INTRIGUE: A phase III, randomized, open-label study to evaluate the efficacy and safety of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib

Journal of Clinical Oncology, vol. 40, pp. 359881

Abstract

359881 Background: Sunitinib is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib, a broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor (TKI), is indicated for the treatment of adult patients (pts) with GIST who received prior treatment with 3 or more TKIs, including imatinib. We compared the efficacy and safety of ripretinib vs sunitinib in pts with advanced GIST who progressed on or were intolerant to imatinib. Methods: This multicenter, global, randomized, open-label phase 3 study (NCT03673501) enrolled adult pts with GIST who progressed on or had intolerance to imatinib. Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Randomization was stratified by KIT mutational status and imatinib intolerance. The primary endpoint was progression-free survival (PFS) by independent radiologic review (IRR) using modified RECIST version 1.1. Key secondary endpoints were objective response rate (ORR) by IRR and overall survival (OS). Hierarchical testing was performed for primary and key secondary endpoints in a prespecified sequence; testing pts with a KIT exon 11 primary mutation (Ex11 intention-to-treat [ITT] population) preceded the all-patient (AP) ITT population. Data cutoff was 1 Sep 2021; final analyses of PFS and ORR and the first interim analysis of OS were conducted. Results: A total of 453 pts were randomized to ripretinib (n = 226; Ex11 ITT, n = 163) or sunitinib (n = 227; Ex11 ITT, n = 164). Median age was 60 yrs (range 18–88) and most pts were white (66.2%) males (62.0%). PFS was not statistically different between ripretinib and sunitinib in the Ex11 ITT (hazard ratio [HR] 0.88, 95% CI 0.66, 1.16; P = 0.36; median 8.3 vs 7.0 mos) or in the AP populations (HR 1.05, 95% CI 0.82, 1.33; P = 0.72; median 8.0 vs 8.3 mos). ORR was numerically higher for ripretinib vs sunitinib in the Ex11 ITT (23.9% vs 14.6%; difference 9.3%, 95% CI 0.7, 17.8; nominal P = 0.03) and AP ITT populations (21.7% vs 17.6%; difference 4.2%, 95% CI −3.2, 11.5; nominal P = 0.27). OS data was highly immature; median OS was not reached in either arm. Fewer pts in the ripretinib arm experienced Grade 3-4 (G3-4) treatment-emergent adverse events (TEAEs) vs sunitinib (41.3% vs 65.6%). Among G3-4 TEAEs with a difference ≥5% between arms, ripretinib had fewer events vs sunitinib (hypertension [8.5% vs 26.7%], palmar-plantar erythrodysesthesia [1.3% vs 10.0%], neutropenia [0% vs 6.3%], and neutrophil count decreased [0% vs 7.2%]). Conclusions: The PFS in both arms was longer than PFS achieved by sunitinib in its pivotal phase 3 trial. While the PFS for ripretinib did not meet the primary endpoint of superiority vs sunitinib, meaningful clinical activity and fewer G3-4 TEAEs were observed in pts with advanced GIST treated with ripretinib after imatinib failure. Clinical trial information: NCT03673501.

Authors 19

1. Michael Charles Heinrich

   Oregon Health & Science University · Portland VA Medical Center · VA Portland Health Care System · OHSU Knight Cancer Institute

   Affiliation as printed

   Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR;

2. Robin L. Jones

   Institute of Cancer Research · Royal Marsden Hospital

   Affiliation as printed

   Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom;

3. Hans A. J. Gelderblom Aachen Department of Medical Oncology

   Leiden University Medical Center

   Affiliation as printed

   Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands;

4. Suzanne George

   Harvard University · Dana-Farber Cancer Institute

   Affiliation as printed

   Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA;

5. Patrick Schöffski

   Universitair Ziekenhuis Leuven

   Affiliation as printed

   Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium;

6. Margaret von Mehren

   Fox Chase Cancer Center

   Affiliation as printed

   Fox Chase Cancer Center, Philadelphia, PA;

7. John Raymond Zalcberg

   Monash University

   Affiliation as printed

   School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia;

8. Yoon‐Koo Kang

   Asan Medical Center

   Affiliation as printed

   Asan Medical Center, Seoul, South Korea;

9. Albiruni Ryan Abdul Razak

   Princess Margaret Cancer Centre

   Affiliation as printed

   Princess Margaret Cancer Centre, Toronto, ON, Canada;

10. Jonathan C. Trent

    University of Miami · Jackson Memorial Hospital · Sylvester Comprehensive Cancer Center

    Affiliation as printed

    University of Miami-Sylvester Comprehensive Cancer Center, Jackson Memorial Hospital, Miami, FL;

11. Steven Attia

    Mayo Clinic in Florida

    Affiliation as printed

    Mayo Clinic, Jacksonville, FL;

12. Axel Le Cesne

    Institut Gustave Roussy

    Affiliation as printed

    Institut Gustave Roussy, Villejuif, France;

13. Ying Su

    Deciphera Pharmaceuticals (United States)

    Affiliation as printed

    Deciphera Pharmaceuticals, LLC, Waltham, MA;

14. Julie Nicole Meade

    Deciphera Pharmaceuticals (United States)

    Affiliation as printed

    Deciphera Pharmaceuticals, LLC, Waltham, MA;

15. Tao Wang

    Deciphera Pharmaceuticals (United States)

    Affiliation as printed

    Deciphera Pharmaceuticals, LLC, Waltham, MA;

16. Matthew Leigh Sherman

    Deciphera Pharmaceuticals (United States)

    Affiliation as printed

    Deciphera Pharmaceuticals, LLC, Waltham, MA;

17. Rodrigo Ruiz‐Soto

    Deciphera Pharmaceuticals (United States)

    Affiliation as printed

    Deciphera Pharmaceuticals, LLC, Waltham, MA;

18. Jean‐Yves Blay

    Centre Léon Bérard

    Affiliation as printed

    Centre Léon Bérard, Lyon, France;

19. Sebastian Bauer

    Essen University Hospital · University of Duisburg-Essen

    Affiliation as printed

    West German Cancer Center, Essen University Hospital, University of Duisburg-Essen, Essen, Germany;