ONCAlert | Upfront Therapy for mRCC

Investigational Approaches for TRK-Fusion Cancers

Targeted Oncology
Published Online:12:00 PM, Wed August 14, 2019

Marcia Brose, MD, PhD: Talk to us a little about other TRK fusion approaches to cancers, maybe a little bit about LOXO-195 and TPX-0005.

Corey Langer, MD: Larotrectinib and entrectinib are not the only agents that are targeting NTRK. There are a number of additional agents that are being developed. LOXO-195 is 1 example. This was just reported at the AACR [American Association for Cancer Research Annual Meeting] in March and April of 2019, and this too works on TRK fusions. Response rates in those with an established TRK abnormality is close to 50%, 9 patients of 20—again, a variety of different cancers. My initial read on the toxicity is that it may be somewhat harder to deal with—nausea and vomiting, myalgias, abdominal pain in addition to fatigue, edema, and constipation. That always is tough when we’re dealing with an oral agent and it needs to be given continuously on a daily basis.

It’s unclear how well these newer agents were bound to work in patients with previous exposure to entrectinib or larotrectinib, at least for LOXO-195. That’s not the case with repotrectinib, another new agent. Again, something with dirty kinase, works on multiple different targets. Response rates to date are 80%, quite a bit higher, 66% in those with prior exposure to other TKIs [tyrosine kinase inhibitors], including crizotinib. It works on ROS1 and specifically works on the resistance mutation G2032R, which is probably 1 of the main mechanisms of resistance in ROS1.

Then there are a number of other agents that have actually been used in other malignancies like midostaurin, FLT3 in acute leukemia, and regorafenib in colorectal cancer, bladder cancer starting out as an angiogenesis inhibitor. These 2 appear to have some activity on TRK, but it’s completely unclear so far just how active they will prove in this patient population. We’re really just awaiting the phase I and phase II data.

A new era has dawned. When I started out as a medical oncologist in the late ’80s—over 30 years ago—I couldn’t have dreamed that we would have targeted therapy of this sort. Now for the first time, we’ve witnessed the marker-specific approval of a new agent, larotrectinib, that’s histology- and tumor-agnostic and clearly is pointing a wave to the future—the way I think we’re going to practice increasingly.

There are a number of trials that are ongoing that are actually addressing this. The MATCH Trial through the Eastern Cooperative Oncology Group and jointly with the other cooperative groups is looking explicitly at marker-specific therapy, establishing the role of various agents in a particular tumor marker, and allowing individuals with relatively rare malignancies or different malignancies to enroll in a single study that essentially examines 15, 18, or 20 different markers and 15 to 20 different agents. No single institution could ever mount studies of this sort—the patients are just too rare.

If you do it in the context of the MATCH trial, that looks at multiple different markers and then matches the patient with the appropriate markers for the appropriate targeted therapy. It makes sense, and it’s really a brilliant academic, community, industry, and federal partnership that’s come through that can address the needs of many of our cancer patients for whom standard therapy, at least traditionally, does not exist.

Larotrectinib is approved. I anticipate entrectinib’s approval sometime in the summer of 2019. Then there are other agents, such as repotrectinib and LOXO195, that will probably be approved in the next year or 2 based on their activity, both of which have shown responses in individuals who’ve had prior NTRK inhibitor exposure. There may be a role for other agents that are already established in other malignancies such as regorafenib and midostaurin.

David Hong, MD: As with all small-molecule inhibitors, we do expect that there will be resistance. As the experience to date has shown, these patients stay on for an awfully long time. Some of them do develop resistance, and when we see these patients, we’ve shown that these patients develop what are called solvent front mutations at the site of the ATP [adenosine triphosphate] pocket. They also develop what are called gatekeeper mutations. There are other alterations and other mutations that are less common, and we do think that there may be kind of alternative pathway signaling processes that may be leaning to resistance, but the most common mechanism of resistance is solvent front.

Marcia Brose, MD, PhD: My understanding is these were expected at the time of the design.

David Hong, MD: Yes. We were expecting this, and kind of another first in this approval was that we began the phase I even before we got the approval for larotrectinib.

Marcia Brose, MD, PhD: The phase I of which drug?

David Hong, MD: Of LOXO-195, and we began enrolling patients who were becoming resistant. In fact, Alex Drilon, MD, and the MSK [Memorial Sloan Kettering Cancer Center] group actually published a small case series of patients who developed mechanisms of resistance—and were able to, through kind of a compassion, put those on before we even started the phase I to actually see responses in these patients.

Marcia Brose, MD, PhD: Were those resistant mutations just for the LOXO-195 study, just coming from the larotrectinib trials or were they also coming from the entrectinib?

David Hong, MD: No, they were also from patients who received entrectinib. I can’t share with you all the data, but David Hyman, MD, did present some of the preliminary data that we have at the AACR, showing significant responses in a number of these different subsets of tumors.

Marcia Brose, MD, PhD: I have a question for you. When you have these resistance mutations and you have a patient who has it, are you seeing progression of multiple sites, or is it usually just 1 site that starts to grow while the others are still responding? Just so that people who are starting to get this drug know what they’re looking for.

David Hong, MD: That’s a really good question. In my experience, Dr Hyman has probably put the most number of patients on the resistant population. My experience—it’s variable. There are patients who seem to be just progressing everywhere, and then there are patients we are following who have the target lesions, and overall they progress by RECIST [response evaluation criteria in solid tumors]. When we rebiopsy those lesions that seem to be progressing they had the cell from, there were other diseases.

Marcia Brose, MD, PhD: That’s really interesting because many times in other kinase inhibitors, many for us, when we get resistance, many times everything is responding and there’s just 1 area that seems to have figured it out.

David Hong, MD: Again, I think it’s variable and we haven’t looked at the full data set. In my experience, a handful of patients had just 1 area of progression because of how we follow these patients by RECIST criteria. There are some other patients in whom it seems less definitive, because they have lung metastases and they may have small lesions, and all those lesions seem to be growing on top of their target lesions as well.

Marcia Brose, MD, PhD: What do you know about the toxicity of [LOXO-195] compared with larotrectinib?

David Hong, MD: I think that’s just preliminary right now. The profile is very similar to the larotrectinib trial.

Marcia Brose, MD, PhD: OK, great. What about TPX-0005? Can you tell us a little bit about that? I know that’s slightly different because it also inhibits ROS1 and ALK.

David Hong, MD: Correct. It’s similar to entrectinib. There are very little data on its effects on NTRK. Clearly, I think some of the data was presented on ROS, and the efficacy seems very good, 80% response rate, in my understanding.

Marcia Brose, MD, PhD: Great. Can you talk about other kinase inhibitors that are out there that also have been documented to inhibit TRK, including things like cabozantinib, regorafenib, and crizotinib? They’re more general inhibitors. I know that they target many things, but can you tell us a little about the experience with TRK in those cases?

David Hong, MD: There’s very little experience. There’s very little that has been reported on these other agents. And from our understanding, they’re not really true TRK inhibitors. Their IC50s [half maximal inhibitory concentration] relative to entrectinib and larotrectinib are very different. My recommendation would not be to give them crizotinib if you find an NTRK fusion patient. There’s an approved drug now for NTRK fusions, which is larotrectinib.

Transcript edited for clarity.

Marcia Brose, MD, PhD: Talk to us a little about other TRK fusion approaches to cancers, maybe a little bit about LOXO-195 and TPX-0005.

Corey Langer, MD: Larotrectinib and entrectinib are not the only agents that are targeting NTRK. There are a number of additional agents that are being developed. LOXO-195 is 1 example. This was just reported at the AACR [American Association for Cancer Research Annual Meeting] in March and April of 2019, and this too works on TRK fusions. Response rates in those with an established TRK abnormality is close to 50%, 9 patients of 20—again, a variety of different cancers. My initial read on the toxicity is that it may be somewhat harder to deal with—nausea and vomiting, myalgias, abdominal pain in addition to fatigue, edema, and constipation. That always is tough when we’re dealing with an oral agent and it needs to be given continuously on a daily basis.

It’s unclear how well these newer agents were bound to work in patients with previous exposure to entrectinib or larotrectinib, at least for LOXO-195. That’s not the case with repotrectinib, another new agent. Again, something with dirty kinase, works on multiple different targets. Response rates to date are 80%, quite a bit higher, 66% in those with prior exposure to other TKIs [tyrosine kinase inhibitors], including crizotinib. It works on ROS1 and specifically works on the resistance mutation G2032R, which is probably 1 of the main mechanisms of resistance in ROS1.

Then there are a number of other agents that have actually been used in other malignancies like midostaurin, FLT3 in acute leukemia, and regorafenib in colorectal cancer, bladder cancer starting out as an angiogenesis inhibitor. These 2 appear to have some activity on TRK, but it’s completely unclear so far just how active they will prove in this patient population. We’re really just awaiting the phase I and phase II data.

A new era has dawned. When I started out as a medical oncologist in the late ’80s—over 30 years ago—I couldn’t have dreamed that we would have targeted therapy of this sort. Now for the first time, we’ve witnessed the marker-specific approval of a new agent, larotrectinib, that’s histology- and tumor-agnostic and clearly is pointing a wave to the future—the way I think we’re going to practice increasingly.

There are a number of trials that are ongoing that are actually addressing this. The MATCH Trial through the Eastern Cooperative Oncology Group and jointly with the other cooperative groups is looking explicitly at marker-specific therapy, establishing the role of various agents in a particular tumor marker, and allowing individuals with relatively rare malignancies or different malignancies to enroll in a single study that essentially examines 15, 18, or 20 different markers and 15 to 20 different agents. No single institution could ever mount studies of this sort—the patients are just too rare.

