Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases--the UK experience

Abstract

Background: The global lapatinib expanded access programme provided access to lapatinib combined with capecitabine for women with HER2-positive metastatic breast cancer (MBC) who previously received anthracycline, taxane and trastuzumab.

Methods: Progression-free survival (PFS) and safety data for 356 patients recruited from the United Kingdom are reported. Efficacy was assessed in 162 patients from the five lead centres, including objective tumour response rate (ORR), time to disease progression (TTP) and efficacy in those with central nervous system (CNS) metastases. Correlation of PFS and ORR with previous capecitabine treatment was also documented.

Results: Overall, PFS for the 356 UK patients was 21 weeks (95% CI: 17.6-24.7). In the 162 assessable patients, ORR was 21% (95% CI: 15-27%) and median TTP was 22 weeks (95% CI: 17-27). Efficacy was greater in capecitabine-naive patients (ORR 23 vs 16.3%, P=0.008). For 34 patients with CNS metastases, ORR was 21% (95% CI: 9-39%), with evidence of improvement in neurological symptoms, and median TTP was 22 weeks (95% CI: 15-28).

Conclusions: Lapatinib combined with capecitabine is an active treatment option for women with refractory HER2-positive MBC, including those with progressive CNS disease.

Figure 1

Time to progression illustrated by a Kaplan–Meier Curve for the 162 patients assessed for response.

Figure 2

Time to progression by previous capecitabine exposure, illustrated by Kaplan–Meier Curves for the cohort of patients assessed for response.

Figure 3

Response of CNS metastases to lapatinib and capecitabine in the absence of previous whole-brain radiotherapy. This 61-year-old woman with HER2-positive breast cancer was diagnosed in 2002. Subsequently, she received three lines of trastuzumab-containing chemotherapy for metastatic breast cancer (paclitaxel, vinorelbine and capecitabine). In July 2007, she developed headache, nausea and vomiting. CT brain revealed three metastases with associated cerebral oedema. She required only a very small dose of steroid and was entered into the LEAP study without previous local therapy (neither neurosurgery nor WBRT) and a combination of capecitabine and lapatinib was her first treatment for CNS disease. She had an excellent clinical response after two cycles, with complete resolution of her headache, nausea and intermittent vomiting, as well as radiological improvement on repeat CT scan with resolution of cerebral oedema and volume reduction of metastases.

Figure 4

Case study 2 and scan pictures illustrating response. This 47-year-old woman was diagnosed in 1995 with HER2-positive primary breast cancer. In June 2005, she developed metastatic disease (bones, liver and lung) and was treated with eight cycles of docetaxel, trastuzumab and pamidronate to which she had a good response, continuing on maintenance trastuzumab and pamidronate with stable disease. In August 2006, she developed headache and left hand tremor, and a CT scan of her brain confirmed multiple cerebral metastases that were treated with whole-brain radiotherapy, whereas her systemic disease remained stable on continued trastuzumab and pamidronate. In February 2007, she developed increasing headache, and a CT scan confirmed CNS disease progression. In March 2007, she commenced capecitabine and lapatinib in the LEAP study, and, within 6 weeks, a repeat CT scan showed a significant reduction in tumour volume. Her CNS disease remained stable for a further 14 cycles of treatment before progressing in March 2008.

Figure 5

Time to progression for the subgroup of patients with brain metastases (n=34), according to previous capecitabine exposure, illustrated by Kaplan–Meier Curves, from the cohort of 162 patients assessed for response.

Figure 6

Changes in LVEF from the overall UK Safety data (n=356) (graph shows the mean LVEF and 95% CI at each time point.).