ABSTRACT

Soft tissue sarcomas are a heterogeneous group of rare malignancies with few effective standard therapies. Our understanding of the underlying biology driving tumorigenesis in these mesenchymal tumors have led to a growth in drug development for soft tissue sarcomas. This review focuses on novel targets in soft tissue sarcomas, describes early clinical trial results of drugs directed at these targets, and discusses the data surrounding the use of these compounds in clinical practice and rationale for possible future US Food and Drug Administration approvals.

INTRODUCTION

Soft tissue sarcomas remain challenging to both classify as well as to treat due to their heterogeneity. Historically, treatment of soft tissue sarcoma has been driven by histologic subtype. However, recent developments in genetic and immunoprofiling have bolstered the development of novel targeted and immunotherapeutic agents. With gastrointestinal stromal tumor (GIST) remaining the model for personalized treatment based on the successful targeting of KIT or platelet-derived growth factor receptor A (PDGFRA), many novel agents have emerged as possible effective therapies for various sarcoma subtypes. In this review, we detail recent clinical trial data and ongoing studies of novel therapies targeting mouse double minute 2 (MDM2), cyclin-dependent kinase 4 (CDK4) gene, NYESO, AXL preferentially expressed antigen in melanoma (PRAME), and integrase interactor (INI), for various subtypes of soft tissue sarcoma.

GASTROINTESTINAL STROMAL TUMOR AS A MODEL

GIST is a kinase-driven cancer that is the most prevalent sarcoma in the gastrointestinal tract.[1] As our knowledge of GIST biology has developed, it has served as a model for drug development in soft tissue sarcomas. We first learned that mutations in the receptor tyrosine kinase protein KIT are seen in the majority of GISTs (80%), and this remains a mechanistic target for continued drug development.[1] The most common mutation of KIT is found on exon 11, encoding the juxtamembrane domain that physiologically inhibits the kinase activation loop, causing a constitutively active KIT. Mutations in exons 8 and 9, which encode the extracellular domain, and mutations in exons 13 and 17, which encode the kinase domain, are implicated in the pathogenesis of GIST as well.[2] Imatinib mesylate is a KIT kinase inhibitor that first demonstrated activity in a phase 3 trial compared to placebo.[1] A total of 713 patients were randomized into two groups: imatinib 400 mg daily (n = 359) and placebo (n = 354). Imatinib significantly improved clinical outcomes and remains a frontline standard of care therapy. The most common adverse events were diarrhea, abdominal pain, and dermatitis. To better understand dosing efficacy, imatinib was given to 746 patients at two different dosing levels: 400 mg imatinib daily (n = 345) and 400 mg imatinib twice daily (n = 349).[1] Results of this trial concluded that there was no significant difference in progression-free survival or overall survival between high-dose imatinib and the normal dose of imatinib. However, there were patients (33%) who developed stable disease or an objective response after going to the high-dose imatinib regimen from the normal dose, but this was at the expense of added toxicity. Further investigation subsequently identified that location of KIT mutations drove response data as exon 8 and 11 mutations were found to be sensitive to imatinib while patients with mutations on exon 9 responded poorly.[2]

Research into emerging resistance mechanisms ultimately led to investigating multikinase inhibitors such as sunitinib for GIST refractory or intolerant to imatinib. The US Food and Drug Administration (FDA) approval of sunitinib was based on a randomized, placebo-controlled trial of sunitinib versus placebo. The most common adverse events with sunitinib were diarrhea, fatigue, nausea, and skin discoloration. Results of this study found an improvement in survival and disease control when patients took sunitinib, leading to FDA approval.

