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Lapatinib shrank brain lesions of patients with heavily pretreated, metastatic, HER2-positive breast cancer in an ongoing, international phase II trial.
Dr. Nancy U. Lin reported that the volume of CNS tumors shrank by 50% or more in 19 (8%) of 241 women. Another 46 women (19%) had their tumors reduced in volume by 20% or more.
Although the objective response was modest at best and the data is preliminary, the researchers confirmed that lapatinib (Tykerb) has single-agent activity against recurrent brain metastases, according to Dr. Lin of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston. Additional phase I and II studies will test it in combination with other chemotherapy agents and with cranial radiotherapy.
Meanwhile, Dr. Lin and her colleagues hope to have more data later this year on the clinical effect of reductions in tumor volume of less than 20%. "We acknowledge that the clinical significance of these lesser degrees of reduction are not fully known, but we are currently analyzing the data with respect to progression-free survival and neurological symptoms."
Dana-Farber investigators conducted the trial in collaboration with Brigham and Women's Hospital, Boston; the Breast Cancer Research Foundation; and GlaxoSmithKline Inc., developer of lapatinib, an oral small-molecule inhibitor of the human epidermal growth factor 2 (HER2) tyrosine kinase receptor.
The U.S. Food and Drug Administration approved lapatinib in March for treatment with capecitabine of advanced or metastatic HER2-positive breast cancer in patients who had previously received therapy with an anthracycline, a taxane, or trastuzumab (Herceptin).
About a third of patients with metastatic HER2-positive disease develop brain metastases, according to Dr. Lin. Yet there is little consensus on appropriate management when these progress. Lapatinib is an inhibitor of the epidermal growth factor receptor and HER2. Because it is a relatively small molecule, the investigators hypothesized it might be active in the central nervous system.
Dr. Lin and her colleagues enrolled 241 patients (median age, 49 years) with confirmed metastases between December 2005 and November 2006. Most had non-CNS involvement as well as a history of two or more regimens containing trastuzumab and whole-brain radiotherapy. About a quarter of the women had had stereotactic radiotherapy.
Dr. Lin reported that 21 patients were still receiving 750 mg of lapatinib orally twice a day. Another 52 patients were taking a combination of lapatinib and capecitabine in an extension arm open to women whose brain metastases progressed while they were on single-agent lapatinib. Patients with stable CNS disease and systemic (non-CNS) progression were allowed to continue lapatinib with the addition of their oncologist's choice of several possibilities (based on phase I safety data), including trastuzumab, capecitabine, paclitaxel, docetaxel, and letrozole.
None of the patients had a complete response, according to CNS composite response criteria that the investigators developed for the trial. In all, 15 patients (6%) had a partial response, and 102 (42%) had stable disease. At 6 months, 22% of the women had no progression of metastatic breast cancer in the brain, body, or both; median progression-free survival was 15.1 weeks. Responders had 25.3 weeks of progression-free survival, compared with 15.3 weeks in nonresponders.
Four patients withdrew because of treatment-related toxicity, but overall lapatinib was well tolerated, Dr. Lin said. Although 13% of the patients had grade 3/4 diarrhea, other toxicities were mostly minor.
Patients who opted to enroll in the trial extension after progressing on lapatinib received 1,250 mg of lapatinib daily and 2,000 mg/m² of capecitabine daily on 14 of 21 days.
Because of the small number of subjects, Dr. Lin emphasized that her report on these patients was descriptive only. Of 40 who could be assessed, eight (20%) had a 50% or better volumetric reduction in their brain tumors and 16 (40%) had a reduction of 20% or more. Only six patients withdrew because of progressive disease.
"Early data suggest that lapatinib/capecitabine has CNS activity," Dr. Lin concluded. "Future lapatinib-based combination studies would be of interest."
In his discussion of the study results, Dr. Stephen R.D. Johnston, of the Royal Marsden Hospital, London, described brain metastasis as an increasing problem in the clinic and said its treatment is an unmet need. "Small-molecule therapeutics may offer new systemic treatment options for brain metatases, and further work in this area is urgently required," he said.
Among questions to be answered, Dr. Johnston listed when to start lapatinib; whether to use it as monotherapy or in combination with other treatments; what to do about non-CNS progression in other sites; and whether brain metastases can be prevented.
"Waiting until patients progress again after their whole brain radiotherapy for many may be too late," he said. "We need to address the role of therapeutics immediately after the diagnosis of brain metastases."
Dr. Johnston disclosed that he has received research funds and served on the speakers' bureau of GlaxoSmithKline.
Lin N.U. EGF105084, a phase II study of lapatinib for brain metastases in patients (pts) with HER2+ breast cancer following trastuzumab (H) based systemic therapy and cranial radiotherapy (RT). Abstract 1012.
Commentary |
These data, as well as those previously presented by the same investigators, show that some patients with brain metastases will attain objective responses to single-agent lapatinib therapy. These cases also demonstrate the ability of lapatinib to cross the blood-brain barrier. The methods used to assess benefit (volumetric changes) are somewhat complicated, and may not be readily duplicated in practice. Some of the key issues going forward were addressed by Dr. Stephen Johnston who suggested work still to be done, including identifying the patients most likely to benefit from lapatinib and whether the effect can be optimized in combination with other agents. — William J. Gradishar, M.D.
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