Lapatinib plus letrozole prolongs disease control in subset of patients

SAN ANTONIO-Lapatinib (Tykerb) plus letrozole (Femara) may delay disease progression in metastatic breast cancer patients, according to an international phase III trial. Patients who benefited from the protocol were those who overexpressed the HER2/neu protein and the epidermal growth factor receptor and were also hormone receptor-positive.

EGF30008 is the largest clinical trial to test whether combined endocrine and targeted HER2 inhibition improves outcomes in patients with HR-positive metastatic breast cancer. Initial results were presented by Stephen Johnston, MA, PhD, of the Royal Marsden NHS Foundation and Trust and Institute of Cancer Research in London.

Cross-talk between the growth factor and steroid receptor pathways has been implicated in endocrine resistance in breast cancer. For HR-positive patients receiving aromatase inhibitors, adding a drug that targets the EGFR (ErbB2) and HER2 pathways is hypothesized to enhance endocrine responsiveness and delay the onset of resistance.

“These patients are currently offered only an aromatase inhibitor. The suggestion from this study is that combined treatment with the orally active dual tyrosine kinase inhibitor lapatinib may be a better approach than letrozole alone,” Dr. Johnston said. He estimated that about 15% of breast cancer patients may be part of this subset.

The EGF30008 trial was a double-blind, placebo-controlled phase III study to explore the benefit of letrozole (2.5 mg/d) with and without lapatinib (1500 mg/d) in the first-line treatment of HR-positive metastatic breast cancer. The study included 1,286 postmenopausal women, 219 of whom were both HR-positive and HER2-positive (abstract 46).

In this cohort, the combination of lapatinib plus letrozole significantly increased median progression-free survival (PFS) from three months with letrozole alone to 8.2 months, representing a 29% reduction in risk of progression, Dr. Johnston reported.

Response rates were significantly increased, from 15% to 28%, with the combination, and clinical benefit (response plus stable disease ≥24 weeks) was observed in 29% and 48%, respectively. Overall survival rates would be premature, but a nonsignificant 26% reduction in risk has been observed so far with the combination.

In the entire population of 1,286 patients, regardless of HER2 status, the intent-to-treat analysis showed less effect; the combination increased PFS by about one month, from 10.8 months to 11.9 months, which was statistically significant. In the HER2-negative population, median PFS was approximately 13.5 months in both arms, with no additional benefit from lapatinib observed.

However, when the HER2-negative population was stratified according to endocrine sensitivity, an interesting finding was observed. In patients who were classified as endocrine resistant (relapse less than six months after tamoxifen discontinuation), median PFS was just 3.1 months with letrozole alone but increased to 8.3 months with lapatinib plus letrozole, for a 22% (but nonsignificant) reduction in risk. For patients who were endocrine sensitive (relapse greater than six months since tamoxifen discontinuation or no prior tamoxifen), median PFS was approximately 15 months in each arm, with no additional benefit gained from the combination, Dr. Johnston reported.

In the resistant population, clinical benefit was achieved in 32% receiving letrozole alone compared with 44% receiving the combination. In the sensitive population, about 63% of each arm experienced clinical benefit.

The combination was well tolerated. As expected, grade 3 or 4 diarrhea was more common with lapatinib (9% versus <1%) but was manageable for most patients. Treatment-related declines in left ventricular ejection fraction occurred in 2% on the combination and 1% with letrozole alone.

Dr. Johnston cautioned that the data regarding differential effects in endocrine-sensitive versus endocrine-resistant HER2-negative patients is exploratory, but maintained that its hypothesis-generating potential appears “fantastic.”