Afamitresgene autoleucel (Tecelra – Adaptimmune), a melanoma-associated antigen A4 (MAGE-A4)-directed genetically modified autologous T-cell immunotherapy, has received accelerated approval from the FDA for one-time treatment of adults with unresectable or metastatic synovial sarcoma who received prior chemotherapy and are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen. It is the first gene therapy to be approved in the US for treatment of synovial sarcoma. Accelerated approval of the immunotherapy was based on the overall response rate and duration of response.

Atezolizumab (Tecentriq – Genentech), an immune checkpoint inhibitor, has been approved by the FDA for treatment of unresectable or metastatic alveolar soft part sarcoma (ASPS) in patients ≥2 years old. It was previously approved for treatment of non-small cell lung cancer, small cell lung cancer, hepatocellular cancer, and melanoma (see Table 1). Atezolizumab is the first drug to be approved in the US for treatment of ASPS. ASPS is a rare disorder that affects mostly adolescents and young adults; <1% of soft tissue sarcomas are ASPS.

Olaratumab (Lartruvo – Lilly), a platelet-derived growth factor receptor alpha (PDGFR-α) blocking monoclonal antibody, has received accelerated approval from the FDA for use in combination with the anthracycline doxorubicin for first-line treatment of adults with soft-tissue sarcoma histologic subtypes considered susceptible to anthracyclines. Approval is limited to locally advanced or metastatic soft-tissue sarcomas that are not amenable to curative radiotherapy or surgery, and is contingent on verification of clinical benefit in a confirmatory phase 3 trial.

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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