Sacituzumab govitecan-hziy (Trodelvy – Gilead) has been approved for treatment of unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in adults who received prior endocrine therapy and ≥2 additional systemic therapies for metastatic disease. It was previously approved for treatment-refractory metastatic triplenegative breast cancer and for treatment of locally advanced or metastatic urothelial cancer in adults who received platinum-based chemotherapy and a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.

The FDA has approved margetuximab-cmkb (Margenza – MacroGenics), a HER2/neu receptor antagonist, for use in combination with chemotherapy for treatment of metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer in adults who received ≥2 prior anti-HER2 regimens, at least one of which was for metastatic disease.

The FDA has approved sacituzumab govitecan-hziy (Trodelvy – Immunomedics), a trophoblast cell-surface antigen-2 (Trop-2)-directed antibody and topoisomerase inhibitor conjugate, for treatment of adults with metastatic triple-negative breast cancer who have received ≥2 prior therapies for metastatic disease. It is the first Trop-2-directed antibody-drug conjugate to become available in the US.

The anthracycline doxorubicin with or without the alkylating agent ifosfamide is the standard first-line treatment for advanced soft-tissue sarcomas. The FDA recently approved the minor groove DNA intercalator trabectedin (Yondelis – Janssen) for treatment of unresectable or metastatic liposarcoma or leiomyosarcoma in patients previously treated with an anthracycline. Trabectedin has been available for years in Europe for treatment of advanced soft-tissue sarcoma. The FDA has also approved the microtubule inhibitor eribulin mesylate (Halaven – Eisai), which was approved earlier for treatment of metastatic breast cancer,1 for treatment of unresectable or metastatic liposarcoma, but not for leiomyosarcoma, in patients previously treated with an anthracycline.

Trabectedin binds guanine residues in the minor groove of DNA, which inhibits active transcription and blocks DNA repair proteins to achieve an antiproliferative effect.2 It has not been shown to be superior to doxorubicin for first-line treatment of advanced soft-tissue sarcomas,3 but has shown activity in anthracycline- and alkylating agent-resistant soft tissue sarcomas.4 FDA approval of trabectedin was based on a randomized, open-label trial comparing it to dacarbazine in 518 heavily pretreated patients with metastatic or recurrent leiomyosarcoma or liposarcoma. Median progression-free survival was significantly longer with trabectedin (4.2 months vs 1.5 months with dacarbazine). Median overall survival, however, was not significantly different (12.4 months with trabectedin vs 12.9 months with dacarbazine).5 Adverse effects of trabectedin include nausea, fatigue, neutropenia, and transient hepatic enzyme elevations.6 Trabectedin is administered over 24 hours through a central venous line every 3 weeks until disease progression or unacceptable toxicity occurs.

Eribulin mesylate is a microtubule-polymerizing drug that sequesters tubulin into nonfunctional aggregates.7 FDA approval of eribulin for treatment of advanced liposarcoma was based on a randomized, open-label trial comparing it to dacarbazine in 452 patients with unresectable or metastatic liposarcoma or leiomyosarcoma previously treated with an anthracycline. Median progression-free survival was 2.6 months in both groups, but overall survival was significantly longer with eribulin (13.5 months vs 11.5 months with dacarbazine). A pre-planned subgroup analysis found that the benefit was limited to patients with liposarcoma.8 Eribulin is the first drug shown to prolong overall survival in patients with advanced liposarcoma. The incidence of grade 3 or 4 adverse effects, particularly leukopenia and neutropenia, was higher with eribulin (67%) than with dacarbazine (56%). Fatigue, alopecia, peripheral neuropathy, nausea, and constipation also occurred. Eribulin is administered IV over 2 to 5 minutes on days 1 and 8 of a 3-week cycle.

1. Eribulin mesylate (Halaven) for breast cancer. Med Lett Drugs Ther 2011; 53:30.
2. AK Larsen et al. Unique features of trabectedin mechanism of action. Cancer Chemother Pharmacol 2015; 77:663.
3. B Bui-Nguyen et al. A phase IIb multicentre study comparing the efficacy of trabectedin to doxorubicin in patients with advanced or metastatic untreated soft tissue sarcoma: the TRUSTS trial. Eur J Cancer 2015; 51:1312.
4. BJ Petek et al. Trabectedin in soft tissue sarcomas. Mar Drugs 2015; 13:974.
5. GD Demetri et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol 2016; 34:786.
6. C Leporini et al. A comprehensive safety evaluation of trabectedin and drug-drug interactions of trabectedin-based combinations. BioDrugs 2014; 28:499.
7. NF Dybdal-Hargreaves et al. Eribulin mesylate: mechanism of action of a unique microtubule-targeting agent. Clin Cancer Res 2015; 21:2445.
8. P Schöffski et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet 2016 February 10 (epub).

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Eribulin mesylate (Halaven – Eisai) has been approved by the FDA for treatment of patients with metastatic breast cancer who have previously received at least 2 chemotherapy regimens for metastatic cancer. Prior therapy should have included an anthracycline and a taxane in either an adjuvant or metastatic setting. Other drugs used to treat anthracycline- and taxane-refractory metastatic breast cancer include capecitabine (Xeloda), gemcitabine (Gemzar, and others) and vinorelbine (Navelbine, and others).