Efforts to better molecularly characterize GIST have identified additional relevant mutations in KIT wild-type GIST.[2] Thirty percent of KIT wild-type GISTs have a mutation in the PDGFRα gene.[3]PDGFRα is a platelet-derived growth factor gene that has mutations that occur on exons 12, 14, and 18. The mutations in PDGFRα have a sensitivity to imatinib, with the exception of exon 18 mutants with a specific point mutation at position 842 (D842V).[4] Of these tumors, there is a small subset (7–15%) of PDGFRα-BRAF mutations, which is most commonly an exon 15 mutation (V600E) that has been identified as potentially actionable by targeting BRAF and/or MEK, as detailed by Falchook et al.[5] The actionability of mutations in succinate dehydrogenase (SDH) or loss of SDH expression itself is also being investigated currently. Among many other mutations of GISTs, some of the more recognizable mutations are found in RAS, RB1, TP53, and NF1.[2] Many of these mutations have yet to be treated effectively, but novel agents targeting these alterations across tumor types continue to be developed.

Avapritinib and ripretinib

Avapritinib (BLU-285) and ripretinib (DCC-2618) are the most notable recent drugs under investigation for GIST. Avapritinib is a selective tyrosine kinase inhibitor of KIT and PDGRA that has demonstrated activity in patients with GIST harboring a PDGRA exon 18 mutation. It was investigated in an open-label, single-arm, multicenter study that enrolled 43 patients.[6] Patients were started on 400 mg orally daily, but due to toxicity, reduced to 300 mg daily. The trial demonstrated an overall response rate of 84% (with 61% of responses lasting 6 months or longer). Avapritinib was approved by the FDA in January of 2020 for GIST patients with a PDGRA exon 18 mutation. An open-label, randomized, phase 3 study to compare its efficacy and impact on quality of life compared to regorafenib is ongoing (NCT02508532). Ripretinib is a tyrosine kinase swift control inhibitor designed to inhibit KIT- and PDGFRA-mutated kinases. It has been proven to inhibit KIT mutations in exons 9,11, 13, 14, 17, and 18 and PDGFRA mutations in exons 12, 14, and 18. A new drug application has been submitted for ripretinib (DCC-2618) for the treatment of patients with GIST who have been previously treated with imatinib, sunitinib, and regorafenib. Ripretinib was investigated in a phase 3 trial that compared it to placebo in previously treated patients. Patients treated with ripretinib saw improvement in progression-free survival, with the median progression-free survival (PFS) being 6.3 months with ripretinib and 1 month with placebo, and a PFS benefit was observed across all patient subgroups. Ripretinib is currently under review by the Oncology Center of Excellence Real-Time Oncology Review pilot program under the FDA. An ongoing randomized trial comparing ripretinib to sunitinib in advanced GIST is ongoing (NCT03353753).

MDM2 AMPLIFICATION

The MDM2 gene codes for a nuclear-localized E3 ubiquitin ligase, which targets tumor suppressor proteins—most commonly p53—for proteasomal degradation. The gene can become oncogenic when overexpressed. Excessive degradation of the p53 protein by the MDM2 protein leads to an inhibition of p53-dependent activities, such as cell apoptosis and cell cycle arrest. As a result, amplification of the gene promotes tumor formation.

The MDM2 gene is known to be amplified in virtually all well-differentiated and dedifferentiated liposarcomas.[7] Several MDM2 inhibitors have been studied thus far, all seeking to block the MDM2–p53 interaction and restore tumor suppressor functioning of p53. Tested in vitro, MDM2 antagonists have been found to reactivate the p53 pathway, impede cell proliferation, and induce cell cycle arrest and apoptosis.[8] The use of MDM2 antagonists for the inhibition of the MDM2–p53 interaction has important implications for the future of targeted sarcoma treatment. MDM2 inhibitors under investigation will be summarized below.

RG7112

A proof-of-mechanism study of the small-molecule MDM2 inhibitor RG7112 was completed in 2012.[9] RG7112 is a member of the nutlin family, a class of imidazoline compounds that had previously been identified as selective small-molecule MDM2 inhibitors, of which RG7112 was the first to be assessed clinically. This molecule mimics the alpha-helical peptide structure of p53 in its binding to MDM2, consequently preventing the binding of MDM2 to p53. The trial treated patients with well-differentiated or dedifferentiated liposarcoma in the neoadjuvant setting as a window of opportunity trial. Patients received up to three 28-day neoadjuvant treatment cycles of 1440 mg/m2 for 10 days. In a pool of 20 patients, the best Response Evaluation Criteria in Solid Tumors response to treatment was a partial response in one patient, stable disease in 14 patients, and progressive disease in five patients. Biomarker analysis suggested that RG7112 effectively enabled reactivation of the p53 pathway in a subset of patients. Notable adverse events included hematotoxicity,[10] which was hypothesized to be related to the role that MDM2 plays in normal hematopoiesis. Subsequently, a more potent and selective compound of the nutlin family was developed, called RG7388 (aka idasanutlin). Idasanutlin demonstrated higher efficacy and a lower degree of side effects than the original compound.[11]

