Individualizing systemic therapy for advanced soft tissue sarcomas based on tumor histology and biology

KEYWORDS:

• Chemotherapy
• immunotherapy
• molecular profiling
• soft tissue sarcoma
• targeted therapy

1. Introduction

Soft tissue sarcomas (STS) are rare, malignant tumors of mesenchymal origin with over 75 subtypes characterized by unique morphology, genomic aberrations, and clinical behavior [1]. Approximately 12,750 patients will be diagnosed in the United States this year [2], and about 40% will develop metastatic disease with a median overall survival (OS) of 12–18 months [3]. In advanced/metastatic STS, response rates to front line anthracycline-based chemotherapy are poor [4]. Despite new drug approvals, such as eribulin for liposarcoma, and trabectedin for liposarcoma and leiomyosarcoma, only modest improvements in outcomes have been observed [5]. Recently, therapies that exploit subtype-specific vulnerabilities have generated new therapeutic options, improved survival, and shifted the paradigm toward investigating subtype-specific therapies.

2. Treatment of advanced STS in unselected subtypes

Due to the rarity and heterogeneity of STS, clinical trials have historically included patients with STS across a variety of individual subtypes. Unfortunately, a number of promising agents failed to improve outcomes in a series of trials enrolling unselected patient populations [6–8]. A recent example of this includes olaratumab, a monoclonal antibody targeting platelet-derived growth factor receptor alpha (PDGFRA). In a randomized phase II study, the combination of doxorubicin with olaratumab in advanced STS met its primary endpoint for improvement in progression-free survival (PFS) and extended median (OS) by 11.8 months [9], leading to accelerated approval. Unfortunately, the phase III trial (ANNOUNCE) did not confirm the results and Food and Drug Administration (FDA) withdrawal is anticipated [8]. While there are several possible contributing factors, the inclusion of a broad number of histological subtypes may partly explain the disappointing results, underscoring the importance of subtype-specific and biologic-driven therapeutic approaches.

2.1. Targeted therapies in STS subtypes

Successful histology-driven therapy in STS began with the approval of imatinib for gastrointestinal stromal tumors (GIST), based on its characteristic addiction to oncogenic KIT/PDGFR signaling [10]. Sunitinib and regorafenib are currently approved as post-imatinib tyrosine kinase inhibitors (TKIs); however, tumors eventually acquire secondary mutations, leading to progressively shorter progression-free intervals. Primary resistance to currently approved TKIs can also occur in GISTs, primarily in those harboring the PDGFRA D842V mutation. Two novel TKIs that specifically target a range of primary and secondary mutations are currently in late-stage clinical trials. In the NAVIGATOR phase I trial exploring avapritinib (BLU-285), patients with GIST who were heavily pre-treated had a 22% response rate, and patients with exon 18 PDGFRA mutations, including the PDGFR D842V mutation, had a remarkable 86% response rate [11]. The international phase III VOYAGER clinical trial (NCT03465722), randomizing patients with locally advanced, unresectable or metastatic GIST to avapritinib versus regorafenib, is currently underway. Ripretinib (DCC-2618), a novel TKI with broad KIT and mutant PDGFR activity, has also demonstrated impressive activity in heavily pre-treated GIST patients. Analysis of phase III randomized, placebo-controlled INVICTUS study revealed significantly prolonged median PFS with ripretinib compared to placebo (6.3 months versus 1 month) [12]. The ongoing INTRIGUE study (NCT03673501) is randomizing patients with advanced GIST, who have failed imatinib, to either ripretinib or sunitinib. These promising agents have arisen from advances in fundamental knowledge of tyrosine kinase activation in GIST, thus supporting efforts to further characterize subtype-specific sarcoma biology.

