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People with advanced HER2-positive breast cancer may soon have some new treatment options after two experimental drugs performed well in clinical trials.
Around 15-20% of people with breast cancer have cells positive for HER2, meaning that they can be treated with drugs which directly target the HER2 protein, most commonly trastuzumab (also known as Herceptin), often in combination with chemotherapy. Around 80% of HER2-positive patients survive for 10 years or more, with most of these people having no signs of disease after this time. However, many people still experience resistance to treatments and the cancer often spreads, meaning new treatment options are urgently required.
The new research, featuring separate studies of two novel therapies for HER2-positive breast cancer, trastuzumab deruxtecan (T-DXd) and tucatinib, was presented today at the San Antonio Breast Cancer Symposium.
The first new therapy, T-DXd, is an example of a antibody-drug-conjugate treatment, where an antibody (in this case targeted to HER2 called trastuzumab) acts like a grappling hook, attaching to cancer cells and delivering a payload of chemotherapy. The chemotherapy drug in this case stops DNA replication, meaning cancer cells cannot effectively divide. However, it isn’t the first HER2-targeting drug of this type. Another, T-DM1, involves trastuzumab combined with a different type of chemotherapy agent, but patients can develop resistance to these drugs, requiring a change of tactics.
T-DXd was granted priority review by the FDA in October after it showed impressive results in a phase I trial of patients with advanced HER2-positive breast cancer who had already been treated with T-DM1 and had become resistant. The study presented at the conference details the results of the phase II trial involving 184 patients who received the prescribed doses of the therapy. All had metastatic cancer and most had received several treatments before getting the experimental therapy. 61% of the patients had some response to T-DXd, with the median progression-free survival time being just over 16 months.
“Both of these measures of efficacy are substantially higher than seen in any other study of patients with pre-treated HER2-positive metastatic breast cancer,” said Ian Krop, MD, PhD, associate chief of the Division of Breast Oncology at Dana-Faber Cancer Institute and leader of the research.
Despite this success, 99% of the patients on the trial experienced side-effects from the treatment, with 57% experiencing grade 3 or above toxicities – considered to be relatively serious. 15% of patients enrolled on the trial discontinued treatment because of these side effects. One of the most serious of these was a condition called interstitial lung disease (ILD), which resulted in four deaths in the study.
“While most of the side effects seen with trastuzumab deruxtecan were mild and manageable, we did identify a specific lung injury called interstitial lung disease as an important risk of trastuzumab deruxtecan,” said Krop noting that all future patients getting the drug need to be closely monitored for symptoms of ILD so appropriate steps can be taken to treat this condition if it does arise.
“Given the unique ability of this drug to control cancers in a high percentage of patients whose cancer had already developed resistance to other therapies, I don’t think the drug’s potential side effects will be a barrier to approval. That being said, we need to work hard to determine approaches to minimize its toxicities,” Krop added.
The second project involved a global trial called HER2CLIMB and tested a new drug called tucatinib, which targets HER2-positive cells. The trial enrolled over 600 patients with advanced HER2-positive breast cancer, nearly half of whom had their cancer spread to the brain. Tucatinib was used in combination with trastuzumab and capecitabine for half of the patients, whilst the other half was given a placebo instead of tucatinib. For those given tucatinib, 45% of patients were alive after two years, compared to 27% of patients who did not receive the drug as part of their treatment.
Particularly interesting was that patients with brain metastases on the tucatinib treatment combination had a 52% reduction in the risk of progression or death during the trial.
“Tucatinib is a well tolerated drug that penetrates into brain tissue more readily than many other agents,” said Eric Winer, MD, Chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute.
“Brain metastases are a particular challenge because of: 1) the blood brain barrier prevents some agents from entering the brain; 2) the microenvironment of the brain is different from other organs; 3) there may be genetic changes in tumors that metastasize to the brain,” added Winer.
The tucatinib was relatively well tolerated by patients, with only 5.7% of the patients receiving the tucatinib combination having to discontinue the treatment due to toxicity.
“As with all therapy, resistance to tucatinib does develop over time. There may be biomarkers that identify patients who derive a particularly large benefit from the drug. There is also interest in combining tucatinib with other novel agents to improve efficacy.” said Winer, adding that he thought it ‘very likely’ that the drug would be approved by the FDA in the next six months.