QINLOCK 50mg tablets medication leaflet

QINLOCK 50 mg tablets

Each tablet contains 50 mg of ripretinib.

Each tablet contains 179 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Tablet.

White to off-white, approximately 9 × 17 mm, oval shaped tablet, debossed with ‘DC1' on one side.

QINLOCK is indicated for the treatment of adult patients with advanced gastrointestinal stromaltumour (GIST) who have received prior treatment with three or more kinase inhibitors, includingimatinib.

QINLOCK should be prescribed by physicians experienced in the administration of anticancer agents.

The recommended dose is 150 mg ripretinib (three 50 mg tablets) taken once daily at the same timeeach day with or without food.

If the patient misses a dose of QINLOCK within 8 hours of the time it is usually taken, the patientshould be instructed to take it as soon as possible and then take the next dose at the regularlyscheduled time. If a patient misses a dose by more than 8 hours of the time it is usually taken, thepatient should be instructed not to take the missed dose and simply resume the usual dosing scheduleon the following day.

In case of vomiting after QINLOCK administration, the patient should not take a replacement doseand should resume the dosing schedule the next day at the usual time.

Treatment with QINLOCK should continue as long as benefit is observed or until unacceptabletoxicity (see section 4.4).

Posology adjustments

Dose interruptions or dose reductions may be required based on individual safety and tolerability. Therecommended dose reduction for adverse reactions is 100 mg orally, once daily.

QINLOCK should be permanently discontinued in patients who are unable to tolerate 100 mg orallyonce daily. The recommended dose modifications for QINLOCK for adverse reactions are provided in

Table 1.

Table 1: Recommended dose modifications for adverse reactions

Adverse reaction Severitya QINLOCK dose modifications

Palmar-Plantar Grade 2 * Withhold until Grade ≤1 or baseline. If recovered within

Erythrodysaesthesia Syndrome 7 days, resume at same dose; otherwise resume at(PPES) (see sections 4.4 and reduced dose.4.8) * Consider re-escalating if maintained at Grade ≤1 orbaseline for at least 28 days.

* If PPES recurs, withhold until Grade ≤1 or baseline andthen resume at a reduced dose regardless of time toimprovement.

Grade 3 * Withhold for at least 7 days or until Grade ≤1 or baseline(maximum 28 days). Resume at a reduced dose.

* Consider re-escalating if maintained at Grade ≤1 orbaseline for at least 28 days.

Hypertension (see sections 4.4 Grade 3 * If symptomatic, withhold until symptoms have resolvedand 4.8) and blood pressure is controlled.

* If blood pressure is controlled to Grade ≤1 or baseline,resume at the same dose; otherwise, resume at reduceddose.

* If Grade 3 hypertension recurs, withhold until symptomshave resolved and blood pressure is controlled. Resumeat a reduced dose.

Grade 4 Permanently discontinue.

Left ventricular systolic Grade 3 or 4 Permanently discontinue.dysfunction (see sections 4.4and 4.8)

Arthralgia or myalgia (see Grade 2 * Withhold until Grade ≤1 or baseline. If recovered withinsection 4.8) 7 days, resume at same dose; otherwise resume atreduced dose.

* Consider re-escalating if maintained at Grade ≤1 orbaseline for at least 28 days.

* If arthralgia or myalgia recurs, withhold until Grade ≤1or baseline and then resume at a reduced dose regardlessof time to improvement.

Grade 3 * Withhold for at least 7 days or until Grade ≤1 or baseline(maximum of 28 days). Resume at a reduced dose.

* Consider re-escalating if maintained at Grade ≤1 orbaseline for at least 28 days.

Other adverse reactions (see Grade 3 or 4 * Withhold until Grade ≤1 or baseline (maximum 28 days),section 4.8) and then resume at a reduced dose; otherwisepermanently discontinue.

* Consider re-escalating if no recurrence of the adversereaction for at least 28 days.

* If Grade 3 or 4 recurs, permanently discontinue.

a Graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI

CTCAE v4.03).

Concomitant medicinal products that are strong or moderate inducers of CYP3A should be avoided(see sections 4.4 and 4.5). If a strong or moderate CYP3A inducer must be co-administered, the

QINLOCK dosing frequency may be increased during the co-administration period. For stronginducers, the dose may be increased from 150 mg once daily to 150 mg twice daily. For patients taking

QINLOCK twice daily, if the patient misses a dose within 4 hours of the time it is usually taken, thepatient should be instructed to take the missed dose as soon as possible and then take the next dose atthe regularly scheduled time. If a patient misses a dose by more than 4 hours of the time it is usuallytaken, the patient should be instructed not to take the missed dose and simply resume the usual dosingschedule. Close monitoring of overall efficacy and safety is recommended in these patients.

