Leaflet VIZIMPRO 30mg film-coated tablets

Vizimpro 15 mg film-coated tablets

Vizimpro 30 mg film-coated tablets

Vizimpro 45 mg film-coated tablets

Vizimpro 15 mg film-coated tablets

Each film-coated tablet contains dacomitinib monohydrate equivalent to 15 mg dacomitinib.

Each film-coated tablet contains 40 mg of lactose monohydrate.

Vizimpro 30 mg film-coated tablets

Each film-coated tablet contains dacomitinib monohydrate equivalent to 30 mg dacomitinib.

Each film-coated tablet contains 81 mg of lactose monohydrate.

Vizimpro 45 mg film-coated tablets

Each film-coated tablet contains dacomitinib monohydrate equivalent to 45 mg dacomitinib.

Each film-coated tablet contains 121 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Vizimpro 15 mg film-coated tablets

Blue film-coated, 6.35 mm, round biconvex tablet, debossed with “Pfizer” on one side and “DCB15”on the other.

Vizimpro 30 mg film-coated tablets

Blue film-coated, 7.5 mm, round biconvex tablet, debossed with “Pfizer” on one side and “DCB30” onthe other.

Vizimpro 45 mg film-coated tablets

Blue film-coated, 9.0 mm, round biconvex tablet, debossed with “Pfizer” on one side and “DCB45” onthe other.

Vizimpro, as monotherapy, is indicated for the first-line treatment of adult patients with locallyadvanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor(EGFR)-activating mutations.

Treatment with Vizimpro should be initiated and supervised by a physician experienced in the use ofanticancer medicinal products.

EGFR mutation status should be established prior to initiation of dacomitinib therapy (see section 4.4).

The recommended dose of Vizimpro is 45 mg taken orally once daily, until disease progression orunacceptable toxicity occurs.

Patients should be encouraged to take their dose at approximately the same time each day. If thepatient vomits or misses a dose, an additional dose should not be taken and the next prescribed doseshould be taken at the usual time the next day.

Dose modifications may be required based on individual safety and tolerability. If dose reduction isnecessary, then the dose of Vizimpro should be reduced as described in Table 1. Dose modificationand management guidelines for specific adverse reactions are provided in Table 2 (see sections 4.4 and4.8).

Table 1. Recommended dose modifications for Vizimpro adverse reactions

Dose level Dose (once daily)

Recommended starting dose 45 mg

First dose reduction 30 mg

Second dose reduction 15 mg

Table 2. Dose modification and management for Vizimpro adverse reactions

Adverse reactions Dose modification

Interstitial lung disease - Withhold dacomitinib during ILD/Pneumonitis diagnostic evaluation.(ILD/Pneumonitis) - Permanently discontinue dacomitinib if ILD/Pneumonitis isconfirmed.

Diarrhoea - For Grade 1 diarrhoea, no dose modification is required. Initiatetreatment with anti-diarrhoeal medicinal products (e.g., loperamide) atfirst onset of diarrhoea. Encourage adequate oral fluid intake duringdiarrhoea.

- For Grade 2 diarrhoea, if not improved to Grade ≤ 1 within 24 hourswhile using anti-diarrhoeal medicinal products (e.g., loperamide) andadequate oral fluid intake, withhold dacomitinib. Upon recovery to

Grade ≤ 1, resume dacomitinib at the same dose level or consider areduction of 1 dose level.

- For Grade ≥ 3 diarrhoea, withhold dacomitinib. Treat withanti-diarrhoeal medicinal products (e.g., loperamide), and adequateoral fluid intake or intravenous fluids or electrolytes as appropriate.

Upon recovery to Grade ≤ 1, resume dacomitinib with a reduction of1 dose level.

Skin-related adverse - For Grade 1 rash or erythematous skin conditions, no dosereactions modification is required. Initiate treatment (e.g., antibiotics, topicalsteroids, and emollients).

- For Grade 1 exfoliative skin conditions, no dose modification isrequired. Initiate treatment (e.g., oral antibiotics and topical steroids).

