Dual HER2 Blockade Fails to Improve Response Rate in HER2-Positive Breast Cancer

Dual HER2 blockade with trastuzumab and lapatinib was no better than trastuzumab alone in producing pathologic complete responses (pCR) in metastatic HER2-positive breast cancer patients in the neoadjuvant setting, according to a new study. Those with hormone receptor–negative disease did see an improvement with the dual blockade.

“In randomized neoadjuvant trials, dual HER2 targeting generally results in higher pCR rates, but the magnitude of this effect has varied,” wrote study authors led by Lisa A. Carey, MD, of the University of North Carolina at Chapel Hill. The new trial was a three-arm study of preoperative therapy in 305 patients with stage II/III HER2-positive breast cancer; 118 patients were randomized to paclitaxel along with trastuzumab and lapatinib, 120 to paclitaxel with trastuzumab alone, and another 67 to paclitaxel along with only lapatinib. That last trial arm was closed early. Results were published online ahead of print in the Journal of Clinical Oncology.

Among 295 evaluable patients, 139 achieved a pCR in the breast. In the trastuzumab and lapatinib arm, the rate was 56%, compared to 46% with trastuzumab alone; this did not reach significance (P = .13). In the lapatinib-alone arm the rate was only 32%, which led to the early closing.

The pCR rate was no different between treatment arms in hormone receptor–positive tumors, but in the hormone receptor–negative group the dual blockade patients did have a higher pCR rate than the trastuzumab alone arm (79% vs 54%; P = .01).

A total of 265 tumors underwent gene expression profiling, and response did vary by intrinsic subtype (P < .001). The pCR rate was approximately double among HER2-enriched tumors compared with luminal A and B tumors, regardless of treatment arm.

“This study suggests that biologic heterogeneity within HER2-positive breast cancer plays an important role in determining response to treatment,” the study authors wrote. “For each of the treatment approaches used in this trial, pCR was markedly higher among HER2-enriched tumors than among HER2-positive tumors of any other subtype.”

The authors also noted that response rates are not necessarily a perfect substitute endpoint for more clinically relevant outcomes including relapse-free and overall survival.

“HER2-targeted drugs are among the most expensive cancer drugs. Trastuzumab-based regimens often exceed $5,000 per month, and dual therapy regimens can exceed $10,000 per month,” they concluded. “Optimizing the selection of HER2-targeted regimens by identifying subpopulations of patients with HER2-positive disease who need more or less therapy could be cost effective and would spare some patients unnecessary exposure to ineffective treatments.”