ONCAlert | Upfront Therapy for mRCC

Entrectinib-A Multitargeted TKI

Targeted Oncology
Published Online:12:00 PM, Wed August 7, 2019

Marcia Brose, MD, PhD: You mentioned entrectinib. Can you tell us a little now about the difference between larotrectinib and entrectinib in the mechanism of action in the design of that drug?

David Hong, MD: Entrectinib is a much less specific inhibitor of NTRK. It also targets ALK/ROS. The initial data sets suggest really significant activity in ROS patients. Investigators do not have a whole lot of NTRK data to compare apples to apples to larotrectinib. I think in the last ESMO meeting [European Society of Medical Oncology Congress 2018], they did report a larger data set of close to 50 some patients with NTRK from the STARTRK studies. The overall response rates were somewhat lower than larotrectinib, I think in the 50% to 60% range. The median progression-free survival in that data set was approximately 10 months. Now, why is there such a difference? It’s not clear right now whether it’s just the patient population that they chose. They definitely had much more CNS [central nervous system]–metastases population, given the fact that 1 of the selling features of entrectinib was that it could also cross the blood-brain barrier and they were trying to enrich for CNS metastases. I think it’s hard right now to compare entrectinib with larotrectinib. I get that question all the time. Which one is a better drug? I’m biased because I was 1 of the PIs [principal investigators] for the larotrectinib trials. But right now I think it’s hard to compare the 2.

Marcia Brose, MD, PhD: I’m just going to try to break down some of this to make sure I get it all because I’m not always sure. What are exactly the targets for entrectinib, and does it target all the NTRK fusions?

David Hong, MD: Yes, it targets all the NTRK fusions: TRK 1, 2, and 3. It also targets ALK and ROS. The more robust data set has been really in the ROS phenotype, so they’ve got a lot more patients on that subset, I think.

Marcia Brose, MD, PhD: I know you said you weren’t an investigator in it, but can you talk about the design of their trials? You mentioned a little bit that they were enriching for CNS, but could you actually just tell us exactly what the trials were and how they were set up?

David Hong, MD: I don’t know the answer to that question. It’s similar to the basket study. The STARTRK trials were, I think, very similar to the Basket trials that we did with NAVIGATE.

Marcia Brose, MD, PhD: So they allowed for multiple different tumor types.

David Hong, MD: Yes, as long as they had NTRK or ROS.

Marcia Brose, MD, PhD: Do you know what kind of responses were seen in the phase I? You were mentioning the overall response was about, I think you said 50% to 60%. Do you know anything about the duration of response or other adverse effects, perhaps?

David Hong, MD: The duration of response, with the most recent data set, median progression-free survival was around 10 to 11 months.

Corey Langer, MD: At this year’s ASCO [American Society of Clinical Oncology Annual] Meeting, Robert Doebele, MD, PhD, from the University of Colorado School of Medicine, has actually done an analysis comparing outcome for entrectinib and crizotinib. Entrectinib is also an NTRK inhibitor, but actually the bulk of data for NTRK has been in ROS1 and ALK. The nice thing about entrectinib is it hits all. It targets ALK, it targets ROS1, and it targets the 3 major variants of NTRK: NTRK 1, 2, and 3.

The drug that we typically use in ALK—alectinib—has no activity in ROS1 and essentially no activity in NTRK. As time goes on, we’re going to need to be more cognizant of the various differences between the tyrosine kinase inhibitors and where the bulk of activity exists. Dr Doebele compared entrectinib in 53 patients with crizotinib and 69 patients in the ROS1 role. This is a bit off topic for NTRK but still generally on topic in this whole realm of targeted therapy and therapies that specifically target gene rearrangements.

You used unique end points. Instead of time-to-tumor progression and time-to-treatment failure, time-to-treatment discontinuation accounts not just for progression but also for folks who may have had smoldering disease, smoldering progression, but were still having a clinical benefit. It’s sort of a real-world endpoint. It’s not the typical endpoint that is used in most clinical trials, but actually has direct application to the world that we actually treat patients in.

And the data are quite impressive. Entrectinib in this group had median time-to-treatment discontinuation of about 14.6 months, compared with about 8.8 months for crizotinib. Survival appears to be better with the second- or third-generation ROS1 inhibitor.

As of 2019’s ASCO, only larotrectinib is approved. We anticipate an approval for entrectinib probably sometime in the end of the second, more likely third quarter, of 2019. It’s hard to read the tea leaves on such approvals. But assuming it does get an approval, entrectinib will be the second NTRK inhibitor that’s commercially available, and now 1 among several agents that will also target ROS1 and ALK.

There are some minor differences in toxicity between larotrectinib and entrectinib. Entrectinib does seem to cause some anemia. Both can cause fluid retention and weight gain, but entrectinib seems to be a bit more pronounced. There is some neuropathy—peripheral paresthesia, peripheral sensory neuropathy—associated with entrectinib. The total incidence is about 13% to 14%, and maybe about 4% or so is grade 3, which is clearly manageable but a bit more pronounced. How these stack up against other agents or other upcoming agents remains to be seen. But I think, for the most part, these patients can be readily managed with the tools that we have currently for adverse effects.