MK-8242

A phase 1 trial of the MDM2 inhibitor MK-8242 in 2017 also presented promising results.[12] MK-8242 prevents the binding of the MDM2 protein to the transcriptional activation domain of the p53 protein, preventing its degradation. The study treated patients with advanced solid tumors and consisted of 27 (57.4%) patients with liposarcoma and 20 (42.6%) patients with a different type of tumor. MK-8242 was administered twice a day on a 7-days-on, 14-days-off basis. An 11.1% response rate was seen in the liposarcoma patients. The study concluded that MK-8242 doses greater than 300 mg were needed to successfully reactivate the p53 pathway and demonstrate efficacy of the drug in patients with liposarcoma.

ALRN-6924

ALRN-6924 is an alpha-helical peptide that disrupts the interaction between p53 and MDM2, allowing the p53 pathway to function as normal to trigger appropriate cell cycle arrest and apoptosis. Thus far, this drug has only undergone a phase 1 study to evaluate its safety and dosing.[13] In a pool of 55 patients, the disease control rate was 45%, indicating beneficial effects of ALRN-6924 on antitumor activity. The trial is currently further evaluating the efficacy of ALRN-6924 in combination with a CDK4 inhibitor, given the frequency with which the two genes are coamplified, discussed below.

SAR405838 (MI-77301)

SAR504838 is another molecule that blocks the MDM2-p53 interaction. In vitro, SAR504838 has been seen to activate wild-type p53. The molecule mimics three key p53 amino acid residues and induces refolding of the MDM2 N-terminal region, allowing it to bind with high specificity. In mice, this has been seen to achieve tumor regression or tumor growth inhibition in several types of cancer.[14] A phase 1 study of the compound in solid tumors revealed that treatment with SAR405838 was associated with increased plasma MIC-1, a reflection of p53 pathway activation. Within 74 patients, of which 89% expressed an MDM2 amplification, the best response was stable disease in 56% and a PFS rate of 32% at 3 months.

Although more testing needs to be done to validate efficacy, specifically in sarcomas, the inhibition of MDM2 is an area of ongoing research. Larger trials and a deeper understanding of the molecular characteristics of those responding to MDM2 inhibitors is needed. Clinical trials are in progress to further evaluate the efficacy of various MDM2 inhibitors, now in combination with checkpoint inhibitors and other novel compounds.

CDK4 AMPLIFICATION

The CDK4 gene is another promising target in the treatment of sarcomas. CDK4 is a key regulator of cell cycle progression and encodes a protein that forms a compound with cyclin D1 and phosphorylates and inactivates the retinoblastoma (Rb) protein. Inactivation of the Rb protein allows for the reactivation of the transcription factor E2F, resulting in advancement from G1 to S phases. Overexpression of CDK4 can lead to cell cycle dysregulation and, consequently, cell proliferation. In a manner similar to that of MDM2, CDK4 is commonly amplified in well-differentiated and dedifferentiated liposarcoma patients (>90%) and is often coamplified with MDM2. Therefore, inhibition of the protein has been investigated, and CKD4/6 inhibitors are clinically used in certain individuals with liposarcoma.

