Gastrointestinal Stromal Tumors
Role of Kinase Switch Control in Gastrointestinal Stromal Tumors
As secondary drug resistance mutations emerge, the kinase inhibitors used to treat gastrointestinal stromal tumors (GIST) may lose their ability to prevent kinase activation of KIT and PDGFRA receptor tyrosine kinases. Next-generation kinase inhibitors such as ripretinib have been developed to treat drug-resistant GIST by targeting the switch control region of these kinases to restore the activation blockade.
“Many primary and secondary resistance mutations in KIT and PDGFRA, such as exons 17 and 18, are located within the conformation-controlling ‘switch regions’ of the protein, which can reside in an active type I or an inactive type II state, depending on whether ATP is present.”
The KIT and PDGFRA receptor tyrosine kinase mutants are important in GIST and in a variety of other malignancies. Many primary and secondary resistance mutations in KIT and PDGFRA, such as exons 17 and 18, are located within the conformation-controlling “switch regions” of the protein, which can reside in an active type I or an inactive type II state, depending on whether ATP is present. These mutations change the structure of the protein in such a way that the kinase is always on. Most of the current tyrosine kinase inhibitors, such as imatinib, sunitinib, and regorafenib, are type II tyrosine kinase inhibitors that prevent ATP from getting to the kinase binding site. However, these agents show only modest benefit once a patient has progressed.
Recently, 2 agents with distinct mechanisms of action have been introduced. Ripretinib, a switch pocket inhibitor, is a newer type II agent that has a different mechanism of action that prevents the kinase from changing conformation, or orientation, inside the switch pocket, to receive ATP and become active. In vitro, ripretinib was able to inhibit a broad spectrum of GIST resistance mutations. Avapritinib, also a newer agent, does not act through switch control inhibition, but rather is technically the only true type I inhibitor (ie, it inhibits these proteins in their active state). Avapritinib was approved by the US Food and Drug Administration for adults with unresectable or metastatic GIST harboring a specific mutation: a PDGFRA exon 18 mutation, including PDGFRA D842V. This was based on the results of the phase 1 NAVIGATOR trial, which showed that 49 out of 56 patients had an overall response.
Ripretinib was approved for the treatment of adults with advanced GIST who have been treated previously with 3 or more kinase inhibitors, including imatinib. The approval was based on the phase 3 INVICTUS trial, a randomized, double-blind, placebo-controlled study in 129 patients with GIST who were previously treated with imatinib, sunitinib, and regorafenib. There was a statistically significant improvement in progression-free survival for patients in the ripretinib arm compared with those in the placebo arm; the authors reported a median progression-free survival of 6.3 months with ripretinib compared with 1.0 month with placebo. Rates of dose modifications for adverse reactions were similar between ripretinib and placebo. As with many tyrosine kinase inhibitors, hand-foot syndrome was relatively common and was reported in more than 10% of patients on ripretinib.
Blay JY, 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 Oncol. 2020;21(7):923-934. doi:10.1016/S1470-2045(20)30168-6
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
Schneeweiss M, Peter B, Bibi S, et al. The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis. Haematologica. 2018;103(5):799-809. doi:10.3324/haematol.2017.179895
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. doi:10.1016/j.ccell.2019.04.006