Transcript edited for clarity.

Marcia Brose, MD, PhD: You mentioned entrectinib. Can you tell us a little now about the difference between larotrectinib and entrectinib in the mechanism of action in the design of that drug?

David Hong, MD: Entrectinib is a much less specific inhibitor of NTRK. It also targets ALK/ROS. The initial data sets suggest really significant activity in ROS patients. Investigators do not have a whole lot of NTRK data to compare apples to apples to larotrectinib. I think in the last ESMO meeting [European Society of Medical Oncology Congress 2018], they did report a larger data set of close to 50 some patients with NTRK from the STARTRK studies. The overall response rates were somewhat lower than larotrectinib, I think in the 50% to 60% range. The median progression-free survival in that data set was approximately 10 months. Now, why is there such a difference? It’s not clear right now whether it’s just the patient population that they chose. They definitely had much more CNS [central nervous system]–metastases population, given the fact that 1 of the selling features of entrectinib was that it could also cross the blood-brain barrier and they were trying to enrich for CNS metastases. I think it’s hard right now to compare entrectinib with larotrectinib. I get that question all the time. Which one is a better drug? I’m biased because I was 1 of the PIs [principal investigators] for the larotrectinib trials. But right now I think it’s hard to compare the 2.

Marcia Brose, MD, PhD: I’m just going to try to break down some of this to make sure I get it all because I’m not always sure. What are exactly the targets for entrectinib, and does it target all the NTRK fusions?

David Hong, MD: Yes, it targets all the NTRK fusions: TRK 1, 2, and 3. It also targets ALK and ROS. The more robust data set has been really in the ROS phenotype, so they’ve got a lot more patients on that subset, I think.

Marcia Brose, MD, PhD: I know you said you weren’t an investigator in it, but can you talk about the design of their trials? You mentioned a little bit that they were enriching for CNS, but could you actually just tell us exactly what the trials were and how they were set up?

David Hong, MD: I don’t know the answer to that question. It’s similar to the basket study. The STARTRK trials were, I think, very similar to the Basket trials that we did with NAVIGATE.

Marcia Brose, MD, PhD: So they allowed for multiple different tumor types.

David Hong, MD: Yes, as long as they had NTRK or ROS.

Marcia Brose, MD, PhD: Do you know what kind of responses were seen in the phase I? You were mentioning the overall response was about, I think you said 50% to 60%. Do you know anything about the duration of response or other adverse effects, perhaps?

David Hong, MD: The duration of response, with the most recent data set, median progression-free survival was around 10 to 11 months.

Corey Langer, MD: At this year’s ASCO [American Society of Clinical Oncology Annual] Meeting, Robert Doebele, MD, PhD, from the University of Colorado School of Medicine, has actually done an analysis comparing outcome for entrectinib and crizotinib. Entrectinib is also an NTRK inhibitor, but actually the bulk of data for NTRK has been in ROS1 and ALK. The nice thing about entrectinib is it hits all. It targets ALK, it targets ROS1, and it targets the 3 major variants of NTRK: NTRK 1, 2, and 3.

The drug that we typically use in ALK—alectinib—has no activity in ROS1 and essentially no activity in NTRK. As time goes on, we’re going to need to be more cognizant of the various differences between the tyrosine kinase inhibitors and where the bulk of activity exists. Dr Doebele compared entrectinib in 53 patients with crizotinib and 69 patients in the ROS1 role. This is a bit off topic for NTRK but still generally on topic in this whole realm of targeted therapy and therapies that specifically target gene rearrangements.

You used unique end points. Instead of time-to-tumor progression and time-to-treatment failure, time-to-treatment discontinuation accounts not just for progression but also for folks who may have had smoldering disease, smoldering progression, but were still having a clinical benefit. It’s sort of a real-world endpoint. It’s not the typical endpoint that is used in most clinical trials, but actually has direct application to the world that we actually treat patients in.

And the data are quite impressive. Entrectinib in this group had median time-to-treatment discontinuation of about 14.6 months, compared with about 8.8 months for crizotinib. Survival appears to be better with the second- or third-generation ROS1 inhibitor.

As of 2019’s ASCO, only larotrectinib is approved. We anticipate an approval for entrectinib probably sometime in the end of the second, more likely third quarter, of 2019. It’s hard to read the tea leaves on such approvals. But assuming it does get an approval, entrectinib will be the second NTRK inhibitor that’s commercially available, and now 1 among several agents that will also target ROS1 and ALK.

There are some minor differences in toxicity between larotrectinib and entrectinib. Entrectinib does seem to cause some anemia. Both can cause fluid retention and weight gain, but entrectinib seems to be a bit more pronounced. There is some neuropathy—peripheral paresthesia, peripheral sensory neuropathy—associated with entrectinib. The total incidence is about 13% to 14%, and maybe about 4% or so is grade 3, which is clearly manageable but a bit more pronounced. How these stack up against other agents or other upcoming agents remains to be seen. But I think, for the most part, these patients can be readily managed with the tools that we have currently for adverse effects.

Transcript edited for clarity.
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