Palbociclib

The first-generation CDK inhibitors were nonselective CDK inhibitors that were successful in blocking CDK4 but were accompanied by unfavorable off-target effects.[15] Second-generation CDK inhibitors such as palbociclib selectively target the ATP-binding site of the CDK4-cyclin D complex. Palbociclib is an orally bioavailable small molecule that functions by inhibiting CDK at nanomolar concentrations and is shown to prevent Rb phosphorylation in vitro, consequently inducing G1 cell cycle arrest. A phase 2 study of the drug supports the argument that these mechanisms may be effective in humans.[16] In this study, patients with well- or dedifferentiated liposarcoma were treated with 125 mg palbociclib once daily for 21 days, every 28 days. Within a population of 60 patients, the overall PFS rate at 12 weeks was 57.2% and the median PFS was 17.9 weeks. These results confirmed that treatment with palbociclib correlates with favorable PFS and occasional response in well-differentiated and dedifferentiated liposarcoma. Palbociclib with the same dosage is FDA approved for use in the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer and is clinically used in practice to treat some liposarcomas as well, based on the above data.

Abemaciclib

Like palbociclib, abemaciclib is a potent CDK4 inhibitor. A phase 2 study tested the activity of abemaciclib in advanced dedifferentiated liposarcoma, with patients receiving 200 mg abemaciclib twice daily, continuously.[7] Among 29 evaluable patients, the observed PFS at 12 weeks was 76% and the median PFS was 30.4 weeks, with one partial response. The results of this trial are indicative of favorable activity of abemaciclib in dedifferentiated liposarcoma with manageable toxicity.

COMBINED TARGETING OF MDM2 AND CDK4

MDM2 and CDK4 are frequently coamplified in sarcomas, particularly well-differentiated and dedifferentiated liposarcoma. Therefore, combined targeting of both genes is proposed to display higher efficacy than the individual targeting of each gene. An in vitro study of the combination of the MDM2 inhibitor idasanutlin and the CDK4 inhibitor palbociclib demonstrated success in suppressing cell proliferation and promoting apoptosis. An in vivo study performed immediately after validated the antitumor activity of the combination of drugs and showed longer PFS in mice treated with both drugs than in those treated with only a singular drug.[18]

The combination of ALRN-6924 (MDM2 inhibitor) and palbociclib (CDK4 inhibitor), discussed above, has also demonstrated enhanced antitumor activity in comparison with treatment with a singular drug in animal models. A clinical trial is currently in progress to evaluate ALRN-6924 and palbociclib activity, and this combination seems promising in MDM2-CDK4 coamplified liposarcomas.[19]

NY-ESO-1

NY-ESO-1 is a gene that codes for a protein in the cancer testis antigen (CTA) family. CTAs are most highly expressed in testis and placenta and are largely involved in germ cell proliferation and differentiation, with low expression in other healthy adult tissues. CTAs are regulated by a series of epigenetic events, including DNA methylation and histone modification. As the name suggests, CTAs are commonly expressed in several kinds of malignant tumors as well. Expression of NY-ESO-1 is seen in a variety of malignancies and noted to be overexpressed in a subset of synovial sarcomas and myxoid/round cell liposarcomas.

NY-ESO-1 is the most immunogenic of CTAs and has been seen to induce immune responses in some cancer patients. The extent of a NY-ESO-1–specific humoral immune response has also been found to be correlated with disease progression; therefore, a decrease in NY-ESO-1 antibodies over time could indicate disease regression and be used for monitoring. Accordingly, NY-ESO-1 antibodies are rarely observed in healthy individuals.[20] As NY-ESO-1 is expressed only in limited types of healthy tissues, targeting of this gene is not likely to induce extensive toxicities. NY-ESO-1 is expressed in up to 80% of synovial sarcomas and 89–100% of myxoid/round cell liposarcomas.[21] This makes it an auspicious prospective target for immunotherapy treatments. Several trials targeting NY-ESO are ongoing in sarcomas, discussed below.

