Toward Personalized Treatment Approaches in Soft Tissue Sarcomas

Ciara Kelly, MBBCh, BAO

Soft-tissue sarcomas (STS) are a rare, heterogeneous collection of tumors with more than 100 histological tumor subtypes, some of which are associated with chromosomal translocations. Treatment for several cancer types follows a trend toward personalized therapy based on tumor molecular profiling. Only a small percentage of sarcoma subtypes, including perivascular epithelioid cell tumors (PEComa) and gastrointestinal stromal tumors (GIST), currently have identified actionable driver alterations. Immune checkpoint blockade has recently been approved for a specific sarcoma subtype. In this article, Ciara Kelly, MBBCh BAO, explores recent advancements toward personalized treatment in sarcoma.

What steps are being taken to reduce the average time to diagnosis of sarcomas?

Kelly: The rarity of sarcomas pose significant diagnostic and management challenges, particularly to providers who do not see them frequently. The most important aspect of optimizing diagnosis and management is ensuring that patients are seen in a Sarcoma Center of Excellence. Sarcomas are complex tumors that require expert opinion and integration of molecular diagnostics with histomorphologic features for an accurate diagnosis. At expert sarcoma centers, incorporating molecular diagnostics into the pathology assessment of sarcomas has been shown to improve diagnostic accuracy in up to 14% of cases.¹

What progress has been made to identify and use diagnostic biomarkers?

Kelly: Significant progress has been made, and we see this with the increasing use of molecular diagnostics, including RNA sequencing, looking particularly for translocation-associated tumor subtypes. The increasing role of next-generation sequencing (NGS) is also evident. A recent study examined NGS in 7500 sarcomas, identifying recurrent and subtype-specific alterations.² In that study, 10.5% of cases had refinement or reassignment of their sarcoma diagnosis. A further 31.7% had actionable alterations, which may have led to potential treatment options.

Several studies showed that it is feasible to detect circulating tumor DNA (ctDNA) in sarcoma cases.³ However, the sensitivity and specificity vary based on the sarcoma subtype. A study presented at ASCO 2023 examined ctDNA as a marker of minimal residual disease (MRD) at diagnosis and postoperatively in patients with large, high-grade sarcomas who underwent neoadjuvant treatment, surgery, and follow-up.⁴ The study showed 80% of patients had detectable ctDNA at baseline, and 94% became MRD-negative after surgery. Also, patients who were ctDNA-positive during surveillance had an 18-fold higher chance of recurrence than ctDNA-negative patients. This study showed the potential of ctDNA, but more work is needed before this will become integrated into the management of sarcoma patients as a standard of care. There have been more GIST-specific studies that included sequenced ctDNA as a correlative assessment. The phase 3 INTRIGUE trial (NCT03673501) examined sunitinib versus ripretinib in the advanced GIST second-line setting. Ripretinib was not found to be superior to sunitinib in terms of progression-free survival. In an exploratory analysis of sequenced ctDNA obtained at baseline, patients with KIT exon 11-mutant GIST harboring secondary KIT exon 17 and/or 18 mutations derived a significant PFS benefit with ripretinib compared to sunitinib. Currently the INSIGHT, randomized, phase III clinical trial will evaluate the efficacy of ripretinib versus sunitinib in patients with advanced GIST that have progressed on imatinib and harbor KIT exon 11 mutations co-occurring with resistance mutation in KIT exon 17 and/or 18 confirmed via sequencing.⁵

How well do sarcomas respond to chemotherapy?

Kelly: Chemotherapy remains the standard-of-care treatment for advanced soft-tissue sarcoma. However, objective response rates to doxorubicin-based or gemcitabine and docetaxel regimens are approximately 20%.⁶ Response rates are lower in the second- and third-line settings. For example, pazopanib was approved based on an improvement in median progression-free survival in the PALETTE trial in soft-tissue sarcomas, excluding liposarcoma, where they demonstrated an objective response rate of 6%.⁷ Another example is trabectedin, which is approved for use in leiomyosarcoma, where the response rate was in the order of 10%.⁸ Despite very low response rates, our standard-of-care chemotherapy options can lead to stabilization of disease. But, on the whole, activity and objective responses to treatments are low and [this] underpins the importance of developing new treatment options for patients with sarcoma.

