patient care perspectives

Approach to Progressive Gastrointestinal Stromal Tumors

by Jonathan C. Trent, MD, PhD

Overview

Gastrointestinal stromal tumors (GIST) may become resistant to imatinib through secondary mutations in the driver mutant kinase. Newer targeted therapies have been developed for use in subsequent lines of treatment for advanced GIST. Additionally, focal ablative strategies and clinical trial participation continue to be important options for many patients with progressive GIST.

Expert Commentary

Jonathan C. Trent, MD, PhD

Professor of Medicine
Associate Director for Clinical Research
Sylvester Comprehensive Cancer Center
University of Miami Miller School of Medicine
Miami, FL

“In our practice at Sylvester Comprehensive Cancer Center, circulating tumor DNA analysis is performed on every patient who progresses on imatinib.”

Jonathan C. Trent, MD, PhD

The current standard of care for GIST consists of surgery for localized cases and adjuvant imatinib in cases with a high risk of recurrence. When imatinib is no longer effective for metastatic GIST, we will typically treat with sunitinib in the second line and then regorafenib in the third line. However, in our practice at Sylvester Comprehensive Cancer Center, circulating tumor DNA analysis is performed on every patient who progresses on imatinib. Exon 13–mutant GIST is treated with sunitinib and exon 17–mutant GIST is treated with regorafenib, as these kinase inhibitors have shown the greatest activity against these respective resistance mutations. Additionally, we now have ripretinib, which was recently approved by the US Food and Drug Administration for adults with advanced GIST after 3 lines of therapy, including imatinib.

Progressive disease can take different forms, and when there are multiple metastases that are all growing, affecting several organs, we consider that to be widespread progression. In patients with GIST that acquire resistance to imatinib, however, one might see a more limited form of progression. For instance, a patient with 10 liver metastases may have a great response to imatinib for many years, and then a single liver metastasis starts enlarging. While the other 9 lesions are still sensitive to imatinib, that 1 solitary resistant nodule can be surgically resected or treated with hepatic arterial embolization. We reported years ago on a series of 110 patients with imatinib-resistant metastatic GIST and found that hepatic arterial embolization was helpful for select patients. So, when there is limited progression, focal techniques may be considered, including stereotactic body radiation therapy in some cases, while the use of targeted therapies would continue against the nonprogressive lesions. If the recurrence is elsewhere in the abdomen (eg, multiple lesions in proximity to the small bowel), radiation therapy may not be an option due to dose-limiting toxicities to the bowel.

Clinical trials should be considered at each phase of the disease continuum. GIST is a rare disease, and referring a patient to a clinical trial helps to further our understanding of the disease and to advance new therapies. The 2 recently introduced GIST therapies, ripretinib and avapritinib, both emerged from clinical trials.

References

ClinicalTrials.gov. Phase 3 study of DCC-2618 vs placebo in advanced GIST patients who have been treated with prior anticancer therapies (invictus). Accessed August 5, 2020. https://clinicaltrials.gov/ct2/show/NCT03353753 

Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24(29):4764-4774. doi:10.1200/JCO.2006.06.2265

Heinrich MC, Jones RL, von Mehren M, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020;21(7):935-946. doi:10.1016/S1470-2045(20)30269-2

Kobayashi K, Gupta S, Trent JC, et al. Hepatic artery chemoembolization for 110 gastrointestinal stromal tumors: response, survival, and prognostic factors. Cancer. 2006;107(12):2833-2841. doi:10.1002/cncr.22336

Landi B, Blay JY, Bonvalot S, et al; Thésaurus National de Cancérologie Digestive (TNCD), Fédération Francophone de Cancérologie Digestive (FFCD), Fédération Nationale de Centres de Lutte Contre les Cancers (UNICANCER), Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR), Société Française de Chirurgie Digestive (SFCD), Société Française de Radiothérapie Oncologique (SFRO), Société Française d’Endoscopie Digestive (SFED), Société Nationale Française de Gastroentérologie (SNFGE). Gastrointestinal stromal tumours (GISTs): French intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO). Dig Liver Dis. 2019;51(9):1223-1231. doi:10.1016/j.dld.2019.07.006

Parab TM, DeRogatis MJ, Boaz AM, et al. Gastrointestinal stromal tumors: a comprehensive review. J Gastrointest Oncol. 2019;10(1):144-154. doi:10.21037/jgo.2018.08.20

Schroeder BA, Kohli K, O’Malley RB, et al. Durable tumor regression in highly refractory metastatic KIT/PDGFRA wild-type GIST following treatment with nivolumab. Oncoimmunology. 2020;9(1):1710064. doi:10.1080/2162402X.2019.1710064

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