No dose adjustment is recommended in patients with mild and moderate renal impairment (seesection 5.2). Only limited clinical data are available in patients with severe renal impairment[creatinine clearance (CLcr) <30 mL/min]. A recommended dose of QINLOCK has not beenestablished in patients with severe renal impairment (see section 5.2).

No dose adjustment is recommended in patients with mild (Child-Pugh A), moderate (Child-Pugh B)or severe hepatic impairment (Child-Pugh C). Data in patients with severe hepatic impairment islimited, thus close monitoring of overall safety is recommended in these patients.

In clinical studies, no clinically relevant differences were observed between elderly (aged >65 years)and younger patients (aged ≤ 65 and ≥ 18 years) (see section 5.1).

The safety and efficacy of QINLOCK in children below 18 years of age have not been established (seesection 5.1). No data are available.

QINLOCK is for oral use.

The tablets should be taken at the same time each day with or without food (see section 5.2).

Prescribers should instruct patients to swallow the tablets whole and not to chew, split, or crush them.

Patients should not ingest the tablets if they are broken, cracked, or otherwise not intact as thepotential effects of these alterations have not been evaluated.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Palmar-Plantar Erythrodysaesthesia Syndrome (PPES)

PPES occurred in patients treated with ripretinib (see section 4.8). Based on severity, ripretinib shouldbe withheld and then resumed at the same or reduced dose (see section 4.2).

Hypertension was observed with ripretinib (see section 4.8). Ripretinib must not be initiated unlessblood pressure is adequately controlled. Blood pressure is to be monitored as clinically indicated.

Based on severity, ripretinib should be withheld and then resumed at same or reduced dose orpermanently discontinue (see section 4.2).

Cardiac failure

Cardiac failure (including cardiac failure, cardiac failure acute, acute left ventricular failure, anddiastolic dysfunction) was observed with ripretinib (see section 4.8). Ejection fraction should beassessed by echocardiogram or multiple-gated acquisition (MUGA) scan prior to initiating ripretiniband during treatment, as clinically indicated. Ripretinib should be permanently discontinued for Grade3 or 4 left ventricular systolic dysfunction (see section 4.2). The safety of ripretinib has not beenassessed in patients with a baseline left ventricular ejection fraction below 50%.

Cutaneous squamous cell carcinoma (CuSCC) and melanoma were reported in patients receivingripretinib (see section 4.8). Dermatological evaluations should be performed when initiating ripretiniband routinely during treatment. Suspicious skin lesions should be managed with excision anddermatopathological evaluation. Ripretinib should be continued at the same dose.

No formal studies to evaluate the effect of ripretinib on wound healing have been conducted. Impairedwound healing complications may occur in patients who receive medicinal products that inhibit thevascular endothelial growth factor (VEGF) signalling pathway. Therefore, ripretinib has the potentialto adversely affect wound healing.

Treatment with ripretinib is to be withheld for at least 3 days prior to and after minor surgery and atleast 5 days prior to and after major surgery. Ripretinib may then be resumed after surgery based onclinical judgement of adequate wound healing.

Embryo-foetal toxicity

Based on findings from animal studies, ripretinib can cause foetal harm when administered to pregnantwomen (see sections 4.6 and 5.3). It is recommended to advise women to avoid pregnancy whiletaking ripretinib. The pregnancy status of females of reproductive potential must be verified prior toinitiating ripretinib and during treatment. Females of reproductive potential and males with femalepartners of reproductive potential must use effective contraception during treatment and for at least1 week after the final dose of ripretinib (see sections 4.6 and 5.3). Effects of ripretinib oncontraceptive steroids have not been studied. A barrier method contraception should be added ifsystemic contraceptive steroids are used.

Ripretinib exhibits a potential for phototoxicity (see section 5.3). It is recommended to advise patientsto avoid or minimise exposure to direct sunlight, sunlamps, and other sources of ultraviolet radiationdue to the risk of phototoxicity associated with ripretinib. Patients should be instructed to usemeasures such as protective clothing (long sleeves and hat) and sunscreen with high sun protectionfactor (SPF).

