Ripretinib

Ripretinib is a tyrosine kinase inhibitor directed at KIT and PDGFRA, the receptor kinases whose abnormal activation drives most gastrointestinal stromal tumours. Its use was studied in INVICTUS, a randomised (2:1), double-blind, placebo-controlled study of 150 mg once daily in patients with unresectable, locally advanced or metastatic GIST who had been treated with, or were intolerant to, at least three prior anticancer therapies including imatinib, sunitinib and regorafenib. The primary outcome was progression-free survival assessed by blinded independent central review.

Mechanism of Action

• KIT and PDGFRA inhibition: ripretinib inhibits the KIT and PDGFRA kinases, including wild-type forms and forms with primary or secondary mutations.
• Dual mode of binding: DrugBank describes binding both to the kinase switch pocket and to the activation loop, which locks the kinase in its inactive state and switches off its ability to drive uncontrolled cell growth.
• Other kinases: in vitro, ripretinib also inhibits PDGFRB, TIE2, VEGFR2 and BRAF. Inhibition of the VEGF pathway is relevant to the warning about wound healing.
• Active metabolite: DP-5439 is an active metabolite; both it and ripretinib are cleared mainly by CYP3A4/5.

Pharmacokinetics

• Absorption: after a single 150 mg dose, peak plasma concentrations are reached at a median of 4 hours. A high-fat meal raised the AUC and Cmax of ripretinib by 30% and 22%, and those of DP-5439 by 47% and 66%; the tablets are taken with or without food. Exposure rises less than in proportion to dose between 20 and 250 mg, especially above 150 mg. Steady state is reached within 14 days.
• Distribution: ripretinib and DP-5439 are bound at 99% or more to plasma proteins. The apparent volume of distribution is about 302 L for ripretinib and 491 L for DP-5439.
• Metabolism: CYP3A4/5 is the major metaboliser of ripretinib and DP-5439; CYP2C8 and CYP2D6 contribute minor pathways.
• Elimination: apparent oral clearance is 15.2 L/h for ripretinib and 17.9 L/h for DP-5439, with half-lives of 12.6 and 15.6 hours. Elimination is not mainly renal: 0.02% (ripretinib) and 0.1% (DP-5439) of the dose appear in urine, and 34% and 6% in faeces.
• Special populations: age (19–87 years), sex, race (White, Black, Asian), body weight (39–138 kg) and tumour type (GIST or other solid tumours) had no clinically significant effect. Mild and moderate renal impairment did not change exposure relevantly.

• Advanced gastrointestinal stromal tumour (GIST): treatment of adult patients with advanced GIST who have received prior treatment with three or more kinase inhibitors, including imatinib.

• Hypersensitivity to ripretinib or to any of the excipients.

The safety profile rests on 392 patients who received at least one dose: those in INVICTUS and a first-in-human study (218 patients at 150 mg once daily). The most frequent reactions (25% or more) were fatigue (51.0%), alopecia (50.8%), nausea (39.8%), myalgia (37.8%), constipation (37.2%), diarrhoea (32.7%), palmar-plantar erythrodysaesthesia syndrome (PPES, 29.8%), weight decreased (26.5%) and vomiting (25.8%). Grade 3 or 4 reactions in 2% or more of patients were increased lipase (14.8%), anaemia (14.0%), abdominal pain (8.2%), hypertension (6.9%), fatigue (4.1%), hypophosphataemia (4.1%), vomiting (2.6%), dyspnoea, diarrhoea and increased blood bilirubin (2.0% each). Serious reactions in 1% or more were anaemia (3.8%), dyspnoea (2.3%), vomiting (2.0%), nausea (1.8%), fatigue (1.5%), increased blood bilirubin (1.3%), constipation (1.0%) and muscular weakness (1.0%).

Very common (≥1/10): seborrhoeic keratosis, hypophosphataemia, headache, hypertension, dyspnoea, cough, nausea, constipation, diarrhoea, vomiting, alopecia, PPES, dry skin, pruritus, myalgia, muscle spasms, arthralgia, back pain, pain in extremity, fatigue, peripheral oedema, weight decreased, increased lipase, increased blood bilirubin.

Common (≥1/100 to <1/10): melanocytic naevus, skin papilloma, squamous cell carcinoma of the skin (including keratoacanthoma and squamous cell carcinoma of the head and neck), fibrous histiocytoma, hypothyroidism, depression, peripheral sensory neuropathy, cardiac failure (including acute cardiac failure, acute left ventricular failure and diastolic dysfunction), tachycardia, stomatitis, upper abdominal pain, hyperkeratosis, maculopapular rash, generalised pruritus, acneiform dermatitis, muscular weakness, musculoskeletal chest pain, increased alanine aminotransferase.

Uncommon (≥1/1,000 to <1/100): malignant melanoma.