- For Grade 2 rash, erythematous or exfoliative skin conditions, no dosemodification is required. Initiate treatment or provide additionaltreatment (e.g., oral antibiotics and topical steroids).

- If Grade 2 rash, erythematous or exfoliative skin conditions persist for72 hours despite treatment, withhold dacomitinib. Upon recovery to

Grade ≤ 1, resume dacomitinib at the same dose level or consider areduction of 1 dose level.

- For Grade ≥ 3 rash, erythematous or exfoliative skin conditions,withhold dacomitinib. Initiate or continue treatment and/or provideadditional treatment (e.g., broad spectrum oral or intravenousantibiotics and topical steroids). Upon recovery to Grade ≤ 1, resumedacomitinib with a reduction of 1 dose level.

Other - For Grade 1 or 2 toxicity, no dose modification is required.

- For Grade ≥ 3 toxicity, withhold dacomitinib until symptoms resolveto Grade ≤ 2. Upon recovery, resume dacomitinib with a reduction of1 dose level.

No starting dose adjustments are required when administering Vizimpro to patients with mild(Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. The starting dose of

Vizimpro should be adjusted to 30 mg once daily in patients with severe (Child-Pugh class C) hepaticimpairment. The dose may be increased to 45 mg once daily based on individual safety and tolerabilityafter at least 4 weeks of treatment (see section 5.2).

No starting dose adjustments are required when administering Vizimpro to patients with mild ormoderate renal impairment (creatinine clearance [CrCl] ≥ 30 mL/min). Limited data are available inpatients with severe renal impairment (CrCl < 30 mL/min). No data are available in patients requiringhaemodialysis. Thus no dosing recommendations can be made for either patient population (seesection 5.2).

No starting dose adjustment of Vizimpro in elderly (≥ 65 years of age) patients is required (see section5.2).

The safety and efficacy of Vizimpro in the paediatric population (< 18 years of age) have not beenestablished. No data are available.

Vizimpro is for oral use. The tablets should be swallowed with water and can be taken with or withoutmeals.

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

Assessment of EGFR mutation status

When assessing the EGFR mutation status of a patient, it is important that a well-validated and robustmethodology is chosen to avoid false negative or false positive determinations.

ILD/pneumonitis, which could be fatal, has been reported in patients receiving Vizimpro (seesection 4.8). Patients with a history of ILD have not been studied.

Careful assessment of all patients with an acute onset or unexplained worsening of pulmonarysymptoms (e.g., dyspnoea, cough, fever) should be performed to exclude ILD/pneumonitis. Treatmentwith dacomitinib should be withheld pending investigation of these symptoms. If ILD/pneumonitis isconfirmed, dacomitinib should be permanently discontinued and appropriate treatment instituted asnecessary (see section 4.2).

Diarrhoea, including severe diarrhoea, has been very commonly reported during treatment with

Vizimpro (see section 4.8). Diarrhoea may result in dehydration with or without renal impairment,which could be fatal if not adequately treated.

Proactive management of diarrhoea should start at the first sign of diarrhoea especially within the first2 weeks of starting dacomitinib, including adequate hydration combined with anti-diarrhoealmedicinal products and continued until loose bowel movements cease for 12 hours. Anti-diarrhoealmedicinal products (e.g., loperamide) should be used and, if necessary, escalated to the highestrecommended approved dose. Patients may require dosing interruption and/or dose reduction oftherapy with dacomitinib. Patients should maintain adequate oral hydration and patients who becomedehydrated may require administration of intravenous fluids and electrolytes (see section 4.2).

Skin-related adverse reactions

Rash, erythematous and exfoliative skin conditions have been reported in patients treated with

Vizimpro (see section 4.8).

For prevention of dry skin, initiate treatment with moisturizers, and upon development of rash, initiatetreatment with topical antibiotics, emollients, and topical steroids. Start oral antibiotics and topicalsteroids in patients who develop exfoliative skin conditions. Consider adding broad spectrum oral orintravenous antibiotics if any of these conditions worsen to greater than or equal to Grade 2 severity.

