Qinlock® (ripretinib, DCC-2618) is a type II switch control tyrosine kinase inhibitor (TKI) that inhibits a broad spectrum of oncogenic and drug-resistant variants of KIT and PDGFRA (platelet-derived growth factor receptor alpha).1 On May 15, 2020, the US Food and Drug Administration (FDA) approved Qinlock as the first drug for the fourth-line treatment of advanced gastrointestinal stromal tumor (GIST).2 The drug is indicated as a fourth-line treatment for adults who have advanced GIST and have previously completed treatment with 3 or more kinase inhibitors, inclusive of imatinib.3 Qinlock is available in the form of 50-mg tablets. It is taken orally once daily at a dose of 150 mg. The tablets are swallowed whole and can be consumed with or without food.4
Mechanism of Action
Ripretinib is a switch control tyrosine kinase inhibitor (TKI). It has been found that both KIT and PDGFRA act as an activating loop switch in the kinase domain and as an inhibitory switch in the juxtamembrane domain. The drug attaches to the switch pocket and to the activation loop, preventing its entry into the switch pocket. When the kinase is put into an off-state by ripretinib, downstream signaling is inhibited. Ripretinib thus has a dual mechanism of action that locks KIT and PDGFRA in an inactive state, so that many secondary and some primary mutations can be inhibited by this drug. In vitro studies have shown that ripretinib has potent antineoplastic effects, inhibiting mutated KIT receptors (exons 9, 11, 13, 14, 17, and 18) and PDGFRA receptors (exons 12, 14, and 18).5 Steady state is reached in 14 days. Metabolism of ripretinib and its active metabolite, DP-5439, occurs via a major pathway that involves the CYP3A4 enzyme. Metabolism via a minor pathway involves CYP2C8 and CYP2D6 for ripretinib, and CYP2C8, CYP2E1, and CYP2D6 for DP-5439. Ripretinib is eliminated in feces (34%) and urine (0.02%). DP-5439 is eliminated in feces (6%) and urine (0.1%).6
Clinical Trial Results
A phase I study enrolled 150 patients with GIST. Those with KIT mutations (141 patients) or PDGFRA mutations (8 patients) received Qinlock at a dose of at least 100 mg/d. One of the patients had SDH–deficient GIST. Of these patients, 114 were treated at a dose of 150 mg daily, including 19, 27, and 68 patients who had previously received 1, 2, or 3 or more prior lines of therapy, respectively. In these 114 patients, the objective response rate (ORR) was 14%, the 3-month disease control rate (DCR) was 70%, and the median progression-free survival (mPFS) was 24 weeks, with 56% of the patients censored. In 46 evaluable patients in the second or third line of treatment, the ORR was 22%, the 3-month DCR was 81%, and the mPFS was 36 weeks, with 61% of the patients censored. Marked clinical benefit was noted with the use of ripretinib (DCC-2618). A favorable tolerability profile in the patients undergoing treatment in the second line or later was also observed. The rates of indicators of clinical benefit (ORR, DCR, and mPFS) were higher in the patients receiving second- or third-line treatment than in the more heavily pretreated patients.7
INVICTUS was a randomized, double-blind, placebo-controlled phase III trial of 154 patients with advanced GIST, who were randomized in a 2:1 ratio to receive ripretinib or placebo. The patients in the study had advanced disease with progression on at least imatinib, sunitinib, and regorafenib or documented inability to tolerate these treatments. The primary endpoint of progression-free survival (PFS) was achieved, with a remarkable improvement in mPFS favoring ripretinib (6.3 vs 1·0 months; hazard ratio [HR], 0.15; 95% CI, 0.09–0.25; P <0.0001). The median overall survival (OS) was 15.1 months in the patients who received ripretinib vs 6.6 months in the placebo group (HR 0.36, 95% CI, 0.21–0.62). The ORR of the patients taking ripretinib was 9%. No evidence of a response was noted in the placebo group. Ripretinib was tolerated well among all patients. The most common treatment-related side effects, seen in 20% or more of patients in the ripretinib group, were nausea, fatigue, diarrhea, alopecia, myalgia, and palmar-plantar erythrodysesthesia.8
Intrigue is a currently ongoing phase III trial that is comparing the efficacy of ripretinib with that of sunitinib in patients who have advanced GIST that has progressed on imatinib or who have shown intolerance of imatinib in the second-line setting.9
Warnings, Precautions, and Adverse Reactions
The most common adverse reactions with their approximate percentages are alopecia (52%), fatigue (42%), nausea (39%), abdominal pain (36%), constipation (34%), myalgia (32%), diarrhea (28%), decreased appetite (27%), vomiting (21%), headache (19%), weight loss (19%), arthralgia (18%), peripheral edema (17%), muscle spasms (15%), hypertension (14%), dyspnea (13%), dry skin (13%), asthenia (13%), pruritus (11%), and stomatitis (11%).4
Get detailed prescribing information on the Qinlock monograph page at Rare Disease Advisor.
