New Interim Phase Ib/II Combination Data Investigate Halaven® (eribulin) With Immunotherapy pembrolizumab in Advanced or Metastatic Triple Negative Breast Cancer

"In preclinical and translational studies, eribulin induced tumour vascular remodeling, reduction of hypoxia and promotion of the less aggressive epithelial phenotype in advanced breast cancer tumour tissue. We hypothesised that these effects of eribulin on tumour biology and microenvironment may increase the drug delivery of immune checkpoint inhibitor, pembrolizumab, in metastatic triple negative breast cancer and further enhance the possibility that pembrolizumab would enable the immune system's T cells to detect and attack tumour cells," comments Sara Tolaney, MD, MPH, Medical Oncologist, Dana-Farber Cancer Institute, Boston.

This single-arm, multicentre phase Ib/II study is investigating the combination of eribulin plus pembrolizumab in 95 patients with metastatic triple negative breast cancer who had previously been treated with up to two lines of chemotherapy. The primary endpoint of the phase I study is to assess the safety and tolerability in combination, while the phase II objectives are response rates, with selected secondary endpoints including progression-free survival, overall survival and duration of response.^[1]

At SABCS, interim data from 39 evaluable patients treated with the combination regimen, show an overall response rate of 33.3%. One patient showed a complete response and twelve patients showed a partial response. In addition, the overall response rate was similar between PD-L1 positive and negative cohorts. The most common treatment-emergent adverse events (incidence greater than or equal to 35%) for the combination regimen were fatigue (74.4%), nausea (51.3%), peripheral neuropathy (43.6%), neutropenia (38.5%) and alopecia (35.9%), with Grade 3 or higher Treatment-Emergent Adverse Events (TEAEs) observed in 66.7% of patients. The two most common Grade 3 or higher TEAEs observed were neutropenia (30.8%) and fatigue (7.7%).^[1]

Further presentation at SABCS includes the design of a phase Ib/II study of eribulin in combination with PEGylated recombinant human hyaluronidase (PEGPH20). This is a randomised global study that will enroll approximately 114 patients with human epidermal growth factor receptor 2-negative (HER2-) high hyaluronan metastatic breast cancer, who were previously treated with up to two lines of systemic anticancer therapy in the metastatic setting.^[3] The primary endpoint in the phase II study will be the objective response rate, and secondary endpoints will include progression-free survival and overall survival.^[3] This study is currently enrolling.

The continued development of Eisai's oncology portfolio underscores its human health care (hhc) mission, the company's commitment to innovative solutions in disease prevention, cure and care for the health and wellbeing of people worldwide. Eisai is committed to the therapeutic area of oncology and to addressing the unmet medical needs of people with cancer and their families.

Notes to Editors    

Phase Ib/II study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer; Tolaney et al (Poster#: P5-15-02)^[1]

The open-label, single-arm, multicentre phase Ib/II study investigated the use of the combination of eribulin in pembrolizumab in 106 patients with metastatic breast cancer who had previously treated with up to two lines of chemotherapy. The primary endpoint of the phase II study was objective response rate and secondary endpoints included progression-free survival, overall survival and duration of response. In this study, the most frequent adverse events of grade 3 or higher included neutropenia (31%) and fatigue (8%). Serious (non-fatal) adverse events occurred in 36% of patients and adverse events leading to dose adjustment were observed in 56% of patients.

About Metastatic Breast Cancer    

More than 300,000 women are diagnosed with breast cancer in Europe every year and about one third subsequently develop metastatic disease.^[4] At this advanced stage, the cancer spreads beyond the breast to other parts
of the body.^[5]

About Halaven^® (eribulin)    

Eribulin is the first in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally, eribulin is a structurally simplified, fully synthetic analog of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. Eribulin exerts antiproliferative effects against cancer cells by inhibiting the growth phase of microtubule dynamics, ultimately preventing cell division and leading to cancer cell death. In addition, preclinical and translational studies in advanced breast cancer also suggest that eribulin has significant non-mitotic effects on tumour biology and the tumour microenvironment.^[6],[7]

The European Commission approved in May 2016 a variation to the terms of the Marketing Authorisation of eribulin for the treatment of adult patients with unresectable liposarcomas who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease.

