expert roundtables

Mutations That Drive Progression and Are Not Inhibited by Currently Available Treatments

by Michael C. Heinrich, MD; Arun Singh, MD; and Jonathan C. Trent, MD, PhD

Overview

Patients on systemic therapy for gastrointestinal stromal tumors (GIST) may progress due to certain well-recognized secondary mutations in specific domains of KIT and PDGFRA that confer resistance. The development of newer targeted therapies that maintain activity despite the presence of these mutations is an ongoing goal.

Q:

Which GIST mutations drive progression on currently available therapies?

Arun Singh, MD

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

“Among these secondary mutations, KIT exon 17 mutations present some of the most significant challenges in terms of resistance to current therapies.”

Arun Singh, MD

The most common primary mutations in KIT are at exons 9 and 11. The resistance mutations, commonly referred to as secondary mutations, are responsible for driving progression on imatinib. Secondary KIT mutations are located primarily in the ATP-binding pocket encoded by exon 13 and the activation loop encoded by exon 17. Among these secondary mutations, KIT exon 17 mutations present some of the most significant challenges in terms of resistance to current therapies. Ripretinib (DCC-2618) does show activity against these mutations in vitro, so it will be interesting to see the corresponding data from ongoing clinical trials. KIT exons 13 and 14 and PDGFRA exons 14 and 15 mutations may be problematic as well with respect to resistance. 

GIST that do not have KIT or PDGFRA primary mutations as drivers are sometimes referred to as wild type for these genes. Succinate dehydrogenase (SDH)–deficient GIST comprise a significant portion within this less common KIT-negative, PDGFRA-negative group. In the setting of SDH-deficient GIST, treatment with vascular endothelial growth factor receptor inhibitors, such as sunitinib and regorafenib, may be appropriate. Temozolomide, the subject of an ongoing clinical trial, could also emerge as an effective agent against SDH-deficient GIST. Further, immune checkpoint inhibitors and combination therapies are being explored in clinical trials of SDH-deficient GIST. Anecdotal reports of patients receiving benefit have been published.

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

“Understanding which of the many actionable mutations are present initially is critical to optimizing therapy for GIST.”

Jonathan C. Trent, MD, PhD

GIST that harbor KIT and PDGFRA mutations can generally be targeted effectively with imatinib. However, GIST with SDH, RAF, NF1, and PDGFRA exon 18 mutations are generally resistant to imatinib. Those with PDGFRA exon 18 mutations, such as PDGFRA D842V, are now amenable to treatment with avapritinib, but these other primary mutations remain challenging. Further, secondary mutations in KIT may result in late progression on imatinib, including KIT mutations in exons 13, 14, 17, and 18. In the setting of widespread progression during imatinib therapy, multiple preexisting clones with secondary mutations may give rise to tumor outgrowth at multiple sites. Studies using circulating tumor DNA are shedding light on key secondary mutations and patterns of resistance to imatinib and other tyrosine kinase inhibitors. The secondary mutations in KIT most commonly cluster in 2 regions: the ATP-binding pocket encoded by exon 13 and the activation loop encoded by exon 17. The exon 13 mutation remains sensitive to sunitinib; however, the exon 17 mutations are resistant to sunitinib.

Understanding which of the many actionable mutations are present initially is critical to optimizing therapy for GIST. Today, if you are going to be treating a patient with GIST using systemic therapy, you really need to perform mutation testing. Failure to test can lead to inappropriate treatment, both in terms of targeting the tumor effectively and exposing the patient to unnecessary side effects and other costs of treatment. For instance, without testing, one could be treating a patient inappropriately with imatinib when the tumor is actually imatinib resistant (eg, in the case of an RAF, a TRK, or an NF1 mutation). The same is true in the adjuvant setting; without testing, a patient might be needlessly committed to imatinib therapy for 3 years following surgical resection. Unfortunately, the rate of mutation testing appears to be low based on our recently published study. We conducted an analysis of the Surveillance, Epidemiology, and End Results database from 2010 to 2015 and found that only 27% of patients diagnosed with GIST ever underwent mutation analysis.