CYP3A inhibitors and inducers

Ripretinib is a CYP3A substrate. Concurrent administration of ripretinib with the strong CYP3A and

P-glycoprotein (P-gp) inhibitor itraconazole resulted in an increase in ripretinib plasma exposure (seesection 4.5). Caution is required when administering ripretinib with agents that are strong CYP3A and

Concurrent administration of ripretinib with the strong CYP3A inducer rifampicin resulted in adecrease in ripretinib plasma exposure. Therefore, chronic administration of agents that are strong ormoderate CYP3A inducers with ripretinib should be avoided (see sections 4.2 and 4.5).

Important information about some excipients

QINLOCK contains lactose.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product.

Both ripretinib and its active metabolite DP-5439 are mainly cleared by CYP3A4/5 and are substratesof P-gp and Breast Cancer Resistance Protein (BCRP).

Effect of other medicinal products on ripretinib

Effect of strong CYP3A/P-gp inhibitors

Co-administration of itraconazole (a strong CYP3A inhibitor) and also a P-gp inhibitor increasedripretinib Cmax by 36% and AUC0-∞ by 99%. DP-5439 Cmax was unchanged; AUC0-∞ increased by 99%.

Strong inhibitors of CYP3A/P-gp (e.g. ketoconazole, erythromycin, clarithromycin, itraconazole,ritonavir, posaconazole, and voriconazole) are to be used with caution and patients should bemonitored. Ingestion of grapefruit juice is not recommended.

Effect of CYP3A inducers

Co-administration of QINLOCK with the strong CYP3A inducer rifampicin decreased ripretinib Cmaxby 18% and AUC0-∞ by 61%, decreased DP-5439 AUC0-∞ by 57%, and increased DP-5439 Cmax by37%.

Concomitant use of QINLOCK with strong CYP3A inducers (e.g. carbamazepine, phenytoin,rifampicin, phenobarbital and St. John’s wort) and moderate CYP3A inducers (e.g. efavirenz andetravirine) must therefore be avoided. If a strong or moderate CYP3A inducer must beco-administered, the QINLOCK dosing frequency may be increased during the co-administrationperiod. For strong inducers, the dose may be increased from 150 mg once daily to 150 mg twice daily.

For patients taking QINLOCK twice daily, if the patient misses a dose within 4 hours of the time it isusually taken, the patient should be instructed to take the missed dose as soon as possible and thentake the next dose at the regularly scheduled time. If a patient misses a dose by more than 4 hours ofthe time it is usually taken, the patient should be instructed not to take the missed dose and simplyresume the usual dosing schedule. Monitor for clinical response and tolerability.

Effect of acid-reducing agents

No clinically significant differences in the plasma exposure to ripretinib and DP-5439 were observedwhen QINLOCK was co-administered with pantoprazole (a proton pump inhibitor).

Drug transporter systems

Based on in vitro data, medicinal products that are inhibitors of BCRP (e.g. cyclosporine A,eltrombopag) should be used with caution in combination with QINLOCK, as increased plasmaconcentrations of ripretinib or DP-5439 may be possible.

Effect of ripretinib on other medicinal products

CYP isoform-selective substrates

In vitro studies suggested ripretinib may inhibit CYP2C8. QINLOCK is to be used with caution incombination with substrates of CYP2C8 (e.g. repaglinide, paclitaxel), as co-administration may lead toincreased exposure of CYP2C8 substrates.

The in vivo net effect of inhibition of CYP3A4 in the intestine and systemic CYP3A4 induction isunknown. Caution is recommended when co-administering ripretinib with sensitive CYP3A4substrates with a narrow therapeutic window (e.g. cyclosporine, tacrolimus) or that are mostlymetabolised in the intestine (e.g. midazolam).

Ripretinib and DP-5439 induced CYP2B6 in vitro. Co-administration of ripretinib with CYP2B6substrates with narrow therapeutic index (e.g. efavirenz) may lead to loss of their efficacy.

Ripretinib and DP-5439 down-regulated CYP1A2 in vitro. Co-administration of ripretinib with

CYP1A2 substrates with narrow therapeutic index (e.g. tizanidine) may lead to increasedconcentrations and monitoring is recommended.

It is unknown whether ripretinib may reduce the effectiveness of systemically acting hormonalcontraceptives, and therefore women using systemically acting hormonal contraceptives should add abarrier method.