How is molecular profiling used to guide treatment decisions in patients with STS?

Kelly: We are using molecular information to guide selection of targeted therapies. For example, PEComa is a malignant perivascular epithelioid cell tumor that had no approved treatment until the FDA approved nab-sirolimus in November 2021 based on the results of a phase 2 single-arm study that demonstrated an objective response rate of 39%. Also, 89% of patients with a TSC2 mutation achieved a confirmed response; 13% of patients without a TSC2 mutation also had a response.⁹

Another recent approval was tazemetostat, an EZH2 inhibitor approved for epithelioid sarcoma with INI1/SMARCB1 loss, based on a 15% response rate in an open-label phase 2 basket study in the epithelioid sarcoma cohort of 62 patients.¹⁰

GIST is a poster child for the utility of molecular profiling in sarcoma. GIST is one of the most common sarcomas of the GI tract and up to 75% harbor mutations in KIT and around 10% to 15% of patients may have mutations in the PDGFRA gene.¹¹ Another 10% to 15% will have other rare, molecularly defined GIST subtypes. With advances in molecular diagnostics and their increased use in GIST, the proportion of true wild-type GIST has been reduced. Several tyrosine kinase inhibitors targeting KIT have been approved for the management of advanced GIST including imatinib, sunitinib, and regorafenib.^12,13,14 Ripretinib was recently approved in the fourth-line setting for patients with advanced GIST based on a median progression-free survival of 6.3 months for the ripretinib arm compared with 1 month for placebo.¹⁵

Avapritinib was approved in January 2020 based on results from the NAVIGATOR trial, which showed that in patients with PDGFRA alpha D842V-mutant GIST—a very rare subtype of GIST for which there was previously no effective treatment—there was an objective response rate of 91% and a clinical benefit rate of 98%. All these studies emphasize the utility of molecular information to appropriately select patients for treatment.¹⁶

Atezolizumab was recently approved in alveolar soft part sarcoma (ASPS). Is there an opportunity for immunotherapy to make a positive impact in other STS types?

Kelly: Atezolizumab was FDA-approved in December 2022 based on a phase 2 study examining adult and pediatric patients with advanced ASPS—a translocation-associated sarcoma subtype.¹⁷ The study demonstrated an objective response of 37% in 52 patients, including 1 complete responder and 18 partial responders with a median time to response of 3.6 months and a median duration of response of 24.7 months. Currently, we do not understand exactly why we are seeing response to immune checkpoint blockade in this subtype, but it does clearly signify the merit of evaluating immunotherapy in sarcoma.

The SARC028 study looked at pembrolizumab monotherapy in both soft-tissue and bone sarcomas, demonstrating an objective response rate of 18% in soft-tissue sarcoma and 5% in bone sarcoma.¹⁸ In the Alliance study 091401, efficacy of nivolumab was evaluated alone or in combination with ipilimumab in patients with soft-tissue sarcoma.¹⁹ The response rate for the nivolumab arm was 5%. For the combination, it was 16%. These results led to an expansion phase in specific subtypes where a response rate of 27% was observed in undifferentiated pleomorphic sarcoma (UPS).

UPS, myxofibrosarcoma, and angiosarcoma are subtypes where we have consistently seen responders with respect to immune checkpoint inhibition. The DART trial evaluated nivolumab and ipilimumab in angiosarcoma and demonstrated a response rate of 25%. Notably, 3 out of the 4 responders had cutaneous angiosarcoma of the head and neck region.²⁰ A study presented at the ASCO 2023 annual meeting explored nivolumab and cabozantinib in patients who have previously progressed on taxane-based treatment and an overall response rate of 62% was observed.²¹ In the cutaneous angiosarcoma population, an objective response rate of 58% was observed. In the non-cutaneous angiosarcoma population, the response rate was 67%. Cutaneous angiosarcomas have a high tumor mutational burden, which lends itself to being sensitive to immune checkpoint inhibition, so there is merit in evaluating immunotherapy in this space. There are some sarcoma subtypes that may benefit from immune checkpoint inhibition, such as UPS/MFS, ASPS and angiosarcoma. But for the majority of sarcomas that have immune cold signatures, more novel combination approaches incorporating immunotherapy in addition to novel immunotherapeutics, chemotherapy, targeted therapies or radiation warrant further evaluation. How can we convert that immune-desert tumor into an immune-stimulated microenvironment?

