Source:

Heinrich, MC. 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. Presented at: ASCO Plenary Series; Jan. 25, 2022.

Disclosures: Deciphera Pharmaceuticals funded this study. Heinrich reports honoraria from Novartis; consultant/advisory roles with Blueprint Medicines, Deciphera Pharmaceuticals, Novartis and Theseus Pharmaceuticals. He also reports his institution holds a patent on a GIST treatment licensed to Novartis.
January 26, 2022
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Ripretinib fails to improve PFS in advanced gastrointestinal stromal tumor

Source:

Heinrich, MC. 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. Presented at: ASCO Plenary Series; Jan. 25, 2022.

Disclosures: Deciphera Pharmaceuticals funded this study. Heinrich reports honoraria from Novartis; consultant/advisory roles with Blueprint Medicines, Deciphera Pharmaceuticals, Novartis and Theseus Pharmaceuticals. He also reports his institution holds a patent on a GIST treatment licensed to Novartis.
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Ripretinib did not extend PFS compared with sunitinib for patients with advanced gastrointestinal stromal tumor who previously received imatinib, according to randomized phase 3 study results presented during the ASCO Plenary Series.

The two agents conferred comparable median PFS; however, researchers reported a higher overall response rate with ripretinib (Qinrock, Deciphera Pharmaceuticals) among patients with KIT exon 11 primary mutations.

Ripretinib also exhibited a more favorable safety profile, according to researcher Michael C. Heinrich, MD, professor of medicine at Oregon Health & Science University.

“[Consequently], ripretinib may provide meaningful clinical benefit to patients with advanced [gastrointestinal stromal tumor] previously treated with imatinib,” Heinrich said.

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. Most patients have activating mutations in KIT (70% to 85%) or platelet-derived growth factor receptor alpha (PDGFRA; 5% to 10%) that drive tumor growth, according to study background.

Most patients with advanced GIST who receive imatinib — a KIT/PDGFRA tyrosine kinase inhibitor — achieve objective response or maintain stable disease, with median PFS of approximately 18 months to 20 months.

“However, over time, most imatinib-treated patients will experience tumor progression due to the development of secondary kinase domain mutations,” Heinrich said during his presentation.

Sunitinib malate (Sutent, Pfizer) —a multitargeted TKI that inhibits KIT, PDGFRA and VEGFR — is approved in the United States for treatment of patients with advanced GIST who failed imatinib, leading to median PFS of about 5.6 months.

Ripretinib is a broad-spectrum KIT and PDGFRA switch-control TKI that demonstrated superior activity to sunitinib in vitro against imatinib-resistant secondary KIT mutations. The agent is approved in the United States for treatment of adults with advanced GIST who underwent prior treatment with at least three TKIs, including imatinib.

Heinrich and colleagues conducted the open-label INTRIGUE study to compare ripretinib with sunitinib for treatment of adults with advanced GIST who experienced disease progression on or had documented intolerance to imatinib.

Researchers enrolled 453 patients from 122 sites in North America, Europe, Asia, Australia and South America.

Researchers randomly assigned 226 patients to ripretinib dosed at 150 mg daily on a continuous schedule. The other 227 patients received sunitinib 50 mg daily in a 4-weeks-on, 2-weeks-off schedule. Study design did not allow for crossover.

Treatment groups appeared well-balanced for age (median, 59.5 years vs. 60 years), sex (male, 61.5% vs. 62.6%), race (white, 65.5% vs. 67%), ECOG performance status (1 or 2, 98.7% vs. 99.6%) and presence of KIT exon 11 mutations (72.1% vs. 72.2%).

PFS in the KIT exon 11 mutation-positive subgroup and in the entire study population served as the primary endpoint. Secondary endpoints included ORR and OS, time to tumor response, quality of life, disease control rate and safety.

At data cutoff, 117 patients (ripretinib, n = 65; sunitinib (n = 52) remained on treatment.

The most common reasons for treatment discontinuation included progressive disease by independent radiologic review or investigator assessment, clinical progression and withdrawal of consent.

Analysis of PFS by independent radiologic review showed no significant differences between ripretinib and sunitinib among patients with KIT exon 11 mutations (8.3 months vs. 7 months; HR = 0.88; 95% CI, 0.66-1.16) or in the intention-to-treat (ITT) population (8 months vs. 8.3 months; HR = 1.05; 95% CI, 0.82-1.33).

Due to the study’s hierarchal statistical testing plan, because ripretinib did not confer a statistically significant PFS benefit compared with sunitinib in the KIT exon 11 ITT population, no further statistical testing could be performed.

Subgroup analysis of PFS by independent radiologic review showed no clear difference between treatment groups with the exception of KIT exon 9-mutated GIST, for whom sunitinib appeared to confer a PFS benefit (median, 5.5 months for ripretinib vs. 13.8 months for sunitinib; HR = 2.85; 95% CI, 1.48-5.48).

Results showed a significantly higher ORR with ripretinib in the KIT exon 11 mutation-positive group (23.9% vs. 14.6%; difference, 9.3%; 95% CI, 0.7-17.8) but not in the entire patient population (21.7% vs. 17.6%; difference, 4.2%; 95% CI, –3.2 to 11.5%).

Sunitinib-treated patients achieved longer median duration of response (20.1 months vs. 16.7 months).

Patients assigned sunitinib more often required dose reduction (50.2% vs. 19.7%) or dose interruption (38% vs. 27.8%).

Almost all patients experienced a treatment-emergent adverse event (99.1% for both ripretinib and sunitinib). However, more patients assigned sunitinib experienced grade 3 or grade 4 treatment-emergent adverse events (65.6% vs. 41.3%) or grade 3/grade 4 drug-related treatment-emergent adverse events (55.2% vs. 26.5%).

The safety profile of ripretinib appeared consistent with its prescribing information, Heinrich said. The most common any-grade treatment-emergent adverse events in this group included alopecia (64.1%) and fatigue (37.7%). The most common any-grade treatment-emergent adverse event in the sunitinib group included palmar-plantar erythrodysesthesia syndrome (51.1%) and hypertension (47.1%).

Incidence of nearly all grade 3/grade 4 treatment-emergent adverse events were lower with ripretinib than sunitinib. Patients assigned sunitinib appeared nearly three times more likely than those assigned ripretinib to develop grade 3 hypertension and nearly seven times more likely to develop grade 3 palmar-plantar erythrodysesthesia syndrome.