NY-ESO-1 cancer vaccines

One area of intrigue is the development of NY-ESO-1 vaccinations designed to induce NY-ESO-1–specific immune responses. Several formulations have undergone trials or are currently in trial to evaluate their ability to enhance CD4+ and CD8+ cell responses, both of which are associated with NY-ESO-1 and prove to be the most immunogenic. Such vaccinations have been observed to elicit both humoral and cellular immune responses with some success.[21]

CMB305 is a prime-boost vaccine regimen specifically targeting NY-ESO-1. This treatment involves the sequenced administration of LV305 and G305 in the prime-boost vaccination manner. LV305 is used as the priming agent that binds to dendritic cells via the DC-SIGN receptor. The dendritic cell takes up the molecule, stimulating the production of the NY-ESO-1 protein. Production of the NY-ESO-1 protein allows for maturation of the dendritic cell, leading to activation of the immune system to send T cells to target cells expressing the NY-ESO-1 gene. The boosting regimen is called G305 and uses a TLR4 agonist and a NY-ESO-1 protein vaccine. A phase 1 trial treating patients with synovial sarcoma and myxoid/round cell liposarcoma demonstrated the ability of the CMB305 regimen to induce T-cell responses specific to NY-ESO-1. Several patients experienced dramatic tumor shrinkage due to the therapy, and overall survival rate was notable, with 76% of patients surviving 18 months after beginning treatment. Although these early data indicate favorable clinical results, the regimen continues to be studied as further validation is needed.[22] The effectiveness of vaccinations specifically targeting NY-ESO-1 continues to be explored in synovial sarcoma and myxoid/round cell liposarcoma as well as other varieties of solid tumors.

Adoptive T-cell therapy

Another immunotherapy route that shows promise is the use of affinity enhanced autologous T cells targeted toward NY-ESO-1. Studies of this method have shown potential in eradicating cancer cells in a range of advanced solid tumors, including synovial sarcoma and myxoid/round cell liposarcoma.[21] A pilot study of NY-ESO-1c259 T cells in advanced myxoid/round cell liposarcoma has demonstrated potential for antitumor activity. The treatment takes autologous T cells and genetically modifies them for increased affinity for NY-ESO-1 cells by transducing them with a lentiviral vector containing the NY-ESO-1c259 T-cell receptor.[23] This study is ongoing, but the most recent available data from August 2018 indicates an overall trend in tumor burden decrease across a majority of the patients enrolled. Expansion of NY-ESO-1c259 T cells was observed postinfusion in all patients, and a 6-month persistence of these T cells was seen in all responders and one of six nonresponders. The treatment is generally well tolerated and continues to be studied both in myxoid/round cell liposarcomas as well as synovial sarcomas.[23] Due to the potential of NY-ESO-1 as a target in the treatment of synovial sarcoma and myxoid/round cell liposarcoma, numerous trials are currently underway and the gene continues to be studied.

AXL

AXL is a receptor tyrosine kinase that is often highly expressed and activated in a number of sarcomas. AXL is activated through its interactions with vitamin K–dependent protein growth arrest-specific 6. Activation of the gene is correlated with enhanced cell survival, proliferation, migration, and cell-cell adhesion; it is also seen to inhibit apoptosis. Therefore, overactivation promotes tumor formation and growth. In vitro and in vivo studies have implicated AXL as a driver of tumor migration.[24] AXL is also thought to play a major role in therapeutic resistance. Studies have shown correlation between AXL expression and chemoresistance in numerous cancers. AXL expression has been linked to resistance against chemotherapy, immune response, and even radiation.[24] Therefore, inhibition of the AXL protein may suggest benefit in antitumor activity as well as increased treatment efficacy. AXL is seen to be most commonly overexpressed in dedifferentiated and pleomorphic liposarcomas.[25] Several clinical trials are underway to determine the benefit of blockage of the AXL pathway in sarcomas and other solid tumors.

ADCT-601

A phase 1 clinical trial is ongoing to determine the safety, tolerability, pharmacokinetics, and antitumor effects of ADCT-601 in advanced solid tumors (NCT03700294). ADCT-601 is an antibody-drug conjugate (ADC) composed of an antibody against human AXL linked to a pyrrolobenzodiazepine (PBD) dimer toxin. ADCT-601 functions by binding to an AXL-expressing cell. The PBD toxin is then internalized and released by intracellular enzymes, which blocks cell division and ultimately leads to cell death.