What progress is being made to identify biomarkers for immunotherapy in STS?

Kelly: There have been several correlative-based studies that have been conducted in the sarcoma community. The SARC028 study suggested that PD-L1 expression on tumor infiltrating lymphocytes, but not on tumor cells, was associated with response to pembrolizumab.¹⁸ However, another study looking at NKTR-214, an IL-2 agonist in combination with nivolumab did not demonstrate this.²² In both of these studies, it was suggested that tumor-infiltrating lymphocytes (TILs) were more common in responders, but were not necessary or sufficient to generate response. There are also data looking at the role of gene expression profiling and developing an immune signature for sarcoma subtypes. Petitprez et al looked at gene expression profiling in 600 sarcomas and identified 5 distinct immune microenvironments representing a spectrum of immune infiltration.²³ The immune-desert cohort had the worst prognosis and no responses to immune checkpoint blockade. The immune-high groups had a better prognosis and more responders to immune checkpoint inhibition. PD-L1 and CD8 T-cell expression were not prognostic here. However, investigators did suggest that tertiary lymphoid structures and expression of B-cell lineage genes were prognostic for outcomes and may be predictive of response to immune checkpoint blockade. There is difficulty in identifying one specific biomarker. It may be the interaction of several biomarkers and biomarkers outside of the tumor itself—looking at hematopoiesis within the bone marrow and myeloid cell makeup, for example—that are important.

How close are we to personalized therapy in sarcomas?

Kelly: We are making some progress, but we have a lot more work to do. Many of the FDA approvals for sarcoma have been focused on more personalized therapy. One example of personalized immunotherapy is the evaluation of the safety and activity of autologous T cells expressing NY-ESO.²⁴ Response rates in patients with synovial sarcoma have been in the order of 50%. Circulating NY-ESO T cells were present post infusion in all patients and persisted for at least 6 months. Unfortunately, we have not reached a point where we can provide personalized therapy for all sarcoma patients, but we are doing this successfully for some patients.

Afamitresgene autoleucel (afami-cel) is another form of adoptive T-cell therapy being developed to treat HLA-A*02–restricted patients with advanced synovial sarcoma that is positive for the cancer testis antigen melanoma-associated antigen A4 (MAGE-A4).²⁵ The long-term outcomespatients with advanced synovial sarcoma treated with afami-cel in SPEARHEAD-1 (NCT04044768), a phase 2, open-label, 2-cohort trial, were recently presented at the Connective Tissue Oncology Society (CTOS) annual meeting in 2023. Among 44 heavily pretreated patients, 17 had a RECIST response by independent review. Responsive patients experienced promising survival probabilities; the 12-month OS probability was 90%, and the 24-month OS probability was 70%.

What is on the horizon for personalized treatment in STS?

Kelly: Novel combination strategies — be that chemotherapy, immunotherapy, or targeted therapy—are on the horizon. On the chemotherapy side of things, an interesting study is currently ongoing to evaluate lurbinectedin and doxorubicin in patients with leiomyosarcoma.²⁶ Phase 1 data that had a number of responders in leiomyosarcoma was presented at ASCO 2023. And now a larger trial is ongoing in leiomyosarcoma, specifically.

I am interested to see if novel immunotherapeutics and combination immunotherapy strategies under evaluation can stimulate the immune microenvironment in immune desert tumors. Other notable research efforts on the horizon are looking at treatment in the neoadjuvant sarcoma setting. Can neoadjuvant therapeutic strategies help to reduce the risk of recurrence and improve survival following optimal local control for localized sarcoma with high-risk features? Research in this area continues to evolve and the neoadjuvant setting in sarcoma lends itself nicely to intratumor-administered therapeutic approaches.

