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Gastrointestinal stromal tumors (GISTs) are rare soft tissue sarcomas of the gastrointestinal tract, with most carrying conserved driver mutations in the tyrosine kinase receptors KIT or PDGFRα. The use of targeted therapy against these mutations in GISTs is one of the most successful examples of precision medicine in solid tumors, beginning in 2002 with the development of imatinib, a small molecule tyrosine kinase inhibitor (TKI) of KIT. In recent years, much progress has been made in understanding the molecular mechanisms of GISTs while unveiling their genetic heterogeneity. Since development of secondary mutations leads to imatinib resistance, the majority of research efforts have focused on identification of novel inhibitors to improve outcomes in imatinib-resistant GISTs. Sunitinib and regorafenib are two TKIs with demonstrated activity after failure of imatinib, which led to the U.S. FDA approval. Pivotal phase 3 clinical trials are ongoing with two novel agents, avapritinib and ripretinib, based on their remarkable activities in the 4th or greater line settings in phase 1/2 studies of these drugs. In this review, we will outline the remarkable diversity of genetic mutations in GISTs, and review the evidence for treatment options of genomic medicine in locally advanced or metastatic gastrointestinal stromal tumors.

Soft tissue sarcomas (STS) are a heterogeneous group of over 100 histologically and genetically distinct mesenchymal tumors. Standard of care for metastatic STS has historically relied on anthracycline-based chemotherapy regimens. Although effective for some patients, conventional chemotherapeutic agents used in STS are associated with substantial toxicity and also are not equally effective in all histologic subtypes of sarcoma. Pazopanib is an orally active antiangiogenic drug that is approved for non-adipogenic sarcomas after failure of at least one line of previous chemotherapy, and has a relatively favorable toxicity profile. Earlier use of pazopanib may be a better choice for patients with subtypes of sarcoma that do not respond well to conventional chemotherapy or those who are unlikely to tolerate chemotherapy. Here we review the evidence for the activity and toxicity profile of pazopanib and consider potential histologic, clinical, and genetic predictive factors that can help to guide treatment choices. Further prospective studies validating these observations may lead to refinement of a precision medicine approach to match ideal sarcoma patients to earlier treatment with pazopanib over traditional chemotherapy.

Modern immunotherapy advances including checkpoint inhibitors and adoptive T cell therapy have created a new era of cancer treatment, with significant activities in a wide variety of hematologic and solid cancers. Sarcomas are rare and aggressive malignancies of bone and soft tissue affecting all ages of patients that are usually incurable when refractory to chemotherapy and surgery. However, a subset of patients with metastatic sarcoma will survive for years, suggesting that immune suppression of residual sarcoma cells may be effective in some cases. Most sarcomas exhibit immune cell infiltrates, but the tumor and immune microenvironment tends to be immunosuppressive. The goal of modern immunotherapy is to revert immunosuppressive conditions towards an activated inflammatory state, promoting antitumor immunity. We review the available literature regarding the immune microenvironment in sarcomas, with emphasis on tumor evasion mechanisms that can be targeted with immunotherapeutic strategies. We also highlight recent clinical trials of immunotherapy that show exciting signals of activity in refractory sarcomas.

Sarcomas are rare cancers of soft tissue and bone, and remain incurable when refractory to standard multimodality treatments. With the recent advances in immunotherapy for other solid tumors, there is heightened interest in the potential link of the immune system with sarcoma physiology. This review aims to summarize the ongoing laboratory and clinical research investigating the applications of immunotherapy in the treatment of sarcomas. With ongoing opportunities in vaccine therapy, adoptive transfer of immune cells, biochemotherapy, and immune checkpoint inhibitors, enrollment in immunotherapy clinical trials is an appealing option for sarcoma patients either in conjunction with traditional treatment modalities, or for those with few standard treatment options.