Halaven (eribulin) demonstrates overall survival benefit in rare soft tissue sarcoma sub-types

Phase III data show Halaven® (eribulin) offers a significant overall survival benefit in people with advanced leiomyosarcoma (LMS) and adipocytic sarcoma (liposarcomas)¹ compared to dacarbazine (13.5 and 11.5 months respectively, HR=0.768, 96% CI 0.618-0.954; P=0.017).¹Eribulin had a toxicity profile consistent with prior experience, with no unexpected or new safety findings. These data were presented Monday 12 October at the DGHO in Basel, Switzerland.

"This is the first phase 3 trial to show overall survival benefit for people previously treated for soft tissue sarcomas. There is a considerable unmet need in this rare, hard-to-treat family of disease, so these results represent a very important milestone in the treatment of soft tissue sarcomas," comments Professor Patrick Schöffski, Head of the Department of General Medical Oncology, University Hospital Leuven, Belgium.

A further study presented at the DGHO showed that women with metastatic breast cancer treated with eribulin in combination with capecitabine (n=42) had an overall response rate of 42.9% (2 [4/8%] complete response and 16 [38.1%] partial response), and median progression free survival of 7.1 months (95% CI:4.4, 9.8).² This study confirms the safety and efficacy of the dose-combination eribulin 1.23mg/m² and capecitabine 1000 mg/m² twice daily. The safety and tolerability profile of the combination was consistent with previous data. These data are supported at DGHO by a case study, which shows that a person treated with 34 cycles of palliative chemotherapy with eribulin tolerated treatment well without notable side effects, and went into continuous partial remission.³

Based on these data, the company has submitted an application to extend the indication of Halaven® (eribulin) in the European Union for the treatment of patients with inoperable soft tissue sarcoma who have received prior chemotherapy for locally advanced or metastatic disease.

Eribulin is currently indicated for the treatment of women with locally advanced or metastatic breast cancer who have progressed after 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.⁴

Two important abstracts at DGHO explore Lenvatinib in its recently licensed indication of differentiated thyroid cancer, and its investigational use in advanced kidney cancer.

The combination of lenvatinib plus everolimus significantly improved progression-free survival compared to everolimus alone in a phase II study of people with metastatic renal carcinoma(mRcc) following prior VEGF-targeted therapy (14.6 months versus 5.5 months respectively (HR=0.40; 95% CI,0.24-0.68; p<0.001)). An updated analysis shows significantly improved overall survival in people treated with lenvatinib plus everolimus compared to everolimus alone (HR 0.51; 95% CI 0.30-0.88; P=0.024).⁵

A second abstract showed people with the papillary type of 131I-refractory differentiated thyroid cancer treated with lenvatinib had a median progression-free survival of 16.4 months compared to 3.5 months for placebo (HR:0.27; 95% CI:0.19-0.38). For people treated with lenvatinib that had the follicular type of thyroid cancer, an overall survival advantage was observed (HR:0.41; CI 0.18-0.97).⁶

"The clinical benefits observed in differentiated thyroid cancer are promising for people with these rare cancer subtypes," saidRosella Elisei, Department of Clinical and Experimental Medicine, University of Pisa.

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).⁷

Halaven® (eribulin)

Eribulin is the first in the halichondrin class of microtubule dynamics inhibitors with a novel mechanism of action. Structurally eribulin is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine spongeHalichondria okadai. Eribulin is believed to work by inhibiting the growth phase of microtubule dynamics which prevents cell division.

About Soft Tissue Sarcomas

Soft tissue sarcoma is a collective term for a diverse group of malignant tumours.

Leiomyosarcomas are one of the more common types of sarcoma to develop in adults. They start from cells in a type of muscle tissue called smooth muscle. Smooth muscles are involuntary muscles that we have no control over. They are found in the walls of muscular organs like the heart and stomach, as well as in the walls of blood vessels throughout the body. This means that leiomyosarcomas can start anywhere in the body. Common places are the walls of the womb (uterus), the trunk of the body, and the arms and legs.⁸

Liposarcomas (adipocytic sarcomas) arise from fat cells and can occur anywhere in the body. Incidence rates in males are twice as high as those in females.⁹ Leiomyosarcomas and liposarcomas make up approximately 30% of all cases of soft tissue sarcomas.¹⁰

In Europe, approximately 29,000 people will be diagnosed with soft tissue sarcomas each year.¹¹ Approximately 11,930 cases of soft tissue sarcomas will be diagnosed in the United States this year.⁹ In Japan, approximately 2,000 cases of soft tissue sarcomas are diagnosed each year.^{12, 13}

Outcomes for patients with advanced disease are poor, with median survival around one year or less. Due to the rarity of these tumours, evidence for prognostic factors is weak and not well understood.¹⁴

Global Phase III Clinical Study 309¹

The primary endpoint of the study was to compare overall survival between both treatment arms, and the additional endpoints included progression free survival and quality of life.

