Adjuvant Lapatinib and Trastuzumab for Early Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Results From the Randomized Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial

Abstract

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

Magee Equation 3 predicts pathologic response to neoadjuvant systemic chemotherapy in estrogen receptor positive, HER2 negative/equivocal breast tumors

“…[19][20][21] Therefore, studies with long term follow-up are valuable in understanding the significance of pathologic complete response in such circumstances. Our study did not test the efficacy of a novel therapeutic agent but rather a predictive tool to assess for pathologic complete response.…”

“…Oncotype DX (Genomic Health, Redwood City, CA, USA), also known as the 21 gene expression assay, is one such test. 4 It is reported as a numerical recurrence score ranging from 0 to 100 and divided into low-risk (o 18), intermediate risk (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and high-risk (≥31) categories, and current guidelines, including National Comprehensive Cancer Network (NCCN), recommend its use in women with early stage ER+ disease. Despite the predictive and prognostic information this and other genomic tests provide, they have limitations, including cost of over $4,000 per test, delay in treatment while awaiting results and restricted availability in settings with limited resources.…”

2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines

“…Ryzyko kardiotoksyczności innych leków anty-HER2 (lapatinib, pertuzumab, T-DM1) wydaje się podobne do ryzyka związanego ze stosowaniem trastuzumabu. W dużej próbie klinicznej u chorych na raka piersi, w której porównano skuteczność adiuwantowego leczenia samym trastuzumabem z terapią trastuzumabem i lapatinibem u ponad 8000 kobiet, częstość występowania kardiotoksyczności podczas mediany 4,5 roku obserwacji wyniosła 2-5%, a HF wystąpiła u 2-3% kobiet [57]. W tej próbie klinicznej, w której czynność serca oceniano prospektywnie, porównując ją z wynikami oceny na początku obserwacji, zastosowano nowoczesne schematy chemioterapii adiuwantowej lub neoadiuwantowej, w tym antracykliny u ponad 70% pacjentek.…”

A phase II trial of neoadjuvant doxorubicin plus cyclophosphamide followed by lapatinib plus docetaxel sequential with adjuvant trastuzumab for treatment of early HER2 positive breast cancers

“…[15] In this adjuvant trial the combination of lapatinib and trastuzumab (sequentially or concurrently) failed to show significant DFS benefit. Importantly, the lapatinib only arm was stopped due to futility after being unable to demonstrate non-inferiority to trastuzumab.…”