No Benefit of Adding Lapatinib to Fulvestrant in Hormone Receptor–Positive Advanced Breast Cancer


Key Points

  • The addition of lapatinib did not improve progression-free survival among all patients, with no apparent effect of HER2 status on outcome.
  • Grade 3 adverse events were more common in the lapatinib group.

In the phase III Cancer and Leukemia Group B (CALGB) 40302/Alliance trial reported in the Journal of Clinical Oncology, Burstein et al found that the addition of the dual EGFR-HER2 inhibitor lapatinib (Tykerb) to endocrine therapy with fulvestrant (Faslodex) did not improve progression-free survival or overall survival and worsened toxicity in postmenopausal women with hormone receptor–positive advanced breast cancer.

Some data suggest that resistance to endocrine agents is associated with acquired overexpression of EGFR or HER2, and there is some evidence indicating that that exposure to EGFR- and HER2-targeting agents can resensitize breast cancers to antiestrogen therapies and endocrine treatments. Given the availability of effective, well-tolerated antiestrogen and dual kinase inhibitor therapies, CALGB 40302 tested the hypothesis that targeting of both estrogen receptor and HER2 signaling would improve outcomes in advanced breast cancer.  

Study Details

In this double-blind trial, 295 patients with stage III or IV estrogen receptor–positive or progesterone receptor–positive tumors, any HER2 status, and prior aromatase inhibitor treatment were randomly assigned to receive fulvestrant 500 mg intramuscularly on day 1 followed by 250 mg on days 15 and 28 and then every 4 weeks, and either daily lapatinib 1,500 mg (n = 146) or placebo (n = 145). The primary endpoint was progression-free survival.

The study planned to accrue 324 patients and was powered to detect a 50% improvement in progression-free survival with lapatinib from 5 to 7.5 months. The study was activated in September 2006. A third planned interim analysis in June 2010 showed a hazard ratio (HR) for progression-free survival of 0.98 (95% confidence interval [CI] = 0.73–1.33), which crossed the futility boundary such that the predicted probability of finding that lapatinib was superior to placebo with continued accrual and follow-up was < 1%. The trial was closed to new accrual in July 2010.

The lapatinib and placebo groups were generally balanced for age distribution (eg, 34% and 37% 50–59 years, 28% and 32% 60–69 years), race (87% and 91% white), prior tamoxifen (57% in both), bone disease only (31% and 30%), Eastern Cooperative Oncology Group performance status (0 in 59% and 72%, 1 in 39% and 27%), prior aromatase inhibitor therapy (97% in both), prior trastuzumab (Herceptin) (2% and 3%), estrogen receptor–positive status (99% and 97%), progesterone receptor–positive status (73% and 68%), HER2-positive status (16% and 21%), number of metastatic sites (one in 37% and 43%, two in 34% in both, three in 20% and 14%), prior chemotherapy for metastatic breast cancer (16% and 17%), and disease-free interval (> 2 years in 48% and 53%).

No Progression-Free Survival Benefit

Median follow-up for surviving patients was 2.8 years. At final analysis, median progression-free survival was 4.7 months in the lapatinib group vs 3.8 months in the placebo group (HR for placebo vs lapatinib = 1.04, P = .37). Median overall survival was 30 vs 26.4 months (HR = 0.91, P = .25).

Median progression-free survival was 4.1 vs 3.8 months (HR for placebo vs lapatinib = 1.00, 95% CI = 0.76–1.30) among patients with HER2-negative tumors and 5.9 vs 3.3 months (HR for placebo vs lapatinib = 1.23, 95% CI = 0.69–0.18) among those with HER2-positive tumors; the differential treatment effect by HER2 status was not significant (P = .53).

Objective Response

Among the 70% of patients with measurable disease, objective response was observed in 20% vs 9% (P = .048); complete response was observed in 2% of patients in each group. Response was observed in 13% vs 23% of patients with HER2-negative disease and 38% vs 17% with HER2-positive disease, but interaction between treatment and HER2 status was not significant (P = .53).

Adverse Events

No grade ≥ 4 adverse events were reported. Lapatinib patients had a higher rate of grade 3 events (19% vs 5%, P < .001), including diarrhea (8% vs 0%), acneiform rash (3% vs 0%), fatigue (3% vs 0%), and increased ALT or AST (4% vs 1%). Treatment was discontinued due to adverse events in 12% vs 2% of patients (P < .001), mostly due to diarrhea, fatigue, and rash. No grade 3 cardiac toxicity was reported.

The investigators concluded: Adding lapatinib to fulvestrant does not improve [progression-free survival] or [overall survival] in advanced [estrogen receptor–]positive breast cancer and is more toxic…. Given the importance of multiple lines of endocrine therapy in the palliation of advanced breast cancer and the opportunities for improving outcomes in the adjuvant setting, other approaches to overcome clinical endocrine resistance are needed.”

Harold J. Burstein, MD, PhD, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit

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