Drug transporter systems

In vitro studies suggested ripretinib is an inhibitor of P-gp and BCRP. DP-5439 is a substrate for P-gpand BCRP. DP-5439 is an inhibitor of BCRP and Multidrug And Toxin Protein 1 (MATE-1).

Medicinal products that are P-gp substrates with narrow therapeutic indices (e.g. digoxin, dabigatranetexilate) should be used with caution in combination with QINLOCK due to the likelihood ofincreased plasma concentrations of these substrates.

QINLOCK is to be used with caution in combination with BCRP substrates (e.g. rosuvastatin,sulfasalazine and irinotecan) and MATE-1 substrates (e.g. metformin) as co-administration of

QINLOCK with BCRP and MATE-1 substrates may lead to an increase of their exposure. Clinicalstudies with BCRP or MATE-1 substrates have not been conducted.

Women of childbearing potential and men with female partners of reproductive potential must beinformed that QINLOCK may cause foetal harm and must ensure effective contraception duringtreatment and for at least 1 week after the final dose of QINLOCK (see section 4.4)

The pregnancy status of females of reproductive potential is to be verified prior to initiating

QINLOCK and during treatment.

Effects of QINLOCK on contraceptive steroids have not been studied. Add a barrier method ifsystemic steroids are used for contraception.

There are no data on the use of ripretinib in pregnant women.

Based on its mechanism of action, ripretinib is suspected to cause foetal harm when administeredduring pregnancy and animal studies have shown reproductive toxicity (see sections 4.4 and 5.3).

QINLOCK should not be used during pregnancy unless the clinical condition of the woman requirestreatment with ripretinib.

It is unknown whether ripretinib/metabolites are excreted in human milk. A risk to the breast-fed childcannot be excluded. Breast-feeding should be discontinued during treatment with QINLOCK and forat least 1 week after the final dose.

There are no data on the effect of ripretinib on human fertility. Based on findings from animal studies,male and female fertility may be compromised by treatment with QINLOCK (see section 5.3).

QINLOCK has no influence on the ability to drive and use machines. In some patients, fatigue hasbeen reported following administration of QINLOCK. If a patient experiences fatigue, this mayinfluence their ability to drive or use machines.

In the Phase 3 double-blind, randomised (2:1), placebo-controlled study (INVICTUS),129 participants with a diagnosis of advanced GIST who had failed at least 3 approved prior lines oftreatment were randomised to QINLOCK (n=85) or placebo (n=44) (see section 5.1). In the Phase 1

Study DCC-2618-01-001, a total of 277 patients with advanced malignancies were enrolled, and218 patients were treated at the recommended Phase 2 dose of 150 mg QINLOCK once daily.

The median duration of treatment for QINLOCK in the double-blind period of the INVICTUS studywas 5.49 months.

The most frequently observed adverse reactions (≥25%) in patients treated with QINLOCK in thepooled safety population (n=392) were fatigue (51.0%), alopecia (50.8%), nausea (39.8%), myalgia(37.8%), constipation (37.2%), diarrhoea (32.7%), PPES (29.8%), weight decreased (26.5%) andvomiting (25.8%).

The adverse reactions (≥10 to <25%) observed in patients treated with QINLOCK in the pooled safetypopulation (n=392) were lipase increased (23.7%), muscle spasms (23.7%), arthralgia (21.2%),headache (20.7%), dyspnoea (20.2%), hypertension (19.4%), dry skin (17.6%), back pain (15.6%),cough (15.6%), blood bilirubin increased (14.0%), oedema peripheral (13.8%), hypophosphataemia(12.2%), pain in extremity (12.0%), pruritus (11.0%) and seborrhoeic keratosis (11.0%).

Grade 3/4 adverse reactions (≥2%) observed in patients treated with QINLOCK in the pooled safetypopulation (n=392) were lipase increased (14.8%), anaemia (14.0%), abdominal pain (8.2%),hypertension (6.9%), fatigue (4.1%), hypophosphataemia (4.1%), vomiting (2.6%), dyspnoea (2.0%),diarrhoea (2.0%) and blood bilirubin increased (2.0%). Serious adverse reactions (≥1%) observed inpatients treated with QINLOCK were anaemia (3.8%), dyspnoea (2.3%), vomiting (2.0%), nausea(1.8%), fatigue (1.5%), blood bilirubin increased (1.3%), constipation (1.0%), and muscular weakness(1.0%).