If you do it in the context of the MATCH trial, that looks at multiple different markers and then matches the patient with the appropriate markers for the appropriate targeted therapy. It makes sense, and it’s really a brilliant academic, community, industry, and federal partnership that’s come through that can address the needs of many of our cancer patients for whom standard therapy, at least traditionally, does not exist.

Larotrectinib is approved. I anticipate entrectinib’s approval sometime in the summer of 2019. Then there are other agents, such as repotrectinib and LOXO195, that will probably be approved in the next year or 2 based on their activity, both of which have shown responses in individuals who’ve had prior NTRK inhibitor exposure. There may be a role for other agents that are already established in other malignancies such as regorafenib and midostaurin.

David Hong, MD: As with all small-molecule inhibitors, we do expect that there will be resistance. As the experience to date has shown, these patients stay on for an awfully long time. Some of them do develop resistance, and when we see these patients, we’ve shown that these patients develop what are called solvent front mutations at the site of the ATP [adenosine triphosphate] pocket. They also develop what are called gatekeeper mutations. There are other alterations and other mutations that are less common, and we do think that there may be kind of alternative pathway signaling processes that may be leaning to resistance, but the most common mechanism of resistance is solvent front.

Marcia Brose, MD, PhD: My understanding is these were expected at the time of the design.

David Hong, MD: Yes. We were expecting this, and kind of another first in this approval was that we began the phase I even before we got the approval for larotrectinib.

Marcia Brose, MD, PhD: The phase I of which drug?

David Hong, MD: Of LOXO-195, and we began enrolling patients who were becoming resistant. In fact, Alex Drilon, MD, and the MSK [Memorial Sloan Kettering Cancer Center] group actually published a small case series of patients who developed mechanisms of resistance—and were able to, through kind of a compassion, put those on before we even started the phase I to actually see responses in these patients.

Marcia Brose, MD, PhD: Were those resistant mutations just for the LOXO-195 study, just coming from the larotrectinib trials or were they also coming from the entrectinib?

David Hong, MD: No, they were also from patients who received entrectinib. I can’t share with you all the data, but David Hyman, MD, did present some of the preliminary data that we have at the AACR, showing significant responses in a number of these different subsets of tumors.

Marcia Brose, MD, PhD: I have a question for you. When you have these resistance mutations and you have a patient who has it, are you seeing progression of multiple sites, or is it usually just 1 site that starts to grow while the others are still responding? Just so that people who are starting to get this drug know what they’re looking for.

David Hong, MD: That’s a really good question. In my experience, Dr Hyman has probably put the most number of patients on the resistant population. My experience—it’s variable. There are patients who seem to be just progressing everywhere, and then there are patients we are following who have the target lesions, and overall they progress by RECIST [response evaluation criteria in solid tumors]. When we rebiopsy those lesions that seem to be progressing they had the cell from, there were other diseases.

Marcia Brose, MD, PhD: That’s really interesting because many times in other kinase inhibitors, many for us, when we get resistance, many times everything is responding and there’s just 1 area that seems to have figured it out.

David Hong, MD: Again, I think it’s variable and we haven’t looked at the full data set. In my experience, a handful of patients had just 1 area of progression because of how we follow these patients by RECIST criteria. There are some other patients in whom it seems less definitive, because they have lung metastases and they may have small lesions, and all those lesions seem to be growing on top of their target lesions as well.

Marcia Brose, MD, PhD: What do you know about the toxicity of [LOXO-195] compared with larotrectinib?

David Hong, MD: I think that’s just preliminary right now. The profile is very similar to the larotrectinib trial.

Marcia Brose, MD, PhD: OK, great. What about TPX-0005? Can you tell us a little bit about that? I know that’s slightly different because it also inhibits ROS1 and ALK.

David Hong, MD: Correct. It’s similar to entrectinib. There are very little data on its effects on NTRK. Clearly, I think some of the data was presented on ROS, and the efficacy seems very good, 80% response rate, in my understanding.

Marcia Brose, MD, PhD: Great. Can you talk about other kinase inhibitors that are out there that also have been documented to inhibit TRK, including things like cabozantinib, regorafenib, and crizotinib? They’re more general inhibitors. I know that they target many things, but can you tell us a little about the experience with TRK in those cases?

David Hong, MD: There’s very little experience. There’s very little that has been reported on these other agents. And from our understanding, they’re not really true TRK inhibitors. Their IC50s [half maximal inhibitory concentration] relative to entrectinib and larotrectinib are very different. My recommendation would not be to give them crizotinib if you find an NTRK fusion patient. There’s an approved drug now for NTRK fusions, which is larotrectinib.

Transcript edited for clarity.
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