The SmPC table lists no reactions as rare or of unknown frequency.

Selected reactions:

• PPES: 22.4% of the 85 patients given ripretinib in INVICTUS and none given placebo (all mild or moderate); 29.8% in the pooled population, Grade 3 in 0.5%. The first event began at a median of 8.1 weeks.
• Hypertension: 19.4% in the pooled population, Grade 3 in 6.9%.
• Cardiac failure: 1.5% in the pooled population, Grade 3 in 1.0%. Grade 3 decreased left ventricular ejection fraction occurred in 2.0% of the 299 patients who had an echocardiogram.
• Cutaneous squamous cell carcinoma: 8.7% in the pooled population, Grade 3 in 0.5%; in INVICTUS, 5.9% of patients on ripretinib and none on placebo.

Ripretinib and DP-5439 are mainly cleared by CYP3A4/5 and are substrates of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

• Strong CYP3A/P-gp inhibitors (ketoconazole, erythromycin, clarithromycin, itraconazole, ritonavir, posaconazole, voriconazole): itraconazole raised the AUC of ripretinib and of DP-5439 by 99% (ripretinib Cmax by 36%). Use with caution and monitor patients. Grapefruit juice is not recommended.
• CYP3A inducers: rifampicin lowered ripretinib AUC by 61% (Cmax by 18%) and DP-5439 AUC by 57%. Strong inducers (carbamazepine, phenytoin, rifampicin, phenobarbital, St John’s wort) and moderate inducers (efavirenz, etravirine) must be avoided. If one is unavoidable, the dosing frequency may be increased during the co-administration period (see Administration and Dosage) with monitoring of response and tolerability.
• Acid-reducing agents: pantoprazole, a proton pump inhibitor, caused no clinically significant change in exposure.
• BCRP inhibitors (ciclosporin A, eltrombopag): based on in vitro data, use with caution because ripretinib or DP-5439 concentrations may rise.
• CYP2C8 and CYP3A4 substrates: ripretinib is a weak CYP2C8 inhibitor (repaglinide AUC rose by 26%; no dose adjustment). A sensitive CYP3A4 probe substrate was unaffected.
• CYP2B6 substrates: ripretinib induced CYP2B6 in vitro, so substrates with a narrow therapeutic index (for example efavirenz) may lose efficacy.
• CYP1A2 substrates: ripretinib down-regulated CYP1A2 in vitro, so concentrations of substrates with a narrow therapeutic index (for example tizanidine) may rise; monitoring is recommended.
• UGT1A substrates: ripretinib inhibits UGT1A1, 1A3, 1A4, 1A7 and 1A8 in vitro. Use with caution with clinical substrates such as bictegravir, cabotegravir, dolutegravir, raltegravir and lamotrigine, whose exposure may increase. No clinical studies have been done.
• Transporter substrates: P-gp substrates with a narrow therapeutic index (digoxin, dabigatran etexilate) should be used with caution because their concentrations are likely to rise. Use with caution with BCRP substrates (rosuvastatin, sulfasalazine, irinotecan) and MATE-1 substrates (metformin), whose exposure may increase; clinical studies have not been done.
• Contraceptive steroids: the effect of ripretinib on them has not been studied; a barrier method should be added if systemic contraceptive steroids are used.

Qinlock should be prescribed by physicians experienced in the administration of anticancer agents. The tablets are taken by mouth once daily at the same time each day, with or without food. They are swallowed whole and must not be chewed, split or crushed. Tablets that are broken, cracked or otherwise not intact should not be taken, because the effect of such changes has not been evaluated.

Recommended Dose

• 150 mg (three 50 mg tablets) once daily.
• Treatment continues for as long as benefit is observed or until unacceptable toxicity.

Dose Adjustments for Side Effects

The recommended dose reduction is 100 mg once daily. Treatment is permanently discontinued if 100 mg once daily is not tolerated. The grades below follow NCI CTCAE v4.03 (SmPC Table 1):

• PPES: for Grade 2, withhold until Grade 1 or baseline; if it recovers within 7 days resume at the same dose, otherwise at the reduced dose, and consider re-escalating after at least 28 days at Grade 1 or baseline; if PPES recurs, withhold and resume at the reduced dose. For Grade 3, withhold for at least 7 days or until Grade 1 or baseline (maximum 28 days) and resume at the reduced dose.
• Hypertension: for Grade 3, if symptomatic, withhold until symptoms resolve and blood pressure is controlled, then resume at the same dose if it is controlled to Grade 1 or baseline, otherwise at the reduced dose; if Grade 3 recurs, withhold and resume at the reduced dose. Grade 4: discontinue permanently.
• Left ventricular systolic dysfunction: discontinue permanently for Grade 3 or 4.
• Arthralgia or myalgia: managed like PPES, with the same Grade 2 and Grade 3 steps.
• Other adverse reactions: for Grade 3 or 4, withhold until Grade 1 or baseline (maximum 28 days) and resume at the reduced dose, otherwise discontinue permanently; consider re-escalating if there is no recurrence for at least 28 days; if Grade 3 or 4 recurs, discontinue permanently.