Pazopanib was the first multitargeted TKI approved in non-GIST STS. The phase III randomized, placebo-controlled PALETTE trial demonstrated improved PFS with pazopanib in patients with non-adipocytic subtypes who had progressed on standard of care therapy [13]. Regorafenib also appears to have activity in non-GIST, non-adipocytic STS, based on the phase II REGOSARC trial [14]. TKIs have also demonstrated activity in other mesenchymal neoplasms, including alveolar soft part sarcoma, clear cell sarcoma, solitary fibrous tumor, and, most recently, desmoid tumors, where a recent phase III randomized controlled trial of sorafenib demonstrated durable responses and improved PFS when compared to a placebo [15].

2.2. Targeting subtype-specific biology

While multitargeted TKIs have shown activity in a broad range of histologic subtypes, a robust understanding of the molecular drivers of disease pathogenesis will hopefully result in further improvements in patient outcomes, particularly in extremely rare sarcoma subtypes. Epithelioid sarcoma, as an example, comprises <1% of STS and is often associated with loss of integrase interactor 1 (INI1) resulting in dependency on enhancer of zeste homolog 2 (EZH2), an epigenetic modifier [16,17]. An understanding of this biology led to an international phase II study of the tazemetostat, an EZH2 inhibitor, in patients with epithelioid sarcoma resulting in an observed response rate of 15% and a disease control rate of 26% [18]. Tazemetostat is currently under priority review with the FDA.

Malignant perivascular epithelioid cell tumors (PEComas) belong to a rare subfamily of STS that are often characterized by dysregulation of the mammalian target of rapamycin (mTOR) pathway as a result of tuberous sclerosis 1 or 2 (TSC1 or TSC2) deletions/mutations. The nonrandomized, open-label, registrational phase II AMPECT trial, exploring a novel nanoparticle albumin-bound (nab)-form of sirolimus in patients with unresectable malignant PEComa, revealed a response rate of 42%, a disease control rate of 77%, and a median PFS of 8.9 months [19].

Tenosynovial giant-cell tumors (TGCT) can be characterized by tumor cells harboring a chromosomal translocation involving chromosome 1p13, resulting in overexpression of colony stimulating factor 1 (CSF1). The phase III ENLIVEN trial evaluated pexidartinib, an oral CSF receptor 1 (CSF-1R) inhibitor in patients with unresectable TGCT. An overall response rate of 39% was observed and improvements were seen in patient symptoms and functional outcomes [20].

Mouse double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) amplifications are a hallmark of dedifferentiated liposarcomas and attractive targets for novel therapeutic agents. The potent CDK4 inhibitor, abemaciclib, is currently under investigation, and demonstrated an encouraging 12-week PFS of 76% in a phase II nonrandomized trial of patients with dedifferentiated liposarcomas [21].

Disease-agnostic molecular observations have also advanced treatment in STS. For example, malignancies harboring neurotrophic tyrosine receptor kinase (NTRK) fusions (including STS) have shown unparalleled, durable responses to the tropomyosin receptor kinase (TRK) inhibitor, larotrectinib [22].

While the value of universal molecular profiling to guide STS management has been debated, retrospective studies do suggest that targeted next-generation sequencing can identify alternative treatment options [23,24]. The ongoing randomized, phase III MULTISARC clinical trial (NCT03784014) compares the standard of care therapy with the utilization of next-generation sequencing (NGS) to enroll patients into sub-arms of targeted therapies. The results of this trial may lead us toward subtype-agnostic approaches that target individualized molecular findings or identify additional histology-specific molecular characteristics that facilitate drug discovery.

2.3. Immunotherapy in STS subtypes

The use of immune checkpoint inhibitors (ICI) in soft tissue and bone sarcomas was first investigated in phase II study SARC028, which explored pembrolizumab, a monoclonal antibody targeting programmed cell death protein 1 (PD-1), in single-arm cohorts of soft tissue and bone sarcoma [25]. While undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (ddLPS) appeared to show activity initially with an overall response rate of 40% and 20%, respectively, expansion cohorts revealed modest response rates of 20% and 10%, respectively [26].

