Dawn of immunotherapy treatment for gastrointestinal stromal tumors

Abstract

© Gastrointestinal Stromal Tumor. All rights reserved. Gastrointest Stromal Tumor 2022 | https://dx.doi.org/10.21037/gist-22-4 Gastrointestinal stromal tumors (GIST) are characterized by pathogenic activating mutations in tyrosine kinases, or less commonly by loss of succinate dehydrogenase (SDH) complex activity through epigenetic silencing or loss of function mutation in one of the SDH subunits (1). A large majority of GIST contain activating mutations in KIT or platelet-derived growth factor receptor-alpha (PDGFRA) which are generally mutually exclusive. Very rarely, loss of neurofibromin-1, activation of RAS, translocation of neurotrophic receptor tyrosine kinase (NTRK) or cryptic genomic changes lead to development of GIST. A recent study suggests that spindle cell neoplasms of the gastrointestinal tract harboring translocations involving NTRK are distinct from GIST, and these malignancies respond to treatment with inhibitors of NTRK activity (2). The development of orally bioavailable small molecule inhibitors of KIT and PDGFRA substantively changed the treatment and survival of patients with locally advanced or metastatic GIST extending medial survival from less than 2 to more than 4 years with about 25% of patients surviving more than 10 years after the start of imatinib (3-5). However, secondary mutations in KIT or PDGFRA leading to resistance to kinase inhibition develop in many patients, and a minority have mutations in GIST that render primary resistance to imatinib. Once resistance to imatinib develops, the tumor progression-free interval generally is much shorter than with initial imatinib therapy (6-8). Moreover, SDH-deficient GISTs are resistant to treatment with imatinib although a minority may respond to treatment with sunitinib or other vascular growth factor receptor inhibitors. Few formal trials of non-tyrosine kinase inhibitor (TKIs) chemotherapy in treatment of advanced GIST have been conducted, but data collected prior to widespread incorporation of TKIs into the treatment of GIST suggests that GIST is resistant to conventional chemotherapy such as DNA-damaging agents (9,10). Thus, there is strong interest in developing alternative treatments for GIST in combination with TKIs in sensitive tumors, or in place of TKIs in resistant tumors. Much has been written about preclinical studies and biomarker analyses that suggests a role for immunotherapy in management of GIST (11-13). However, we are in the dawn of immunotherapy for GIST, and much needs to be learned to translate our understanding of GIST immunobiology into standard clinical care. A pilot study of imatinib combined with interferon-α2b in patients with imatinib-naïve GIST showed objective partial response in all patients treated (N=8); but, to my knowledge, a larger trial to confirm the high response rate has not been conducted (14). A pilot trial of lowdose metronomic oral cyclophosphamide combined with pembrolizumab in 10 patients with GIST produced no objective responses (although 1 patient had minor reduction in GIST) and a median PFS of 1.4 months (15). The hypothesis that immunostimulatory effects of metronomic cyclophosphamide would prime the environment for Editorial Commentary