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Switch Control Inhibitor for GISTs Harboring Drug-Resistance Mutations: The INVICTUS Trial


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Heikki Joensuu, MD, PhD

Heikki Joensuu, MD, PhD

In May 2020, the U.S. Food and Drug Administration (FDA) approved ripretinib for patients who have received prior treatment with three or more kinase inhibitors, including imatinib, for advanced gastrointestinal stromal tumors (GIST). The approval was largely based on the findings of the randomized INVICTUS trial, reported in The Lancet Oncology  1 and reviewed in this issue of The ASCO Post. In INVICTUS, ripretinib improved progression-free survival—the primary endpoint—from 1.0 month with placebo to 6.3 months in a patient population with GIST that had progressed on imatinib, sunitinib, and regorafenib (the approved first-line, second-line, and third-line agents for advanced GIST, respectively) or who had documented intolerance to any of these drugs.

The 5-month improvement in the median progression-free survival is modest, but the patients assigned to ripretinib survived longer than those assigned to placebo (15.1 months vs 6.6 months, hazard ratio [HR] = 0.36, 95% confidence interval [CI] = 0.21–0.62), despite two-thirds of the patients on placebo crossing over to ripretinib after the primary endpoint was met. These overall survival data were based on relatively small event numbers, and owing to the hierarchical endpoint testing procedure, overall survival could not be formally tested for statistical significance. Yet the median overall survival gain of 8.5 months achieved with ripretinib appears substantial in the fourth-line setting and beyond.

Novel Mode of Action: Switch Pocket Inhibition

Ripretinib is a tyrosine kinase inhibitor with a novel mode of action. Most tyrosine kinase inhibitors, such as imatinib, sunitinib, and regorafenib, mimic ATP and compete with ATP for binding to the ATP-binding pocket of the kinase, whereas ripretinib binds to another kinase pocket—the switch pocket—located adjacent to the ATP-binding pocket in the kinase. Besides the switch pocket, ripretinib also binds to the activation loop of the kinase, forcing the activation loop (and the kinase) into an inactive conformation.2

Most GISTs are driven by an activating mutation in either KIT (75%–80%) or PDGFRA (10%–15%). In addition to the activation loop switch (encoded by KIT exons 17 and 18 and PDGFRA exons 18 and 19), the KIT and PDGFRA kinases also harbor an inhibitory switch (encoded by KIT exon 11 and PDGFRA exon 12). Besides locking the kinase activation switch, ripretinib also reinforces the kinase inhibitory switch. The dual inhibition could lead to more complete control of the kinase activity.

“Ripretinib might have an advantage over the approved ATP-mimicking tyrosine kinase inhibitors when treating patients with acquired mutations that confer imatinib resistance.”
— Heikki Joensuu, MD, PhD

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Ripretinib might have an advantage over the approved ATP-mimicking tyrosine kinase inhibitors when treating patients with acquired mutations that confer imatinib resistance. In GIST, imatinib-resistance mutations cluster either in KIT exons 13 and 14, which encode for the ATP-binding pocket of the kinase, interfering with imatinib binding to the kinase, or in the KIT exons, which encode for the activation loop. Advanced imatinib-resistant GISTs often simultaneously harbor several clones with different KIT mutations that may confer drug resistance.3 Both sunitinib and regorafenib are effective for only some imatinib-resistance mutations.

Of note, in one study, ripretinib efficiently inhibited in vitro not only wild-type KIT and PDGFRA and the most common primary KIT and PDGFRA mutations found in GISTs not treated with tyrosine kinase inhibitors, but all evaluated secondary KIT and PDGFRA mutations leading to imatinib resistance as well.2 In this study, the spectrum of KIT and PDGFRA mutations inhibited by ripretinib was broader than that of the comparator drugs imatinib, sunitinib, sorafenib, and avapritinib.

Resistance to Ripretinib

The broad KIT and PDGFRA mutation inhibition spectrum observed with ripretinib in vitro,2 and the possibility that the switch pocket could be under a lower mutational pressure than the ATP-binding pocket during inhibitor therapy, suggest substantial and durable clinical activity. Yet resistance to ripretinib developed often relatively rapidly in the INVICTUS trial in heavily pretreated patients with GIST, since about 50% of those in the ripretinib group had a progression-free survival event within the first 6 months on treatment, and events continued to accumulate thereafter.1

Little is known about the molecular mechanisms that lead to resistance to switch control inhibitors. In one study, ripretinib showed relatively low potency for ATP-binding pocket mutations and -PDGFRA mutations in preclinical models.4 Mutations at gene sites that encode for the kinase switch pocket region or result in activation of cell-signaling pathways independent of KIT or PDGFRA could also lead to resistance.

Acceptable Safety Profile

Ripretinib was relatively well tolerated in the INVICTUS trial, but it inhibits the kinome more widely than imatinib.4 Besides KIT and PDGFRs, ripretinib also inhibits the vascular endothelial growth factor receptor 2 (VEGFR2), the angiopoietin-1 receptor, and the discoidin domain-containing receptor 2 at low (50% inhibitory concentration [IC50] < 10 nM) concentrations.2 Almost half of the patients had grade 1 or 2 hair loss and 21% had grade 1 or 2 palmar plantar erythrodysesthesia syndrome, which are infrequent side effects during imatinib therapy. The molecular mechanisms leading to alopecia are not clear. VEGFR2 inhibition may result in hypertension, which was observed in 9% of patients.1

Next Step: INTRIGUE Trial

Ripretinib is currently being compared with sunitinib in the phase III INTRIGUE trial (ClinicalTrials.gov identifier NCT03673501) as second-line treatment of patients whose GIST has progressed on imatinib or who are intolerant to imatinib. The results are awaited with interest. 

Dr. Joensuu is Professor of Oncology at the Helsinki University Hospital and University of Helsinki.

DISCLOSURE: Dr. Joensuu has been employed by Orion Corporation; has served in a leadership position for Sartar Therapeutics; holds stock or other ownership interests in Sartar Therapeutics and Orion Corporation; has served as a consultant or advisor to Orion Corporation and Neutron Therapeutics; and holds intellectual property in Sartar Therapeutics.

REFERENCES

1. Blay JY, Serrano C, Heinrich MC, et al: Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): A double-blind, randomised, placebo-controlled, phase III trial. Lancet Oncol 21:923-934, 2020.

2. 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 35:738-751, 2019.

3. Liegl B, Kepten I, Le C, et al: Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol 216:64-74, 2008.

4. Banks E, Grondine M, Bhavsar D, et al: Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors. Sci Transl Med 12:eaaz2481, 2020.


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