Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer.

Abstract

500 Background: Recent trials in HER2-positive (HER2+) breast cancer (BrCa) demonstrate increased pathological complete response (pCR) using dual HER2-targeting in the neoadjuvant setting and increased progression-free survival in metastatic disease. CALGB 40601 aimed to further quantify the pCR rates of weekly paclitaxel (T) and trastuzumab (H) alone or combined HER2-blockade of H with the small molecule lapatinib (L), and to identify biomarkers of sensitivity to these HER2-targeted agents. Methods: Eligible patients had newly diagnosed, noninflammatory stage II-III HER2+ BrCa and were randomized to receive T (80mg/m2/week IV) + H (4mg/kg then 2mg/kg/week IV) alone (TH) or with the addition of L (750 mg/d PO) (THL) for 16 weeks preoperatively. A third arm, T + L (1500 mg/d) (TL), was closed early when negative efficacy and toxicity data emerged from preliminary analysis of ALTTO. After surgery, 4 cycles of adjuvant dose-dense AC and 1 year H was recommended. Tumors were biopsied for research before therapy; post-Rx samples of residual disease were requested. The primary endpoint was in-breast pCR rate; the study had 85% power to detect an increase from 30% (TH) to 50% (THL). Results: 305 patients were randomized (118 THL, 120 TH, 67 TL); 68% were clinical stage II and 59% hormone receptor-positive. Grade 3+ toxicity was higher among L-containing arms, including neutropenia (12% TL, 7% THL, 2% TH), rash (15% TL, 14% THL, 2% TH), and diarrhea (20% TL, 20% THL, 2% TH). Breast pCR rates with 95% confidence limits were: 51% (42-60%) THL, 40% (32-49%) TH, 32% (22-44%) TL. pCR rate in the TH arm was higher than previous studies, and was not significantly different from THL (p=0.11). We will present molecular subtype, sequence and gene copy number abnormalities in primary tumors and residual disease. Conclusions: pCR rate was higher with combined THL compared with standard TH but did not reach statistical significance. These results are qualitatively similar to other neoadjuvant studies in HER2+ BrCa, and contribute to estimates of pCR rates after these agents. Tissue-based studies may illuminate which patients benefit from HER2-targeting using these agents. Clinical trial information: NCT00770809.