There are ongoing efforts to enhance the activity of ICI in STS through predictive biomarker development and combination therapies, including multimodality approaches. For example, radiation therapy increases pro-inflammatory cytokines and neoantigens, suggesting possible synergy with ICI [27,28]. SARC032 is an ongoing randomized phase II trial investigating neoadjuvant pembrolizumab in combination with preoperative radiation therapy and surgery in patients with localized UPS and ddLPS. Additionally, the combination of PD-1/programmed death-ligand 1 (PDL1) inhibitors with inhibition of other immune regulatory molecules such as CD40, lymphocyte-activating gene 3 (LAG-3), and semaphorin 4D are also being explored in preclinical studies and clinical trials. ICIs combined with TKIs have also shown promise, particularly in alveolar soft part sarcoma (ASPS), possibly owing to its characteristic molecular aberration. In this subtype, the ASPSCR1-TFE3 fusion gene leads to the upregulation of vascular endothelial growth factor (VEGF), which can promote tumor immune evasion. Based on these biological underpinnings, a phase II trial enrolled 33 patients with STS, enriched for ASPS (36%), exploring the combination of pembrolizumab with the VEGF receptor inhibitor, axitinib. Clinical benefit was observed in 53% of the patients enrolled and in 73% of the ASPS cohort [29]. Atezolizumab, a monoclonal antibody targeting PD-L1, is currently under investigation in a phase II trial of unresectable ASPS (NCT03141684).

While many of the trials investigating immunotherapies are being studied independent of sarcoma subtype, the use of adoptive T-cell transfer with enhanced affinity for tumor-specific antigens (such as New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) and melanoma antigen gene type A4 (MAGE-A4)) are also showing early promise in STS, particularly in synovial sarcoma [30,31]. Lentiviral (LV)-based vaccine approaches, such as CMB305, which combines LV305, a dendritic cell-targeting LV encoding NY-ESO-1, with a toll-like receptor 4 agonist, G305, are also under investigation in clinical trials. While the co-administration of CMB305 with atezolizumab led to increases in radiographic and immune responses in patients with NY-ESO-1+ tumors, compared with atezolizumab alone, the combination did not result in a statistically significant improvement in patient outcomes [32].

3. The future of histology-directed therapies

While recent advances have expanded the repertoire of available therapies and improved outcomes for patients, it is important to validate observations suggesting histology-specific activity with randomized, when feasible, prospective clinical trials. Despite available evidence that certain STS subtypes have differential chemotherapy sensitivity in the metastatic setting, a recent randomized trial failed to show improvement in outcomes using a histology-tailored treatment approach for patients with high risk, localized disease [33].

The discovery and investigation of subtype-specific STS therapies require several key efforts. First, designing clinical trials that restrict or enrich study populations with STS subtypes based on preclinical studies and biomarkers should be done when feasible. Enrolling patients with ultra-rare STS subtypes will require that we continue fostering international collaborative efforts and a commitment to refer patients when clinical trial opportunities arise. Our ability to conduct well-designed clinical trials, select appropriate patients, and develop novel therapies will all rely on a deeper understanding of the biological underpinnings of STS subtypes. Prioritizing and funding efforts to determine mechanisms of therapeutic action, validate biomarkers of therapy response and resistance, and harness the hypothesis-generating potential of big data will pave the way for continued advancement toward individualizing STS therapy and improving outcomes for patients.

Declaration of interest

Richard Riedel has received contracted clinical research support from Aadi Bioscience Inc, Arog Pharmaceuticals Inc, Daiichi Sankyo Inc, Ignyta Inc, Immune Design, Karyopharm Therapeutics, Lilly, NanoCarrier Co Ltd, Novartis, Oncternal Therapeutics, Plexxikon Inc, Roche, Threshold Pharmaceuticals, and TRACON Pharmaceuticals Inc. Richard Riedel has also received advisory board/consultant fees from Bayer HealthCare Pharmaceuticals, Blueprint, Daiichi Sankyo Inc, Ignyta, Loxo Oncology Inc, and NanoCarrier Co Ltd. 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

This paper received no funding.