NE Oncology Issue – May 2014

Wilks S, et al. SABCS 2013:P4-12-12

Background

Eribulin mesylate is a nontaxane inhibitor of microtubule dynamics of the halichondrin class of antineoplastic drugs. It has demonstrated a survival benefit relative to commonly used agents in women with metastatic breast cancer (MBC) who have previously received at least two chemotherapeutic regimens for metastatic disease. At SABCS 2013, Swain and colleagues presented final data from a phase II study that evaluated efficacy and safety of eribulin plus trastuzumab as first-line therapy for patients with locally advanced or metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer.1

Study design

  • This was a multicentre, single-arm, phase II trial of eribulin in combination with trastuzumab in women with HER2+ MBC.
  • Patients received six cycles of eribulin mesylate 1.4 mg/m2 intravenous (iv) infusion over 2 to 5 minutes on days 1 and 8 of each 21-day cycle and trastuzumab 8 mg/kg iv over 90 minutes on day 1 of cycle 1. Thereafter, trastuzumab 6 mg/kg was infused over 30 minutes on day 1 of each subsequent 21-day cycle.
    • Dose reductions for eribulin, but not for trastuzumab, were permitted; eribulin could be continued as monotherapy if trastuzumab was discontinued.
  • The primary endpoint was objective response rate (ORR), defined as the proportion of subjects who achieved a complete response (CR) plus those who achieved a partial response (PR), based on Response Evaluation Criteria in Solid Tumours version 1.1.
  • Secondary endpoints included safety and tolerability, time to first response (TTR) and duration of response (DOR) for patients whose best overall response was CR or PR, and progression-free survival (PFS). Quality of life (QoL) was also assessed.
  • All efficacy analyses were based primarily on the full analysis set (i.e., patients who received ≥1 dose of study treatment).

Key findings

  • A total of 52 patients entered the study; 45 patients completed the treatment phase (six cycles of treatment) and nine discontinued due to treatment-emergent adverse events (TEAEs) (n = 3), progressive disease (PD) (n = 3), or other reasons (n = 3).
    • There were eight patients still in the extension phase of treatment at the time of clinical data cutoff.
  • At baseline, the mean age of patients was 59.5 years, with metastatic disease reported in 98.1% of patients (48.1%, 46.2%, and 36.5% with liver, lung, and bone metastases, respectively).
  • Prior treatment with a taxane and/or anthracycline was reported by 48.1% of patients and prior treatment with trastuzumab or lapatinib was reported by 42.3% of patients.
  • The median number of cycles received per patient was 10.0 (range, 0–38) for eribulin and 11.0 (range, 1–37) for trastuzumab.
  • The ORR was 71.2% (95% CI: 56.9–82.9%), the disease control rate was 96.2% (95% CI: 86.8–99.5%), and the clinical benefit rate was 84.6% (95% CI: 71.9–93.1%). (Table 1)
    • Investigator assessments indicated CR and PR in 5.8% and 65.4% of patients, respectively.
  • The median percentage change from baseline in the total sum of target lesion diameters was –62.4%.
  • The median PFS was 11.6 months (95% CI: 9.1–13.9 months; N = 52), and Kaplan-Meier estimates for the 3-, 6-, 9-, and 12-month PFS rates were 96%, 82%, 67%, and 49%, respectively. (Figure 1)
  • For all patients, median TTR (patients with CR or PR) was 1.3 months (95% CI: 1.2–1.4 months; N = 37) and median DOR was 11.1 months (95% CI: 6.7–17.8 months; N = 37).
  • All patients reported TEAEs, which were considered to be related to either eribulin or trastuzumab. TEAEs with a Common Terminology Criteria for Adverse Events (CTCAE version 4) of grade ≥3 were reported in 71.2% of patients. (Table 2)
  • TEAEs led to dose adjustment of eribulin, trastuzumab, or both, in 36 patients (69.2% of patients):
    • Dose reduction, interruption, or discontinuation occurred in 21 (40.4%), 22 (42.3%), and 11 (21.2%) patients, respectively;
    • Peripheral neuropathy led to discontinuations, dose reduction, and interruption in 13.5%, 19.2%, and 9.6% of patients, respectively.
    • Neutropenia led to dose reductions in 11.5% of patients and dose interruptions in 21.2% of patients, but did not lead to any discontinuations.
  • Serious TEAEs occurred in 15 patients (28.8%). Neutropenia occurred in 8 patients (15.4%), febrile neutropenia in 4 patients (7.7%), peripheral neuropathy in 3 patients (5.8%), and vomiting in 3 patients (5.8%).
  • One death occurred during the study, which was considered to be possibly related to the study drug. A 59-year-old patient died due to chronic heart failure 15 days after her last dose of study treatment, a total treatment duration of 274 days.

Key conclusions

  • The combination of eribulin plus trastuzumab as first-line therapy for locally recurrent or metastatic HER2+ breast cancer
    resulted in an ORR of 71.2% with a median PFS of 11.6 months and an acceptable safety profile.
  • Safety was consistent with known profiles for eribulin and trastuzumab.
    • Alopecia, fatigue, peripheral neuropathy, neutropenia, nausea, and diarrhea were the most frequent TEAEs (all grades;
      occurring in >30% of patients).
    • The most common grade 3/4 TEAE was neutropenia, occurring in 20 patients (38.5%).

Reference: 1. Wilks S, Puhalla S, O’Shaughnessy J, et al. Phase 2, multicenter, single-arm study of eribulin mesylate plus trastuzumab as first-line therapy for locally recurrent or metastatic HER2-positive breast cancer. SABCS Abstracts 2013:P4-12-12.

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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.

 

dr-stewart

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.