Ripretinib Given as Intra-Patient Dose Escalation Shows Clinically Meaningful PFS in GIST After Disease Progression

Dose escalation with ripretinib (Qinlock) following disease progression on the 150-mg daily dose led to a clinically meaningful benefit in patients with advanced gastrointestinal stromal tumor (GIST), according to phase 1 results presented at the 2020 CTOS Annual Meeting.¹

The benefit in progression-free survival (PFS) was observed in the second-, third- and fourth-line settings when ripretinib was given at 150 mg twice daily, identified as the intra-patient dose escalation (IPDE) method.

PFS1 comprised PFS on ripretinib at 150 mg daily defined as day 1 of cycle 1 until disease progression, while PFS2 comprised PFS on ripretinib at 150 mg twice daily defined as the date of IPDE to disease progression or death. Results showed that the median PFS1 was 11.0 months, 8.3 months, and 5.5 months in patients with GIST who received intra-patient dose escalation the second-, third, and fourth-line setting. For PFS2, the medians were 5.6 months, 3.3 months, and 4.6 months in these respective settings.

In May 2020, the FDA approved ripretinib for the fourth-line treatment of patients with advanced GIST. Ripretinib is specifically indicated for adult patients who have received prior treatment with 3 or more kinase inhibitor therapies, including imatinib (Gleevec).¹

The approval was based on findings from the phase 3 INVICTUS trial, in which the investigational switch control, broad-spectrum KIT and PDGFRα inhibitor led to an 85% reduction in the risk of disease progression or death compared with placebo for heavily pretreated patients with advanced GIST.²

In the phase 1 intra-patient dose-escalation study (NCT02571036), patients with GIST were started on ripretinib at 150 mg daily in 28-day cycles (n = 142) and were then dose escalated to 150 mg twice daily following disease progression (n = 67). Patients were receiving ripretinib in either the second-, third-, or fourth-line setting.

The primary end point was PFS per RECIST v1.1 criteria based on local review. Investigators specifically looked at PFS at both dosing schedules, reported as PFS1 and PFS2.

In the IPDE patients, the median age was 61.1 years, with 33% of patients being at least 65 years old. Sixty-four percent of patients were male, and more than half (54%) of patients had an ECOG performance status of 0. When stratified by mutation status, patients harbored either KIT exon 11 mutation (72%), KIT exon 9 (21%), KIT other exons (3%), or PDGFRA (5%).

At the data cutoff of May 8, 2020, the mPFS2/mPFS1 rates were 51%, 40%, and 84% in the second-, third-, and fourth-line settings, respectively.

Regarding safety, grade 3/4 treatment-emergent adverse events (TEAEs) in the 150-mg once-daily ripretinib dosing period was diarrhea (1.5%), increased lipase (21%), hypertension (3.0%), and hypokalemia (1.5%). When combined with the 150-mg twice-daily dosing period, grade 3/4 TEAEs included fatigue (3.0%), diarrhea (3.0%), abdominal pain (10%), increased lipase (24%), decreased appetite (1.5%), hypertension (4.5%), anemia (6.0%), dyspnea (3.0%), headache (1.5%), and hypokalemia (3.0%).

“The comparison of reported TEAEs demonstrate that the safety profile for ripretinib a 150-mg twice daily is similar to ripretinib at 150 mg once daily,” Suzanne George, MD, of Dana-Farber Cancer Institute, and co-investigators wrote in the presentation.

The multicenter, open-label, phase 3 INTRIGUE study (NCT03673501) is recruiting patients with advanced GIST who have progressed on prior imatinib and will be randomized to receive ripretinib or sunitinib (Sutent).

References

1. George S, Chi P, Heinrich M, et al. Ripretinib intra-patient dose escalation following disease progression provides clinically meaningful progression-free survival in gastrointestinal stromal tumor in phase 1 study. Presented at: 2020 CTOS Annual Meeting; November 18-21, 2020; virtual. Abstract 25.
2. van Mehren M, Serrano C, Bauer S, et al. INVICTUS: a phase 3, international, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as >4th line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753). Ann Oncol. 2019;30(suppl 5; abstr LBA87). doi:10.1093/annonc/mdz394.087