Advances in Sarcoma Treatment and Future Directions

As a sarcoma medical oncologist, the No. 1 question I am asked by my patients pertain to whether drugs indicated for other cancer types would be beneficial to them. For many years, I have been asked about what impact immunotherapy would have on sarcomas, especially more recently, as significant progress on this front has been made in other malignancies. This progress is highly publicized and often makes its way into popular media outlets. On June 23, 2022, The New England Journal of Medicine published “PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer.” In this study, 12 patients with mismatch repair–deficient stage 2 or 3 adenocarcinoma completed treatment with Jemperli (dostarlimab) and have undergone at least six months of follow-up. All 12 patients had a clinical complete response, with no evidence of tumor on MRI, PET, endoscopic evaluation, digital rectal examination or biopsy. Naturally, patients with sarcoma who see these articles would ask why these immunotherapy treatments cannot be applied to their tumors.

Sarcoma is the general term for a broad group of cancers that begin in the bones and in the soft (also called connective) tissues (soft tissue sarcoma). Sarcomas are a rare cancer accounting for 1% of adult malignancies, with the average patient being 61 years of age. For those patients with tumors that are not surgically resectable or who have metastatic disease, drug therapy tends to be the only choice of treatment. Historically, we relied on chemotherapeutic agents with varying degrees of toxicities and had varying, often unpredictable, degrees of patient response — both with respect to tumor shrinkage and to the toxic side effects.

For many years we have used drugs such as doxorubicin, gemcitabine, docetaxel, ifosfamide and dacarbazine. In the last decade, we started to incorporate Yondelis (trabectedin), Halaven (eribulin) and the first tyrosine kinase inhibitor to be approved for a wide variety of soft tissue sarcomas called Votrient (pazopanib).

As patients with melanoma, lung cancer, head and neck cancers, gastrointestinal cancers and other malignancies were receiving immunotherapy, our patients remained on chemotherapy and targeted therapies, with few patients receiving immunotherapy on or off clinical trials.

Over the last several years, our approach to patients with sarcomas have dramatically changed. We have now incorporated the use of next-generation sequencing to assist with our understanding of the genetic makeup of tumors to discern their biology as well as treatment options. For many patients with soft tissue sarcomas, we have integrated the role for immunotherapy. Currently, the National Comprehensive Cancer Network guidelines has incorporated immunotherapy for the care of certain patients with a sarcoma diagnosis. These guidelines are the recognized standard for clinical direction and policy in cancer care, and are the most thorough and frequently updated clinical practice guidelines available in any area of medicine. Currently patients with myxofibrosarcoma, undifferentiated pleomorphic sarcomas, cutaneous angiosarcomas and undifferentiated sarcomas can be treated with immunotherapy, as recommended by the guidelines.

We anticipate that the field of sarcoma management will change drastically over the next several years, with the inclusion of T-cell therapies for patients with synovial sarcomas myxoid round-cell liposarcoma. Currently, there are ongoing T-cell therapy clinical trials for these patients, and data from these trials will be used to support a Food and Drug Administration (FDA) biologic license application submission next year, which may achieve approval and access for many more patients with sarcoma.

Most of the exciting advances that we bring to the field of sarcoma treatment lie within our clinical trial portfolio. At any given time, a sarcoma specialist will be conducting 10 to 20 different clinical trials with the goal of bringing a drug to the FDA for approval. We have been successful with this feat over the last decade with the additions of sirolimus protein-bound particles for injectable suspension (albumin-bound), Tazverik (tazemetostat), Turalio (pexidartinib), Qinlock (ripretinib) and Ayvakit (avapritinib), to name a few. Our work in clinical trials continues to drive us towards achieving the best therapies for our patients so that we can match an individual patient with an individual treatment, decrease the drug toxicities delivered to the patient and improve patient-reported outcomes. Our goal remains to provide precision medicine to our patients, which can be defined as looking at the genetics, environment and lifestyle of a person in order to select treatment that could work best for them. It is our duty to ensure that patients can have the most comfortable lifestyle possible during treatment and minimize the worry associated with treatments, both because of side effects and fear of ineffectiveness.

While we have come a long way from a chemotherapy-only approach, as clinical, translation and basic science researchers, we aim to continue to improve upon these successes.

Dr. Mark Agulnik

Section Chief of Sarcoma Medical Oncology, Department of Medical Oncology & Therapeutics Research

Professor, Department of Medical Oncology & Therapeutics Research

City of Hope Comprehensive Cancer Center, Duarte, CA, USA

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