Currently available therapies are not very effective against NF1-mutant, RAF-mutant, or SDH-deficient GIST. For NF1 mutants, our protocol is to target downstream of NF1 with selumetinib; patients with SDH-deficient GIST, when in need of systemic therapy for advanced disease, are started on a KIT inhibitor with vascular endothelial growth factor receptor activity, such as sunitinib or regorafenib.

Michael C. Heinrich, MD

Professor of Medicine
Professor of Cell and Developmental Biology
OHSU Knight Cancer Institute
Oregon Health & Science University School of Medicine
Portland, OR

“While KIT and PDGFRA mutations generally can be targeted, not all of them can be effectively treated with current therapies.”

Michael C. Heinrich, MD

We can identify the driver mutation in the vast majority of GIST. The challenge is that not all of these driver mutations are targetable. And while KIT and PDGFRA mutations generally can be targeted, not all of them can be effectively treated with current therapies. Most primary KIT mutations are associated with GIST oncogenesis and remain present throughout the life span of the tumor. Of these, KIT exon 11 mutation is most common, and GIST with primary KIT exon 11 mutation exposed to imatinib or other tyrosine kinase inhibitors are subject to the development of resistance by secondary mutations (eg, in exons 13 or 17).

Less commonly, GIST are KIT negative and PDGFRA negative (ie, the so-called wild-type GIST). A variety of oncogenic drivers are believed to be involved in this group, including those that lead to SDH deficiency; mutations in NF1, RAF, and BRAF; and NTRK gene fusions. SDH-deficient GIST are by far the most common among the uncommon forms of GIST. Conceptually, the use of MEK inhibition in NF1-mutant GIST is definitely something that should be studied in clinical trials. We have seen BRAF-mutant and NTRK-mutant GIST that have had impressive results with targeted therapies. Therefore, identifying the driver mutation is critical to the selection of the most appropriate therapy at the outset. GIST therapy has consisted of starting with imatinib, followed by sunitinib for second-line treatment, and then regorafenib for third-line therapy. Historically, this succession was somewhat agnostic to the underlying driver mutation. Such a paradigm may be appropriate for KIT-mutant GIST, but today you would not want to initiate imatinib in a patient with PDGFRA D842V, for instance. In the setting of SDH-deficient tumors, it can be a challenge to find the best approach, and, ultimately, I think that better therapies are needed for that subset. 

References

Arshad J, Ahmed J, Subhawong T, Trent JC. Progress in determining response to treatment in gastrointestinal stromal tumor. Expert Rev Anticancer Ther. 2020;20(4):279-288.

ClinicalTrials.gov. Mitogen activated protein kinase (MEK1/2) inhibitor selumetinib (azd6244 hydrogen sulfate) in people with neurofibromatosis type 1 (NF1)) mutated gastrointestinal stromal tumors (GIST). https://clinicaltrials.gov/ct2/show/NCT03109301. Accessed May 4, 2020.

ClinicalTrials.gov. Temozolomide (TMZ) in advanced succinate dehydrogenase (SDH)-mutant/deficient gastrointestinal stromal tumor (GIST). https://clinicaltrials.gov/ct2/show/NCT03556384. Accessed May 4, 2020.

Florindez J, Trent J. Low frequency of mutation testing in the United States: an analysis of 3866 GIST patients. Am J Clin Oncol. 2020;43(4):270‐278.

Mazzocca A, Napolitano A, Silletta M, et al. New frontiers in the medical management of gastrointestinal stromal tumours. Ther Adv Med Oncol. 2019; 11:1758835919841946. Published 2019 May 17. doi:10.1177/1758835919841946

Serrano C, Mariño-Enríquez A, Tao DL, et al. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours [published correction appears in Br J Cancer. 2019;121(3):281]. Br J Cancer. 2019;120(6):612-620.

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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