Leptomeningeal Disease: Phase 1 Trial of BBB-Penetrant HER2 Inhibitor in Metastatic Breast Cancer Nicholas McAndrew MD
By Nicholas McAndrew, MD, MSCE
DZD1516 is a is a new compound, it’s a new oral tyrosine kinase inhibitor that was designed by the company. When the company initially was developing this drug. They were seeking compounds that were going to be highly HER2 selective and blood-brain barrier penetrant. Because HER2 positive breast cancer is a high rate of CNS metastases, and so it remains 1 of the biggest challenges, although we do now have some compounds out on the market like Tucatinib and and TDX-d, which seem to have. Some good activity in their brain, it still remains a big challenge and further compounds are needed. And pre-clinically this drug was selected based on its preclinical high blood brain barrier activity that they saw in mouse models as well as its high HER2 selectivity, so those were some of the features that was studied in the phase 1 study, which were presenting the updated results of today.
What is the standard of care in this disease state. And why do you choose to pursue the DZD1516 trial?
The standard of care in in metastatic HER2 positive breast cancer, specifically in patients with brain metastases after progression on first line Taxane plus Herceptin or Plus Trastuzumab in Pertuzumab would be typically a Tucatinib containing regimen. So tyrosine kinase inhibitors are oftentimes considered the standard of care in patients specifically with CNS metastases. However a lot of the drug development didn’t specifically focus on a lot of the pharmacokinetic data as it applies to the CSF with other compounds in this space. And so in pursuing this clinical trial there was specific study design pharmacokinetics that were implemented into the for several cycles of the study.
So patients underwent lumbar punctures on this study to try and ensure that when. When this drug is being developed, it’s actually making its way into the CNS as we hoped it would, rather than relying on some, either just preclinical models or on objective responses that we may see in later phases of drug development.
Can you please tell us about the trial design and why it was set up this way?
In terms of the specific trial design, it was designed as a 3+3 phase 1 dose escalation, first in human study there are several parts to it, this is the first part, to which is the monotherapy dose escalation in which we started at the lowest dose of 25 milligrams twice a day orally. And in a traditional 3+3 design, stepped up each dose until we reached the maximum tolerated dose. So the 300 milligram dose twice a day was the dose that it was the highest dose that we reached, and we did reach some drug some dose limiting toxicities at 300 milligrams twice a day, most notably headache, myalgias and vomiting. But coming back down to 250 milligrams twice a day seemed to be the recommended phase 2 dose that was well tolerated with manageable treatment related adverse events.
Can you give us significant data from the DZD1516 trial?
Keeping in mind that this was a first inhuman study, the goal of this particular study was to determine the safety and dose of the drug. Now, all the patients in this trial had previously progressed on a HER2 tyrosine kinase inhibitor. So everyone had seen some type of HER2 tyrosine kinase inhibitor and had progressed on that, so we weren’t necessarily hoping, we weren’t necessarily expecting a significant response rate. In this trial, we’re really just trying to find out what’s the safe dose of the drug. And so we did find that at 250 milligrams BID, twice a day. I think the, but despite that, we did see, several patients have best response of stable disease at greater than three months. And and most importantly, there were no of EGFR or off HER2 target side effects. So this was designed as a HER2 specific drug and we didn’t see a lot of the EGFR related side effects that we tend to see with other tyrosine kinase inhibitors. Not really a lot of diarrhea like we see with the other approved HER2 TKIs and really just mild headache. Some emesis, but it was mostly controlled and and a little bit of nausea as well. I think some of the most important and impressive data that we saw with the updated results, especially as it applies to the preclinical results really informed what’s next for this drug. The, some of the preclinical data that was updated was looking at different combinations in mouse models with this drug. And they had combined the the study drug DZD1516 with DSAV201A, which is Trastuzumab Deruxtecan, and looking at relative bioluminescence in mouse models for brain metastases. So decreases in bioluminescence would mean essentially response in the brain. The combination of the DZD1516 with Trastuzumab Deruxtecan seemed to be synergistic in reducing the amount of bioluminescence in this updated preclinical data. So essentially there was, there were somewhat similar results in decrease in bioluminescence between the monotherapy DZD1516 and monotherapy Trastuzumab Deruxtecan, but when combined it came down significantly lower and even lower than they had previously looked at when combined with T-DM1 and other preclinical data that they did. So I think as the study moves on into phase 2, it’ll be very interesting to see what what these combinations look like specifically with regard to response in the brain.
