Duke is leading an active single-arm, open-label, phase 2 clinical trial testing whether the tyrosine kinase inhibitor asciminib combined with the current standard-of-care monoclonal antibody therapy trastuzumab is safe and effective in treating HER2-positive breast cancer that has metastasized to the brain. If the combination is safe and effective at stopping or slowing tumor growth in the brain, it could be a promising treatment option for patients with advanced disease. 

“The ASCENdANT trial is built on foundational research from the Pendergast Lab at Duke,” says Carey K. Anders, MD, medical oncologist, principal investigator of the ASCENdANT trial, and Director of the Duke Center for Brain and Spine Metastasis (DCBSM). “Lab and animal studies found that inhibiting the Abl kinase pathway downregulates the HER2 protein and slows down metastasis,” she adds. 
In animal studies led by researcher Ann Marie Pendergast, PhD, the leukemia drug asciminib blocked the kinase signaling network, which stopped HER2 protein accumulation in breast cancer cells. This, in turn, reduced cancer cell proliferation and spreading.

“These findings support further exploration into whether asciminib combined with our current standard-of-care therapy, trastuzumab, is safe and effective for patients with metastatic disease after other treatments become ineffective,” says Anders. “We hope that this combination therapy is synergistic and shows positive outcomes.”

Asciminib is FDA-approved as a first-line treatment for chronic myelogenous leukemia. “We have a good sense of asciminib’s safety and efficacy as an oncologic therapy, but this will be the first human trial to test it in combination with trastuzumab,” says Anders. 

The study is designed with a safety lead-in. Patients start with an 80 mg daily dose of asciminib and escalate up to 200 mg twice per day if well tolerated.

To qualify for the study, patients must have HER2-positive breast cancer with an active, measurable lesion in the brain. Patients may have received prior treatments to the brain, such as radiation or surgery, as well as standard-of-care trastuzumab.

Anders notes that the study is underway with several patients enrolled and currently in the dose escalation period. “Once we get through this dose escalation period with clear safety, we will move into the expansion phase of the study with more patients,” says Anders.

Anders explains, “We’re looking at the intracranial response rate — a promising signal is reduction of the target lesion size. We’re also looking at other metrics such as progression-free survival, time to next radiation, quality of life, and circulating tumor DNA assays to assess the disease burden,” she adds. 

Study participants are evaluated every three weeks in clinic and receive brain MRIs to monitor progress at regular intervals. They are assessed for stability, response, and progression, with close monitoring to ensure continuing in the study is in the patient’s best interest. 

If successful, this treatment fills an important gap in available third-line treatments for metastatic breast cancer. “A third of patients with advanced HER2-positive breast cancer eventually develop brain metastasis,” says Anders. “I hope that we will see this drug combination as tolerable and efficacious in reducing tumor burden in a meaningful way with a pathway to a randomized study.”

According to Anders, “In addition to providing excellence in care for metastatic disease, the DCBSM has a strong partnership with basic scientists at the Duke Cancer Institute (DCI). As they are discovering new ways to treat brain metastasis in the lab, our team can quickly translate the science into bedside care through trials.” 

The DCI and DCBSM are equally committed to improving the lives of all patients across all histologies. “We’re excited about the ASCENdANT trial for breast cancer and also other studies that are looking at other solid tumor types, including lung cancer. It’s a great illustration of the DCBSM’s dedication to finding new treatments for patients with advanced disease,” Anders concludes. 

The ASCENdANT study was made possible through Novartis and a grateful patient donation to the DCBSM. “It’s a beautiful thing to have patients willing to contribute to science that could greatly impact the lives of many more patients in a positive way,” says Anders.