Rash, erythematous and exfoliative skin conditions may occur or worsen in areas exposed to the sun.

Advise patients to use protective clothing and sunscreen before exposure to the sun. Patients mayrequire dosing interruption and/or dose reduction of therapy with dacomitinib (see section 4.2).

Hepatotoxicity and transaminases increased

Transaminases increased (alanine aminotransferase increased, aspartate aminotransferase increased,transaminases increased) have been reported during treatment with Vizimpro (see section 4.8). Among

NSCLC patients treated with dacomitinib 45 mg daily, there have been isolated reports ofhepatotoxicity in 4 (1.6%) patients. Across the dacomitinib program, hepatic failure led to a fataloutcome in 1 patient. Therefore, periodic liver function testing is recommended. In patients whodevelop severe elevations in transaminases while taking dacomitinib, treatment should be interrupted(see section 4.2).

Medicinal products metabolised by cytochrome P450 (CYP)2D6

Vizimpro may increase exposure (or decrease exposure of active metabolites) of other medicinalproducts metabolised by CYP2D6. Concomitant use of medicinal products predominantly metabolisedby CYP2D6 should be avoided unless such products are considered necessary (see section 4.5).

Other forms of interactions

Concomitant use of proton pump inhibitors (PPIs) with dacomitinib should be avoided (seesection 4.5).

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinalproduct.

This medicinal product contains < 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium-free”.

Co-administration of dacomitinib with agents that increase gastric pH

The aqueous solubility of dacomitinib is pH dependent, with low (acidic) pH resulting in highersolubility. Data from a study in 24 healthy subjects indicated that co-administration of a single 45 mgdacomitinib dose with the PPI rabeprazole 40 mg once daily for 7 days decreased dacomitinib Cmax,

AUC0-96h (area under the concentration-time curve from time 0 to 96 hours), and AUCinf (AUC fromtime 0 to infinity) (n=14) by approximately 51%, 39%, and 29%, respectively, when compared to asingle 45 mg dose of dacomitinib administered alone. PPIs should be avoided while receivingtreatment with dacomitinib (see section 4.4).

Based on data from observations in 8 patients from Study A7471001, there was no apparent effect oflocal antacid administration on Cmax and AUCinf of dacomitinib. Based on pooled data in patients, therewas no apparent effect of histamine-2 (H2) receptor antagonists on steady-state trough concentrationof dacomitinib (geometric mean ratio of 86% (90% CI: 73; 101). Local antacids and H2 receptorantagonists may be used if needed. Dacomitinib should be administered 2 hours before or at least10 hours after taking H2 receptor antagonists.

Co-administration of dacomitinib and CYP2D6 substrates

Co-administration of single 45 mg oral dose of dacomitinib increased the mean exposure (AUClast and

Cmax) of dextromethorphan, a probe CYP2D6 substrate, 855% and 874%, respectively, compared withadministration of dextromethorphan alone. These results suggest that dacomitinib may increaseexposure of other medicinal products (or decrease exposure to active metabolites) primarilymetabolised by CYP2D6. Concomitant use of medicinal products predominantly metabolised by

CYP2D6 should be avoided (see section 4.4). If concomitant use of such medicinal products isconsidered necessary, they should follow their respective labels for dose recommendation regardingco-administration with strong CYP2D6 inhibitors.

Effect of dacomitinib on drug transporters

Based on in vitro data, dacomitinib may have the potential to inhibit the activity of P-glycoprotein(P-gp) (in the gastrointestinal [GI] tract), Breast Cancer Resistance Protein (BCRP) (systemically and

GI tract), and organic cation transporter (OCT)1 at clinically relevant concentrations (see section 5.2).

Woman of childbearing potential/Contraception

Women of childbearing potential should be advised to avoid becoming pregnant while receiving

Vizimpro. Women of childbearing potential who are receiving this medicinal product should useadequate contraceptive methods during therapy and for at least 17 days (5 half-lives) after completingtherapy.

