib response rate. Although certainly these cross-study comparisons have to be done with caution. And the relatively small numbers of patients, especially in the entrectinib program, mean that the confidence intervals around those  response rate point estimates need to be interpreted with caution. Again, there were some differences in the patient population. The other notable feature from an efficacy standpoint in the entrectinib study was that for the duration of response, the amount of time that the responders spent on therapy, the median was under 1 year.

By comparison, in the larotrectinib program, in the most recent data update, at a median follow-up of 18 months, the median duration of response had not yet been reached. We don’t know what the median ultimately will be in the duration of response with larotrectinib, and we don’t know exactly what drives the difference of the duration of response that’s been reported in these clinical trials, whether it has something to do with the drug itself or whether it has to do with the study populations. But we can at least observe those differences and that may be something that is a consideration at the bedside.

David S. Hong, MD: Dr Alex Drilon, who’s a friend of mine, has really been at the forefront of trying to understand how both larotrectinib and entrectinib affect brain metastases. His oral presentation at this ASCO [the American Society of Clinical Oncology annual meeting] showed that larotrectinib in patients with brain metastasis had significant efficacy, approximately 60% response rate. The entrectinib data, which are more mature in the sense that they have more patients—he was also a significant senior author on that abstract—showed approximately 55% response rate, probably equivalent brain penetration.

What was interesting about the larotrectinib data was that in central nervous system GBM [glioblastoma multiforme], the response rates are lower, around 35%, which contrasts with pediatric central nervous diseases such as pontine gliomas, etcetera, which invariably respond. Almost every one of those patients respond. I think what this tells us is that we just don’t have enough mature data to really understand the response rates in adult gliomas or GBM CNS [central nervous system] disease relative to pediatric disease, where there truly is some difference. But we’ll see. We’ll see as the data mature and more patients are enrolled.

Transcript Edited for Clarity
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