Optimization of Therapeutic Strategies for Patients With Gastrointestinal Stromal Tumors
Novel therapies are being developed and clinically tested to overcome the mechanisms of resistance after treatment with the US Food and Drug Administration–approved tyrosine kinase inhibitors (TKIs) for gastrointestinal stromal tumors (GIST). In addition, agents for GIST that are driven by rarer molecular events are being pursued.
Are there any agents on the horizon that might help to optimize the treatment of patients with advanced and metastatic GIST?
“One therapeutic strategy is to target cell surface receptors on GIST. This approach is currently being explored with tidutamab, a bispecific antibody that contains both a somatostatin receptor 2 binding domain and a T-cell binding domain.”
We have talked about immunotherapy and targeting the intracellular kinases. One therapeutic strategy is to target cell surface receptors on GIST. This approach is currently being explored with tidutamab, a bispecific antibody that contains both a somatostatin receptor 2 binding domain and a T-cell binding domain.
I would also like to point out that we have not fully given up on chemotherapy for GIST. For instance, temozolomide is an alkylating agent that is currently being studied for use in patients with wild-type GIST. With regard to targeted therapies, people are looking at individual downstream combinations of the KIT tyrosine kinases. For instance, a trial from Memorial Sloan Kettering Cancer Center is studying MEK162 (also known as binimetinib), a selective inhibitor of the kinase MEK, used in combination with imatinib. Further, there are some clinical trials in which TKIs have been given in combination with ipilimumab, which is a type of immunotherapy. Trying to find the right combination is going to take some work, and probably some empiricism more than anything at this point.
Professor of Medicine
“We remain very optimistic about these approaches, but we need to learn how to execute them effectively.”
GPR20 is an orphan GPCR that is selectively and abundantly expressed in GIST but not in normal cells. We are interested in the potential use of an antibody-drug conjugate known as DS-6157a with the idea that it would bind specifically to and become internalized by GIST cells. When the intracellular pH changes, the chemotherapy, a topoisomerase-type inhibitor, is clipped off from the antibody and becomes activated. The chemotherapy moiety has been approved for use as an HER2-targeted drug in breast cancer. We are very interested in this highly specific target and in learning whether we can get a response in GIST cells. This is a phase 1 study and is in dose escalation at a number of centers. We hope that later in the year, maybe at an upcoming meeting, we will have some preliminary data from that study that we can present.
The NeoRay study is taking a similar approach by using a ligand to a receptor on the cell to carry radiation to the cell. The approach has been used primarily in other solid tumors, but there was a report out of Germany about targeting with this agent in GIST cells. This was a small series of approximately 10 patients in which approximately 75% had targeting with this agent, indicating that this approach might be feasible as a therapeutic strategy.
Some interesting work in a GIST mouse model showed that, initially, when you treat the GIST mutant mouse with imatinib, you see a pro-immune response. However, after a while, it becomes an anti-immune response. Immune responses are inhibited by the TKI, so we get both good and bad effects on the immune system from TKIs. Going forward, we may need to learn whether we should somehow sequence these agents, and whether we have to integrate TKI therapy or find immuno-oncology drugs that would synergize or cooperate with TKIs to get the desired effects. We remain very optimistic about these approaches, but we need to learn how to execute them effectively.
Professor of Medicine
“I would like to see the concept of immunotherapy developed more broadly for patients with GIST. . . ."
I would like to see the concept of immunotherapy developed more broadly for patients with GIST, hoping that we can figure out some way to make more tumors sensitive to immune checkpoint inhibitors, whether that is with a combination with a KIT inhibitor or some other immunotherapy agent such as interferon, to further activate the immune system.
Therapies for succinate dehydrogenase–deficient GIST are also definitely needed. We currently use sunitinib, regorafenib, and sometimes ripretinib for this type of GIST, but we need more efficacious treatments. That is a clear unmet need in that we require more research, and we need to develop better therapies for patients with this type of GIST.
ClinicalTrials.gov. [177Lu]-NeoB in patients with advanced solid tumors and with [68Ga]-NeoB lesion uptake (NeoRay). Accessed July 15, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03872778
Iida K, Abdelhamid Ahmed AH, Nagatsuma AK, et al. Identification and therapeutic targeting of GPR20, selectively expressed in gastrointestinal stromal tumors, with DS-6157a, a first-in-class antibody-drug conjugate. Cancer Discov. 2021;11(6):1508-1523. doi:10.1158/2159-8290.CD-20-1434
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National Comprehensive Cancer Network. Treatment by cancer type. Gastrointestinal stromal tumors. Version: 1.2021. Accessed July 15, 2021. https://www.nccn.org/professionals/physician_gls/default.aspx#gist
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Xencor presents initial data from the phase 1 study of tidutamab in neuroendocrine tumors at NANETS’ Multidisciplinary NET Medical Virtual Symposium. News release. Xencor, Inc. October 2, 2020. Accessed July 15, 2021. https://investors.xencor.com/news-releases/news-release-details/xencor-presents-initial-data-phase-1-study-tidutamab