A new drug combination shrunk brain tumors in HER2-positive breast cancer patients whose cancer had spread to the brain, showing it is active as a first-line brain metastases treatment. Lapatinib (Tykerb) combined with capecitabine(Drug information on capecitabine) (Xeloda) showed similar efficacy to whole-brain radiotherapy, the current standard of care for patients with brain metastases.
The results of the LANDSCAPE phase II single-arm trial are published in the Lancet Oncology. Results were also presented at the 2012 European Society for Medical Oncology Congress in September. Thomas Bachelot, MD, of the Centre Léon Bérard in Lyon, France, and colleagues led the trial as part of the French cooperative group UNICANCER.
Ball-and-stick model of capecitabineOf the 45 patients recruited to the trial, 29 had an objective response in the brain of at least 50% tumor shrinkage by volume. Overall, 37 patients had some brain tumor shrinkage. Nine patients had at least an 80% reduction of their brain tumors. The median time to whole-brain radiotherapy on study was 8.3 months. Patients did not have previous brain radiotherapy or lapatinib.
“I think the trial provides a systemic therapy for patients with brain metastasis that can be used either before or after whole-brain radiotherapy,” said Massimo Cristofanilli, MD, medical oncologist and breast cancer researcher at Fox Chase Cancer Center. Cristofanilli noted that cost may be a deterring factor in widespread use of the regimen.
Lapatinib is a dual tyrosine kinase inhibitor that blocks both the HER2 and the epidermal growth factor receptor (EGFR) pathways. The oral drug is approved in combination with the oral chemotherapy agent capecitabine for HER2-positive metastatic breast cancer patients who have been previously treated with other therapies, including trastuzumab(Drug information on trastuzumab). Lapatinib is also approved in combination with letrozole(Drug information on letrozole) (Femara) for women with hormone-positive metastatic breast cancer that overexpresses HER2. Lapatinib, unlike trastuzumab, is assumed to pass through the blood-brain barrier.
Alternatives to whole-brain radiation will reduce cognitive impairment seen among patients treated with whole-brain radiotherapy. However, the combination comes with its own toxicity. The study found that 22 patients (49%) experienced a grade 3 or 4 adverse event related to treatment. The most common severe adverse events seen in patients were diarrhea (20%) and hand-foot syndrome (20%). One-third of patients had at least one severe toxicity event. Four patients discontinued treatment because of toxicity.
“I think that if we find asymptomatic disease by imaging such as MRI, we can certainly present this new option to patients. There are less cognitive problems with this combination therapy,” said Cristofanilli.
In a commentary on the study publication, Rupert Bartsch, MD, of the Medical University of Vienna, Austria, stated that despite the limitations of the study, the combination “might already be a valid treatment option” for those breast cancer patients with multiple brain metastases.
One of the shortcomings of the trial, Bartsch pointed out in his editorial, is no quality of life evaluation for this combination regimen to place into context of radiotherapy treatment. To understand whether lapatinib plus capecitabine can replace radiotherapy in breast cancer patients with brain metastases, “a direct randomized comparison of capecitabine plus lapatinib to whole-brain radiotherapy is urgently warranted,” stated Bartsch.
According to Bachelot, these phase II results provide enough evidence to propose this combination to selected patients. A phase III international trial is being discussed in Europe with GlaxoSmithKline, the manufacturer of lapatinib.
As treatments for breast cancer improve, patients are living longer with their disease, resulting in a greater incidence of brain metastases. Brain metastases occur in approximately 30% to 50% of HER2-positive metastatic breast cancer patients. Breast cancer in general is the second leading cause of brain metastases among solid tumors.
But while advancements in the treatment of HER2-positive disease, such as the first approval of trastuzumab back in 1998, has resulted in prolonged survival in breast cancer patients, according to Cristofanilli, “we have not necessarily focused on treatments that target the metastatic process and therefore we see an apparent increase in brain metastases.” Inflammatory breast cancers are also associated with a higher incidence of brain metastases.
“We need to increase our focus on research aiming at the understanding and treatment of brain metastases,” said Cristofanilli who believes that brain metastases are the last barrier to a possible cure for metastatic breast cancer.