What are the most common questions you get from your colleagues about this study on Leptomeningeal Disease (LMD)?
I think the most common question we get is, what does it look like in combination with other drugs? Certainly, from a drug development standpoint, it’s important to pick the right partner and also pick the right time to study this drug in terms of where you’re going to place the study in sequence with other prior lines of care. And I know that’s been a somewhat of a moving target as the standard of care data matures. And so the the partner in will most likely be an antibody drug conjugate in the phase 2 study, is a common question. And the updated results seem that when it’s combined with Trastuzumab Deruxtecan these are updated preclinical results, it hopefully will have synergy in the brain.
What were the primary end points of the DZD1516 trial in Leptomeningeal Disease (LMD) in Breast Cancer and where they met?
The primary endpoint given that it was a phase 1 study was evaluating safety and efficacy or the safety of the drug and recommended phase 2 dose. So we did determine the recommended phase 2 dose and defined the safety profile as relatively manageable and expected within highly selective HER2 tyrosine kinase inhibitors mostly headache and emesis.
What is Leptomeningeal Disease (LMD) in Breast Cancer?
Leptomeningeal disease (LMD) is a rare but serious complication of breast cancer that occurs when cancer cells spread to the membranes surrounding the brain and spinal cord (leptomeninges). The cancer cells can invade the cerebrospinal fluid, leading to inflammation and damage to the nerves in the brain and spinal cord. This can cause a range of symptoms, including headaches, nausea, vomiting, seizures, vision changes, weakness, and difficulty thinking and speaking.
LMD (Leptomeningeal disease) is a rare but serious complication of breast cancer that occurs when cancer cells spread to the membranes surrounding the brain and spinal cord (leptomeninges). The cancer cells can invade the cerebrospinal fluid, leading to inflammation and damage to the nerves in the brain and spinal cord. This can cause a range of symptoms, including headaches, nausea, vomiting, seizures, vision changes, weakness, and difficulty thinking and speaking.
LMD (Leptomeningeal disease) is more common in advanced or metastatic breast cancer, but it can occur at any stage of the disease. Treatment options for LMD (Leptomeningeal disease) are limited, and may include chemotherapy, radiation therapy, targeted therapy, and supportive care. Prognosis is generally poor, with a median survival of a few months, but individual outcomes can vary depending on factors such as the extent of the disease, the response to treatment, and the overall health of the patient. is more common in advanced or metastatic breast cancer, but it can occur at any stage of the disease. Treatment options for LMD (Leptomeningeal disease) are limited, and may include chemotherapy, radiation therapy, targeted therapy, and supportive care. Prognosis is generally poor, with a median survival of a few months, but individual outcomes can vary depending on factors such as the extent of the disease, the response to treatment, and the overall health of the patient.
What were the key takeaways from this research and data about Leptomeningeal Disease (LMD)?
I think the main takeaway is that this is a, this is a new oral, HER2 highly selective tyrosine kinase inhibitor that was designed in the lab to get into the brain really well and to be highly HER2 selective. And the pharmacokinetic data from this study shows that it definitely gets into the brain. We took CSF samples from patients on study and looked at the presence of JUG and its active metabolite in the brain. It was clearly there, so it clearly got into the brain well. And then the side effects of the drug were very consistent with a drug that’s highly HER2 selective and doesn’t have a lot of off-target. EGFR related side effects, which is important for patient tolerability. And then also the preclinical data, which this company is very I think impressive with its preclinical models, suggests that when combined with an antibody drug conjugate, it seems to be synergistically effective in brain metastasis mice models. And so that’s where we’re hoping to move this drug in the future.
Nicholas McAndrew, MD, MSCE – About The Author, Credentials, and Affiliations
Dr. Nicholas McAndrew practices as a hematologist-oncologist in Beverly Hills and Santa Monica at UCLA Health. His primary scientific and clinical interests are in breast cancer. His certifications include internal medicine and medical oncology.
Dr. McAndrew got his medical degree from the University of Pennsylvania’s Perelman School of Medicine and completed his internal medicine residency and hematology/oncology fellowship at the University of Pennsylvania Hospital. His bachelor’s degree in biology was awarded by Villanova University.
Dr. McAndrew is also a clinical researcher. At the University of Pennsylvania, he got a Master of Science in Clinical Epidemiology with a focus on clinical trials. His research is mostly about making new medicines for breast cancer and figuring out how to use biomarkers to predict how a treatment will work. Several active clinical trials at UCLA are led by him as the lead investigator.