Some serious side effects, which include hypertension, impaired wound healing, cardiac disease, palmar-plantar erythrodysesthesia syndrome, embryo-fetal toxicity, and new primary cutaneous malignancies have also been observed. The ejection fraction should be assessed with an echocardiogram or a multiple-gated acquisition (MUGA) scan before Qinlock is started, during the course of treatment, and as indicated clinically. Qinlock should be permanently discontinued in cases of grade 3 or 4 left ventricular systolic dysfunction.10
Administration of Qinlock together with a potent CYP3A inhibitor can increase exposure to the drug and its active metabolite (DP-5439), causing adverse reactions. In such cases, patients should be monitored more frequently. Exposure to Qinlock and DP-5439 is decreased if Qinlock is administered with a moderate CYP3A inducer, which can reduce the anti-tumor effect of the drug. Thus, the concomitant use of Qinlock and potent CYP3A inducers should be avoided.10
- Nemunaitis J, Bauer S, Blay JY, et al. Intrigue: phase III study of ripretinib versus sunitinib in advanced gastrointestinal stromal tumor after imatinib. Future Oncol. 2020;16(1):4251-4264. doi:10.2217/fon-2019-0633
- FDA approves first drug for fourth-line treatment of advanced gastrointestinal stromal tumors. FDA News Release. May 15, 2020.
- QINLOCK (ripretinib) for the treatment of gastrointestinal stromal tumour. Clinical Trials Arena. Accessed August 11, 2021.
- Haarberg S. Ripretinib (Qinlock™). Oncology Times. 2020;42(16):18. doi:10.1097/01.COT/0000696436.82268.ff
- Mohammadi M, Gelderblom H. Systemic therapy of advanced/metastatic gastrointestinal stromal tumors: an update on progress beyond imatinib, sunitinib, and regorafenib. Exp Opin Invest Drugs. 2021;30(2):143-152. doi:10.1080/13543784.2021.1857363
- Ripretinib (Rx): Pharmacology. Medscape. Accessed August 11, 2021.
- George S, Heinrich M, Chi P, et al. Initial results of Phase I study of DCC-2618, a broad-spectrum KIT and PDGFRa inhibitor, in patients (pts) with gastrointestinal stromal tumor (GIST) by number of prior regimens. Ann Oncol. 2018;29(Suppl 8):viii576-viii577. doi:10.1093/annonc/mdy299/.002
- Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol. 2020;21(7):e341]. Lancet Oncol. 2020;21(7):923-934. doi:10.1016/S1470-2045(20)30168-6
- A study of DCC-2618 vs. sunitinib in advanced gist patients after treatment with imatinib (intrigue) 2020. Clinicaltrials.gov. Last update posted: January 6, 2021. Accessed August 11, 2021.
- QINLOCK® (ripretinib) tablets, for oral use. US Food and Drug Administration. Revised June 2021. Accessed August 11, 2021.
Reviewed by Debjyoti Talukdar, MD, on 8/17/2021.