Neoadjuvant Chemotherapy Plus Two Anti-HER2 Agents Optimal for HER2-Positive Breast Cancer

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For women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, combining two anti-HER2 agents with chemotherapy is the most effective treatment modality in the neoadjuvant setting, according to a meta-analysis published in the Journal of the National Cancer Institute.

The study found that chemotherapy with trastuzumab (Herceptin) plus lapatinib (Tykerb), or with trastuzumab plus pertuzumab (Perjeta), resulted in a statistically significant larger number of patients achieving pathologic complete response than did chemotherapy alone, chemotherapy with a single targeted therapy, or two anti-HER agents without chemotherapy. Ranking of treatment arms indicated that chemotherapy with trastuzumab plus pertuzumab “had the highest probability of being the best treatment arm in terms of [pathologic complete response],” the investigators stated.

“The growing number of HER2-targeted agents has created the need to define the optimal neoadjuvant therapy for HER2-positive breast cancer,” the researchers wrote in explaining the rationale for the study. While other trials have been conducted to compare treatments, “it is difficult to integrate information on the relative efficacy of all tested regimens, since each trial has compared only a few treatments,” the investigators noted.

For this study, the researchers used network meta-analysis, which they called “a promising but much-debated extension of systematic reviews” that “synthesizes information from a network of trials and combines direct and indirect evidence on the relative effectiveness of the treatments.” Network analysis, they added, “helps interpret the randomized evidence from a network of trials and can rank many different treatments, going beyond the classical focus on simple direct comparison.”

Data From 10 Studies

A database search of randomized trials comparing different anti-HER2 regimens in the neoadjuvant setting identified 10 studies meeting the eligibility criteria. A total of 2,247 patients in seven different treatment arms were assessed. The treatment arms were: chemotherapy alone; chemotherapy with trastuzumab, lapatinib, or pertuzumab; trastuzumab and pertuzumab; chemotherapy with trastuzumab and lapatinib; and chemotherapy with trastuzumab and pertuzumab. Most of the neoadjuvant chemotherapy regimens used included anthracyclines and taxanes. HER2-positive breast tumors accounted for 34% to 61% across all 10 studies.

In direct comparisons, pathologic complete response was statistically significantly greater in patients who received dual anti-HER2 agents with chemotherapy than in other treatment arms. No statistically significant difference was found among treatment arms of a single anti-HER2 agent with chemotherapy, but chemotherapy with lapatinib “was associated with inferior efficacy” compared with chemotherapy with trastuzumab.

Treatment arms with lapatinib “showed statistically significantly less treatment completion with more incidence of diarrhea and skin disorder” compared with chemotherapy and trastuzumab. Trastuzumab plus pertuzumab “had statistically significantly less incidence of neutropenia” compared with treatment arms with chemotherapy. “The incidence of cardiac events did not show any statistically significant difference among all the treatment arms,” the authors added.

Indirect Comparisons

Network meta-analysis allowed for 21 indirect comparisons and found 12 statistically significant differences in pathologic complete response, plus others in treatment completion and adverse effects. These results demonstrated that dual anti-HER2 agents with chemotherapy had a statistically significantly higher incidence of pathologic complete response than chemotherapy with trastuzumab (chemotherapy plus trastuzumab plus pertuzumab vs chemotherapy plus trastuzumab, odds ratio [OR] = 2.29, 95% confidence interval = 1.02–5.02, P = .02).

Chemotherapy alone or chemotherapy plus lapatinib had a statistically significantly lower incidence of pathologic complete response compared with chemotherapy plus trastuzumab. “This finding strengthened the results of the direct comparisons,” the researchers stated.

“This promising result of dual targeting therapy will lead us to the argument about whether the dual targeting therapy should be used in a neoadjuvant setting, adjuvant setting, or metastatic setting to have the best outcome as a whole,” the researchers added.

“The major findings from both the direct and indirect analyses were consistent with the gestalt regarding dual therapy with lapatinib and pertuzumab—both are inferior to trastuzumab as single agents, both augment [pathologic complete respone] when added into trastuzumab-based regimens, none induces substantial acute cardiac damage, and lapatinib is more toxic than the other drugs,” according to an accompanying editorial. The editorial authors, Lisa A. Carey, MD, of the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill, and William Barry, PhD, of Dana-Farber Cancer Institute in Boston, noted that neoadjuvant trials are smaller and “underpowered for the clinically relevant endpoints of relapse and survival” and that pooled analyses can help provide better estimates of treatment effects.

“Our challenge now is to determine if there is a quantitative relationship between improvement in [pathologic complete response] and better long-term outcomes so that these trials can be used in lieu of, rather than in addition to, large adjuvant trials,” Drs. Carey and Barry wrote. “If we cannot identify such a relationship, then the clinical value of neoadjuvant trials is lost in terms of predicting survival endpoints; their value will only be in the opportunity for tissue-based studies, important academically but of limited clinical usefulness.” ■

Nagayama A, et al: J Natl Cancer Inst 106(9):dju203, 2014.

Carey LA, Barry W: J Natl Cancer Inst 106(9):dju259, 2014.