Binimetinib: Combination Insights on the Treatment Strategy of Breast Cancer from SABCS 2022 Saranya Chumsri MD

By Saranya Chumsri, MD

This particular study is a phase 1/2 trial of Pembrolizumab in combination with Binimetinib (brand name MEKTOVI), which is a MEK inhibitor. So previous preclinical and clinical studies show that activation of the MAP kinase pathway is associated with a reduction in the tumor infiltrating lymphocytes, and when we use the MEK inhibitor in combination with the anti-PDL1, it's actually synergistic in the clinical model, which led us to conduct this particular trial.

Right now the current standard of care in patient with PD-L1 positive TR metastatic triple-negative breast cancer would be pembrolizumab in combination with chemotherapy. Unfortunately, up to about 60% of patients with metastatic triple-negative will consider as PD-L1 negative and are not eligible for.

For pembrolizuma, this particular trial include patients with metastatic triple negative breast cancer with either PD-L1 status to be enrolled into the trial. And this particular trial does not have chemotherapy backbone, which does, has have significant adverse events. So we combining to targeted therapy with the immune checkpoint inhibitor to hope to improve the outcome in, patients with metastatic triple negative breast cancer, especially the ones that are PD-L1 negative.

Can you please tell us about the trial design and why it was set up this way?  

So the trial design is a phase 1/2 trial. The phase one part include three dose levels for Binimetinib (brand name MEKTOVI), starting at dose level zero or 45 milligram twice daily. When we conducted the trial, unfortunately, we ran into 2 dose limiting toxicity in the first four patients. So the trial had to reduce the dose of the Binimetinib down to dose level minus one, which is 30 milligram twice daily. And what we found is that this particular dose is better tolerating and it was the dose that was picked for a random the phase 2 portion.

Can you give us significant data from the Binimetinib clinical trial?  

So with what we found was that we enrolled a total of 22 patients. Some patients were treated in the dose level zero, which was not available for the response since the phase 2 dose was the dose that was picked was the dose level minus one. So we have a total of 17 available patient from response that treated with the phase 2 dose.

What we found was that the treatment was somewhat well tolerated and the objective response rate with this combination is about 29.4%. The clinical benefit rate is about, 35% on the other hand, because previous preclinical data showed that liver metastasis may actually confer poor response to immune checkpoint inhibitor because of the sequestration of the CD8 T-cells from the macrophage driven immune macro-environment in the liver metastases, we did the subset analysis of patients with and without liver metastasis. And we found that all of the five patients who had liver metastasis actually did not respond to this particular combination. On the other hand, if we take, you take out these patients that had liver metastasis, the objective response rate go up to 55.5% with the clinical benefit rate of over 66%. This is the group of patients that might not be a good patient population to evaluate for immune checkpoint inhibitor.

What are the most common questions you get from your colleagues about the Binimetinib clinical trial?  

I guess my other colleague would ask me what would be a benefit of this particular combination or what would be the indication I would consider with the future study. So I would Feel that this particular study, we might need more patient larger clinical trials so that we can confirm the finding in our smaller study. But this particular combination seems to be promising particularly in patients with no liver metastasis and likely either first or second line of therapy as we seen in other immune checkpoint inhibitor it usually works well in the first or second line treatment.

What were the primary end points of the Binimetinib trial and where they met?  

The primary endpoint was the objective response in patients that treated with recommended phase 2 dose, which we found that the objective response rate was 29 % in all comers. And the clinical benefit rate was the secondary endpoint which was 35%. But on the other hand, as I mentioned, patients with liver metastasis, if you take out those patient, the objective response rate go up to 55% and the clinical benefit rate was 66%.

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What are the key takeaways from the Binimetinib research and data?  

So I believe that this particular combination is a promising combination for patients with metastatic breast cancer. The other thing that we found was that the duration of response in these patients are remarkable. The median time to response is actually has not been reached, and there are patients that still has ongoing response over 32 months among patients who responded and this particular combination does not have chemotherapy, common chemotherapy side effects (E.g. high blood pressure, pulmonary embolism, blurred vision, breathing problems...). So it is quite appealing in model many patients. And we are in the process now of looking at additional correlative study that looking at PD-L1 status and other baseline biomarker to predict for response. So this particular study is promising and we are hoping to conduct a larger clinical trial to confirm our findings and hopefully may offer new treatment options for patients in the future. 

What is Binimetinib?

Binimetinib is a type of cancer treatment that belongs to a class of drugs called mitogen-activated protein kinase (MEK) inhibitors. It is used to treat advanced or metastatic breast cancer in patients whose cancer has specific genetic mutations, such as BRAF V600E or NRAS mutations.

Binimetinib works by blocking a specific protein in the MEK signaling pathway that helps cancer cells grow and divide. By blocking this pathway, binimetinib can slow down or stop the growth of cancer cells and potentially shrink tumors.

Clinical trials have shown that binimetinib, when used in combination with other drugs, can improve progression-free survival and overall response rates in patients with advanced breast cancer. However, binimetinib is not effective for all types of breast cancer, and it can have adverse events, including nausea, vomiting, diarrhea, fatigue, and skin rash.

Overall, binimetinib is a promising targeted therapy for breast cancer patients with specific genetic mutations and is being studied in ongoing clinical trials to further evaluate its efficacy and safety.

Saranya Chumsri, MD - About The Author, Credentials, and Affiliations

Saranya Chumsri, MD, is a highly skilled healthcare professional and accomplished researcher at the Mayo Clinic. She is a Professor of Medicine at the Mayo Clinic in Jacksonville, Florida. She works in the Division of Hematology and Oncology and the Department of Medicine.

Dr. Chumsri obtained her medical degree from Chulalongkorn University in Bangkok, Thailand, before completing her residency in internal medicine at the University of Texas Southwestern Medical Center. She then pursued a fellowship in hematology and oncology at the Mayo Clinic in Rochester, Minnesota, where she subsequently served on the faculty before moving to the Jacksonville campus in 2015.

With over two decades of clinical experience in hematology and oncology, Dr. Chumsri is an expert in the diagnosis and management of a wide range of cancers, including breast cancer, ovarian cancer, and lung cancer. She is particularly known for her expertise in the treatment of triple-negative breast cancer, an aggressive form of breast cancer that can be difficult to treat.

Dr. Chumsri works as a healthcare professional, but she is also an active researcher. She is especially interested in finding new ways to treat breast cancer. Her research has been published in a number of high-impact journals, and the National Cancer Institute and other well-known organizations have given her money to help her with her work.

Dr. Chumsri is committed to providing compassionate, personalized care to each of her patients and is dedicated to advancing the field of hematology and oncology through her research and clinical practice. She has a lot of respect from both her colleagues and her patients because of her knowledge, professionalism, and drive to do her best.