NCCN Guidelines List Ripretinib as Preferred Fourth-Line Option in Gastrointestinal Stromal Tumor

Version 1.2022 of the National Comprehensive Cancer Network (NCCN) guidelines now include ripretinib (Qinlock) as a category 1 fourth-line treatment option for patients with advanced gastrointestinal stromal tumor (GIST) and as an additional TKI for consideration prior to surgery.¹

The decision to include ripretinib at a dose of 150 mg once daily as a preferred fourth-line therapy following treatment with 3 or more kinase inhibitors, including imatinib (Gleevec), was based on findings from the pivotal phase 3 INVICTUS trial (NCT03353753) and subsequent FDA approval of the agent in this setting in May 2020.

Additionally, the guidelines state that additional clinical benefit may be obtained when given at a dose of 150 mg twice daily after progression on once-daily dosing.

Findings from INVICTUS demonstrated a median progression-free survival (PFS) of 6.3 months (95% CI, 4.6-6.9) with ripretinib vs 1.0 month (95% CI, 0.9-1.7) with placebo, which was statistically significant (HR, 0.15; 95% CI, 0.09-0.25; P < .0001).^2,3

The median overall survival (OS) was 15.1 months (95% CI, 12.3-15.1) and 6.6 months (95% CI, 4.1-11.6) in the ripretinib and placebo arms, respectively (HR, 0.36; 95% CI, 0.21-0.62).2 Additionally, the overall response rate was 9% (95% CI, 4.2%-18%) in the ripretinib arm and 0% in the placebo arm (95% CI, 0%-8%), with a P value of .0504 that was not statistically significant.^2,3

INVICTUS enrolled 129 patients with unresectable, locally advanced, or metastatic GIST who received prior treatment with imatinib, sunitinib (Sutent), and regorafenib (Stivarga). Patients were randomized 2:1 to 150 mg of ripretinib (n = 85) or placebo (n = 44) once daily. Patients in the placebo arm were allowed to receive ripretinib at the time of disease progression, and 66% were subsequently treated with the kinase inhibitor.³

In terms of safety, the most common adverse effects (AEs; ≥20%) with ripretinib were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting.

AE-related dose reductions occurred in 7% of patients. The AEs that led to permanent discontinuation in at least 1% of patients included general physical health deterioration (2.4%) and anemia, cardiac failure, plantar erythrodysesthesia, and vomiting, each of which affected 1.2% of patients.³

Regarding patient-reported outcome data (PRO), which were presented at the 2020 ASCO Virtual Scientific Program, investigators reported a clinically significant difference in quality of life (QOL) between ripretinib and placebo. Five QOL measures were assessed: physical functioning, role functioning, visual analog scale, overall health, and overall QOL. PROs were compiled with the EuroQol-5D and European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire.⁴

The findings indicated that the average physical functioning score increased 1.6 points with ripretinib and decreased 8.9 points with placebo (P = .004; improvement or no change, 68% vs 44%).⁴

Role functioning was also improved with ripretinib, increasing an average of 3.5 points vs a decrease of 17.1 points with placebo (P = .001; improvement or no change, 77% vs 50%). Visual analog scale scores improved an average of 3.7 points from baseline to cycle 2, day 1, with ripretinib vs an average decline of 8.9 points with placebo (P = .004; improvement or no change, 67% vs 41%). The overall health and QOL scores increased an average of 0.20 and 0.28 points, respectively, with ripretinib, and decreased 0.78 and 0.76 points with placebo (both P = .001; improvement or no change, 74% vs 47% and 79% vs 59%, respectively).⁴

Ripretinib was also evaluated in the phase 3 INTRIGUE study (NCT03673501) vs sunitinib in patients with advanced GIST who progressed on or were intolerant to frontline imatinib.

Findings from this study, which were presented at the 2022 January ASCO Plenary Series, failed to show a statistically significant improvement in PFS with the kinase inhibitor vs sunitinib, missing the primary end point of the study.⁵ 

References

1. NCCN Guidelines for Gastrointestinal Stromal Tumors (GISTs) V.1.2021– Annual on 07/08/20. NCCN. Accessed February 23, 2022.
2. FDA approves ripretinib for advanced gastrointestinal stromal tumor. FDA. May 15, 2020. Accessed February 23, 2022. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ripretinib-advanced-gastrointestinal-stromal-tumor/
3. Qinlock. Prescribing information. Deciphera Pharmaceuticals; 2020. Accessed February 23, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213973s000lbl.pdf
4. Heinrich MC, George S, Zalcberg JR, et al. Quality of life (QoL) and self-reported function with ripretinib in ≥4th-line therapy for patients with gastrointestinal stromal tumors (GIST): analyses from INVICTUS. J Clin Oncol. 2020;38(suppl 15):11535-11535. doi:10.1200/JCO.2020.38.15_suppl.11535
5. Heinrich MCC, Jones RLL, Gelderblom H, et al. 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. J Clin Oncol. 2022;40(suppl 36):359881. doi:10.1200/JCO.2022.40.36_suppl.359881