The incidence of central nervous system metastases in patients with metastatic breast cancer treated with lapatinib-capecitabine or trastuzumab-capecitabine: results from the CEREBEL study

During the 2012 annual meeting of the European Society for Medical Oncology (ESMO) results were presented of the phase III CEREBEL study evaluating the incidence of central nervous system (CNS) metastases in women with metastatic breast cancer treated with capecitabine plus lapatinib or trastuzumab plus capecitabine. Due to the low incidence of CNS metastases in the study these results were however inconclusive. However, investigators did observe that the progression-free survival (PFS) was significantly longer for patients treated with trastuzumab-capecitabine. Interestingly, this PFS advantage was only seen in the subgroup of patients that was not previously treated with trastuzumab.

The combination of lapatinib and capecitabine is approved for the treatment of patients with HER2-positive metastatic breast cancer who have progressed on prior trastuzumab treatment in the metastatic setting. In addition to this, trastuzumab combined with capecitabine also demonstrates clinical activity in this setting. However, the incidence of CNS metastases is a major concern in 28 to 43% of metastatic breast cancer patients treated with trastuzumab. This incidence of CNS metastases was lower for lapatinib combined with capecitabine and in order to study this in more detail, the EMEA requested a confirmatory study.

In this study, called CEREBEL, HER2-positive metastatic breast cancer patients who received prior anthracyclines or taxanes were randomised between lapatinib (1250mg/day) plus capecitabine (2000mg/m2/day, days 1-14 q21 days), or trastuzumab (6mg/kg q21 days) plus capecitabine (2000mg/m2/day, days 1-14 q21 days). Before patients could enter the study, they had to undergo a very stringent screening process in order to be sure that they did not have CNS metastases. Through this stringent process investigators detected asymptomatic CNS metastases in 20% of the subjects with HER2-positive metastatic breast cancer. The initial accrual goal of the trial was 650 patients, but based on a recommendation of the IDMC, the study was terminated prematurely when a total of 540 patients was included. The primary endpoint of CEREBEL was the incidence of CNS as site of first relapse, while secondary objectives included progression-free survival, overall survival (OS), overall response rate (ORR), time to first CNS progression and safety.

Due to the low incidence of CNS metastases (3% for lapatinib-capecitabine vs. 5% for trastuzumab-capecitabine) in the study, the results for the primary endpoint were inconclusive. However, investigators did show a significantly longer PFS for patients treated with trastuzumab plus capecitabine compared to lapatinib-capecitabine (8 vs. 6.6 months; HR[95%CI]: 1.30[1.04-1.64]; p=0.021). In addition to this, OS was also prolonged in the trastuzumab-capecitabine arm, although this difference was not significant (27.3 vs. 22.7 months; HR[95%CI]: 1.34[0.95-1.90]; p=0.095). Interestingly, the PFS and OS benefit observed for trastuzumab-capecitabine was only observed in patients who did not receive prior trastuzumab therapy.

In summary, due to the low incidence of CNS metastases, CEREBEL was inconclusive for its primary endpoint. This low incidence can probably be attributed to the stringent CNS screening at baseline. Interestingly, the study did demonstrate a significant PFS prolongation with trastuzumab-capecitabine compared to lapatinib-capecitabine. However, this advantage was confined to trastuzumab-naïve patients and was not observed in patients that were previously treated with trastuzumab.

Reference

Pivot X, Zurawski B, Allerton R et al. CEREBEL (EGF111438): an open label randomised phase III study comparing the incidence of CNS metastases in patients with HER2+ metastatic breast cancer, treated with lapatinib plus capecitabine versus trastuzumab plus capecitabine. Presented at ESMO 2012, Abstract LBA11.