Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1–2% of gastrointestinal neoplasms. About 75–80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5–10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10–15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).

Clinicopathological Features, Clinical Efficacy on 101 Cases of Rectal Gastrointestinal Stromal Tumors, and the Significance of Neoadjuvant Therapy

“…However, for patients with tumor diameter > 5 cm, univariate analysis (P = 0.002) and multivariate analysis (P = 0.028) both indicated neoadjuvant therapycan improve DFS. So, it was the same as Vallilas's report that IM neoadjuvant therapy for speci c sites or large tumors can improve the prognosis [15]. Meanwhile, it is worth mentioning that in our study, whether the surgical margin was positive or not did not affect the prognosis and there was no need for further surgical resection, which was consistent with Cavnar's and Gronchi's report [24,25].…”

“…The malignant risk of rectal GIST is higher than that ofstomach and is closer to that of intestinal GIST. Yasui, et al reported that the proportion of rectal high risk GISTs was 45%, while the MSKCC single center reported 72.3% [4,15]. For the 70 patients that underwent direct surgery, 45 cases were at high risk after surgery, accounting for 64.3%, which was higher than the result obtained by Yasui.…”

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

“…Taken together, all of these findings show that there is growing evidence in favor of the marked immunogenicity of PDGFRA-mutant GIST, likely specific of D842V mutants only, providing a possible proof of principle for testing immune-therapeutic approaches in this subset of GIST patients, which remains poor in terms of therapeutic options [39,40]. In particular, several phase I and II clinical trials are evaluating the role of ICIs, as monotherapy or in combination with other anticancer agents, in advanced GIST ( Table 1).…”

Succinate dehydrogenase-deficient gastrointestinal stromal tumor: from diagnostic dilemma to novel personalised therapy in 2 case reports

“…Interpretation of OS is limited in this setting due to small numbers, limited follow up, TKI as a comparator arm, and cross over, however, sequential use of TKIs will improve survival compared to time under imatinib alone. The recent development of novel molecular compounds is promising, and will enable more personalized therapy (17). Alternating TKIs, immunotherapy, and combination treatments are also being explored (17)(18)(19).…”

“…The recent development of novel molecular compounds is promising, and will enable more personalized therapy (17). Alternating TKIs, immunotherapy, and combination treatments are also being explored (17)(18)(19). Patients with WT GIST have primary resistance to TKIs due to up-regulation of alternate oncogenic pathways.…”