With CYP3A Inducers

Strong or moderate CYP3A inducers should be avoided. If one must be given, the dosing frequency may be increased during co-administration; for strong inducers the dose may rise from 150 mg once daily to 150 mg twice daily. A twice-daily dose missed by up to 4 hours is taken as soon as possible, and one missed by more than 4 hours is skipped. Overall efficacy and safety are monitored closely.

Special Populations

• Elderly: no clinically relevant differences were seen between patients over 65 years and younger adults.
• Renal impairment: no adjustment in mild or moderate impairment. Clinical data are limited in severe impairment (creatinine clearance below 30 mL/min), and a recommended dose has not been established.
• Hepatic impairment: no adjustment in mild (Child-Pugh A), moderate (Child-Pugh B) or severe (Child-Pugh C) impairment. Data in severe impairment are limited, so close monitoring of overall safety is recommended.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed or Vomited Dose

If a dose is missed by up to 8 hours, take it as soon as possible and take the next dose at the usual time. If it is missed by more than 8 hours, skip it and resume the usual schedule the next day. After vomiting, do not take a replacement dose; resume the next day at the usual time.

Palmar-plantar Erythrodysaesthesia Syndrome

PPES occurs with ripretinib. Depending on severity, the dose is withheld and then resumed at the same or a reduced dose.

Hypertension

Ripretinib must not be started unless blood pressure is adequately controlled. Blood pressure is monitored as clinically indicated, and the dose is withheld, reduced or permanently stopped according to severity.

Cardiac Failure

Cardiac failure (including acute left ventricular failure and diastolic dysfunction) has been observed. Ejection fraction is assessed by echocardiogram or MUGA scan before starting and during treatment as clinically indicated. Ripretinib is permanently discontinued for Grade 3 or 4 left ventricular systolic dysfunction. Its safety has not been assessed in patients with a baseline left ventricular ejection fraction below 50%.

Cutaneous Malignancies

Cutaneous squamous cell carcinoma and melanoma have been reported. Dermatological evaluation is performed when starting and routinely during treatment. Suspicious skin lesions are managed with excision and dermatopathological evaluation, and ripretinib is continued at the same dose.

Wound Healing

No formal studies on wound healing have been done. Medicines that inhibit VEGF signalling can impair wound healing, so ripretinib may adversely affect it. Treatment is withheld for at least 3 days before and after minor surgery and at least 5 days before and after major surgery, and resumed afterwards when the clinician judges that wound healing is adequate.

Phototoxicity

Ripretinib has a potential for phototoxicity. Patients should avoid or minimise exposure to direct sunlight, sunlamps and other sources of ultraviolet radiation, and use protective clothing (long sleeves and hat) and sunscreen with a high sun protection factor.

CYP3A Inhibitors and Inducers

Ripretinib is a CYP3A substrate. See Drug Interactions for strong inhibitors, grapefruit juice and inducers.

Pregnancy, Breastfeeding and Fertility

• Contraception and pregnancy testing: females of reproductive potential and males with female partners of reproductive potential must use effective contraception during treatment and for at least 1 week after the last dose. Pregnancy status must be verified before starting and during treatment. A barrier method should be added if systemic contraceptive steroids are used, because their interaction with ripretinib has not been studied.
• Pregnancy: there are no data in pregnant women. Ripretinib is suspected to cause foetal harm on the basis of its mechanism of action, and animal studies showed reproductive toxicity. It should not be used in pregnancy unless the woman’s clinical condition requires it.
• Breastfeeding: it is unknown whether ripretinib or its metabolites pass into human milk and a risk to the child cannot be excluded. Breastfeeding should be stopped during treatment and for at least 1 week after the last dose.
• Fertility: there are no human data. Animal studies suggest that male and female fertility may be compromised.

Lactose

Each tablet contains 179 mg of lactose monohydrate, which the SmPC lists as an excipient with known effect; see the SmPC for the related advice on lactose.

Effect on Driving

Qinlock has a minor influence on the ability to drive and use machines. Fatigue has been reported and may affect the ability to drive or use machines.

Qinlock tablets do not require any special temperature storage conditions. Store them in the original package with the bottle tightly closed, to protect from light and moisture. Each bottle holds 30 or 90 tablets and one desiccant canister of silica gel; not all pack sizes may be marketed.

5 years.

Prescription only (Rx), on restricted medical prescription (Annex II B of the marketing authorisation), prescribed by physicians experienced in the administration of anticancer agents. Ripretinib is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.