The overall safety profile of QINLOCK is based on pooled data from 392 patients (pooled safetypopulation) who received at least 1 dose of QINLOCK. Two clinical studies with QINLOCK in adultpatients with advanced malignancies were conducted and form the primary basis of the overallevaluation of safety: a pivotal phase 3 study in adult patients with GIST, Study DCC-2618-03-001(INVICTUS) (see section 5.1) and an open-label, first-in-human study in adult patients with advancedmalignancies (Study DCC-2618-01-001).

The double-blind period of the INVICTUS study formed the primary basis of the determination ofadverse reactions. The treatment emergent adverse events that were at least 5% higher in QINLOCKarm as compared to the placebo arm and those that were at least 1.5 times greater in the QINLOCKarm than those compared to placebo arm in INVICTUS were considered adverse drug reactions.

Treatment emergent adverse events identified within the INVICTUS study were also evaluated acrossthe pooled safety population (n=392). These events were considered adverse drug reactions per the

Sponsor assessment. They are classified according to System Organ Class and the most appropriate

MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

The severity of adverse drug reactions was assessed based on the Common Terminology Criteria for

Adverse Events (CTCAE), defining Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade4=life threatening, and Grade 5=death.

Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated fromthe available data) and are shown in Table 2. Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

Table 2: Adverse drug reactions reported in INVICTUS and study DCC-2618-01-001

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Very common Seborrhoeic keratosis

Common Melanocytic naevus, skin papilloma, squamous cell carcinoma of skina, fibroushistiocytoma

Uncommon Malignant melanoma

Common Hypothyroidism

Very common Hypophosphataemia

Common Depression

Very common Headache

Common Peripheral sensory neuropathy

Common Cardiac failureb, tachycardia

Very common Hypertensionc

Very Common Dyspnoea, cough

Very common Nausea, constipation, diarrhoea, vomiting

Common Stomatitis, abdominal pain upper

Very common Alopecia, PPES, dry skin, pruritus

Common Hyperkeratosis, rash maculopapular, pruritus generalised, dermatitis acneiform

Very common Myalgia, muscle spasms, arthralgia, back pain, pain in extremity

Common Muscular weakness, musculoskeletal chest pain

Very common Fatigue, oedema peripheral

Very common Weight decreased, lipase increased, blood bilirubin increased

Common Alanine aminotransferase increasedaSquamous cell carcinoma of skin (Squamous cell carcinoma of skin, Keratoacanthoma, Squamous cellcarcinoma of head and neck)bCardiac Failure (Cardiac failure, Acute left ventricular failure, Cardiac failure acute, Diastolic dysfunction)cHypertension (Hypertension, Blood pressure increased)

Description of selected adverse drug reactions

In the double-blind period of the INVICTUS study, PPES was reported in 19 of 85 (22.4%) patients inthe QINLOCK arm and no patients in the placebo arm. PPES led to dose discontinuation in 1.2% ofpatients, dose interruption in 3.5% of patients, and dose reduction in 2.4% of patients. All events weremild or moderate in severity (58% Grade 1 and 42% Grade 2).

In the pooled safety population, PPES occurred in 29.8% of 392 patients, including Grade 3 adversereactions in 0.5%. The median time to onset and duration of the first event was 8.1 weeks (range:0.3 week to 112.1 weeks) and 24.3 weeks (range: 0.9 week to 191.7 weeks), respectively. Seesections 4.2 and 4.4 for additional information.

In the double-blind period of the INVICTUS study, there was a higher incidence of hypertension (allevents regardless of causality) in patients treated with QINLOCK (15.3%) vs. 4.7% of patients whoreceived placebo.

In the pooled safety population, hypertension occurred in 19.4% of 392 patients, including Grade 3adverse reactions in 6.9%. See sections 4.2 and 4.4 for additional information.

Cardiac failure

In the double-blind period of the INVICTUS study, cardiac failure (all events regardless of causality)occurred in 1.2% of the 85 patients who received QINLOCK. Cardiac failure led to dosediscontinuation in 1.2% of the 85 patients who received QINLOCK.

In the pooled safety population, cardiac failure occurred in 1.5% of 392 patients, including Grade 3adverse reactions in 1.0%.

In the pooled safety population, 299 of 392 patients had a baseline and at least one post-baselineechocardiogram. Grade 3 decreased left ventricular ejection fraction occurred in 4.0% of the299 patients.

See section 4.4 for additional information.

In the double-blind period of the INVICTUS study, CuSCC (all events regardless of causality) wasreported in 5.9% of the 85 patients receiving QINLOCK. CuSCC of the skin was not reported inplacebo-treated patients. See sections 4.2 and 4.4 for additional information.

