Gastrointestinal Stromal Tumors
Immunotherapy and New Targets for Advanced Gastrointestinal Stromal Tumors
Newer targets and combinations are being explored to help bridge the gap for patients with advanced gastrointestinal stromal tumors (GIST). Our featured expert comments on the study of novel immune- and nonimmune-targeted combinations for metastatic GIST.
Professor of Medicine
“We would like to be able to improve on the activity that has been observed in clinical trials of immunotherapy in advanced GIST. I think that we should investigate additional tyrosine kinase inhibitor–based combinations, potentially including other immune and nonimmune targets.”
Overall, we have not yet seen a strong efficacy signal in clinical trials of immunotherapy for advanced GIST. However, at least 1 patient had a complete response in the recent phase 2 study by Singh and colleagues, which evaluated nivolumab plus ipilimumab vs nivolumab monotherapy. They enrolled 36 patients, and, among the 16 individuals who were treated with the combination, 4 had stable disease and 1 had a complete response.
We would like to be able to improve on the activity that has been observed in clinical trials of immunotherapy in advanced GIST. I think that we should investigate additional tyrosine kinase inhibitor–based combinations, potentially including other immune and nonimmune targets. This might include targets such as CD40, or perhaps the use of interferons or other cytokines to augment the immune response.
While some soft tissue sarcomas are characterized by complex genomic variations that might allow for more immunogenicity, GIST oncogenesis is more typically driven by a mutation in the proto-oncogene c-Kit, which encodes a transmembrane receptor tyrosine kinase. Patients with advanced disease may have a higher mutational burden, but those mutations are generally in the oncogene. There is still much to be learned in immuno-oncology, and it might be that immune escape via PD-1 and CTLA-4 is not an important mechanism in KIT-mutant GIST.
In early phase trials, other kinase inhibitors continue to be studied. For instance, the BCR-ABL inhibitor olverembatinib was evaluated in a phase 1b/2 trial in 39 patients with KIT- or PDGFRA-mutant GIST post imatinib therapy and produced stable disease in 13 of the 39 patients. Two of the 6 patients with succinate dehydrogenase (SDH)–deficient GIST achieved a partial response, and another had stable disease for 36 cycles. SDH deficiency leads to HIF1 and HIF2 overexpression, which causes increased angiogenesis and neovascularization and, in theory, the overexpression of the VEGF receptor. Thus, some of the KIT inhibitors that are active against the VEGF receptor (eg, regorafenib) may have some activity in patients with SDH-deficient GIST.
Another potential avenue for research is the use of apoptosis-enhancing approaches such as BH3 mimetics, which inhibit BCL-2. The majority of patients with GIST do have tumors that express BCL-2, and this may be a mechanism of resistance that could be targeted with a BCL-2 inhibitor such as venetoclax. The induction of apoptosis with ripretinib and MEK inhibitors has also been explored in preclinical models of GIST and systemic macrocytosis.
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