References

1. Italiano A, Di Mauro I, Rapp J, et al. Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study. Lancet Oncol. 2016;17(4):532-538. doi:10.1016/s1470-2045(15)00583-5
2. Gounder MM, Agaram NP, Trabucco SE, et al. Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma. Nat Commun. 2022;13(1):3406. doi:10.1038/s41467-022-30496-0
3. Coombs CC, Dickherber T, Crompton BD. Chasing ctDNA in patients with sarcoma. Am Soc Clin Oncol Educ Book. 2020;(40):e351-e360. doi:10.1200/edbk_280749
4. Salawu A, Demicco E, Chung PWM, et al. Molecular residual disease (MRD) detection using bespoke circulating tumor DNA (ctDNA) assays in localized soft tissue sarcoma (STS). J Clin Oncol. 2023;41(suppl 16):11509. doi:10.1200/JCO.2023.41.16_suppl.11509
5. Serrano C, Bauer S, Gómez-Peregrina D, et al. Circulating tumor DNA analysis of the phase III VOYAGER trial: KIT mutational landscape and outcomes in patients with advanced gastrointestinal stromal tumor treated with avapritinib or regorafenib. Ann Oncol. 2023;34(7):615-625. doi:10.1016/j.annonc.2023.04.006
6. Kelly CM, Antonescu CR, Bowler T, et al. Objective response rate among patients with locally advanced or metastatic sarcoma treated with talimogene laherparepvec in combination with pembrolizumab: a phase 2 clinical trial. JAMA Oncol. 2020;6(3):402-408. doi:10.1001/jamaoncol.2019.6152
7. van der Graaf WTA, Blay J-Y, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886. doi:10.1016/S0140-6736(12)60651-5
8. Demetri GD, von Mehren M, Jones RL, et al. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. J Clin Oncol. 2016;34(8):786-793. doi:10.1200/jco.2015.62.4734
9. Wagner AJ, Ravi V, Riedel RF, et al. nab-Sirolimus for patients with malignant perivascular epithelioid cell tumors. J Clin Oncol. 2021;39(33):3660-3670. doi:10.1200/jco.21.01728
10. Gounder M, Schöffski P, Jones RL, et al. Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study. Lancet Oncol. 2020;21(11):1423-1432. doi:10.1016/s1470-2045(20)30451-4
11. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865-878. doi:10.1038/nrc3143
12. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26(4):626-632. doi:10.1200/jco.2007.13.4452
13. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006;368(9544):1329-1338. doi:10.1016/S0140-6736(06)69446-4
14. Demetri GD, Reichardt P, Kang Y-K, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302. doi:10.1016/S0140-6736(12)61857-1
15. Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(7):923-934. doi:10.1016/s1470-2045(20)30168-6
16. Jones RL, Serrano C, von Mehren M, et al. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021;145:132-142. doi:10.1016/j.ejca.2020.12.008
17. Chen AP, Sharon E, O’Sullivan-Coyne G, et al. Atezolizumab for advanced alveolar soft part sarcoma. N Engl J Med. 2023;389(10):911-921. doi:10.1056/NEJMoa2303383
18. Tawbi HA, Burgess M, Bolejack V, et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 2017;18(11):1493-1501. doi:10.1016/s1470-2045(17)30624-1
19. D’Angelo SP, Mahoney MR, Van Tine BA, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018;19(3):416-426. doi:10.1016/s1470-2045(18)30006-8
20. Wagner MJ, Othus M, Patel SP, et al. Multicenter phase II trial (SWOG S1609, cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma: a substudy of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). J Immunother Cancer. 2021;9(8):e002990. doi:10.1136/jitc-2021-002990
21. Grilley-Olson JE, Allred JB, Schuetze S, et al. A multicenter phase II study of cabozantinib + nivolumab for patients (pts) with advanced angiosarcoma (AS) previously treated with a taxane (Alliance A091902). J Clin Oncol. 2023;41(suppl 16):11503. doi:10.1200/JCO.2023.41.16_suppl.11503
22. Diab A, Tannir NM, Bentebibel SE, et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov. 2020;10(8):1158-1173. doi:10.1158/2159-8290.Cd-19-1510
23. Petitprez F, de Reyniès A, Keung EZ, et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature. 2020;577(7791):556-560. doi:10.1038/s41586-019-1906-8
24. D’Angelo SP, Melchiori L, Merchant MS, et al. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 (c259) T cells in synovial sarcoma. Cancer Discov. 2018;8(8):944-957. doi:10.1158/2159-8290.Cd-17-1417
25. van Tine BA. Outcomes of patients with advanced synovial sarcoma treated with afamitresgene autoleucel (afami-cel). presented at: Connective Tissue Oncology Society Annual Meeting; November 1-4, 2023, Dublin, Ireland.
26. Cote GM, Haddox CL, Choy E, et al. Efficacy of combination lurbinectedin (LURBI) + doxorubicin (DOX) from the phase 1B soft-tissue sarcoma (STS) lead-in to a randomized phase 2 trial in leiomyosarcoma (LMS). J Clin Oncol. 2023;41(suppl 16):11507. doi:10.1200/JCO.2023.41.16_suppl.11507

