Two thirds of patients achieved a partial response; half experienced grade 3 or 4 adverse effects.
As new targeted agents have improved outcomes in HER2-positive breast cancer, studies have suggested that survivors might have a longer time to be at risk for developing brain metastases. Radiation therapy is the mainstay for treatment of breast-cancer brain metastases, but it causes adverse effects, and whole-brain radiotherapy (WBRT) impairs cognitive function. Alternatively, systemic therapy seems to have relatively little penetration into the central nervous system (CNS), and evidence of it producing a CNS antitumor effect is lacking. However, recent studies have shown that the oral tyrosine kinase inhibitor lapatinib — administered as monotherapy or in combination with capecitabine — might be an effective treatment. To determine whether this approach could delay radiation therapy, French investigators conducted an industry-funded, single-arm, open-label, phase II (LANDSCAPE) trial of lapatinib and capecitabine involving 44 evaluable patients with HER2-positive breast cancer who had not received whole brain radiotherapy (WBRT).
Treatment was administered in 21-day cycles: patients received oral lapatinib (1250 mg) daily and oral capecitabine (2 gm/m2) on days 1 to 14. Clinical assessments of toxicity and neurological effects were conducted every 3 weeks. Patients underwent computed tomography and magnetic resonance imaging studies to detect CNS lesions every 6 weeks. More than 90% of patients had received prior trastuzumab, 57% had neurological signs and symptoms at enrollment, and 84% had extra-CNS sites of disease, most commonly in bone, liver, and lung. The primary end point of the study was the rate of objective CNS response, defined as a 50% volumetric reduction in CNS lesions without progression of symptoms, extra-CNS disease, or use of steroids.
At median follow-up of 21.2 months, 66% of patients achieved objective CNS responses, all of which were partial responses. Patients were equally likely to attain CNS response whether previously treated with trastuzumab or not. Median time to CNS progression was 5.5 months, and median time to radiotherapy was 8.3 months. The majority of patients (78%) had CNS as the first site of disease progression. Nearly 50% of patients had at least one grade 3 or 4 adverse event, most commonly diarrhea or hand-foot syndrome.
Comment: Brain metastases remain a significant therapeutic challenge, and patients who have a relatively long survival after WBRT might experience some of the well-described cognitive and functional deficits. The LANDSCAPE trial offers patients with HER2-positive brain metastases the potential to delay radiation therapy. However, the combination of lapatinib and capecitabine has the potential to produce substantial adverse effects, which can also negatively affect quality of life.