There are no data on the use of dacomitinib in pregnant women. Studies in animals have shownlimited effects on reproductive toxicity (lower maternal body weight gain and food consumption inrats and rabbits, and lower foetal body weight and higher incidence of unossified metatarsals in ratsonly) (see section 5.3). Based on its mechanism of action, dacomitinib may cause foetal harm whenadministered to a pregnant woman. Dacomitinib should not be used during pregnancy. Female patientstaking dacomitinib during pregnancy or who become pregnant while taking dacomitinib should beapprised of the potential hazard to the foetus.

It is not known whether dacomitinib and its metabolites are excreted in human milk. Because manymedicinal products are excreted in human milk, and because of the potential for serious adversereactions in breast-fed infants from exposure to dacomitinib, mothers should be advised againstbreast-feeding while receiving this medicinal product.

Fertility studies have not been performed with dacomitinib. Non-clinical safety studies showedreversible epithelial atrophy in the cervix and vagina of rats (see section 5.3).

Vizimpro has minor influence on the ability to drive and use machines. Patients experiencing fatigueor ocular adverse reactions while taking dacomitinib should exercise caution when driving oroperating machinery.

The median duration of treatment with Vizimpro across the pooled data set was 66.7 weeks.

The most common (> 20%) adverse reactions in patients receiving dacomitinib were diarrhoea(88.6%), rash (79.2%), stomatitis (71.8%), nail disorder (65.5%), dry skin (33.3%), decreased appetite(31.8%), conjunctivitis (24.7%), weight decreased (24.3%), alopecia (23.1%), pruritus (22.4%),transaminases increased (22.0%), and nausea (20.4%).

Serious adverse reactions were reported in 6.7% of patients treated with dacomitinib. The mostfrequently (≥ 1%) reported serious adverse reactions in patients receiving dacomitinib were diarrhoea(2.0%), interstitial lung disease (1.2%), rash (1.2%), and decreased appetite (1.2%).

Adverse reactions leading to dose reductions were reported in 52.2% of patients treated withdacomitinib. The most frequently reported (> 5%) reasons for dose reductions due to any adversereactions in patients receiving dacomitinib were rash (32.2%), nail disorder (16.5%), and diarrhoea(7.5%).

Adverse reactions leading to permanent discontinuation were reported in 6.7% of patients treated withdacomitinib. The most common (> 0.5%) reasons for permanent discontinuations associated withadverse reactions in patients receiving dacomitinib were: rash (2.4%), interstitial lung disease (2.0%),and diarrhoea (0.8%).

Table 3 presents adverse reactions for Vizimpro. Adverse reactions are listed according to systemorgan class (SOC). Within each SOC, the adverse reactions are ranked by frequency, with the mostfrequent reactions first, using the following convention: very common (≥ 1/10); common (≥ 1/100 to< 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 3. Adverse reactions reported in dacomitinib clinical studies (N=255)

System organ class Very common Common

Metabolism and nutrition disorders Decreased appetite Dehydration

Hypokalaemiaa

Nervous system disorders Dysgeusia

Eye disorders Conjunctivitisb Keratitis

Respiratory, thoracic and mediastinal Interstitial lung disease*cdisorders

Gastrointestinal disorders Diarrhoea*

Stomatitisd

Nausea

Skin and subcutaneous tissue disorders Rashe Skin exfoliationi

Palmar-plantar Hypertrichosiserythrodysaesthesiasyndrome

Skin fissures

Dry skinf

Pruritusg

Nail disorderh

Alopecia

General disorders and administration site Fatigueconditions Asthenia

Investigations Transaminases increasedj

Weight decreased

Data based on pool of 255 patients who received Vizimpro 45 mg once daily as starting dose for first-linetreatment of NSCLC with EGFR-activating mutations across clinical studies.

