NE Oncology Issue – May 2014

Piccart-Gebhart M, et al. SABCS 2013:S1-01

Background

The NeoALTTO study demonstrated a significantly higher breast pathological complete response (pCR) rate with dual human epidermal growth factor receptor 2 (HER2) blockade using lapatinib and trastuzumab compared with single HER2 blockade using either lapatinib or trastuzumab (51.3% vs. 24.7% vs. 29.5%, respectively; p <0.01 for both) in HER2-positive (HER2+) primary breast cancer (BC). The survival follow-up analysis of the NeoALTTO study, including event-free survival (EFS) and overall survival (OS), was presented at SABCS 2013.1

Study design

  • From January 2008 to December 2009, 455 patients were randomized from 99 participating sites in 23 countries.
  • Patients were randomized to receive one of the following for a total of 6 weeks:
    • Lapatinib 1,500 mg/day (n = 154);
    • Trastuzumab 4 mg/kg intravenous (iv) loading dose followed by 2 mg/kg iv weekly (n = 149); or
    • Lapatinib 1,000 mg/day plus trastuzumab as above (n = 152).
  • After this biological window, patients continued on the same targeted therapy plus weekly paclitaxel 80 mg/m² for a further 12 weeks, until definitive surgery (i.e., a total neoadjuvant therapy duration of 18 weeks).
  • After surgery, patients received three cycles of adjuvant fluorouracil, epirubicin, and cyclophosphamide, followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (i.e., to complete 52 weeks of anti-HER2 therapy), with ongoing follow-up planned until 10 years after the last randomized patient.
  • Secondary objectives included EFS and OS, following a protocol amendment:
    • Amendments were made to the protocol secondary objectives (released in May 2013):
      • Disease-free survival was replaced by EFS from randomization;
      • OS from surgery was correspondingly replaced with OS from randomization; and
      • Examination of the association between these survival endpoints and locoregional pCR (pT0/is pN0) was added as a secondary objective.
  • The analyses of EFS and OS by treatment arm are underpowered and are intended to be descriptive.
    • Assuming a hazard ratio of 0.78 for the combination group, the study has a power of approximately 20%.
    • Analysis was adjusted for stratification factors (hormone receptor [HR] status, tumour size, lymph node status, and breast conservation).
  • The clinical cutoff date for the first planned analysis of these secondary objectives was on May 26, 2013 (with a database freeze on November 13, 2013), three years after the date of the last breast cancer surgery.

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Key findings

  • Median clinical follow-up was 3.77 years (95% CI: 3.72–3.98 years), and median survival follow-up was 3.84 years (95% CI: 3.77–3.98 years).
  • Stratification factors were well balanced between the treatment arms.
  • Lapatinib completion in the lapatinib-containing arms of the study:
    • Approximately two thirds of patients were able to complete lapatinib treatment in the neoadjuvant or adjuvant phases;
    • Discontinuation in the neoadjuvant and the adjuvant phases were primarily due to adverse events, not progression or recurrence.
  • Trastuzumab completion in the trastuzumab-containing arms of the study:
    • At least 90% of patients completed treatment in the neoadjuvant phase and approximately 80% of patients completed it in the adjuvant phase.
  • Results of the EFS analyses by treatment arm showed: (Figure 1)
    • For all patients, the hazard ratios comparing either lapatinib plus trastuzumab or lapatinib alone with trastuzumab alone were 0.78 (p = 0.33) and 1.06 (p = 0.81), respectively;
    • For all patients, the three-year EFS rate in the lapatinib plus trastuzumab arm was 84%, compared with 78% and 76% in the lapatinib and trastuzumab arms, respectively;
    • There was little difference between treatment arms in the EFS curves for patients with HR-positive (HR+) BC. However, the combination of lapatinib plus trastuzumab showed a potential advantage over lapatinib or trastuzumab alone in patients with HR-negative (HR–) BC.
  • Results of the OS analyses by treatment arm are shown in Figure 2.
    • The three-year OS rate for all patients in the lapatinib plus trastuzumab arm was 95%, compared with 93% and 90% in the lapatinib and trastuzumab arms, respectively.
    • At this time, there was little difference between treatment arms in the OS curves for patients with HR+ or HR– BC.
  • Results of the EFS and OS analyses by pCR status, independent of treatment arm, showed:
    • Patients who had a pCR had much improved EFS and OS than patients who did not experience a pCR (EFS: hazard ratio = 0.38, p = 0.0003; OS: hazard ratio = 0.35, p = 0.005) (Figures 3 and 4);
    • For patients who had a pCR (vs. no pCR), there was a larger divergence towards improvement in the EFS and OS curves for those with HR– BC than for those with HR+ BC (EFS for HR– BC by pCR: hazard ratio = 0.34, p = 0.001; OS: hazard ratio = 0.29, p = 0.003).
  • By treatment arm, patients who experienced a pCR had improved EFS and OS compared with patients who did not experience a pCR, in all three treatment groups.
  • The main differences in adverse events (AEs) by treatment arm were (lapatinib vs. trastuzumab vs. lapatinib plus trastuzumab, %):
    • Diarrhea: 83 vs. 35 vs. 87 (severe AEs: 25 vs. 3 vs. 26);
    • Hepatobiliary AEs: 50 vs. 28 vs. 48 (severe AEs: 22 vs. 7 vs. 11); and
    • Rash: 70 vs. 36 vs. 68 (severe AEs: 5 vs. <1 vs. 5).
  • Very few cardiac events were recorded; primary cardiac events (i.e., severe congestive heart failure) occurred in 0%, 0.68%, and 1.34% of patients in the lapatinib, trastuzumab, and combination of lapatinib plus trastuzumab arms, respectively.