In vitro and in vivo studies have demonstrated antitumor activity of ADCT-601. It has proven highly potent and selective in AXL-expressing cell xenografts, while it is insignificant in an AXL-negative xenograft model.[26] This trial is a first in human, single-arm study with a dose-escalation phase followed by a dose-expansion phase. It is being conducted to evaluate the effects of ADCT-601 in humans. The study is estimated to be completed in January of 2021.

BA3011

BA3011 is another ADC in testing to evaluate its efficacy in treating solid tumors. Similar to ADCT-601, it is composed of an active antibody against AXL conjugated to a cytotoxic agent called monomethyl auristatin E (MMAE). This specific anti-AXL antibody is activated only under conditions that are present in the tumor microenvironment. Therefore, it will presumably cause harm only to tumor cells and be harmless to normal tissue cells, reducing the risk of side effects and toxicity. A phase 1/2 trial is currently recruiting to evaluate the safety and effectiveness of BA3011 in patients with advanced solid tumors (NCT03425279). The study begins with a dose-escalation phase and is followed by a dose-expansion phase. The trial is expected to end in January of 2022.

PRAME

PRAME is a gene that encodes a CTA that is known to be overexpressed in melanomas. A recent analysis by Roszik et al.[27] identified that PRAME is overexpressed in sarcomas and uterine carcinosarcomas, as well. Not only does PRAME expression likely give a growth advantage to cancer cells by acting as a repressor of retinoic acid receptor, but it also negatively interacts with genes involving antigen presentation, which may make cells less receptable to immunotherapies. PRAME is shown to have an association with cytotoxic T-cell activation. For these reasons, PRAME is a promising target in the treatment of various types of sarcoma.

Tumor-associated antigen–specific cytotoxic T lymphocytes

A phase 1 dose-escalation study is currently underway to investigate the antitumor activity of special tumor-associated antigen (TAA)–specific cytotoxic T lymphocytes in solid tumors (NCT02239861). These lymphocytes make up a new experimental therapy that specifically targets five common TAAs: NY-ESO-1, MAGEA4, PRAME, survivin, and SSX. Eligible patients are those with a solid tumor who have not gained benefit from previous treatments. Patients receive up to six doses of intravenous injections of tumor-specific T cells and are evaluated for dose-limiting toxicity and disease response. The study is expected to conclude in December 2024. A number of preclinical studies have been conducted or are currently underway to further understand PRAME and the consequences of its inhibition. The safety and efficacy of drugs that target PRAME continue to be studied in humans.

INTEGRASE INTERACTOR (INI)

Integrase interactor 1 (INI-1) loss has been implicated in the pathogenesis of epithelioid sarcomas and malignant rhabdoid tumors. INI-1 encodes a subunit of the SWI-SNF protein complex, which regulates gene expression through chromatin remodeling. Although the specific function of INI-1 is still poorly understood and continues to be studied, it is believed that loss of the INI-1 gene causes oncogenic dependence on other pathways for cell proliferation.[28]

Tazemetostat

Tazemetostat (also formerly known as E7438 and EPZ-6438) is currently under development for the treatment of tumors with INI-1 loss. Tazemetostat is a selective, orally bioavailable, small-molecule inhibitor of EZH2 (enhancer of zeste homolog 2) enzymatic activity. EZH2 encodes a histone methyltransferase and has been implicated to serve an oncogenic role in several cancer types.[29] In tumors with INI-1 loss, EZH2 dependence is hypothesized to drive cancer cell proliferation. EZH2 therefore serves as a promising target in this subset of sarcomas.

The early phase study of tazemetostat in patients with INI-1–negative tumors of any solid tumor with an EZH2 gain-of-function mutation (NCT02601950) enrolled 32 patients. In the study there were three PRs and 13 SDs observed. Overall, treatment with tazemetostat resulted in long-term clinical benefit in 2/13 patients with INI-1–negative sarcomas and 1/16 with INI-1–negative solid tumors. These data led to the phase 2 trial of tazemetostat in patients with epithelioid sarcoma. Updated data on this cohort as of the September 17, 2018, cutoff date report a 15% objective response rate and a 26% disease control rate.

