What Is Ripretinib (Qinlock)? FDA Approval, Licensing in Turkey, and Reimbursement Status

• FDA Approval: Yes, First Approval Date: May 15, 2020
• Brand Name: Qinlock
• Active Ingredient: Ripretinib
• Route of Administration: Oral tablets
• Class: Type 2 Kinase Inhibitor (broad-spectrum KIT and PDGFRA inhibitor)
• Category: Antineoplastic / Targeted Therapy
• Manufacturer: Deciphera Pharmaceuticals, Inc.
• Availability in Turkey: Not yet licensed in Turkey.
• Approved Cancer Indications: Advanced or metastatic gastrointestinal stromal tumor (GIST), as fourth-line treatment; used in patients whose disease has progressed after three or more previous kinase inhibitor treatments (e.g., imatinib, sunitinib, regorafenib).

What Is Ripretinib? How Does It Work?

Ripretinib is an oral targeted cancer medicine used to treat certain advanced soft tissue cancers, such as gastrointestinal stromal tumors (GIST). It is used particularly as fourth-line treatment in patients previously treated with several tyrosine kinase inhibitors (TKIs).

Mechanism of Action

Ripretinib is a tyrosine kinase inhibitor that targets the products of the KIT and PDGFRA genes, which are commonly mutated in GIST. The receptor tyrosine kinases encoded by these genes are important components of signaling pathways that regulate cell proliferation, survival, and differentiation.

A distinctive feature of ripretinib is its ability to inhibit both the active (open) and inactive (closed) conformations of these kinases. This dual inhibition may also make it effective against mutant isoforms that have developed drug resistance. As a result, in tumor cells:

• Abnormal signal transmission is blocked.
• Cell proliferation is halted.
• Apoptosis (programmed cell death) is triggered.

This broad-spectrum inhibitory effect enables ripretinib to work particularly in patients who have previously developed resistance to agents such as imatinib, sunitinib, and regorafenib.

FDA (US Food and Drug Administration) Approval History

• May 15, 2020 Approval: The FDA approved Qinlock (ripretinib) for fourth-line treatment of gastrointestinal stromal tumor (GIST).
• February 12, 2020 Announcement: Deciphera Pharmaceuticals announced that the FDA had accepted its New Drug Application for ripretinib in patients with advanced GIST and granted it priority review status.
• December 16, 2019 Application: Deciphera Pharmaceuticals announced that it had submitted a New Drug Application for ripretinib in patients with advanced gastrointestinal stromal tumors to the US Food and Drug Administration (FDA).
• August 13, 2019 Clinical Data: Deciphera Pharmaceuticals reported updated positive results from the Phase 1 study of ripretinib in gastrointestinal stromal tumors.

Licensing in Turkey

This medicine has not yet been licensed in Turkey. It is on the TİCK overseas medicines list and can be obtained with permission.

Mechanism of Resistance

Although ripretinib has a broad activity profile that can target numerous primary and secondary mutations in KIT and PDGFRA kinases, resistance to this treatment can also develop over time. Resistance can be either primary (lack of efficacy from the outset) or secondary (initial response followed by loss of efficacy).

Secondary KIT/PDGFRA Mutations (Main Resistance Mechanism)

The KIT and PDGFRA genes, the main targets of ripretinib, may develop new mutations during treatment. These mutations can occur:

• In the ATP-binding site
• In the activation loop
• In the kinase domain

and reduce the effectiveness of drug binding. Combinations of multiple secondary mutations in particular reduce the drug's inhibitory effect and lead to resistance.

Activation of Alternative Signaling Pathways

Tumor cells may survive by activating growth and proliferation pathways other than KIT or PDGFRA:

• RAS/RAF/MEK/ERK pathway
• PI3K/AKT/mTOR pathway
• JAK/STAT signaling

These alternative pathways can sustain tumor growth even when KIT is inhibited.

Increased Drug Efflux Pumps

Cancer cells can increase efflux pumps, such as P-glycoprotein (P-gp), which transport drugs out of the cell, preventing the drug from accumulating at adequate intracellular levels. This reduces efficacy.

Tumor Heterogeneity

GISTs can contain cell subpopulations with different mutations within the same tumor. This heterogeneity allows some cells to escape ripretinib treatment and proliferate under selective pressure.

Pharmacokinetic Factors

An effective concentration may not be achieved because of low drug bioavailability, rapid metabolism, or drug–drug interactions.

Absorption

• Ripretinib is administered orally as a tablet and is well absorbed from the gastrointestinal tract.
• It reaches its maximum plasma concentration (Tmax) in approximately 4 hours.
• Taking it with fatty meals may cause small changes in the rate of absorption but does not significantly affect overall bioavailability.
• Its high bioavailability allows an effective amount to enter the systemic circulation.

