Clinical Benefit of Ripretinib Dose Escalation After Disease Progression in Advanced Gastrointestinal Stromal Tumor: An Analysis of the INVICTUS Study

Abstract

Background. Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumor (GIST) as ≥fourth-line therapy. In INVICTUS, ripretinib intra-patient dose escalation (IPDE) to 150 mg twice daily (BID) was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg BID after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study. Materials and Methods. Tumor imaging was performed every 28-day cycle for the first 4 cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg BID period. Among the ripretinib IPDE patients, progression-free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg BID to PD or death.Results. Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7-6.4) and median PFS2 was 3.7 months (95% CI, 3.1-5.3). Median overall survival was 18.4 months (95% CI, 14.5-not estimable). Ripretinib 150 mg BID (median duration of treatment 3.7 months) was well tolerated with new or worsening Grade 3-4 TEAEs of anemia in 6 (14%) and abdominal pain in 3 (7%) patients. Ripretinib 150 mg BID was discontinued due to TEAEs in 7 (16%) patients. Conclusion. Ripretinib 150 mg BID after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with ≥fourth-line GIST.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT03353753 (INVICTUS) The Oncologist 2021;9999:• • Implications for Practice: Of the 85 patients with advanced gastrointestinal stromal tumor having received ≥3 prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase 3 INVICTUS study, 43 underwent ripretinib intrapatient dose escalation (IPDE) to 150 mg twice daily (BID) after progressive disease (PD). Median progression-free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg BID was acceptable.

Compassionate Use of Ripretinib for Patients With Metastatic Gastrointestinal Stromal Tumors: Taiwan and Hong Kong Experience

“…For patients who demonstrated disease progression following treatment with 150 mg of ripretinib, an additional clinical benefit may be obtained by increasing the dose of ripretinib to 300 mg ( 15 ). However, the standard treatment beyond ripretinib failure is uncertain; therefore, referral to a clinical trial is strongly recommended for patients still experiencing disease progression after an increase in ripretinib dose.…”

Ripretinib Versus Sunitinib in Patients With Advanced Gastrointestinal Stromal Tumor After Treatment With Imatinib (INTRIGUE): A Randomized, Open-Label, Phase III Trial

“…29 Ripretinib demonstrated good tolerability across all mutation types; The highest-grade severity for alopecia is grade 2. although not tested in this study, similar to imatinib, a higher dose of ripretinib may benefit some patients (particularly those with KIT exon 9 mutations) and would be interesting to investigate. [30][31][32] Similar to INVICTUS, alopecia was the most common TEAE of any grade observed with ripretinib in INTRIGUE; however, most patients who experienced alopecia were of grade 1 severity (, 50% hair loss). 17,33 Patients who received ripretinib were less likely to experience grade 3/4 TEAEs compared with sunitinib.…”

Efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma

“…Interestingly, a trend toward additional clinical benefit was observed with ripretinib dose escalation to 150 mg BID in patients with KIT-altered metastatic melanoma, consistent with recent studies employing a similar strategy in patients with advanced GIST. 33,34 Ripretinib had an acceptable safety profile in KIT-altered metastatic melanoma. Consistent with the safety profile observed in !fourth-line advanced GIST in the pivotal study, lipase increase was the only treatment-related grade 3 TEAE occurring in >5% of patients.…”