HER2-Positive Patients Benefit From Combination Therapy of Trastuzumab and Lapatinib

Two new studies suggest that dual inhibition of human epidermal growth factor 2 (HER2) might serve as a better approach to treating patients with HER2-positive breast cancer in the neoadjuvant setting.

Results from the Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) study, published online in The Lancet, enrolled 455 patients with HER2-positive primary breast cancer across 23 countries between January 5, 2008 and May 27, 2010. The randomized, open-label, phase III study assigned patients into groups receiving either lapatinib (n=154), trastuzumab (n=149), or a combination of the two therapies (n=152). The primary endpoint of the trial was the rate of pathological complete response (pCR) at the time of surgery.

The study showed that patients in the combination arm of the study had a significantly higher rate of pCR (51.3%; 95% CI,43.1%-59.5%) than patients who received trastuzumab alone (29.5%; 95% CI, 22.4%-37.5%) or lapatinib alone (24.7%; 95% CI, 18.1%-32.3%). Side effects included grade 3 diarrhea, which was higher in the combination arm (n=32, 21.1%) and the lapatinib arm (n=36, 23.4%) than the trastuzumab arm (n=3, 2.0%). Grade 3 liver enzyme alterations were also higher in the lapatinib arm (n=27, 17.5%) and the combination arm (n=15, 9.9%) than the trastuzumab arm (n=11, 7.4%).

The authors noted that the pCR rate after taking trastuzumab and lapatinib together was higher in patients with hormone receptor (HR)-negative tumors (61.33%,;95% CI, 49.38%-72.36%) than those with HR-positive tumors (41.56%; 95% CI, 30.43%-53.36%). Likewise, the rate of pCR in the combination group was higher in patients with tumors that were less than or equal to 5 cm (55.21%; 95% CI, 41.71%-65.37%) than those whose tumors were greater than 5 cm in size (42.59%; 95% CI, 29.23%-56.79%).

“This is the first demonstration that adding a second anti-HER2 therapy, lapatinib, to trastuzumab is superior to trastuzumab alone in patients with early breast cancer,” said José Baselga, MD, PhD, chief of Hematology/Oncology at Massachusetts General Hospital Cancer Center, lead author of the study, in a statement. “It opens up the concept of dual HER2 blockade as a better approach for patients with early, nonmetastatic, HER2 breast cancer.”

In another study that was published in The Lancet Oncology, trastuzumab was compared to lapatinib when each was combined with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44). The randomized phase III trial enrolled 620 eligible patients with untreated HER2-positive, operable or locally advanced, breast cancer between November 7, 2007 and July 9, 2010. Of the eligible patients, 309 received chemotherapy with trastuzumab, while the remaining 311 patients received chemotherapy with lapatinib.

The study found that 30.3% of patients in the trastuzumab arm (n=93) and 22.7% of patients in the lapatinib arm (n=70) achieved pCR (OR=0.68; 95% CI, 0.47-0.97; P=.04). Because the rate of pCR was lower in the lapatinib arm, the authors suggest that the drug should not be administered as a single-agent anti-HER2 treatment outside of clinical trials.

In a commentary accompanying the study, Stephen K. Chia, MD, a senior scientist in the Division of Medical Oncology at the British Columbia Cancer Agency, noted that lapatinib was associated with greater toxic effects than trastuzumab, and because it had a lower pCR rate, he agreed with the authors’ conclusion that lapatinib should not be used outside of clinical trials as single anti-HER2-treatment in combination with neoadjuvant chemotherapy.

“Moving forward into the future, no adjuvant trials should be done without an adequate signal from preoperative trials showing safety, efficacy, target modulation, and, ideally, the identification of predictive biomarkers such that we no longer pick a loser to study in larger and more resource-intensive adjuvant trials,” Chia wrote.