expert roundtables

Novel Treatments for Patients With Advanced Gastrointestinal Stromal Tumors

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

Overview

The recent US Food and Drug Administration (FDA) approval of avapritinib and ripretinib for select patients with gastrointestinal stromal tumors (GIST) expands the available treatment options and will improve outcomes. Novel strategies are currently being studied.

Q:

What are some of the new and potentially novel treatment options for patients with GIST? 

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

“Both avapritinib and ripretinib were intentionally designed to improve upon existing therapies, and we are hopeful that, as we go forward, other approaches will also be informed by structural biology and we will continue to develop better kinase inhibitors.”

Michael C. Heinrich, MD

Last year was exciting because, for the first time, 2 GIST drugs were approved by the FDA in a single year. First, avapritinib was approved for the treatment of a subset of patients with GIST harboring mutations involving PDGFRA exon 18, including the PDGFRA D842V mutation, for which we previously had no effective treatments. Later in the year, ripretinib received FDA approval for use in the fourth line or later based on the results of the phase 3 INVICTUS study. Ripretinib is currently being tested in a phase 3 study in which patients with intolerance to imatinib or who had progression on imatinib are being randomized to ripretinib vs sunitinib for second-line treatment. We are anticipating that sometime in 2021, perhaps in the second half of the year, we will get the top-line data from that trial. Ultimately, if the study shows that ripretinib is superior to sunitinib, it would transform GIST treatment, as it would then indicate that ripretinib should be used as the second-line agent rather than sunitinib.  

The heterogeneity of GIST increases with lines of therapy. In the frontline setting, we are treating the primary drivers of GIST. In the case of KIT-mutant GIST, we use imatinib and then secondary mutations may arise. As we use our second-, third- and fourth-line therapies, our goal is to inhibit as many secondary mutations as we can, realizing that we are using imperfect drugs lacking a complete spectrum of activity against all relevant secondary mutations. Both avapritinib and ripretinib were intentionally designed as novel kinase inhibitors. Avapritinib binds to the active conformation of the kinase domain; this is unlike imatinib, sunitinib, or regorafenib, which have no useful activity against D842V-mutant GIST. Ripretinib is completely novel in that it binds to what is known as the switch pocket region and inhibits the kinase from being activated. These drugs were intentionally designed to improve upon existing therapies, and we are hopeful that, as we go forward, other approaches will also be informed by structural biology and we will continue to develop better kinase inhibitors.

Arun Singh, MD

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

“We know from earlier work that there is a subset of patients with GIST who benefit from immunotherapy.”

Arun Singh, MD

With respect to the tyrosine kinase inhibitors, phase 2 data for cabozantinib, which targets KIT/MET/AXL/VEGFR, in patients with refractory GIST were presented at the American Society of Clinical Oncology meeting a little over a year ago, and the clinical efficacy looked very good. Cabozantinib has been added to contemporary treatment guidelines and is listed among the agents that might be considered in patients with advanced GIST.

We have studied nivolumab (a PD-1 inhibitor) alone or in combination with ipilimumab (a CTLA-4 inhibitor) in patients with advanced GIST. The results of this trial have been presented in preliminary form, and we saw that, in a heavily pretreated GIST population, responses and disease control were observed in both of those arms (ie, nivolumab and nivolumab with ipilimumab). To date, the drugs have been well tolerated and no new safety signals have been observed in this disease state. The full paper is currently in press and should be available soon; however, because the findings have not been completely disclosed, I cannot discuss it fully here, although I am enthusiastic about the findings. We know from earlier work that there is a subset of patients with GIST who benefit from immunotherapy. This indicates that there is more going on besides the mutant KIT and mutant PDGFRA in this disease.

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

“As we learn more about the molecular drivers of GIST, we will be better able to tailor a precision medical approach to the treatment of our patients.”