About Pembrolizumab   

Pembrolizumab is marketed under the brand name Keytruda^® by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside the US and Canada) in the European Union.

Pembrolizumab as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults.

Pembrolizumab is also indicated for the treatment of locally advanced or metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received approved therapy for these mutations prior to receiving pembrolizumab.

PEGPH20   

PEGPH20 (PEGylated recombinant human hyaluronidase) is a novel targeted agent that degrades hyaluronan (HA) within the tumour microenvironment.^[8] PEGPH20 may remodel the stroma of high-HA tumours to increase the access and efficacy of anticancer therapies.^[9],[10]

Eisai in Oncology    

Eisai is committed to the development and delivery of highly beneficial new treatments for people with cancer. The development of therapeutic options in oncology is a major strategic area for Eisai in Europe, the Middle East, Africa, Russia and Oceania (EMEA). In the European Union, Eisai currently has three marketed treatments across four indications:

• Lenvima^® (lenvatinib) is indicated for the treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma (DTC) refractory to radioactive iodine (RAI).
• Kisplyx^® (lenvatinib) is indicated in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF)-targeted therapy.
• Halaven^® (eribulin) is indicated for the treatment of adults with locally advanced or metastatic breast cancer who have received at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting, unless patients were not suitable for these treatments. Halaven^® (eribulin) is also indicated for the treatment of adult patients with unresectable liposarcoma who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease.

About Eisai Co., Ltd.   

Eisai Co., Ltd. is a leading global research and development-based pharmaceutical company headquartered in Japan. We define our corporate mission as "giving first thought to patients and their families and to increasing the benefits health care provides," which we call our human health care (hhc) philosophy. With over 10,000 employees working across our global network of R&D facilities, manufacturing sites and marketing subsidiaries, we strive to realise our hhc philosophy by delivering innovative products in multiple therapeutic areas with high unmet medical needs, including Oncology and Neurology.

As a global pharmaceutical company, our mission extends to patients around the world through our investment and participation in partnership-based initiatives to improve access to medicines in developing and emerging countries.

For more information about Eisai Co., Ltd., please visit http://www.eisai.com.

References    

1. Tolaney, et al. Phase Ib/II study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. San Antonio Breast Cancer Symposium (SABCS) Meeting 2016, Poster#: P5-15-02

2. SmPC Halaven (updated August 2016). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002084/WC500105112.pdf Accessed December 2016

3. Alvarez H, Savulsky C, et al. A randomized, open-label, multicenter, phase Ib/II study of eribulin mesylate in combination with PEGylated recombinant human hyaluronidase in patients with human epidermal growth factor receptor 2-negative, high-hyaluronan metastatic breast cancer. San Antonio Breast Cancer Symposium (SABCS) Meeting 2016, Poster#: OT2-02-02

4. World Health Organization. Atlas of Health in Europe. 2003. World Health Organization, Regional Office of Europe, Copenhagen, Denmark.

5. Cancer Research UK, Breast Cancer - Outlook by Grade - Available at: http://www.cancerresearchuk.org/about-cancer/type/breast-cancer/treatment/statistics-and-outlook-for-breast-cancer#overall Accessed December 2016

6. Ueda S, et al. In vivo imaging of eribulin-induced reoxygenation in advanced breast cancer patients: a comparison to bevacizumab. Br J Cancer. 2016;114:1212-1218.

7. Goto W, et al. Clinical verification of antitumor autoimmune response in eribulin chemotherapy for breast cancer. Cancer Research. 2016;76(14):5127-5127

8. Thompson CB et al. Mol Cancer Ther. 2010; 9(11):3052-3568

9. Provenzano PP, et al. Cancer Cell. 2012;21(3):418-429.

10. Jacobetz MA, et al. Gut. 2013;62(1):112-120.

December 2016

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