In a 7-year follow-up of the phase III CALGB 40601/Alliance neoadjuvant trial reported in the Journal of Clinical Oncology, Fernandez-Martinez et al found that paclitaxel combined with trastuzumab/lapatinib was associated with improved survival outcomes vs paclitaxel/trastuzumab in women with HER2-positive breast cancer, with no differences observed between paclitaxel/trastuzumab and paclitaxel/lapatinib. Gene expression analysis identified signatures associated with treatment outcomes.
In the trial, 305 women with previously untreated stage II or III disease were randomly assigned between December 2008 and February 2012 to receive weekly paclitaxel plus trastuzumab/lapatinib (n = 118), paclitaxel/trastuzumab (n = 120), or paclitaxel/lapatinib (n = 67). Treatment consisted of paclitaxel (80 mg/m2 once per week), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), lapatinib (1,500 mg/day), or both (lapatinib at 1,000 mg/day when used in combination) for 16 weeks. Due to reports of inferiority and higher toxicity, the paclitaxel/lapatinib arm was closed early, with patients randomly assigned to that group completing treatment. It was recommended that all patients receive dose-dense doxorubicin and cyclophosphamide and complete 1 year of trastuzumab in the adjuvant setting. The primary endpoint was pathologic complete response; secondary endpoints included relapse-free survival, overall survival, and gene expression analysis.
Pathologic Complete Response and Survival Outcomes
In the intent-to-treat population, pathologic complete response rates were 57% in the paclitaxel plus trastuzumab/lapatinib group, 45% in the paclitaxel/trastuzumab group, and 30% in the paclitaxel/lapatinib group. After surgery, 51% of patients received doxorubicin/cyclophosphamide and 73% completed 1 year of trastuzumab.
After median follow-up of 83 months, relapse-free survival events were observed in 26.9% of the paclitaxel/lapatinib group, 20% of the paclitaxel/trastuzumab group, and 6.8% of the paclitaxel plus trastuzumab/lapatinib group. Corresponding 7-year relapse-free survival rates were 69%, 79%, and 93%. For the paclitaxel plus trastuzumab/lapatinib vs paclitaxel/trastuzumab group, the hazard ratio (HR) was 0.32 (95% confidence interval [CI] = 0.14–0.71, P = .005). For the paclitaxel/lapatinib vs paclitaxel/trastuzumab group, the HR was 1.50 (95% CI = 0.82–2.77, P = .191).
Death from any cause occurred in 13.4% of patients in the paclitaxel/lapatinib group, 11.7% of the paclitaxel/trastuzumab group, and 3.4% of the paclitaxel plus trastuzumab/lapatinib group, with corresponding 7-year overall survival rates of 84%, 88%, and 96%. The HR for the paclitaxel plus trastuzumab/lapatinib vs paclitaxel/trastuzumab group was 0.34 (95% CI = 0.12–0.94, P = .037). The HR for the paclitaxel/lapatinib vs paclitaxel/trastuzumab group was 1.17 (95% CI = 0.51–2.71, P = .711).
Results for relapse-free and overall survival were not affected by receipt of adjuvant doxorubicin/cyclophosphamide or whether the 1 year of adjuvant trastuzumab was completed.
In analysis including all treatment groups, there was a significant association between pathologic complete response and improved relapse-free survival. Relapse-free survival events occurred in 14 (9.9%) of 141 patients with pathologic complete response vs 35 (23%) of 154 patients with residual disease (HR = 0.42, 95% CI = 0.23–0.78, P = .006). Similarly, death occurred in 6 (4%) of patients with pathologic complete response vs 20 (13%) with residual disease (HR = 0.3, 95% CI = 0.12–0.74, P = .009).
Outcomes According to HER2-Enriched Status
Pathologic complete response was achieved in 89 (61%) of 146 HER2-enriched patients vs 29 (25%) of 118 non–HER2-enriched patients (odds ratio = 3.8, P < .001). Significant differences in relapse-free survival were observed among subtypes. For example, patients with luminal A tumors had the lowest pathologic complete response rate (14.3%), but these tumors were associated with the best relapse-free survival outcome, with no events observed during 7 years of follow-up. In comparison, patients with HER2-enriched tumors, who had the highest pathologic complete response rate, had significantly worse relapse-free survival, with events occurring in 30 patients (20.5%); however, relapse-free survival events occurred in only 10 (11%) of 89 HER2-enriched patients with pathologic complete response vs 20 (35%) of 57 HER2-enriched patients with residual disease.
Effect of Gene Expression
mRNA sequencing was performed in 264 pretreatment samples. Among 688 gene expression signatures initially evaluated in the patient population, significant associations with both pathologic complete response and relapse-free survival were found for 22 (3.2%). In particular, eight immune signatures (including two IgG signatures, a B-cell/plasma cell signature, a T-helper signature, and a T-cell/B-cell cooperation signature) were significantly associated with both higher pathologic complete response and higher relapse-free survival rates. In contrast, tumor subtype biomarkers were associated either with poorer pathologic complete response rates and better relapse-free survival or with higher pathologic complete response rates and worse relapse-free survival. Among patients with residual disease, an IgG-high signature was an independent predictor of better relapse-free survival, whereas the HER2-enriched signature was associated with poorer relapse-free survival.
The investigators concluded, “In CALGB 40601, dual HER2-targeting resulted in significant relapse-free survival and overall survival benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pathologic complete response and relapse-free survival, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.”
Lisa A. Carey, MD, of the Division of Oncology, University of North Carolina at Chapel Hill, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Cancer Institute, National Institutes of Health, GlaxoSmithKline, and others. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.