In the pooled safety population, CuSCC occurred in 8.7% of 392 patients including Grade 3 adversereactions in 0.5%.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no known specific antidote for overdose with QINLOCK.

In the event of suspected overdose, QINLOCK must be discontinued immediately, best supportivecare should be initiated by a medical professional, and the patient must be observed until clinicalstabilisation.

Pharmacotherapeutic group: Antineoplastic agents, other protein kinase inhibitors; ATC Code:

L01EX19

Ripretinib is a novel tyrosine kinase inhibitor that inhibits KIT proto-oncogene receptor tyrosinekinase and PDGFRA kinase, including wild type, primary, and secondary mutations. Ripretinib alsoinhibits other kinases in vitro, such as PDGFRB, TIE2, VEGFR2, and BRAF.

INVICTUS (DCC-2618-03-001 study)

The efficacy and safety of QINLOCK were evaluated in a randomised (2:1), double-blind,placebo-controlled study (INVICTUS study) in patients with unresectable, locally advanced ormetastatic GIST who had been previously treated with or are intolerant to at least 3 prior anticancertherapies including treatment with imatinib, sunitinib, and regorafenib. Randomisation was stratifiedby prior lines of therapy (3 versus ≥4) and Eastern Cooperative Oncology Group (ECOG) performancestatus (0 versus 1 or 2).

The primary efficacy outcome measure was progression-free survival (PFS) based on diseaseassessment by blinded independent central review (BICR) using modified RECIST 1.1 criteria, inwhich lymph nodes and bone lesions were not target lesions and a progressively growing new tumournodule within a pre-existing tumour mass must meet specific criteria to be considered unequivocalevidence of progression. Secondary efficacy endpoints included objective response rate (ORR) by

BICR, overall survival (OS), and patient-reported health state, physical function (PF), and rolefunction (RF).

Participants were randomised to receive 150 mg QINLOCK (n=85) or placebo (n=44) orally oncedaily administered in continuous 28-day cycles. Treatment continued until disease progression orunacceptable toxicity. Individual treatment arms were unblinded at the time of disease progression asassessed by BICR review and all patients on placebo arm were offered to cross-over to QINLOCK.

The demographic characteristics were median age of 60 years (29 to 83 years) with 79 (61.2%) ofpatients aged 18-64 years, 32 (24.8%) of patients aged 65-74 years, and 18 (13.9%) patients aged≥ 75 years (no patients ≥ 85 years old were randomised); male (56.6%); white (75.2%); and ECOGperformance status of 0 (41.9%), 1 (49.6%), or 2 (8.5%). Sixty-three percent (63%) of patientsreceived 3 prior therapies and approximately 37% received 4 or more prior therapies. Sixty-six percent(66%) of patients randomised to placebo crossed over to QINLOCK during the open-label period.

At the primary analysis (data cut-off date 31 May 2019) QINLOCK was compared to placebo in the

INVICTUS study. QINLOCK demonstrated benefit in all assessed patient subgroups for PFS. Median

PFS as determined by BICR (months) (95% CI) was 6.3 (4.6, 6.9) for QINLOCK versus 1.0 (0.9, 1.7)for placebo, HR (95% CI) 0.15 (0.09, 0.25) p-value < 0.0001. The secondary endpoint ORR (%) was9.4 (4.2, 18) for QINLOCK versus 0 (0, 8) for placebo, p-value 0.0504 and not statistically significant.

Median OS (months) (95% CI) was 15.1 (12.3, 15.1) for QINLOCK versus 6.6 (4.1, 11.6) for placebo,nominal p-value 0.0004. OS was not evaluated for statistical significance as a result of the sequentialtesting procedure for the secondary endpoints of ORR and OS.

PFS, ORR and OS results from a more recent data cut-off (10 August 2020) are shown in Table 3 and

Figures 1 and 2. PFS results were similar across subgroups based on age, sex, region, ECOG statusand number of previous lines of therapy.

