ASCO Expert Perspective
“In this, large, phase 3 trial, ripretinib was not found to be better than sunitinib in controlling gastrointestinal stromal tumor which has progressed on imatinib. It is important to recognize that the side effect profile of ripretinib is more favorable with lower rates of hypertension, hand-foot skin reaction, and neutropenia. This is an important factor in considering treating options for patients.”
– Muhammad Shaalan Beg, MD, ASCO Expert in Gastrointestinal Cancer

In patients with advanced gastrointestinal stromal tumors (GIST) that progressed on or were intolerant to imatinib, the efficacy of ripretinib was comparable to sunitinib. These findings from the INTRIGUE trial were presented during the January session of the American Society of Clinical Oncology (ASCO) Plenary Series. 

Approximately 80% of patients with GIST have primary mutations in KIT.^1,2 Imatinib is effective against KIT-mutated GIST, but the vast majority of patients with GIST will ultimately develop resistance to imatinib, most commonly due to the development of secondary mutations in KIT.³ Sunitinib is effective against some imatinib-resistant mutations. 

In this international, multicenter study conducted in 122 active sites across 22 countries, 453 patients were randomized to ripretinib (226 patients; 163 with Exon 11) or sunitinib (227; 164 with Exon 11).

• Overall, median progression free survival (mPFS) for ripretinib was 8 months compared to 8.3 months for sunitinib. In patients with a KIT exon 11 primary mutation, mPFS for ripretinib was 8.3 months compared to 7 months for sunitinib arm (Hazard Ratio [HR] 0.88, p=0.360).  
• The overall objective response rate (ORR) for ripretinib was 21.7% (49 patients) compared to 17.6% (40 patients) for sunitinib. In patients with a KIT exon 11 primary mutation, the ORR for ripretinib was 23.9% (39 patients) compared to 14.6% (24 patients) for sunitinib. 

Ripretinib was generally well tolerated. Fewer patients in the ripretinib arm experienced grade 3-4 adverse events compared to sunitinib (41.3% vs 65.6%). Patients receiving sunitinib were 3 times more likely to develop grade 3 hypertension compared with patients receiving ripretinib (26.7% vs 8.5%) and 7 times more likely to develop grade 3 hand-foot syndrome (a side effect of some chemotherapy treatments that can cause redness, swelling, and blistering on the palms of the hands and soles of the feet) compared to patients receiving ripretinib (10% vs 1.3%). Fewer patients receiving ripretinib experienced a moderate to extremely large impact on their lives as measured by the Dermatology Life Quality Index. Patients receiving ripretinib also experienced less deterioration in their ability to engage in either work or leisure activities during treatment.

“Even though the INTRIGUE study did not meet its primary endpoint of improved PFS, ripretinib and sunitinib efficacy appeared comparable. Although ripretinib was not superior to sunitinib as a second-line treatment for GIST, ripretinib has remarkable activity as a fourth-line or later agent and remains the only FDA-approved agent in this setting,” said lead author Michael C. Heinrich, MD, FACP. “Our goal is to provide the full results of this study to the oncology community to help treating physicians make well-informed decisions on the best treatment for their patients with advanced GIST.”

From the January 2022 ASCO Plenary Series: 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, Michael C. Heinrich, et al. SCROLL DOWN TO VIEW FULL EMBARGOED ABSTRACT

View Dr. Beg’s Disclosures

View Author Disclosures

ATTRIBUTION TO THE ASCO PLENARY SERIES IS REQUESTED IN ALL COVERAGE.
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Abstract 359881: 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 

Authors: Michael C. Heinrich, Robin Lewis Jones, Hans Gelderblom, Suzanne George, Patrick Schöffski, Margaret von Mehren, John Raymond Zalcberg, Yoon-Koo Kang, Albiruni Ryan Abdul Razak, Jonathan C. Trent, Steven Attia, Axel Le Cesne, Ying Su, Julie Nicole Meade, Tao Wang, Matthew L. Sherman, Rodrigo Ruiz-Soto, Jean-Yves Blay, Sebastian Bauer; Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR; Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands; Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA; Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium; Fox Chase Cancer Center, Philadelphia, PA; School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia; Asan Medical Center, Seoul, South Korea; Princess Margaret Cancer Centre, Toronto, ON; University of Miami-Sylvester Comprehensive Cancer Center, Jackson Memorial Hospital, Miami, FL; Mayo Clinic, Jacksonville, FL; Institut Gustave Roussy, Villejuif, France; Deciphera Pharmaceuticals, LLC, Waltham, MA; Centre Léon Bérard, Lyon, France; West German Cancer Center, Essen University Hospital, University of Duisburg-Essen, Essen, Germany 

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. 

 [1] Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Clin Pathol 2008;216(1):64-74. 
 [2] Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol.  2003;21(23):4342-9.
 [3] Kee D, Zalcberg JR. Current and emerging strategies for the management of imatinib-refractory advanced gastrointestinal stromal tumors. Ther Adv Med Oncol 2012;4(5):255-70.