In a 7-year follow-up of the phase III CALGB 40601/Alliance trial reported in the Journal of Clinical Oncology, ­Aranzazu Fernandez-Martinez, MD, of Lineberger Comprehensive Center, University of North Carolina, Chapel Hill, and colleagues found that neoadjuvant paclitaxel combined with a dual HER2-targeting regimen of 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.¹

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 (THL, n = 118), paclitaxel/trastuzumab (TH, n = 120), or paclitaxel/lapatinib (TL, 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/d), or both (lapatinib at 1,000 mg/d when used in combination) for 16 weeks. Due to reports of inferiority and higher toxicity, the TL arm was closed early, upon completion of treatment by patients randomly assigned to that group. It was recommended that all patients receive dose-dense doxorubicin and cyclophosphamide (AC) and complete 1 year of trastuzumab in the adjuvant setting. The primary endpoint was pathologic complete response, and secondary endpoints included relapse-free survival, overall survival, and gene-expression analysis.

ranzazu Fernandez-Martinez, MD

Key Outcomes

In the intent-to-treat population, pathologic complete response rates were 57% in the THL group, 45% in the TH group, and 30% in the TL group. After surgery, 51% of patients received AC and 73% completed 1 year of trastuzumab.

After a median follow-up of 83 months, relapse-free survival events were observed in 26.9% of the TL group, 20% of the TH group, and 6.8% of the THL group. Corresponding 7-year relapse-free survival rates were 69%, 79%, and 93%. For the THL vs TH group, the hazard ratio was 0.32 (95% confidence interval [CI] = 0.14–0.71, P = .005). For the TL vs TH group, the hazard ratio was 1.50 (95% CI = 0.82–2.77, P = .191).

Death from any cause occurred in 13.4% of the TL group, 11.7% of the TH group, and 3.4% of the THL group, with corresponding 7-year overall survival rates of 84%, 88%, and 96%. The hazard ratio for the THL vs TH group was 0.34 (95% CI = 0.12–0.94, P = .037). The hazard ratio for the TL vs TH group was 1.17 (95% CI = 0.51–2.71, P = .711).

Results for relapse-free and overall survival were not affected by the receipt of adjuvant AC or whether the 1 year of adjuvant trastuzumab was completed.

In an 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 of 141 patients (9.9%) with pathologic complete response vs 35 of 154 patients (23%) with residual disease (hazard ratio [HR] = 0.42, 95% CI = 0.23–0.78, P = .006). Similarly, death occurred in six patients (4%) with pathologic complete response vs 20 (13%) with residual disease (HR = 0.3, 95% CI = 0.12–0.74, P = .009).

Subtype Analysis

Among 264 patients with available data, pathologic complete response was achieved in 89 of 146 HER2-enriched patients (61%) vs 29 of 118 non–HER2-enriched patients (25%; odds ratio = 3.8, P < .001). Significant differences in relapse-free survival were observed among intrinsic subtypes (overall P = .04). For example, patients with luminal A tumors (n = 28, 11% of sample) had the lowest pathologic complete response rate (14%) but 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 (21%)—although relapse-free survival events occurred in just 10 of 89 HER2-enriched patients (11%) with a pathologic complete response vs 20 of 57 HER2-enriched patients (35%) with residual disease.

With regard to other subtypes, patients with a luminal B subtype (n = 35, 13%) had a pathologic complete response rate of 23% and experienced nine events (26%); those with a normal-like subtype (n = 33, 12%) had a pathologic complete response rate of 33% and experienced four events (12%); and those with a basal-like subtype (n = 22, 8%) had a pathologic complete response rate of 50% and experienced two events (9%).

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 immunoglobulin G [IgG] signatures, one B-cell/plasma cell signature, one T-helper signature, and one T-cell/B-cell cooperation signature) were significantly associated with both higher pathologic complete response and higher relapse-free survival rates. In contrast, intrinsic subtype-related biomarkers (all obtained by the PAM50 predictor) were associated either with poorer pathologic complete response rates and better relapse-free survival (eg, luminal A signature, chemoendocrine score, luminal A–HER2-enriched score) or with higher pathologic complete response rates and worse relapse-free survival (eg, HER2-enriched signature, risk of recurrence subtype, risk of recurrence subtype/proliferation). 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 the means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.”  

DISCLOSURE: The study was supported by the National Cancer Institute, GlaxoSmithKline, and others. Dr. Fernandez-Martinez reported no conflicts of interest.

REFERENCE

1. Fernandez-Martinez A, Krop IE, Hillman DW, et al: Survival, pathologic response, and genomics in CALGB 40601 (Alliance), a neoadjuvant phase III trial of paclitaxel-trastuzumab with or without lapatinib in HER2-positive breast cancer. J Clin Oncol. October 23, 2020 (early release online).