ONCAlert | Upfront Therapy for mRCC

TRKi: High Response Rate in Patients With Primary CNS Disease

Targeted Oncology
Published Online:12:00 PM, Mon August 5, 2019

Marcia Brose, MD, PhD: With these wonderful responses, I know there have been some experiences with patients who had metastatic disease in the CNS [central nervous system] and in the brain. Can you tell us a little more about that and what the experience was in the trial?

David Hong, MD: Yeah. Alex Drilon, MD, will present in an oral presentation this ASCO [American Society of Clinical Oncology Annual] Meeting looking at particularly those patients who develop brain metastases and also primary CNS disease. Clearly in patients who developed brain metastases—and there was a series of these patients—the response rates are very similar: 60% overall response rate.

Marcia Brose, MD, PhD: In the brain?

David Hong, MD: In the brain, and this is similar data to what’s been reported with entrectinib. I think entrectinib response rate is around 55%, 56%. The CNS disease is a little more complicated. Part of this is because we don’t have enough patients.

Marcia Brose, MD, PhD: Is it CNS primary disease?

David Hong, MD: CNS primary—glioblastoma [GBM]. We know in children who have these rare oligodendromas and other haunting gliomas that these responses are uniformly dramatic and significant. In GBM, for example, Dr Drilon’s data sets are just about a 35% response rate. I think there were 6 or 7 patients on that cohort. It’s hard to say exactly if that’s just because of the small numbers or at this point. We need to add more patients to see what the overall response rate is.

There may be—and I say this only because I’ve seen such activity with larotrectinib—a difference in pediatric CNS disease versus GBM. With that said, 35% response rate in GBM is still amazing for a disease that really has had no new therapies over the last several decades.

Marcia Brose, MD, PhD: We’ll have to see how the responses are also. In CNS, I know following the responses can be tricky because I know that sometimes there can be what appears to be worsening but is actually just part of the scan.

David Hong, MD: Correct.

Marcia Brose, MD, PhD: We’ll have to figure out that out.

Corey Langer, MD: It’s true for entrectinib, and it’s also true for larotrectinib—it has high CNS penetrance. Patients with brain involvement will frequently respond. In the original phase I and phase II studies, the overall response rate again was in the order of 70%, 75%. It was a 55% intracranial response. We would never see that with standard systemic chemotherapy. We are seeing that increasingly with our newer generation of tyrosine kinase inhibitors. We’re certainly seeing that with alectinib in ALK-positive disease, with brigatinib in ALK-positive tumors, and now with entrectinib in ROS1- and, I dare say, in NTRK-positive patients. Those with CNS disease were also responding.

Transcript edited for clarity.

Marcia Brose, MD, PhD: With these wonderful responses, I know there have been some experiences with patients who had metastatic disease in the CNS [central nervous system] and in the brain. Can you tell us a little more about that and what the experience was in the trial?

David Hong, MD: Yeah. Alex Drilon, MD, will present in an oral presentation this ASCO [American Society of Clinical Oncology Annual] Meeting looking at particularly those patients who develop brain metastases and also primary CNS disease. Clearly in patients who developed brain metastases—and there was a series of these patients—the response rates are very similar: 60% overall response rate.

Marcia Brose, MD, PhD: In the brain?

David Hong, MD: In the brain, and this is similar data to what’s been reported with entrectinib. I think entrectinib response rate is around 55%, 56%. The CNS disease is a little more complicated. Part of this is because we don’t have enough patients.

Marcia Brose, MD, PhD: Is it CNS primary disease?

David Hong, MD: CNS primary—glioblastoma [GBM]. We know in children who have these rare oligodendromas and other haunting gliomas that these responses are uniformly dramatic and significant. In GBM, for example, Dr Drilon’s data sets are just about a 35% response rate. I think there were 6 or 7 patients on that cohort. It’s hard to say exactly if that’s just because of the small numbers or at this point. We need to add more patients to see what the overall response rate is.

There may be—and I say this only because I’ve seen such activity with larotrectinib—a difference in pediatric CNS disease versus GBM. With that said, 35% response rate in GBM is still amazing for a disease that really has had no new therapies over the last several decades.

Marcia Brose, MD, PhD: We’ll have to see how the responses are also. In CNS, I know following the responses can be tricky because I know that sometimes there can be what appears to be worsening but is actually just part of the scan.

David Hong, MD: Correct.

Marcia Brose, MD, PhD: We’ll have to figure out that out.

Corey Langer, MD: It’s true for entrectinib, and it’s also true for larotrectinib—it has high CNS penetrance. Patients with brain involvement will frequently respond. In the original phase I and phase II studies, the overall response rate again was in the order of 70%, 75%. It was a 55% intracranial response. We would never see that with standard systemic chemotherapy. We are seeing that increasingly with our newer generation of tyrosine kinase inhibitors. We’re certainly seeing that with alectinib in ALK-positive disease, with brigatinib in ALK-positive tumors, and now with entrectinib in ROS1- and, I dare say, in NTRK-positive patients. Those with CNS disease were also responding.

Transcript edited for clarity.
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