T able 3: INVICTUS efficacy results (as of 10 August 2020)

QINLOCK Placebo(n = 85) (n = 44)

PFSa

Number of events (%) 68 (80) 37 (84)

Progressive disease 62 (73) 32 (73)

Deaths 6 (7) 5 (11)

Median PFS (months) (95% CI) 6.3 (4.6, 8.1) 1.0 (0.9, 1.7)

HR (95% CI)b 0.16 (0.10, 0.27)

ORRa

ORR (%) 11.8 0(95% CI) (5.8, 20.6) (0, 8)

OS

Number of deaths (%) 44 (52) 35 (80)

Median OS (months) (95% CI) 18.2 (13.1, NE) 6.3 (4.1, 10.0)

HR (95% CI)b 0.42 (0.27, 0.67)

BICR = Blinded Independent Central Review; CI = Confidence Interval; HR = Hazard Ratio; ORR = Objective Response

Rate; NE = not estimable; PFS = Progression Free Survival; OS = Overall Survivala Assessed per BICR.b Hazard ratio is based on Cox proportional regression model. This model includes treatment and randomisationstratification factors as fixed factors.

Figure 1: INVICTUS Kaplan-Meier curve of progression-free survivala

Median PFS (Months) 95% CI

Ripretinib 150 mg QD: 6.3 (4.6, 8.1)

Placebo: 1.0 (0.9, 1.7)+ Censored

Progression Free Survival (Months)

Ripretinib 150 mg QD Placebo

Number of Patients at Risk

Ripretinib 150 mg QD 85 54 37 24 15 11 8 4 2 0

Placebo 44 4 1 1 0a Data cut off 10 August 2020

Survival Probability (%)

Figure 2: INVICTUS Kaplan-Meier curve of overall survivala

Median OS (Months) 95% CI

Ripretinib: 18.2 (13.1, NE)

Placebo: 6.3 (4.1, 10.0)+ Censored

Overall Survival (Months)

Ripretinib Placebo

Patients at Risk:

Ripretinib 85 76 59 49 39 32 12 2 0

Placebo 44 29 17 12 12 12 4 1 0a Data cut off 10 August 2020

The European Medicines Agency has waived the obligation to submit the results of studies with

QINLOCK in all subsets of the paediatric population in the treatment of GIST (see section 4.2 forinformation on paediatric use).

Ripretinib reaches peak plasma concentrations at a median of 4 hours after oral administration ofsingle dose ripretinib 150 mg (given as three tablets each containing 50 mg). The mean (CV%)

AUC0-∞ after a single dose of 150 mg of ripretinib was 9,856 (39%) and 8,146 (56%) ng*h/mL forripretinib and DP-5439, respectively.

Administration with a high-fat meal increased ripretinib AUC0-24 and Cmax by 30% and 22%,respectively. DP-5439 AUC0-24 and Cmax were higher by 47% and 66%, respectively.

Both ripretinib and its active metabolite DP-5439 bind to plasma proteins at ≥ 99%. The mean (CV%)apparent volume of distribution (Vss/F) is approximately 302 (35%) L for ripretinib and 491 (38%) Lfor DP-5439.

CYP3A4/5 is the major metaboliser of ripretinib and its active metabolite DP-5439, while CYP2C8and CYP2D6 are minor metabolisers.

Following oral administration of single dose ripretinib 150 mg in humans, mean (CV%) apparent oralclearance (CL/F) was 15.2 (39%) and 17.9 (56%) L/hr for ripretinib and DP-5439, respectively. Mean(CV%) half-life (t½) was 12.6 (17%) and 15.6 (23%) hours for ripretinib and DP-5439, respectively.

Systemic elimination of ripretinib was not primarily attributed to the kidney with 0.02% and 0.1% ofthe ripretinib dose excreted as ripretinib and DP-5439, respectively, in urine and 34% and 6% of theripretinib dose excreted as ripretinib and DP-5439, respectively, in faeces.

Survival Probability (%)

Dose proportionality

Across the dose range of 20-250 mg, ripretinib and DP-5439 PK appeared to be less than doseproportional, especially at ripretinib doses higher than 150 mg.

Time dependency

Steady-state conditions are achieved within 14 days.

No clinically significant differences in the pharmacokinetics of QINLOCK were observed based onage (19 to 87 years), sex, race (White, Black, and Asian), body weight (39 to 138 kg), and tumour(GIST or other solid tumours).

In clinical studies, no relevant differences in exposure were observed between patients with mild andmoderate renal impairment (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault) and patients withnormal renal function. Based on a population pharmacokinetic analysis, no dose adjustment isrecommended in patients with mild and moderate renal impairment. The pharmacokinetics and safetyof QINLOCK in patients with severe renal impairment (CLcr 15 to 29 mL/min estimated by

Cockcroft-Gault) is limited. No dosing recommendation can be made in patients with severe renalimpairment (see section 4.2).

