Mixed results in phase II and III clinical trials leave open the question of whether lapatinib can prevent brain metastases in women with HER2-positive breast cancer.
Lapatinib (Tykerb) did not decrease the development of brain metastases when compared with trastuzumab (Herceptin) – each added to capecitabine (Xeloda) – in the open-label phase III CEREBREL trial. The results were inconclusive, however, for the primary end point of the incidence of central nervous system events as a first sign of relapse.
Favorable findings were reported from the 45-patient phase II LANDSCAPE study. Two-thirds of patients had an objective CNS response to up-front lapatinib plus capecitabine in the single-arm study.
Investigators from both trials reported outcomes at the European Society for Medical Oncology Congress.
‘No Conclusion Can Be Made…’
In the CEREBREL trial, 251 women were treated with lapatinib in combination with capecitabine. Eight (3%) exhibited CNS progression as the first site of relapse. In comparison, 12 (5%) of 250 women given trastuzumab plus capecitabine exhibited CNS progression (P = .360).
The incidence of CNS progression at any time (7% vs. 6%, respectively) and the median time to first CNS progression (5.7 vs. 4.4 months) also did not differ significantly.
Sara Freeman/IMNG Medical Media
Dr. Xavier Pivot
“No conclusion should be made from these results,” said Dr. Xavier Pivot of the Université de Franche-Comté in Besançon, France.
Dr. Pivot noted that a very low rate of CNS events had occurred in the trial because of the stringent accrual process, undermining the conclusions that can be drawn.
Trial Excluded Asymptomatic Brain Metastases
“The CEREBREL study was a front-line study, but the problem was that asymptomatic brain metastases were being screened out of the population,” Dr. Stephen Johnston, who was not involved the study, commented in an interview.
“The overall incidence of brain metastases that they found in the study was a lot lower than they were anticipating, so they were never going to meet their end point,” added Dr. Johnston, a consultant medical oncologist and director of clinical research and development at the Royal Marsden and the Institute of Cancer Research in London.
CEREBREL enrolled 540 of a planned 650 women with HER2-positive metastatic breast cancer who had received prior treatment with an anthracycline or taxane but who had no CNS metastases. To ensure that no metastases were present, patients had a baseline MRI scan, with 20% of women excluded because they had asymptomatic lesions.
In total, 271 women received lapatinib (1,250 mg/day) plus capecitabine (2,000 mg/m2/day on days 1-14 every 21 days) and 269 trastuzumab (6 mg/kg every 21 days) plus capecitabine (2,500 mg/m2/day on days 1-14 every 21 days).
PFS Longer with Trastuzumab and Capecitabine
The trial results also showed that median progression-free survival (PFS) was longer in patients who received trastuzumab in combination with the chemotherapy than in those who received lapatinib (8 months vs. 6.6 months, hazard ratio 1.3, P = .021).
This effect dissipated, however, when prior treatment with trastuzumab was considered; it had been received by 62% of patients in the lapatinib-containing arm and 59% of patients in the trastuzumab-containing arm.
While there was no difference in PFS among patients who had previously been treated with trastuzumab, those who had never received the drug before the trial appeared to obtain a greater benefit.
Commenting on these data, Dr. Johnston noted that they do seem to suggest that the combination of lapatinib and capecitabine was not equivalent and was actually inferior to trastuzumab plus capecitabine.
Nevertheless, “I think the question about the effects of lapatinib on brain metastases is still relevant,” he said.
“We’re doing a trial [LANTERN] of lapatinib-capecitabine versus continuing the trastuzumab and adding in capecitabine, to see if switching the HER2-targeting keeps the brain disease under control for longer,” Dr. Johnston explained. “This is where lapatinib may still have a role.”
LANDSCAPE Results Favorable
The primary hypothesis of the phase II LANDSCAPE study was that up-front treatment with lapatinib might help prevent brain metastasis in HER2-positive metastatic breast cancer and delay the need for whole-brain radiation and its associated neurotoxicity, said study investigator Dr. Thomas Bachelot, on behalf of the Unicancer Federation Française group.
Dr. Bachelot of INSERM in Lyon said the response and overall survival results compared favorably with published data for whole-brain radiotherapy (WBRT).
Two thirds (66%) of patients treated with lapatinib and capecitabine exhibited a CNS objective response: 46% achieved a reduction in brain metastases of 50%-80%, and 20% exhibited a reduction in brain metastases of 80% or more. The median time to progression was 5.5 months, and the median time to WBRT was 7.8 months. Median overall survival was 17 months.
“This strategy could help delay whole-brain radiotherapy and its associated [neurological] toxicity,” Dr. Bachelot concluded, noting that the up-front use of lapatinib and capecitabine warrants further evaluation.
The first analysis of the LANDSCAPE trial was presented at the American Society of Clinical Oncology (ASCO) in 2011.
Both the CEREBREL and LANDSCAPE studies were supported by funding from GlaxoSmithKline. All authors have received research support or consultancy fees from GlaxoSmithKline and Roche. Dr. Bachelot and Dr. Johnston have also received consultancy fees from Novartis.