* Fatal events were reported.a Hypokalaemia includes the following preferred terms (PTs): Blood potassium decreased, Hypokalaemia.b Conjunctivitis includes the following PTs: Blepharitis, Conjunctivitis, Dry eye, Noninfectiveconjunctivitis.c Interstitial lung disease includes the following PTs: Interstitial lung disease, Pneumonitis.d Stomatitis includes the following PTs: Aphthous ulcer, Cheilitis, Dry mouth, Mucosal inflammation,

Mouth ulceration, Oral pain, Oropharyngeal pain, Stomatitis.e Rash (also referred to as Rash and erythematous skin conditions) includes the following PTs: Acne,

Dermatitis acneiform, Erythema, Erythema multiforme, Rash, Rash erythematous, Rash generalised, Rashmacular, Rash maculo-papular, Rash papular.

f Dry skin includes the following PTs: Dry skin, Xerosis.g Pruritus includes the following PTs: Pruritus, Rash pruritic.

Table 3. Adverse reactions reported in dacomitinib clinical studies (N=255)

System organ class Very common Commonh Nail disorder includes the following PTs: Ingrowing nail, Nail bed bleeding, Nail bed inflammation, Naildiscolouration, Nail disorder, Nail infection, Nail toxicity, Onychoclasis, Onycholysis, Onychomadesis,

Paronychia.

i Skin exfoliation (also referred to as Exfoliative skin conditions) includes the following PTs: Exfoliativerash, Skin exfoliation.

j Transaminases increased includes the following PTs: Alanine aminotransferase increased, Aspartateaminotransferase increased, Transaminases increased.

Very common adverse reactions in patients occurring in at least 10% of patients in Study ARCHER1050 are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in

Table 4.

Table 4. Very common adverse reactions in Phase 3 Study ARCHER 1050 (N=451)

Dacomitinib Gefitinib(N=227) (N=224)

Adverse Reactionsa All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4% % % % % %

Decreased appetite 30.8 3.1 0.0 25.0 0.4 0.0

Hypokalaemiab 10.1 4.0 0.9 5.8 1.8 0.0

Conjunctivitisc 23.3 0.0 0.0 8.9 0.0 0.0

Diarrhoead 87.2 8.4 0.0 55.8 0.9 0.0

Stomatitise 69.6 4.4 0.4 33.5 0.4 0.0

Nausea 18.9 1.3 0.0 21.9 0.4 0.0

Rashf 77.1 24.2 0.0 57.6 0.9 0.0

Palmar-plantar 14.5 0.9 0.0 3.1 0.0 0.0erythrodysaesthesiasyndrome

Dry sking 29.5 1.8 0.0 18.8 0.4 0.0

Pruritush 20.3 0.9 0.0 14.3 1.3 0.0

Nail disorderi 65.6 7.9 0.0 21.4 1.3 0.0

Alopecia 23.3 0.4 0.0 12.5 0.0 0.0

Asthenia 12.8 2.2 0.0 12.5 1.3 0.0

Transaminases 23.8 0.9 0.0 40.2 9.8 0.0increasedj

Weight decreased 25.6 2.2 0.0 16.5 0.4 0.0a Only adverse reactions with ≥ 10% incidence in the dacomitinib arm are included.b Hypokalaemia includes the following preferred terms (PTs): Blood potassium decreased, Hypokalaemia.c Conjunctivitis includes the following PTs: Blepharitis, Conjunctivitis, Dry eye, Noninfective conjunctivitis.d 1 fatal event was reported in the dacomitinib arm.e Stomatitis includes the following PTs: Aphthous ulcer, Cheilitis, Dry mouth, Mucosal inflammation, Mouthulceration, Oral pain, Oropharyngeal pain, Stomatitis.f Rash includes the following PTs: Acne, Dermatitis acneiform, Erythema, Rash, Rash erythematous, Rashgeneralised, Rash macular, Rash maculo-papular, Rash papular.g Dry skin includes the following PTs: Dry skin, Xerosis.