The effect of varying degrees of hepatic impairment as defined by Child-Pugh classification on thepharmacokinetics of ripretinib and DP-5439 was studied in a clinical trial (Study DCC-2618-01-004).

In participants with mild hepatic impairment, there was no impact on the pharmacokinetics ofripretinib or DP-5439. In participants with moderate hepatic impairment, ripretinib AUC0-tlast wasapproximately 99% higher while Cmax was unchanged compared to matched healthy participants. Thecombined AUC0-tlast of ripretinib and DP-5439 was higher by approximately 51%. In participants withsevere hepatic impairment, ripretinib AUC0-tlast was approximately 163% higher, Cmax wasapproximately 24% lower, and the combined AUC0-tlast of ripretinib and DP-5439 was approximately37% higher, compared to matched healthy participants. The observed magnitude of increase inripretinib exposure is unlikely to be clinically relevant based on the known safety profile of ripretinib.

Fraction of unbound ripretinib and DP-5439 was highly variable and no trend was apparent betweenprotein binding and degree of hepatic impairment.

No dose adjustment is recommended in patients with mild (Child-Pugh A), moderate (Child-Pugh B),or severe hepatic impairment (Child-Pugh C).

The preclinical safety profile of ripretinib was assessed in rats and dogs for up to 13 weeks duration.

Inflammation responses correlated with skin changes (discoloured, lesions) were recorded in rats(approximately 1.12 times the human exposure at 150 mg once daily). Elevated hepatic enzymeactivity was reported in both species (approximately 1.12 and 1.3 times the human exposure at 150 mgonce daily for rats and dogs, respectively). Dogs presented gastrointestinal effects (emesis and/orabnormal faeces) (approximately 1.3 times the human exposure at 150 mg once daily), andinflammatory responses illustrated by adverse skin lesions (approximately 0.14 times the humanexposure at 150 mg once daily).

Carcinogenicity studies have not been conducted with ripretinib.

Ripretinib was found to be positive in an in vitro micronucleus assay. Ripretinib was not mutagenic inin vitro bacterial reverse mutation (Ames) assay nor in an in vivo rat bone marrow micronucleus assay,demonstrating the absence of significant genotoxic risk.

Dedicated fertility studies in male and female animals were not conducted with ripretinib. However, ina 13-week repeat-dose toxicity study in male rats, there were findings of degeneration in theseminiferous epithelium of the testes, and cellular debris of the epididymis in males administered 30 or300 mg/kg/day but were considered of sufficient severity to affect reproduction at dose 300 mg/kg/dayonly (approximately 1.4 times the human exposure at 150 mg once daily).

In a pivotal embryofoetal development study, ripretinib was teratogenic in rats, inducing dose-relatedmalformations primarily associated with the visceral and skeletal systems at a maternal dose of20 mg/kg/day (approximately 1.0 times the human exposure at 150 mg once daily). Additionally,skeletal variations were already observed at 5 mg/kg/day. The developmental NOAEL for ripretinibwas therefore established at 1 mg/kg/day (approximately 0.02 times the human exposure at 150 mgonce daily).

A study investigating effects of ripretinib on the pre-/postnatal development was not performed.

Ripretinib indicates a potential for photoirritation/phototoxicity based on absorption in the UV visiblerange (above 290 nm). In vitro phototoxicity assessment in 3T3 mouse fibroblast cells suggest thatripretinib exhibits a potential for phototoxicity at clinically relevant concentrations following exposureto UVA and UVB radiation.

Crospovidone (E1202)

Hypromellose acetate succinate

Lactose monohydrate

Magnesium stearate (E470b)

Microcrystalline cellulose (E460)

Silica, colloidal hydrated (E551)

Not applicable.

4 years.

This medicinal product does not require any special temperature storage conditions.

Store in the original package and keep bottle tightly closed in order to protect from light and moisture.

White high-density polyethylene (HDPE) bottle with an aluminium foil/polyethylene (PE) tamperevident seal and a white polypropylene (PP) child-resistant closure, together with one PE desiccantcanister containing silica gel. Each bottle contains 30 or 90 tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Deciphera Pharmaceuticals (Netherlands) B.V.

Atrium Building 4th Floor

Strawinskylaan 30511077ZX, Amsterdam

Netherlands

EU/1/21/1569/001

EU/1/21/1569/002

Date of first authorisation: 18 November 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.