CHICAGO – Lapatinib was not superior to trastuzumab when used as a component of neoadjuvant therapy for operable HER2-positive breast cancer in a randomized cooperative group trial. And neither was a combination of both drugs in the population overall.
About 50%-60% of the 529 patients studied had a pathological complete response (pCR) whether they received trastuzumab (Herceptin) only, lapatinib (Tykerb) only, or lapatinib plus trastuzumab, each in addition to standard chemotherapy in the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-41 trial, investigators reported.
However, patients whose tumors had a high level of HER2 overexpression on immunohistochemistry, scored as 3+ staining, were more likely to have a pCR if they received lapatinib plus trastuzumab than if they received trastuzumab alone, Dr. Andre Robidoux told attendees at the annual meeting of the American Society of Clinical Oncology.
Of note, the rate of grade 3 or worse diarrhea was higher with lapatinib alone or in combination, the investigators found. And patients in those groups were less likely to complete their treatment.
"Combined HER2-targeted therapy produced a numerically higher pCR percentage than single-agent HER2-directed therapy, but the difference was not statistically significant," said Dr. Robidoux of the Centre Hospitalier de l’Université de Montréal
"Unplanned analysis based on immunohistochemical staining intensity suggests that combined HER2-targeted therapy may be of greatest value in patients with tumors with a high degree of protein overexpression," he added.
Dual Blockade Supported
Discussant Dr. Gunter von Minckwitz of the German Breast Group and the University of Frankfurt noted that neoadjuvant trastuzumab therapy increases the likelihood of residual ductal carcinoma in situ (DCIS) at surgery, which is a negative prognostic factor for disease-free survival (J. Clin. Oncol. 2012;30:901-3). "So maybe the NSABP investigators should also analyze their data for an even more pure pCR definition," he proposed.
"We have seen now a series of studies either combining lapatinib and trastuzumab or combining trastuzumab and pertuzumab [Perjeta] showing higher pCR rates compared to patients who got only one of the anti-HER2 treatments," he maintained. "So this is the way we have to go. ... Dual blockade appears to be the most promising approach for the future."
"We have to wait, of course, to see how far the neoadjuvant results are predicting the outcome of adjuvant treatment; therefore, ALTTO and APHINITY are crucial," Dr. von Minckwitz added, referring to two trials.
"However, I believe the results from the neoadjuvant setting are quite consistent with the results that are now obtained in other settings – the adjuvant and metastatic settings. Therefore, this might open a regulatory path for conditional approval of agents in early development," as recently proposed by the Food and Drug Administration (N. Engl. J. Med. 2012 May 30).
Giving background on NSABP B-41, Dr. Robidoux noted that doxorubicin (Adriamycin) plus cyclophosphamide, followed by weekly paclitaxel plus trastuzumab, has been a standard neoadjuvant therapy for HER2-positive breast cancer since 2005. But lapatinib, an oral dual tyrosine kinase inhibitor of HER2 and the epidermal growth factor receptor (EGFR), has a different mechanism of action and shows synergy with trastuzumab.
"The next logical step was to evaluate the addition of a second agent that interrupts HER2 signaling through a different mechanism than trastuzumab," he said.
PCR Rates Indistinguishable
Women enrolled in the trial had a palpable tumor measuring at least 2 cm, a left ventricular ejection fraction of at least 50%, and HER2-positive disease, defined as gene amplification by fluorescence in situ hybridization (FISH) or a score of 3+ by immunohistochemistry.
All women received four cycles of doxorubicin plus cyclophosphamide. Thereafter, they received weekly paclitaxel plus trastuzumab only (as a control), plus lapatinib only, or plus both. They then underwent surgery and received trastuzumab postoperatively.
The main results showed that the rate of clinical complete response with lapatinib alone (69.9%) was lower than that with trastuzumab alone (82%) (P = .014). But it did not differ significantly between trastuzumab and lapatinib plus trastuzumab (76.8%).
The rates of pCR in the breast with lapatinib alone (53.2%) or lapatinib combined with trastuzumab (62%) were statistically indistinguishable from that seen with trastuzumab alone (52.5%).
This pattern was the same in subgroups having hormone receptor–positive and negative disease. However, in a finding that Dr. Robidoux called "intriguing," the pCR rate among those with 3+ immunohistochemical staining for HER2 was higher with lapatinib plus trastuzumab (71%) than with trastuzumab alone (54.7%) (P = .006).
The overall rate of grade 3 or worse toxicity was 50% with trastuzumab alone, 62% with lapatinib alone, and 61% with lapatinib plus trastuzumab. Grade 3 or worse diarrhea was by far more common in both lapatinib groups (P less than .001), but grade 3 or worse febrile neutropenia and hepatotoxicity were similarly common.