The final analysis of phase III data for trabectedin were consistent with interim results by showing a lack of improvement for the primary endpoint of overall survival in patients with advanced soft tissue sarcoma.
Shreyaskumar R. Patel, MD
The final analysis of phase III data for trabectedin (Yondelis) were consistent with interim results by showing a lack of improvement for the primary endpoint of overall survival (OS) in patients with advanced soft tissue sarcoma, according to data presented at the 2015 European Cancer Congress (ECC).1
After a 21-month follow-up, the median OS with trabectedin was 13.7 months compared with 13.1 months with dacarbazine (HR, 0.93; 95% CI, 0.75-1.15; P = .492). The median progression-free survival (PFS) with trabectedin was 4.2 versus 1.5 months with dacarbazine (HR, 0.55; 95% CI, 0.44-0.70; P <.001).
In the data presented by Shreyaskumar R. Patel, MD, the lack of OS was explained by a 47% longer median time to initiation of subsequent therapies in patients treated with trabectedin. The next therapy was initiated after a median of 6.8 months in those receiving trabectedin versus 3.5 months for those in the dacarbazine arm (HR, 0.53; P <.0001).
"Sensitivity analyses of OS showed a consistent favorable trend for the trabectedin group, supporting a potential confounding effect of additional post-study therapies, which were instituted earlier in the dacarbazine group," Patel, from the MD Anderson Cancer Center, and colleagues wrote in the abstract.
In the open-label trial, 518 patients were randomized in a 2:1 ratio to 1.5 mg/m2 of trabectedin (n = 345) or 1.0 g/m2 of dacarbazine (n = 173) once every 3 weeks until disease progression or unacceptable toxicity. Patients in the trabectedin arm received 20 mg of IV dexamethasone as a premedication. The study enrolled participants across a variety of soft tissue sarcoma histologies, including leiomyosarcoma, nonuterine, uterine, liposarcoma, dedifferentiated, myxoid, and pleomorphic.
In the dacarbazine arm patients received a median of 2 treatment cycles versus 4 in the trabectedin group. The median duration of response with trabectedin was 6.5 months compared with 4.2 months with dacarbazine (HR, 0.47; P = .14). The objective response rates were 9.9% versus 6.9% and the clinical benefit rate (response plus stable disease rate) was 34% and 19%, for trabectedin and dacarbazine, respectively.
OS findings were consistent across a planned subgroup analysis. In a multivariate analysis, OS was improved by trabectedin for patients who received only 1 prior line of chemotherapy versus ≥2 and for those with an ECOG PS of 0 versus 1 (P <.05).
"Some patients get extremely good responses and durable stability of their disease [with trabectedin], sometimes lasting 4 to 5 years with metastatic sarcomas," lead investigator George D. Demetri, MD, director, Center for Sarcoma and Bone Oncology at Dana Farber Cancer Center, told OncLive. "The problem is that we don't know who those people are who will get the extraordinary benefits."
Approximately 70% of patients in each group went on to receive additional treatment. During the course of the trial, the angiogenesis inhibitor pazopanib (Votrient) was approved for patients with soft tissue sarcoma—an event that may have confounded the OS analysis, according to Demetri. In fact, 18% of patients in the trabectedin arm received subsequent pazopanib compared with 28% in the dacarbazine arm.
"It was a difficult study to implement, patients once randomized did not have the option to crossover to the other therapy if the disease progressed," Demetri explained. "Overall survival is a difficult endpoint, because it measures not just what you're doing with the patient in that particular trial but also whatever happens to the patient when the tumor gets worse and the patient comes off the study. Overall survival is a controversial endpoint in our world of sarcoma management."
In data published in the Journal of Clinical Oncology in mid-September,2 the most commonly reported all-grade adverse events (AEs) with trabectedin versus dacarbazine were nausea (73% vs 49%), fatigue (67% vs 51%), neutropenia (49% vs 29%), increased ALT levels (45% vs 6%), vomiting (44% vs 21%), anemia (39% vs 29%), constipation (36% vs 28%), increased AST levels (35% vs 5%), and diarrhea (34% vs 23%).
Grade 3 AEs with the highest frequency in the trabectedin arm were increased ALT levels (25% vs 1%), neutropenia (21% vs 11%), anemia (14% vs 11%) and increased AST levels (12% vs 0%). Sixteen percent of patients receiving trabectedin had grade 4 neutropenia compared with 10% in the dacarbazine group.
Treatment-related discontinuation rates were 7.7% and 12.6% in the dacarbazine and trabectedin arms, respectively. There were treatment-associated deaths within 30 days of the last dose among 2.1% of patients receiving trabectedin compared with none in the dacarbazine arm. These were related to sepsis/septic shock (n = 3), rhabdomyolysis/sepsis (n = 1), renal failure (n = 1), renal failure/cardiac arrest (n = 1), or multiorgan failure (n = 1).
Trabectedin, which is approved in Europe and many other countries, was also explored in a phase IV study that was presented at ECC.3 In this study, which represented a "real world" scenario for use in Europe, trabectedin was explored in patients with advanced soft tissue sarcoma who had received a median of 1 prior therapy, with 10.1% of patients being chemotherapy-naïve.
“The results from this interim analysis are in line with the efficacy demonstrated in clinical trials and, more important, are consistent with what we find in clinical practice,” lead author Nicolas Penel, MD, PhD, Department of Medical Oncology, Centre Oscar Lambret, France, said in a statement. “Patients with soft tissue sarcoma are certainly benefiting from this treatment, and studies such as this one continue adding value to the management of patients treated with trabectedin.”
The 217 patients enrolled in the study received a median of 6 cycles of trabectedin, with 56% of patients receiving ≥6 cycles and some receiving a maximum of 44 cycles. The median treatment duration was 5.5 months and the median PFS was 5.5 months (95% CI, 4.8-7.1).
When comparing response by Choi criteria and RECIST, there was a staggering difference observed in PFS. By Choi criteria, the median PFS with trabectedin was 15.3 months (95% CI, 6.9-21.2) versus 8.1 months with RECIST (95% CI, 5.3-10.7).
The most common grade 3/4 AEs were neutropenia (17.9%) and transaminase increase (7.9%). Febrile neutropenia was reported in 2.7% of patients. The most common treatment-related AEs were fatigue (3.7%), nausea (1.4%), and vomiting (1.4%). One patient experienced a grade 5 pulmonary embolism.
“It was interesting to see how more than half of the patients receive 6 cycles or more of this treatment and 16.1% of the patients received the drug for 1 year or more," Penel said. "Given the manageable safety profile of trabectedin, the data underscore the clinical benefit for these patients.”
Data from the phase III study of trabectedin were submitted to European regulatory agencies, which moved the drug from an authorization under "exceptional circumstances" to a full approval on May 27, 2015. The treatment was first granted marketing authorization in September 2007.
In the United States, an application for trabectedin was submitted to the FDA for patients with advanced soft tissue sarcoma who received prior chemotherapy in late 2014. A final approval decision is expected from the FDA before the end of 2015. The application was previously granted a priority review, with a deadline set in August 2015; however, this date has passed leaving a final decision ambiguous.