Table 4. Very common adverse reactions in Phase 3 Study ARCHER 1050 (N=451)

Dacomitinib Gefitinib(N=227) (N=224)

Adverse Reactionsa All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4% % % % % %h Pruritus includes the following PTs: Pruritus, Rash pruritic.i Nail disorder includes the following PTs: Ingrowing nail, Nail discolouration, Nail disorder, Nail infection,

Nail toxicity, Onychoclasis, Onycholysis, Onychomadesis, Paronychia.j Transaminases increased includes the following PTs: Alanine aminotransferase increased, Aspartateaminotransferase increased, Transaminases increased.

ILD/pneumonitis adverse reactions were reported in 2.7% of patients receiving Vizimpro, and

Grade ≥ 3 ILD/pneumonitis adverse reactions were reported in 0.8%, including a fatal event (0.4%)(see section 4.4).

The median time to the first episode of any grade ILD/pneumonitis was 16 weeks and the median timeto the worst episode of ILD/pneumonitis was 16 weeks in patients receiving dacomitinib. The medianduration of any grade and Grade ≥ 3 ILD/pneumonitis was 13 weeks and 1.5 weeks, respectively (seesection 4.4).

Diarrhoea was the most frequently reported adverse reaction in patients receiving Vizimpro (88.6%)and Grade ≥ 3 diarrhoea adverse reactions were reported in 9.4% of patients. In a clinical study, onepatient (0.4%) had a fatal outcome (see section 4.4).

The median time to the first episode of any grade diarrhoea was 1 week and the median time to theworst episode of diarrhoea was 2 weeks in patients receiving dacomitinib. The median duration of anygrade and Grade ≥ 3 diarrhoea was 20 weeks and 1 week, respectively (see section 4.4).

Skin-related adverse reactions

Rash, erythematous and exfoliative skin condition adverse reactions were reported in 79.2% and 5.5%,respectively, of patients receiving Vizimpro. Skin-related adverse reactions were Grades 1 to 3.

Grade 3 rash and erythematous skin condition adverse reactions were the most frequently reported

Grade 3 adverse reactions (25.5%). Grade 3 exfoliative skin conditions were reported in 0.8% ofpatients (see section 4.4).

The median time to the first episode of any grade rash and erythematous skin conditions wasapproximately 2 weeks and the median time to the worst episode of rash and erythematous skinconditions was 7 weeks in patients receiving dacomitinib. The median duration of any grade and

Grade ≥ 3 rash and erythematous skin conditions was 53 weeks and 2 weeks, respectively. The mediantime to the first episode of any grade exfoliative skin conditions was 6 weeks and the median time tothe worst episode of exfoliative skin conditions was 6 weeks. The median duration of any grade and

Grade ≥ 3 exfoliative skin conditions was 10 weeks and approximately 2 weeks, respectively.

Transaminases increased

Transaminases increased (alanine aminotransferase increased, aspartate aminotransferase increased,transaminases increased) were reported in 22.0% of patients receiving Vizimpro and were Grades 1 to3, with the majority Grade 1 (18.4%) (see section 4.4).

The median time to the first episode of any grade of transaminases increased was approximately12 weeks and the median time to the worst episode of transaminases increased was 12 weeks inpatients receiving dacomitinib. The median duration of any grade and Grade ≥ 3 transaminasesincreased was 11 weeks and 1 week, respectively.

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.

The adverse reactions observed at doses greater than 45 mg once daily were primarily gastrointestinal,dermatological, and constitutional (e.g., fatigue, malaise, and weight loss).

There is no known antidote for dacomitinib. The treatment of dacomitinib overdose should consist ofsymptomatic treatment and general supportive measures.

Pharmacotherapeutic group: Anti-neoplastic agents, protein kinase inhibitors, ATC code: L01EB07

Dacomitinib is a pan-human epidermal growth factor receptor (HER) (EGFR/HER1, HER2, and

HER4) inhibitor, with activity against mutated EGFR with deletions in exon 19 or the L858Rsubstitution in exon 21. Dacomitinib binds selectively and irreversibly to its HER family targetsthereby providing prolonged inhibition.