Responses were noted to be durable in many instances, with duration of response ranging from 7.1+ weeks to 103.0+ weeks (median: not reached) with a median overall survival of 82.4 weeks (95% CI: 47.4, not estimable) for all 62 patients. Tazemetostat was generally well tolerated. Treatment-emergent adverse events were generally mild to moderate, with the most commonly reported adverse events being fatigue (24/62; 39%) and nausea (22/62; 35%). These data led to the recent accelerated approval for tazemetostat in refractory epithelioid sarcomas. A frontline study of tazemetostat plus Adriamycin is ongoing (NCT04204941). Research is ongoing to better understand the role of INI-1 loss in epithelioid and rhabdoid sarcomas, as well.

NTRK

Tumor agnostic targets such as neurotrophic tyrosine receptor kinase (NTRK) continue to be explored in sarcomas, as well. The NTRK gene family encodes three TRK receptors that contribute to central and peripheral nervous system development and function. NTRK fusions are known to be oncogenic and result from intrachromosomal or interchromosomal rearrangements. Fusions promote tumorigenesis through the overexpression of the chimeric protein and activation of intracellular biological pathways that enable cell proliferation. NTRK fusions are observed across many cancer types, including GIST and infantile fibrosarcoma. The estimated prevalence of NTRK fusions in sarcoma ranges from 1% in adult-type sarcomas to 92% in congenital fibrosarcomas.[30]

Larotrectinib

Larotrectinib is a highly selective TRK inhibitor that has been FDA approved for solid tumors with NTRK fusions. A study evaluating efficacy among 55 patients with locally advanced or metastatic solid tumors harboring a variety of TRK fusions had an overall response rate of 75%.[30] Encouragingly, responses were observed across soft tissue sarcoma subtypes enrolled on trial. It was noted that two locally advanced infantile fibrosarcomas had sufficient tumor shrinkage to allow for curative, R0 limb-sparing surgeries.

Entrectinib

Entrectinib is another TRK inhibitor that has also been shown to have antitumor activity in NTRK gene fusion–positive solid tumors. Based on the results of several clinical trials that demonstrated its efficacy, entrectinib was approved by the FDA in 2019 for adults and pediatric patients 12 years of age and older with solid tumors that harbor an NTRK gene fusion without a known acquired resistance mutation. Among 54 patients, overall response rate in NTRK-fusion cancers was found to be 57%, with the most common cancer types evaluated being sarcomas (24% of patients on trial).[31]

Unfortunately, some tumors remain resistant to first-generation TRK inhibitors, and others develop secondary resistance. For example, NTRK3 p.G623R is a point mutation that mediates the resistance of ETV6-NTRK3–rearranged tumors to treatment with either entrectinib or larotrectinib. LOXO-195 is a highly selective second-generation pan-TRK inhibitor currently under development that seeks to overcome NTRK1 p.G595R–mediated resistance to TRK inhibitors (NCT03215511). Similarly, MGCD-516, a novel small-molecule multikinase inhibitor that targets MET, AXL, MER, PDGFR, DDR2, and TRK families, is being investigated in an attempt to overcome resistance to first-generation TRK inhibitors. MGCD-516 is currently being administered in a phase 1/2 trial enrolling patients with advanced solid tumors (NCT02219711)

CONCLUSION

While soft tissue sarcomas have historically been difficult to treat, with few effective standard of care options, recent advances in genetic and immunoprofiling have bolstered the development of novel targeted and immunotherapeutic agents. The recent FDA approvals of avapritinib and tazemetostat are examples of targeted therapies for specific sarcoma subtypes that are driving further drug development in sarcomas. In the coming years, further development of agents targeting MDM2, CDK4, NYESO, AXL PRAME, and INI for various subtypes of soft tissue sarcoma provide further hope for novel therapies in this difficult to treat cancer.

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Competing Interests

Source of Support: None. Conflict of Interest: Shiraj Sen receives research funding for clinical trials (paid in full to his institution) from LOXO, Jacobio, Exelixis, GSK, BioAtla, Xencor, Epizyme, Abbisko, Fujifilm, Synthorx, Turning Point Therapeutics, Daiichi Sankyo, Tesaro. The other authors have nothing to disclose.