The challenge of finding new therapeutic avenues in soft tissue sarcomas

Abstract

Soft tissue sarcomas are rare malignancies of mesenchymal origin comprising about 1% of all adult cancers. Systemic therapies for locally advanced and metastatic disease have been restricted for decades to very few effective and approved agents such as doxorubicin and ifosfamide. However, new therapeutic avenues including new drug developments and registrations such as trabectedin, pazopanib and eribulin as well as numerous clinical trial options have recently enriched the therapeutic armamentarium in the treatment of patients with advanced soft tissue sarcomas. The challenges and pitfalls of finding such new therapeutic avenues in recent years for the treatment benefit of patients with soft tissue sarcomas will be presented in this chapter within the thematic series on “Challenges in Sarcoma”.

Circulating Tumor Cells and Biomarker Modulation with Olaratumab Monotherapy Followed by Olaratumab plus Doxorubicin: Phase Ib Study in Patients with Soft-Tissue Sarcoma

“…Single-agent doxorubicin, introduced in the early 1970s, remains the standard treatment option for many patients with metastatic STS [4,5]. Several randomized trials have failed to show any survival benefit for combination therapies of doxorubicin and novel agents compared with single-agent doxorubicin [6][7][8][9][10][11].…”

SELNET clinical practice guidelines for soft tissue sarcoma and GIST

“…For leiomyosarcoma, doxorubicin and dacarbazine could be considered, instead of anthracyclines plus ifosfamide, since this latter could be even detrimental in this specific subtype according to retrospective comparisons. [IV, B] [38]. The combination of gemcitabine plus docetaxel is not recommended as a first-line option for the treatment of advanced STS [39].…”

Larotrectinib efficacy and safety in adult patients with tropomyosin receptor kinase fusion sarcomas

“…Systemic therapy options vary according to histologic subtype and include cytotoxic chemotherapies (doxorubicin and/or ifosfamide-based regimens), anti-angiogenic multikinase inhibitors (such as pazopanib, regorafenib, sunitinib, and cabozantinib), and multikinase inhibitors that target NTRK, ROS1, and ALK (entrectinib). 3,8,[20][21][22] Despite the availability of multiple treatment options, there remains an unmet need for effective targeted treatments.…”

“…However, no statistically significant OS benefit could be demonstrated by the addition of other chemotherapy to doxorubicin. 8 Moreover, a recent partitioned survival modeling study that estimated the long-term comparative effectiveness of larotrectinib and standard of care in adult patients with STS showed that patients receiving larotrectinib gained 5.56 additional life years and 1.99 quality-adjusted life years compared with doxorubicin/ifosfamide. 23 Pazopanib, indicated for the treatment of adults with advanced STS, 24 demonstrated an ORR of 9%, median PFS of 4.6 months, and OS of 12.5 months in a phase 3 trial.…”

“…1,6,7 This heterogeneity makes management difficult, with limited treatment options for advanced sarcomas following failure of first-line cytotoxic chemotherapy. 6 The prognosis of adult patients with locally advanced or metastatic sarcoma is poor, with median overall survival (OS) ranging from 12 to 18 months, [7][8][9] demonstrating the unmet need for effective treatment options. As NTRK gene fusions can arise in a variety of sarcoma subtypes, TRK fusion proteins are a potential therapeutic target in sarcomas.…”