Vizimpro in first-line treatment of NSCLC patients with EGFR-activating mutations (ARCHER 1050)

The efficacy and safety of Vizimpro was studied in a Phase 3 study (ARCHER 1050) conducted inpatients with locally advanced, not amenable to curative surgery or radiotherapy, or metastatic

NSCLC harbouring activating mutations of EGFR, to demonstrate the superiority of dacomitinibversus gefitinib. A total of 452 patients were randomised 1:1 to dacomitinib or gefitinib in amulticentre, multinational, randomised, open-label Phase 3 study.

Treatment was administered orally on a continuous daily basis until disease progression, institution ofnew anticancer therapy, intolerable toxicity, withdrawal of consent, death, or investigator decisiondictated by protocol compliance, whichever occurred first. Stratification factors at randomisation wererace (Japanese versus mainland Chinese versus other East Asian versus non-East Asian, as stated bythe patient), and EGFR mutation status (exon 19 deletion versus the L858R mutation in exon 21).

EGFR mutation status was determined by a standardised and commercially available test kit.

The primary endpoint of the study was progression-free survival (PFS) as determined by blinded

Independent Radiology Central (IRC) review. Key secondary endpoints included objective responserate (ORR), duration of response (DoR), and overall survival (OS).

The demographic characteristics of the overall study population were 60% female; median age atenrolment was 62 years with 10.8% being ≥ 75 years old. Thirty percent had baseline Eastern

Cooperative Oncology Group (ECOG) performance status (PS) 0 and 70% had ECOG PS 1; 59% hadan exon 19 deletion, and 41% had a L858R mutation in exon 21. Race was 23% White, 77% Asian,and < 1% Black. Patients with brain metastases or leptomeningeal disease or ECOG PS ≥ 2 wereexcluded from the study.

A statistically significant improvement in PFS as determined by the IRC was demonstrated for patientsrandomised to dacomitinib compared with those randomised to gefitinib, see Table 5 and Figure 1.

Subgroup analyses of PFS per IRC review based on baseline characteristics were consistent with thosefrom the primary analysis of PFS. In particular, the hazard ratios (HRs) for PFS per IRC review in

Asian and non-Asian patients were 0.509 (95% CI: 0.391, 0. 662) and 0.889 (95% CI: 0.568, 1.391),respectively. In Asian patients, median PFS was 16.5 months for dacomitinib arm and 9.3 months forgefitinib arm. In non-Asian patients, median PFS was 9.3 months for dacomitinib arm and 9.2 monthsfor gefitinib arm.

OS results from the final analysis (data cut-off date of 17-Feb-2017) when 48.7% of events hadoccurred showed a HR of 0.760 (95% CI: 0.582, 0.993) and a gain of 7.3 months in median OS(median OS: 34.1 months [95% CI: 29.5, 37.7] and 26.8 months [95% CI: 23.7, 32.1] in thedacomitinib and gefitinib arm, respectively). However, according to the hierarchical testing approach,the analysis was stopped with the testing of ORR as the statistical significance was not reached.

Therefore, the statistical significance of OS improvement could not be formally assessed.

Table 5. Efficacy results from ARCHER 1050 in patients with previously untreated

NSCLC with EGFR-activating mutations - ITT population⃰

Dacomitinib Gefitinib

N=227 N=225

Progression-Free Survival (per IRC)

Number of patients with event, n (%) 136 (59.9%) 179 (79.6%)

Median PFS in months (95% CI) 14.7 (11.1, 16.6) 9.2 (9.1, 11.0)

HR (95% CI)a 0.589 (0.469, 0.739)2-sided p-valueb < 0.0001

Objective Response Rate (per IRC)

Objective Response Rate % (95% CI) 74.9% (68.7, 80.4) 71.6% (65.2, 77.4)2-sided p-valuec 0.3883

Duration of Response in Responders (per IRC)

Number of responders per IRC review, 170 (74.9) 161 (71.6)n (%)

Median DoR in months (95% CI) 14.8 (12.0, 17.4) 8.3 (7.4, 9.2)

HR (95% CI)a 0.403 (0.307, 0.529)2-sided p-valueb < 0.0001⃰ Data based on data cut-off date of 29 July 2016.

