QINLOCK Tablet Ref.[10190] Active ingredients: Ripretinib

Exposure-Response Relationships

Ripretinib exposure-response relationships and the time course of pharmacodynamics have not been fully characterized.

Cardiac Electrophysiology

No large mean increase in QTc interval (i.e. >20 ms) was detected following treatment with QINLOCK at the recommended dose of 150 mg taken orally once daily.

The pharmacokinetics of ripretinib and its equally active metabolite (DP-5439) were evaluated following single doses in healthy subjects and multiple doses in patients with advanced malignancies; the results are summarized in Table 5.

Table 5. Pharmacokinetic Parameters of Ripretinib and DP-5439:

^a Estimated based on cycle 1, day 15
^b After a single oral dose of 150 mg
^c A high fat meal consisted of approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively
CV=coefficient of variation; C_max=maximum plasma concentration; AUC_0-12h=area under the plasma concentration-time curve from time zero to 12 hours; AUC_0-24h=area under the plasma concentration-time curve from time zero to 24 hours; T_max=time to maximum concentration

Specific Populations

No clinically significant differences in the pharmacokinetics of ripretinib were observed based on age (19 to 87 years), sex, race (White, Black, and Asian), body weight (39 to 138 kg), tumor (GIST or other solid tumors), prior gastrectomy, mild to moderate renal impairment (CLcr 30 to <90 mL/min estimated by Cockcroft-Gault), and mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin 1 to 1.5 × ULN and AST any). The effects of severe renal impairment (CLcr 15 to 29 mL/min) or moderate to severe hepatic impairment (total bilirubin >1.5 × ULN, AST any) on the pharmacokinetics of ripretinib have not been studied.

Drug Interaction Studies

Clinical Studies

Strong CYP3A Inhibitors: Coadministration of QINLOCK with itraconazole (a strong CYP3A inhibitor and also a P-gp inhibitor) increased ripretinib C_max by 36% and AUC_0-INF by 99% and also increased DP-5439 AUC_0-INF by 99% with no change in its C_max.

Strong CYP3A Inducers: The effect of coadministration of QINLOCK with a strong CYP3A inducer has not been studied. Ripretinib and DP-5439 are metabolized by CYP3A.

Proton Pump Inhibitors: No clinically significant differences in the plasma exposure to ripretinib and DP-5439 were observed when QINLOCK was coadministered with pantoprazole (a proton pump inhibitor).

In Vitro Studies

CYP Enzymes: Ripretinib and DP-5439 are inhibitors of CYP2C8. Ripretinib and DP-5439 are not inducers of CYP1A2, CYP2B6, or CYP3A4.

Transporter Systems: Ripretinib is an inhibitor of P-gp (P-glycoprotein) and BCRP (Breast Cancer Resistance Protein). DP-5439 is a substrate for P-gp and BCRP. DP-5439 is an inhibitor of BCRP and MATE1 (Multidrug And Toxin Extrusion Protein 1).

Carcinogenicity studies have not been conducted with ripretinib.

Ripretinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in either an in vitro human lymphocyte culture micronucleus assay or an in vivo rat bone marrow micronucleus assay.

Dedicated fertility studies in male animals were not conducted with ripretinib. Findings in male reproductive organs occurred in repeat-dose toxicity studies and included degeneration of the testes and cellular debris of the epididymis in males administered ≥30 mg/kg/day (approximately one half of the human exposure at the recommended dose of 150 mg).

The efficacy of QINLOCK was evaluated in INVICTUS, an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (NCT03353753). Eligible patients had unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST) and had received prior treatment with imatinib, sunitinib, and regorafenib. Randomization was stratified by prior lines of therapy (3 versus ≥4) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1 or 2). Patients received QINLOCK 150 mg or placebo orally once daily until disease progression or unacceptable toxicity. Tumor response assessments were performed every 28 days through for the first 4 months and then every 56 days thereafter. The major efficacy outcome measure was progression-free survival (PFS) based on disease assessment by blinded independent central review (BICR) using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a pre-existing tumor mass must meet specific criteria to be considered unequivocal evidence of progression. Additional efficacy outcome measures included objective response rate (ORR) by BICR and overall survival (OS). Patients randomized to receive placebo could be treated with QINLOCK at the time of disease progression.

A total of 129 patients were randomized, 85 to QINLOCK and 44 to placebo.

Patient characteristics of the intent-to-treat (ITT) population in INVICTUS were median age of 60 years (range: 29 to 83 years), with 39% aged ≥65 years; 57% were male; 75% were White; and 92% had an ECOG performance status of 0 or 1. Sixty-three percent (63%) of patients received 3 prior therapies and 37% received 4 or more prior therapies. Sixty-six percent (66%) of patients randomized to placebo switched to QINLOCK after disease progression.

Efficacy results from INVICTUS are summarized in Table 6.

Table 6. Efficacy Results of INVICTUS:

BICR=Blinded Independent Central Review; CI=Confidence Interval
^a Assessed per BICR.
^b p-value is based on 2-sided stratified log-rank test.
^c Hazard ratio is based on Cox proportional regression model. This model includes treatment and randomization stratification factors as fixed factors.
^d Based on Fisher’s exact test. The p-value is not statistically significant.
^e Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints of ORR and OS.

Figure 1. Kaplan-Meier Curve of Progression-Free Survival in INVICTUS:

Figure 2. Kaplan-Meier Curve of Overall Survival in INVICTUS: