Trabectedin demonstrated a significant increase in progression-free survival compared to best supportive care in advanced soft-tissue sarcoma

Trabectedin, a single agent that perturbs cell cycle progression, has demonstrated efficacy in pre-treated patients with ASTS in previous clinical trials, as well as in other STS histologies. Although these trials led to its approval in Europe for ASTS in 2007, a negative review from the French health authority Commission de la Transparence in 2013 meant that reimbursement for trabectedin was not renewed. For a number of French patients, progressing after doxorubicin and/or ifosfamide and unable to use pazopanib, the lack of access potentially had a real impact on their quality of care.

“We have to fight with the authorities of the countries reimburse the drug… sometimes it’s a disaster for patients”
Dr le Cesne, Medical Oncologist, Institut Gustave Roussy, France

The French Sarcoma Group and other supportive groups stressed to the French authorities the clear importance of the drug, requesting for reconsideration of the decision. This is a significant problem, Dr le Cesne explained, “we have to fight with the authorities of the countries [to] reimburse the drug, already approved by EMA or FDA… so it becomes complicated, and sometimes it’s a disaster for patients.” As a result of their complaint, trabectedin was issued reimbursement for a limited amount of time, providing that new efficacy data was sought to justify its use.

The phase III trial T-SAR was therefore initiated. 103 patients were randomised 1:1 to receive either BSC or trabectedin, 1.5 mg/m2 by 24-hour intravenous infusion every 3 weeks. Patients included in the study had ASTS with disease progression after ≥1 lines of therapy with an anthracycline-based regimen and <3 lines of chemotherapy. They were stratified by lipo-leiomyosarcoma (L-STS; 60.2%, n=62) and non-L-STS (39.8%, n=41). Patients had ≥1 measurable lesions according to RECIST criteria (version 1.1), a WHO performance status score of 0-1 and adequate haematological and hepatic functions.

The primary endpoint was PFS; secondary endpoints included risk reduction, safety, quality of life, cost effectiveness and overall survival (OS). The analysis found PFS to be 1.4 months for patients receiving BSC and 3.0 months for patients receiving trabectedin (hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.26-0.63, p<0.0001).

Most notably, patients with L-STS had median PFS of 1.4 months with BSC and 5.8 months for trabectedin (HR 0.33, 95% CI 0.17-0.62, p=0.0003). For those in the non L-STS cohort, median PFS was 1.3 months with BSC and 2.6 months with trabectedin (HR 0.49, 95% CI 0.26-0.94, p=0.03).

The findings were similar to those observed in two recent trials from the US and Japan. In the US trial, 2016, PFS was 1.5 months with dacarbazine and 4.2 months with trabectedin (HR 0.55, p<0.001). In the 2015 Japanese trial, studying patients with translocation-related sarcomas only, PFS with BSC was 0.9 months (95% CI 0.7-1.0) and 5.6 months with trabectedin (95% CI 4.1-7.5). The safety data reconfirm that trabectedin is a well-tolerated therapy.

Dr le Cesne explained that, unlike other conditions that have a wider choice of treatment options, “there are only four drugs they consider to be active in STS, so if we lose one drug, not reimbursed, it’s a pity for the patient.”

Looking to the future of trabectedin, he summarised, “the benefit of trabectedin is very high in this group [patients with L-STS]. So, if we can have reimbursement of the drug at least in L-STS, it will be very useful for the patient and for the scientific community.” Further analyses of secondary endpoints OS, quality of life and cost effectiveness will be presented in 2017.

Based on le Cesne A, Blay J et al. Results of a prospective randomized phase III T-SAR trial comparing trabectedin vs best supportive care (BSC) in patients with pretreated advanced soft tissue sarcoma (ASTS) (1396O). Presented on Saturday 8 October 2016.

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