Patients were aged ≥18 years with advanced high/intermediate grade leiomyosarcoma or dedifferentiated, myxoid, round cell or pleomorphic variants of adipocytic sarcoma (ADI) incurable by surgery and/or radiotherapy were enrolled. Patients had ECOG status ≤2 and had received ≥2 standard systemic treatment regimens including an anthracycline. Patients were randomized 1:1 to eribulin mesilate (1.4 mg/m², IV on D1 and D8) or dacarbazine (850-1200 mg/m², IV on D1) every 21 days until disease progression.

Overall, 452 patients (67% female; 79% <65 years) were randomized (228 eribulin; 224 dacarbazine). Median OS for eribulin and dacarbazine was 13.5 and 11.5 months, respectively (HR=0.768, 95% CI 0.618-0.954; P=0.017). PFS was 2.6 months in both arms (HR=0.877, 95% CI 0.710-1.085; P=0.229). PFS rate at week 12 was 33% and 29% for eribulin and dacarbazine, respectively. Eribulin had a toxicity profile consistent with prior experience, with no unexpected or new safety findings. In this study, the most common adverse events observed in the eribulin arm were neutropenia, fatigue, nausea, alopecia and constipation, which is consistent with the known profile of eribulin.

About Lenvatinib

Lenvatinib, discovered and developed by Eisai, is an oral molecular tri-specific targeted therapy that possesses a potent selectivity and a binding mode of action different to other tyrosine kinase inhibitors (TKI). Lenvatinib simultaneously inhibits the activities of several different receptors including vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), RET, KIT and platelet-derived growth factor receptors (PDGFR). This potentially makes lenvatinib the first TKI that simultaneously inhibits the kinase activities of FGFR 1-4 as well as VEGFR 1-3. In addition, lenvatinib was found to have a new Type V binding mode of kinase inhibition that is distinct from existing compounds.

About Lenvatinib's Novel Binding Mode (Type V)^{15, 16}

Kinase inhibitors are categorized into several types (Type I to Type V) depending on the binding site and the conformation of the targeted kinase in complex with them. Most of the currently approved tyrosine kinase inhibitors are either Type I or Type II, however according to X-ray crystal structural analysis, lenvatinib was found to possess a new Type V binding mode of kinase inhibition that is distinct from existing compounds. In addition, lenvatinib was confirmed via kinetic analysis to exhibit rapid, durable and potent inhibition of kinase activity, and it is suggested that this may be attributed to its novel binding mode.

About SELECT¹⁷

The SELECT (Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid) study is a multicentre, randomised, double-blind, placebo-controlled Phase III study to compare the PFS of patients with radioactive iodine refractory differentiated thyroid cancer and radiographic evidence of disease progression within the prior 13 months, treated with once-daily, oral lenvatinib (24mg) versus placebo. The study enrolled 392 patients in over 100 sites in Europe, North and South America and Asia and was conducted by Eisai in collaboration with the SFJ Pharmaceuticals Group.

Participants were stratified by age (≤65, >65 years), region and ≤1 prior VEGFR-targeted therapies and randomised 2:1 to either lenvatinib or placebo therapy (24mg/d, 28-d cycle). The primary endpoint was PFS assessed by independent radiologic review. The secondary endpoints of the study included overall response rate (ORR), overall survival (OS) and safety. Rates of complete response were 1.5% (4 patients) for the lenvatinib group and zero in the placebo group. The results for partial response were 63.2% (165 patients) in the lenvatinib group and 1.5% (2 patients) in the placebo arm. The median exposure duration was 13.8 months for lenvatinib and 3.9 months for placebo and the median time to response for lenvatinib was 2.0 months.

The six most common lenvatinib treatment-related adverse events (TRAEs) of any grade were hypertension (67.8%), diarrhea (59.4%), fatigue (59.0%), decreased appetite (50.2%), weight loss (46.4%) and nausea (41.0%). TRAEs of Grade 3 or higher (Common Terminology Criteria for Adverse Events) included hypertension (41.8%), proteinuria (10.0%), weight loss (9.6%), diarrhoea (8.0%), and decreased appetite (5.4%).

About Thyroid Cancer

Thyroid cancer refers to cancer that forms in the tissues of the thyroid gland, located at the base of the throat near the trachea.¹⁸ It is more common in women than in men and most are in their 40s or 50s at time of diagnosis.¹⁹

Thyroid cancer affects more than 52,000 people in Europe each year.²⁰ The incidence of thyroid cancer has increased significantly in the last decade by 69% and 65% in men and women, respectively. The most common types of thyroid cancer, papillary and follicular (including Hurthle cell), are classified as differentiated thyroid cancer (DTC) and account for approximately 90% of all cases.²¹ The remaining cases are classified as either medullary (5-7% of cases) or anaplastic (1-2% of cases).²²

RAI Refractory-DTC is a rare, difficult-to-treat type of cancer, characterised by aggressive growth and spread. While most DTC patients are curable with surgery and radioactive iodine treatment, the prognosis for those patients who do not respond is poor.²¹ There are limited treatment options for this life-threatening and treatment-refractory form of thyroid cancer.²²