Distribution

• Ripretinib has a high plasma protein binding rate (~99%), particularly binding to albumin.
• Its large volume of distribution indicates that it distributes into tissues and can reach intracellular targets.
• Data on whether it crosses the blood–brain barrier are limited.

Metabolism

• It is metabolized in the liver, mainly by the CYP3A4 enzyme.
• Its active metabolite, DP-5439, has similar biological activity and is present in the systemic circulation.
• It may also undergo metabolism to a lesser extent through CYP2C8 and CYP2D6.
• There is therefore a risk of drug interactions with CYP3A4 inhibitors or inducers.

Excretion

• Ripretinib and its metabolites are excreted primarily in the feces (64%).
• A smaller proportion is excreted in the urine (around 14%).
• The mean elimination half-life has been reported as:
• Approximately 15 hours for ripretinib,
• Approximately 17 hours for its active metabolite DP-5439.

Dosage

Dose: 150 mg

How to Take It: 1 time a day, with or without food

Duration of Treatment: Taken continuously until disease progression or the development of intolerable adverse effects.

If a patient develops serious adverse effects (such as hand–foot syndrome, hypertension, skin rash, diarrhea, etc.), the dose may be reduced as follows:

• First Dose Reduction: 100 mg/day
• Second Dose Reduction: 50 mg/day

The medicine may be discontinued if further toxicity occurs.

Drug Interactions

CYP3A4 Inhibitors (Increase Ripretinib Levels)

These medicines can slow the breakdown of ripretinib, increasing its plasma levels and the risk of toxicity.

• Ketoconazole
• Itraconazole
• Clarithromycin
• Ritonavir
• Verapamil

Concomitant use should be avoided or patients should be closely monitored. Dose reduction should be considered if necessary.

CYP3A4 Inducers (Reduce Ripretinib Levels)

These medicines can accelerate ripretinib metabolism and reduce its efficacy.

• Rifampin
• Phenytoin
• Carbamazepine
• St. John's Wort

Concomitant use should be avoided.

P-glycoprotein (P-gp) Substrates

Ripretinib or its metabolite may interact with medicines transported by P-gp. These interactions may alter the intracellular or plasma levels of certain medicines.

• Digoxin
• Dabigatran
• Aliskiren

Acid Suppressants (Effect Unclear)

Ripretinib solubility may depend on gastric pH, but whether this has a clinically meaningful effect is not entirely clear.

• PPIs (e.g., omeprazole)
• H2 receptor antagonists

Clinical monitoring is needed; concomitant use may be avoided unless essential.

Conditions Requiring Attention

Skin Reactions and Hand–Foot Syndrome

• Hand–foot skin reactions, with symptoms such as redness, peeling, and pain on the palms and soles, can be common.
• Dry skin, rash, and itching may also occur.
• Skin care should be recommended; dose reduction or temporary interruption should be considered if necessary.

Hypertension

• Increased blood pressure is commonly observed during treatment.
• Blood pressure should be closely monitored before and during treatment; antihypertensive therapy may need to be started.

Cardiac Effects (Reduced Left Ventricular Function)

• There is a rare risk of heart failure.
• Particular caution is needed in patients with pre-existing heart disease; echocardiography should be performed if symptoms develop.

Gastrointestinal Toxicity

• Nausea, vomiting, diarrhea, and loss of appetite may be common.
• Fluid and electrolyte balance should be maintained, with supportive treatment provided if necessary.

Myelosuppression (Bone Marrow Suppression)

• Anemia, leukopenia, and thrombocytopenia may develop.
• Blood counts should be checked regularly; if counts fall, dose adjustment or supportive treatment (transfusion, G-CSF) should be considered.

Skin Cancer Risk (New or Secondary)

• Squamous cell carcinomas of the skin may develop with long-term use.
• Skin examinations should be performed regularly, and new lesions should prompt referral to dermatology.

Drug Interactions

• Concomitant use with CYP3A4 inhibitors and inducers requires caution.
• The physician must be informed about any medicines being taken concurrently.

Pregnancy and Breastfeeding

• It is contraindicated during pregnancy because of its potential fetal toxicity.
• Effective contraception should be used, and the medicine must not be taken while breastfeeding.

Hepatic Impairment

Because it is metabolized by the liver, caution is needed in patients with impaired liver function, and dose adjustment may be necessary.

Side Effects

• Alopecia (hair loss): 52%
• Fatigue: 42%
• Nausea: 39%
• Musculoskeletal pain: 36%
• Diarrhea: 34%
• Rash: 32%
• Decreased appetite: 32%
• Constipation: 28%
• Vomiting: 27%
• Abdominal pain: 24%
• Hand–foot syndrome (PPES): 21%
• Anemia: 20%
• Leukopenia: 15%
• Hypertension: 14%
• Dry mouth: 13%
• Taste disturbance (dysgeusia): 13%
• Itching: 11%
• Thrombocytopenia: 10%