NE Oncology Issue – May 2014

Perez EA, et al. SABCS 2013:P2-16-10

Background

Human epidermal growth factor receptor 2 (HER2) overexpression or amplification occurs in approximately 20% of breast cancers and is associated with poorer prognosis compared with HER2-normal/nonamplified breast cancer. Trastuzumab and pertuzumab are humanized monoclonal antibodies that bind to different HER2 subdomains, inhibiting HER2 signaling. In a previous study (HERNATA1), first-line treatment of patients with HER2-positive (HER2+) metastatic breast cancer (MBC) with vinorelbine plus trastuzumab had similar efficacy results to treatment with docetaxel plus trastuzumab, but with fewer adverse events (AEs). In a recent study (CLEOPATRA2), pertuzumab plus trastuzumab and docetaxel significantly improved progression-free survival (PFS) and overall survival (OS) compared with trastuzumab plus docetaxel in patients with HER2+ first-line MBC.

The objective of the VELVET study was to investigate the efficacy and safety of pertuzumab plus trastuzumab and vinorelbine for first-line treatment of HER2+ MBC. At SABCS 2013, Perez and colleagues presented the interim safety data for cohort 1.3

Study design

  • VELVET is a multicentre, open-label, single-arm, two-cohort, phase II study.
  • The key eligibility criteria for patients in this study were:
    • HER2+ MBC or locally advanced breast cancer (LABC);
    • Eastern Cooperative Oncology Group performance status of 0 or 1;
    • Left ventricular ejection fraction (LVEF) of ≥55% at baseline;
    • No prior systemic nonhormonal anticancer therapy in the metastatic setting;
    • No prior breast cancer treatment with anti-HER2 agents, except trastuzumab and/or lapatinib in the (neo)adjuvant setting (but no disease progression while on treatment);
    • Disease-free interval ≥6 months from completion of (neo)adjuvant nonhormonal therapy to disease recurrence.
  • Patients received one of two treatment regimens:
    • Patients in cohort 1 received pertuzumab, trastuzumab, and vinorelbine from separate infusion bags; or
    • Patients in cohort 2, from cycle 2 onwards, received pertuzumab and trastuzumab from a single infusion bag, followed by vinorelbine.
  • Study drugs for cohort 1 were administered as follows:
    • Pertuzumab: initial dose of 840 mg on day 1 of cycle 1, followed by 420 mg on day 1 of each subsequent cycle, every three weeks (q3w);
    • Trastuzumab: initial dose of 8 mg/kg on day 2 of cycle 1, followed by 6 mg/kg on day 1 or 2 of each subsequent cycle, q3w;
    • Vinorelbine: initial dose of 25 mg/m2 on day 2 and day 9 of cycle 1, followed by 30–35 mg/m2 on day 1 or 2 and day 8 or 9 of each subsequent cycle, q3w.
  • Patients received all study drugs until disease progression or unacceptable toxicity. At the discretion of the investigator, pertuzumab/trastuzumab, and/or vinorelbine, could be stopped early.
  • The interim safety data from cohort 1 were presented, which had a data cutoff point of September 10, 2013.
  • The primary endpoint of the study was objective response rate, assessed by best overall response.
  • The secondary endpoints were PFS, time to progression, OS, time to response, duration of response, safety and tolerability, and health-related quality of life.

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Key findings

  • Patients in cohort 1 (N = 106) had the following baseline characteristics:
    • Median age (range), years: 56 (30–82);
    • Median interval (range) between initial diagnosis of breast cancer and enrollment, years: 2.6 (0–24);
    • Disease stage III/IV at initial diagnosis, %: 29.2/33.0;
    • Disease stage at advanced BC diagnosis (LABC/ MBC), %: 13.2/86.8;
    • Prior systemic cancer therapy, %: 61.3
    • Prior trastuzumab therapy (neoadjuvant/adjuvant), %: 10.4/34.0.
  • At the time of data cutoff, treatment was ongoing for 51 patients, and 55 patients had discontinued all three drugs, 49 of whom were still in follow-up.
  • A median number of 12.0 cycles of pertuzumab and trastuzumab, and 9.0 cycles of vinorelbine were received. Four patients completed less than three cycles of study treatment.
    • The median dose intensity of vinorelbine during the first six treatment cycles was 14.99 (6.4–23.1) mg/m2/week.
  • The proportion of patients that had discontinued pertuzumab, trastuzumab, and vinorelbine due to an adverse event (AE)/ unacceptable toxicity was 7.5%, 5.7%, and 21.7%, respectively.
  • The incidences of all-grade AEs and grade ≥3 AEs are presented in Table 1 and Table 2, respectively.
  • Thirty patients (28.3%) experienced serious AEs. Serious AEs that occurred in ≥2 patients were: febrile neutropenia, hypersensitivity, abdominal pain, drug hypersensitivity (i.e., only when both AE and drug were reported), and pyrexia.
  • The incidence of febrile neutropenia at each of the first 17 cycles, plus concomitant granulocyte-colony stimulating factor administration, is shown in Figure 1.
  • There was no overall decrease in mean LVEF from baseline. (Figure 2A)
  • The proportion of patients with LVEF declines to <50% at cycles 3, 6, 9, 12, and 15 was 1.1%, 2.5%, 2.8%, 3.8%, and 6.7%, respectively; the profile over time of these patients is shown in Figure 2B.
  • At the time of data cutoff, two patients had died due to an AE: one had a myocardial infarction and one had septic shock; neither event was considered to be study-drug related.
  • A cross-study comparison of the incidence of selected AEs suggests that the safety profile to date in VELVET compares favourably with those seen previously in CLEOPATRA and HERNATA, although it is difficult to compare results from different clinical trials. (Table 3)

Key conclusions

  • There was an acceptable safety profile with the combination of pertuzumab, trastuzumab, and vinorelbine, and no new safety signals were observed.
  • The incidences of alopecia and of grade ≥3 hematologic AEs are currently lower than those observed previously with trastuzumab plus vinorelbine1 or with pertuzumab plus trastuzumab plus docetaxel.2
  • Based on encouraging interim safety data, enrollment into cohort 2 began in April 2013 and completed in September 2013. Final efficacy data from both cohorts are expected in 2015.

Reference: 1. Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol 2011;29:264–71. 2. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109–19. 3. Perez EA, López-Vega JM, Del Mastro L, et al. Safety of pertuzumab plus trastuzumab plus vinorelbine for first-line treatment of patients with HER2- positive locally advanced or metastatic breast cancer. SABCS Abstracts 2013:P2-16-10.

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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.