Doxorubicin and Trabectedin Combo Impresses in Soft Tissue Sarcoma

The combination of doxorubicin and trabectedin displayed encouraging activity as first-line therapy in patients with metastatic uterine and soft tissue leiomyosarcoma in the phase 2 LMS-02 trial, surpassing historical standards, explained lead study author, Patricia Pautier, MD.

In the trial, patients with chemotherapy-naïve, metastatic or unresectable locally relapsed uterine or soft tissue leiomyosarcoma received 60 mg/m2 of doxorubicin plus 1.1 mg/m2 of trabectedin over a 3-hour infusion on day 1 for 6, 3-week cycles. Surgery for residual disease was allowed.

The disease-control rate (DCR) served as the primary end point of the study. Progression-free survival (PFS) and overall survival (OS) were among key secondary end points.

In uterine leiomyosarcoma, the objective response rate (ORR) was 59.6%, and the DCR was 87.2%. In soft tissue leiomyosarcoma, the ORR and DCR was 39.3% and 91.8%, respectively.

At a median follow-up of 7 years, the median PFS was 8.3 months (95% CI, 7.4-10.3) in uterine leiomyosarcoma and 12.9 months (95% CI, 9.2-14.1) in soft tissue leiomyosarcoma, translating to an overall median PFS of 10.1 months (95% CI, 8.5-12.6).

The median OS was 27.5 months (95% CI, 17.9-38.2) in uterine leiomyosarcoma and 38.7 months (95% CI, 31.0-52.9) in soft tissue leiomyosarcoma, translating to an overall median OS of 34.4 months (95% CI, 26.9-42.7).

The results of the trial, in addition to demonstrating the activity of the combination, underscore the poorer prognosis of patients with uterine leiomyosarcoma and the need for histologic stratification in clinical trials.

“These are interesting results,” said Pautier. Now, we are waiting for the results of a phase 3 study [NCT02997358], which is comparing doxorubicin alone versus [the combination of doxorubicin and trabectedin] followed by trabectedin for patients who do not progress after 6 cycles [of treatment].”

In an interview with OncLive, Pautier, head of the Medical Day Hospital Unit at the Institut Gustave Roussy Cancer Campus, discussed the rationale for the study, the importance of histologic stratification, and ongoing challenges in soft tissue sarcoma.

OncLive: Could you provide some background on the LMS-02 study?

Pautier: Soft tissue sarcomas are rare and relatively heterogenous. There are no dedicated studies to specific histologic subtypes [of soft tissue sarcoma]. As such, the goal of the study was to evaluate metastatic leiomyosarcoma with a stratification between uterine and other soft tissue sarcoma.

[Historically], the first-line treatment has been doxorubicin alone. We know that the use of trabectedin in the second-line setting has good PFS and disease control. By adding trabectedin to doxorubicin, our goal was to enhance the response rate, the DCR, and perhaps survival.

We performed a phase 1/2 study to [identify the optimal dose of the combination], and then we performed a phase 2 study. The first results [from the LMS-02 study were] published in 2013 and showed a DCR of about 90% in both groups and a response rate of about 60% in uterine leiomyosarcoma, which is quite good. We also saw a 40% [response rate] in other soft tissue leiomyosarcomas.

One of the secondary end points of the study, with a medium follow-up of 7 years, was to evaluate OS. The updated results were encouraging, reflecting a median OS of about 34.4 months in the entire population. The results were less impressive in patients with uterine leiomyosarcoma with a median OS of 28 months. [However, the median OS was] 39 months in patients with soft tissue leiomyosarcoma.

In comparison, we have 2 phase 3 studies in the first-line setting in the same population, with a median OS ranging from 22 to 29 months with doxorubicin alone or doxorubicin [in combination with another agent].

Besides the phase 3 trial, what are some questions that still need to be answered with this regimen?

We’ll need to determine whether [the combination] is better than doxorubicin alone. The results of LMS-04 trial, which we anticipate will be presented at the 2020 ESMO Virtual Congress, [will shed light on this].

How is the combination tolerated versus doxorubicin alone?

The combination has a high rate of hematologic toxicity, but it’s quite manageable with G-CSF. No deaths were reported in the study. We were able to offer surgery after 6 cycles [of treatment] in this particular study. A quarter of patients in both groups can benefit from surgery, with improved response rates, PFS, and OS.

What are the biggest challenges that still remain in this treatment paradigm?

There’s no specific target, so we have no other therapy apart from chemotherapy. The challenge is, of course, to enhance the survival of patients in the first-line setting, and to develop drugs other than classical chemotherapy. In this particular disease, it’s difficult to conduct specific studies because there are different histologic subtypes. Response rates and the evolution of disease is different among the different histologic subtypes. The goal is to dedicate specific studies to specific histologic subtypes with different drugs in the future.

It’s difficult to have access to drugs in this rare disease and to conduct randomized studies. We’ll have to conduct international studies to [increase response rates] in [individual] histologic subtypes.

Are there any interesting targets that are currently in development?

It has been difficult [to develop targets in leiomyosarcoma]. Immunotherapy alone or in combination with doxorubicin is not active. We’ll have to develop other combinations, perhaps with targeted drugs. Some uterine leiomyosarcoma, but also soft tissue sarcomas express hormonal receptors.

Is there anything else about the study that you want to emphasize?

We’ve shown that there is a different evolution in uterine leiomyosarcoma [compared with soft tissue sarcoma]. Despite a higher response rate, [patients with uterine leiomyosarcoma] have a poorer prognosis than patients with other soft tissue sarcomas. If we conduct leiomyosarcoma studies, we’ll have to stratify between uterine and other soft tissue leiomyosarcomas.

Reference

Pautier P, Floquet A, Chevreau C, et al. A single-arm multicenter phase II trial of doxorubicin (doxo) in combination with trabectedin (trab) given as first-line treatment to patients with metastatic/advanced uterine (U-LMS) and soft tissue leiomyosarcoma (ST-LMS): final results of the LMS-02 study. J Clin Oncol. 2020;38(15 suppl):11506. doi:10.1200/JCO.2020.38.15_suppl.11506