Jonathan C. Trent, MD, PhD

When we talk about GIST, we usually refer to specific subtypes such as KIT-mutated GIST, PDGFRA receptor–mutated GIST, and BRAF-mutated GIST. Several NTRK inhibitors are currently available for patients whose tumors are, in fact, driven by NTRK gene fusions or translocation. As we learn more about the molecular drivers of GIST, we will be better able to tailor a precision medical approach to the treatment of our patients.

The combination of PLX9486 plus sunitinib was studied in an expanded phase 1/2 study, and the results were reported at the Connective Tissue Oncology Society 2020 Virtual Annual Meeting. The combination is compelling for several reasons. For example, 1 agent binds the active conformation and the other binds the inactive conformation of KIT. The ATP binding pocket is certainly 1 area where binding occurs. PLX9486 is effective at inhibiting exon 17–resistant mutations and sunitinib is effective at inhibiting exon 13 resistance mutations. Thus, these agents are complementary in their ability to inhibit the 2 most common sites of resistance mutations. In this phase 1/2 study, the combination was tolerated just as well as sunitinib alone.

References

Blay J-Y, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol. 2020;21(7):e341]. Lancet Oncol2020;21(7):923-934. doi:10.1016/S1470-2045(20)30168-6

ClinicalTrials.gov. A study of DCC-2618 vs sunitinib in advanced GIST patients after treatment with imatinib (intrigue). Accessed April 16, 2021. https://clinicaltrials.gov/ct2/show/NCT03673501

Farag S, Smith MJ, Fotiadis N, Constantinidou A, Jones RL. Revolutions in treatment options in gastrointestinal stromal tumours (GIST): the latest updates. Curr Treat Options Oncol. 2020;21(7):55. doi:10.1007/s11864-020-00754-8

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 [published correction appears in Lancet Oncol. 2020;21(9):e418]. Lancet Oncol. 2020;21(7):935-946. doi:10.1016/S1470-2045(20)30269-2

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

Muhlenberg T, Ketzer J, Heinrich MC, et al. KIT-dependent and KIT-independent genomic heterogeneity of resistance in gastrointestinal stromal tumors—TORC1/2 as a salvage strategy. Mol Cancer Ther. 2019;18(11):1985-1996. doi:10.1158/1535-7163.MCT-18-1224

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

Schöffski P, Mir O, Kasper B, et al. Activity and safety of cabozantinib in patients with gastrointestinal stromal tumor after failure of imatinib and sunitinib: EORTC phase II trial 1317 CaboGIST. J Clin Oncol. 2019;37(15 suppl):11006. doi:10.1200/JCO.2019.37.15_suppl.11006

Schöffski P, Mir O, Kasper B, et al. Activity and safety of the multi-target tyrosine kinase inhibitor cabozantinib in patients with metastatic gastrointestinal stromal tumour after treatment with imatinib and sunitinib: European Organisation for Research and Treatment of Cancer phase II trial 1317 'CaboGIST'. Eur J Cancer. 2020;134:62-74. doi:10.1016/j.ejca.2020.04.021

Singh AS, Chmielowski B, Hecht JR, et al. A randomized phase II study of nivolumab monotherapy versus nivolumab combined with ipilimumab in advanced gastrointestinal stromal tumor (GIST). J Clin Oncol. 2019;37(15 suppl):11017. doi:10.1200/JCO.2019.37.15_suppl.11017

Somwar R, Hofmann NE, Smith B, et al. NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors. Commun Biol. 2020;3(1):776. doi:10.1038/s42003-020-01508-w

Trent J, Tap WD, Chugh R, et al. The potent and selective KIT inhibitor PLX9486 dosed in combination with sunitinib demonstrates promising progression free survival (PFS) in patients with advanced gastrointestinal stromal tumor (GIST): final results of a phase 1/2 study. Accessed April 16, 2021. https://2eb88d5a26c9d8f57ffb-aeafbf82c2963100e9056663ea595989.ssl.cf1.rackcdn.com/CTOS_3180_ZOVPIUNM_597_3458521.pdf

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