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better prepared to:

Describe recent advances in targeted and immunotherapy in soft tissue sarcomas.

Identify remaining unmet needs in soft tissue sarcomas.

RELEASE DATE: January 1, 2024

EXPIRATION DATE: January 1, 2025

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Faculty, Staff, and Planners’ Disclosures

In accordance with ACCME Guidelines, PER® has identified and resolved all COI for faculty, staff, and planners prior to the start of this activity by using a multistep process.

Disclosures (Dr Kelly): Grant/Research Support (paid to institution): Amgen, Curadev Pharma, Merck, Regeneron, Xencor; Consultant: ChemoCentryx, Kartos Therapeutics; Speaker: Deciphera; Advisory Board: Servier; Other (spouse): Daiichi Sankyo.

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Physicians’ Education Resource, LLC, designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credits.™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Activity Overview

Soft-tissue sarcomas (STS) are a rare, heterogeneous collection of tumors. Only a small percentage of sarcoma subtypes, including perivascular epithelioid cell tumors (PEComa) and gastrointestinal stromal tumors (GIST), currently have identified actionable driver mutations. Immunotherapy options have recently been approved for specific subtypes, suggesting new lines of inquiry in other STS subtypes. In this article, Ciara Kelly, MBBCh BAO, reviews the current standard of care and emerging therapies on the horizon in STS.

Acknowledgment of Support

This activity is funded by PER.®

Faculty

Ciara Kelly, MBBCh, BAO

Assistant Attending Physician

Sarcoma Oncologist

Department of Medicine

Memorial Sloan Kettering Cancer Center

Assistant Professor of Medicine Weill Cornell Medical College

New York, NY

This activity was written by PER editorial staff under faculty guidance and review. The Q&A portion of the activity was transcribed from a recorded interview with the faculty and edited by faculty and PER editorial staff for clarity.

Faculty, Staff, and Planners’ Disclosures
In accordance with ACCME Guidelines, PER has identified and resolved all COI for faculty, staff, and planners prior to the start of this activity by using a multistep process.

Disclosures

The staff of PER® have no relevant financial relationships with commercial interests to disclose.

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CME Activity Table of Contents

Pretest

Toward Personalized Treatment Approaches in Soft Tissue Sarcomas

Posttest

Activity

Pretest

1. Which of the following drugs recently received FDA approval for the treatment of sarcoma?
   1. Atezolizumab for alveolar soft part sarcoma
   2. Cabozantinib for GIST
   3. Nivolumab combined with ipilimumab for undifferentiated pleomorphic sarcoma
   4. Pembrolizumab for PEComa
2. Gene expression profiling of 600 sarcomas was recently conducted. What was 1 conclusion from this study?
   1. High PD-L1 expression was prognostic for response to immunotherapy.
   2. CD8 serves as a robust biomarker when used alone.
   3. Immune-high microenvironments correlated with poorer outcomes.
   4. Five distinct immune microenvironments were identified.
3. Response rates to targeted therapy in the second- and third-line settings often fall into which range?
   1. 0%-25%
   2. 26%-50%
   3. 51%-75%
   4. 76%-100%