Farletuzumab Ecteribulin: A well-tolerated antibody-drug conjugate in ovarian cancer.

Ovarian cancer starts in the ovary, fallopian tube, or peritoneum and develops due to the uncontrolled growth of abnormal cells in these regions. Ovarian cancer is often diagnosed at advanced stages, making the treatment difficult. The quest for more effective therapies continues, even though surgery and chemotherapy remain the standard treatments [1].

One promising approach is the combination of farletuzumab and eribulin, offering hope to patients. In this blog, we explored the potential of this therapy and its impact on ovarian cancer.

Understanding ovarian cancer

The symptoms of ovarian cancer are typically subtle and may remain unnoticed until the disease has advanced severely. They are frequently misdiagnosed as other less serious conditions. Because of this, diagnosis is frequently made when it is too late, which lowers survival rates. Surgery to remove as much of the tumor as possible has traditionally been the cornerstone of treatment, followed by chemotherapy, typically utilizing platinum-based medications [1].

Farletuzumab: A new approach

Farletuzumab (MORAb-003), is a fully humanized monoclonal antibody that targets the folate receptor alpha (FRα), a protein present on the surface of many ovarian cancer cells. This receptor is a prime target for therapy because it is not generally found in healthy tissue. Farletuzumab blocks certain cancer-promoting pathways by binding to FRα and activates an immune response against the cancer cells.

The clinical studies on farletuzumab have demonstrated promising findings including:

• In a phase I trial, farletuzumab showed safety when used alone in heavily pretreated patients with epithelial ovarian cancer.

• Later, in a phase II trial, the combination of farletuzumab, carboplatin, and a taxane followed by farletuzumab maintenance therapy revealed a favorable overall response rate of 75% in relapsed platinum-sensitive epithelial ovarian cancer [2].

Eribulin: An established player

Eribulin is a synthetic, macrocyclic ketone analog of Halichondrin B. Eribulin was approved by the US Food and Drug Administration in 2010 for patients with metastatic breast cancer who have already received treatment with anthracycline and a taxane.

According to preclinical research, eribulin:

• inhibits mitosis.

• stimulates vascular remodeling.

• prevents tumor cell migration and invasion.

• reverses the malignancy-related epithelial-to-mesenchymal transition.

It also acts by preventing microtubule dynamics within cancer cells, further inhibiting their growth and proliferation. Eribulin is now being explored in the context of ovarian cancer, offering a novel approach to treatment [3].

The synergy: Farletuzumab and eribulin

Farletuzumab ecteribulin (MORAb-202) is a novel antibody-drug conjugate (ADC) composed of farletuzumab linked to eribulin by a cathepsin-B cleavable linker. FRα-expressing tumor cells are the target of farletuzumab ecteribulin. After binding, free eribulin is released through a lysosomal breakdown of the ADC. Upon hydrolysis, eribulin exerts its antitumor activity [2].

By binding to FRα, farletuzumab precisely targets ovarian cancer cells, giving it an ideal companion for eribulin. This targeted approach minimizes damage to healthy cells and reduces the side effects associated with chemotherapy. Several preclinical and clinical studies have been conducted or are ongoing to assess the safety and efficacy of farletuzumab ecteribulin in treating ovarian cancer.

Farletuzumab ecteribulin showed potential anticancer effect in patients with folate receptor-α-positive ovarian cancer in the phase I study (ClinicalTrials.gov Identifier: NCT03386942), and in these patients, farletuzumab ecteribulin was generally well tolerated at the tested doses. However, the maximal tolerated dose of farletuzumab ecteribulin was not reached. The most typical treatment-related adverse events were pneumonitis, neutropenia, leukopenia, anemia, interstitial lung disease and/or gastrointestinal problems such as nausea, vomiting, constipation, and diarrhea [4].

Takeaway

A fascinating advancement in the treatment of ovarian cancer is the combination of farletuzumab with eribulin. This conjugate has the potential to enhance outcomes for patients with ovarian cancer, particularly those who have developed resistance to conventional therapies. While the preliminary results are encouraging, it is important to note that further research is required to properly comprehend the long-term advantages and potential adverse effects of this treatment regimen.

References

1. Chandra, A. et al. 'Ovarian cancer: Current status and strategies for improving therapeutic outcomes'. Cancer Medicine. (2019) 8(16), 7018–7031. DOI: 10.1002/cam4.2560.

2. Veneziani, A.C. et al. 'Emerging peptide therapeutics for the treatment of ovarian cancer'. Expert Opinion on Emerging Drugs. (2023) 28(2), 129–144. DOI: 10.1080/14728214.2023.2218643.

3. Swami, U. et al. 'Eribulin in Cancer Treatment'. Mar Drugs. (2015) 13(8), 5016–5058. DOI: 10.3390/md13085016.

4. Shimizu, T. et al. 'First-in-Human Phase 1 Study of MORAb-202, an Antibody-Drug Conjugate Comprising Farletuzumab Linked to Eribulin Mesylate, in Patients with Folate Receptor-α-Positive Advanced Solid Tumors'. Clin Cancer Res. (2021) 27(14), 3905–3915. DOI: 10.1158/1078-0432.CCR-20-4740.