Key conclusions

  • Patients who achieved pCR had significantly better EFS and OS compared with no pCR from the landmark, irrespective of treatment arm.
  • The NeoALTTO trial was powered to detect pCR differences but underpowered to detect moderate differences in EFS and OS.
  • The ALTTO trial will provide a robust answer on the effect of dual HER2 blockade on long-term outcome.
  • At approximately four years (median follow-up), and in line with previous observations, dual HER2 blockade appears to provide superior benefit (pCR, EFS, OS) in patients with HER2+/HR– tumours. A follow-up analysis is planned in 2.5 years.
  • This trial provides further evidence that HER2+/HR– and HER2+/HR+ subgroups are two different diseases.
  • AEs were consistent with known safety profiles of lapatinib and/or trastuzumab.

Reference: 1. Piccart-Gebhart M, Holmes AP, de Azambuja E, et al. The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study (BIG 1-06). SABCS Abstracts 2013:S1–01.

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Canadian Perspectives

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Carolyn Owen, MD

Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, UK. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre & Tom Baker Cancer Centre, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.

 

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Douglas A. Stewart, BMSc, MD, FRCPC
Dr. Douglas A. Stewart is currently a professor in the Departments of Oncology and Medicine, and Chief of the Division of Hematology and Hematological Malignancies at the University of Calgary. Since July 1994, he has been practising medical oncology at the Tom Baker Cancer Centre in Calgary, where he is a member of the Breast Cancer and Hematology Tumour Groups, Leader of the Hematology/Blood and Marrow Transplant Program, and Provincial Leader of the Hematology Tumour Team for the Alberta Health Services Cancer Care Program. His research interests focus on clinical trials involving hematological malignancies and hematopoietic stem cell transplantation. Dr. Stewart has authored over 80 peer-reviewed manuscripts and over 120 abstracts.

Investigator Commentary

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Richard R. Furman, MD

Dr. Furman is a member of the Lymphoma/Myeloma Service in the Division of Hematology/ Oncology at the New York Weill Cornell Medical Center. He is head of the chronic lymphocytic leukemia (CLL) and Waldenstrom’s macroglobulinemia (WM) program at Weill Medical College, and focuses on identifying new and promising therapies for patients with CLL and WM. Along with collaborators at Columbia Presbyterian, Johns Hopkins, Roswell Park Cancer Institute, and Ohio State University, Dr. Furman has initiated the Waldenstrom’s Research Consortium in order to enhance treatment and understanding of WM.