clinical topic updates

New Directions for Gastrointestinal Stromal Tumor Clinical Research

by Arun Singh, MD

Overview

Newer targeted therapies for patients with gastrointestinal stromal tumors (GIST) are being developed to inhibit primary and drug-resistant KIT/PDGFRA mutations. Another promising area of research centers on utilizing circulating tumor DNA (ctDNA) to characterize the mutational status of GIST.

Expert Commentary

Arun Singh, MD

Associate Professor
David Geffen School of Medicine
UCLA Medical Center
Santa Monica, CA

“We are really excited about studies with newer molecules that are designed to address the problem of resistance to the established kinase inhibitors. Additionally, the use of ctDNA to profile one’s GIST mutational status shows great promise.

Arun Singh, MD

Clinical research on GIST is very active right now, with advances in several different areas. We are really excited about studies with newer molecules that are designed to address the problem of resistance to the established kinase inhibitors. Newer targeted therapies are being developed to inhibit primary and drug-resistant KIT/PDGFRA mutations. Additionally, the use of ctDNA to profile one’s GIST mutational status shows great promise.

Imatinib, sunitinib, and regorafenib are the established US Food and Drug Administration (FDA)–approved tyrosine kinase inhibitors (TKIs) used for GIST in the first, second, and third lines, respectively. The clinical problem is that, after failure on imatinib, the benefits of sunitinib and regorafenib are increasingly diminished. Two newer molecules in various stages of development are ripretinib and avapritinib. Ripretinib (DCC-2618) is a switch control kinase inhibitor with a broad range of preclinical activity against primary and secondary GIST mutants. While it works on the inactive kinase conformation, its mechanism of action differs from that of imatinib, sunitinib, and regorafenib. In vitro, ripretinib has been shown to inhibit a wide range of mutations in KIT and PDGFRA that are not inhibited by the established tyrosine kinase inhibitors. It is currently being evaluated in 2 phase 3 clinical trials: the INVICTUS study and the Intrigue study. The INVICTUS study concluded in late 2019, with results that led to the recent FDA approval of ripretinib for adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. The ongoing Intrigue study compares the efficacy of ripretinib to sunitinib in the second-line setting. In addition to ripretinib, avapritinib is another newer kinase inhibitor that was approved by the FDA for a specific group of patients with GIST that harbor a PDGFRA exon 18 mutation, including D842V mutations. 

Another promising area of research centers on utilizing ctDNA to characterize the mutational status of GIST. It is important to know the mutational status of any patient with GIST, and the current approach to diagnosis involves tissue biopsy and mutation testing. However, biopsies are done on 1 metastatic deposit and do not always reflect the complete mutational status of all lesions, as there can be clonal mutational heterogeneity. Theoretically, ctDNA should be more reflective of the entire spectrum of GIST mutations in an individual patient, as it reflects DNA from all lesions. There is potential for ctDNA to be used as a prognostic tool as well, but more data are needed. As a predictive biomarker, ctDNA might be used to determine which therapies would be most appropriate for a patient’s mutational status, but, again, the use of ctDNA in this way is still considered investigational. Thus, ctDNA is an emerging technology that is exciting but needs validation in various settings, and there are important limitations to its use.

References

ClinicalTrials.gov. A study of DCC-2618 vs sunitinib in advanced GIST patients after treatment with imatinib (intrigue). https://clinicaltrials.gov/ct2/show/NCT03673501. Accessed April 28, 2020.

ClinicalTrials.gov. (NAVIGATOR) study of BLU-285 in patients with gastrointestinal stromal tumors (GIST) and other relapsed and refractory solid tumors. https://clinicaltrials.gov/ct2/show/NCT02508532. Accessed April 28, 2020.

ClinicalTrials.gov. Phase 3 study of DCC-2618 vs placebo in advanced GIST patients who have been treated with prior anticancer therapies (invictus). https://clinicaltrials.gov/ct2/show/NCT03353753. Accessed April 28, 2020.

Serrano C, Vivancos A, López-Pousa A, et al. Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors. BMC Cancer. 2020;20(1):99.

Smith BD, Kaufman MD, Lu WP, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell. 2019;35(5):738-751.e9.

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