In HER2 breast cancer, lapatinib works better with trastuzumab than without

The drug lapatinib (Tykerb) is not as effective as trastuzumab (Herceptin) as single-agent chemotherapy for presurgical treatment of women with human epidermal growth factor 2 (HER2)-positive breast cancer. However, combining the two drugs nearly doubles the effectiveness seen with either one alone, although lapatinib causes more side effects.

In one of the two separate studies that generated this overall conclusion, investigators compared the efficacy and safety of the addition of lapatinib vs trastuzumab to anthracycline-taxane-based neoadjuvant chemotherapy in women with untreated HER2-positive operable or locally advanced breast cancer. Of 307 patients randomized to chemotherapy with trastuzumab, 93 (30.3%) had a pathological complete response (the absence of any residual invasive cancer in the breast and the absence of any metastatic cells in the regional lymph nodes), compared with 70 of 308 patients (22.7%) of those assigned to chemotherapy with lapatinib.

The lapatinib group reported 87 serious adverse events compared with 70 among the trastuzumab users. Trastuzumab treatment was associated with more edema (occurring in 39.1% of patients vs 28.7%) and dyspnea (29.6% vs 21.4%). However, lapatinib caused more diarrhea (75.0% vs 47.4%) and skin rash (54.9% vs 31.9%). Ultimately, 33.1% of the lapatinib users discontinued therapy due to toxic effects, compared with 14.0% of the trastuzumab patients.

Based on these results, the researchers recommended against using lapatinib outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy (Lancet Oncol. 2012;13[2]:135-144). But another study, published by The Lancet, points to the combined effectiveness of lapatinib and trastuzumab.

In the latter trial, previously untreated women with HER2-positive primary breast cancer with tumors greater than 2 cm in diameter were randomly assigned to 6 weeks of treatment with lapatinib (n=154), trastuzumab (n=149), or both (n=152), and then an additional 12 weeks of the same regimen plus weekly paclitaxel (Taxol). Tumors were surgically removed within 4 weeks of the final paclitaxel dose.

The dual-agent users achieved a significantly higher pathological complete response (reached by 51.3% of that group's members) than did the trastuzumab-only group (29.5%). No significant difference in pathological complete response was seen between the women taking lapatinib alone (24.7%) and those taking trastuzumab alone.

No major cardiac dysfunctions occurred among study participants. Lapatinib patients and lapatinib-plus-trastuzumab patients had more frequent grade 3 diarrhea than did the women given trastuzumab only (23.4%, 21.1%, and 2.0%, respectively). Similarly, grade 3 liver-enzyme alterations were more frequent with lapatinib (17.5%) and with lapatinib plus trastuzumab (9.9%) than with trastuzumab alone (7.4%).

“Dual inhibition of HER2 might be a valid approach to treatment of HER2-positive breast cancer in the neoadjuvant setting,” concluded José Baselga, MD, PhD, chief of oncology at Massachusetts General Hospital Cancer Center in Boston, and colleagues.

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