What’s the latest with investigational drugs for soft tissue sarcoma?

ABSTRACT

Introduction

Despite extensive research undertaken in the past 20–30 years, the treatment for soft tissue sarcoma (STS) has remained largely the same, with anthracycline-based chemotherapy remaining the first choice for treating advanced or metastatic STS.

Areas covered

This review focuses on newly approved drugs for STS and current research directions, including recent results of late-phase trials in patients with STS. We cover several different histological subtypes, and we discuss the role of adoptive cell transfer (ACT) therapies for the treatment of synovial and myxoid/round cell (high-grade myxoid) liposarcoma, one of the most promising areas of treatment development to date. We searched clinicaltrials.gov and pubmed.ncbi.nih.gov, as well as recent year proceedings from the annual conferences of the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and Connective Tissue Oncology Society (CTOS).

Expert opinion

Immune-oncology drugs (IOs) show promise in certain subtypes of STS, but it is recognized that PD-1/PD-L1 axis inhibition is not enough on its own. Better trial stratifications based on the molecular categorization of different subtypes of STS are needed, and more evidence suggests that ‘one size fits all’ treatment is no longer sustainable in this heterogeneous and aggressive group of tumors.

KEYWORDS:

• Soft tissue sarcoma
• STS
• immunotherapy
• adoptive cell therapy
• combination therapy
• targeted therapy
• tyrosine-kinase inhibitors

Article highlights

• Tazemetostat, an inhibitor of the methyltransferase EZH2, received FDA approval in January 2020 for the treatment of epithelioid sarcoma, following the results of the phase 2 basket study EZH-202, which demonstrated an overall response rate (ORR) of 15%.

• Nab-sirolimus has anti-tumoral activity in patients with malignant perivascular epithelioid (PEComa) cell tumors and received FDA approval in November 2021 for this indication.

• MAK683 shows promising activity in early-phase trials for the treatment of epithelioid sarcoma, with an overall response rate of 14% and disease control rate of 57% in this difficult-to-treat subtype of STS.

• Adoptive cell therapy (ACT) using affinity-enhanced T cell receptor (TCR), demonstrated an impressive tumoral response in synovial sarcoma and myxoid liposarcoma, where high expressions of NY-ESO and MAGE-A4 have been noticed. Only patients with HLA-A-02 haplotypes are currently eligible for this new therapy.

• Anlotinib, a novel tyrosine kinase inhibitor, has entered phase 3 clinical trials for the treatment of synovial sarcoma, after showing anti-tumoral activity in multiple subtypes of STS including leiomyosarcoma and alveolar soft tissue sarcoma.

• LMS-02 and LMS-04 investigated the benefit of trabectedin in the first-line setting for leiomyosarcoma, in combination with doxorubicin. Both overall survival and progression-free survival are significantly longer in the combination of trabectedin and doxorubicin arm, but with more grade 3-4 side effects observed.

• Trametinib demonstrated a 7% partial response rate in the treatment of epithelioid hemangioendothelioma (EHE). Eribulin is currently being investigated in a phase 2 trial enrolling patients with either EHE or angiosarcoma, which have locally advanced, metastatic, or progressive disease.

• Combination trials of the PD-1/PD-L1 inhibitors and chemotherapeutic agents or tyrosine kinase inhibitors proved to be more effective than single-agent inhibition of PD-1/PD-L1 axis in certain subtypes of STS.

• Nintedanib failed to improve survival in second-line treatment compared to single-agent ifosfamide in advanced or metastatic STS.

This box summarizes key points contained in the article.

Declaration of interest

RL Jones declares the receipt of grants and research support from MSD and GSK, as well as receipt of consultation fees from Adaptimmune, Astex, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Immunicum, Karma Oncology, Lilly, Merck, Mundipharma, Pharmamar, Springworks, SynOx, Tracon, and Upto Date.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.