Abbreviations: CI=confidence interval; EGFR=epidermal growth factor receptor; HR=hazard ratio;

IRC=independent radiologic central; ITT=Intent-to-treat; IWRS=interactive web response system;

N/n=total number; NSCLC=non-small cell lung cancer; PFS=progression-free survival; DoR=Duration of

Response.

a. From stratified Cox Regression. The stratification factors were Race (Japanese vs mainland Chinese andother East Asian vs non-East Asian) and EGFR mutation status (exon 19 deletion vs the L858Rmutation in exon 21) at randomisation per IWRS.

b. Based on the stratified log-rank test. The stratification factors were Race (Japanese vs mainland Chineseand other East Asian vs non-East Asian) and EGFR mutation status (exon 19 deletion vs the L858Rmutation in exon 21) at randomisation per IWRS.

c. Based on the stratified Cochran-Mantel-Haenszel test. The stratification factors were Race (Japanese vsmainland Chinese and other East Asian vs non-East Asian) and EGFR mutation status (exon 19 deletionvs the L858R mutation in exon 21) at randomisation per IWRS.

Figure 1. ARCHER 1050 - Kaplan-Meier curve for PFS per IRC review - ITT population

Abbreviations: CI=confidence interval; HR=hazard ratio; IRC=independent radiologic central;

ITT=Intent-To-Treat; N=total number; PFS=progression-free survival.

The European Medicines Agency has waived the obligation to submit the results of studies withdacomitinib in all subsets of the paediatric population in NSCLC indication (see section 4.2 forinformation on paediatric use).

Following the administration of a single 45 mg dose of dacomitinib tablets, the mean oralbioavailability of dacomitinib is 80% (range: 65% to 100%) compared to intravenous administration,with Cmax occurring 5 to 6 hours after oral dosing. Following dacomitinib 45 mg daily dosing,steady-state was reached within 14 days. Food does not alter bioavailability to a clinically meaningfulextent. Dacomitinib is a substrate for the membrane transport proteins P-gp and BCRP. However,based on the oral bioavailability of 80%, these membrane transport proteins are unlikely to have anyimpact on dacomitinib absorption.

Dacomitinib is extensively distributed throughout the body with a mean steady-state volume ofdistribution of 27 L/kg (patient of 70 kg) [coefficient of variation (CV%): 18%] following intravenousadministration. In plasma, dacomitinib binds to albumin and 1-acid glycoprotein and the fractionunbound is approximately 2% in vitro and ex vivo in healthy volunteers.

In humans, dacomitinib undergoes oxidation and glutathione conjugation as the major metabolicpathways. Following oral administration of a single 45-mg dose of [14C] dacomitinib, the mostabundant circulating metabolite was O-desmethyl dacomitinib. This metabolite exhibited in vitropharmacologic activity that was similar to that of dacomitinib in the in vitro biochemical assays. Infaeces, dacomitinib, O-desmethyl dacomitinib, a cysteine conjugate of dacomitinib, and amono-oxygenated metabolite of dacomitinib were the major drug-related components. In vitro studiesindicated that CYP2D6 was the major CYP isozyme involved in the formation of O-desmethyldacomitinib, while CYP3A4 contributed to the formation of other minor oxidative metabolites.

O-desmethyl dacomitinib accounted for 16% of human plasma radioactivity and is formed mainly by

CYP2D6 and to a lesser extent CYP2C9. The inhibition of CYP2D6 translated into approximately a90% reduction in metabolite exposure and an approximate 37% increase in dacomitinib exposure.

Other information on drug-drug interactions

Effect of dacomitinib and O-desmethyl dacomitinib on CYP enzymes

In vitro, dacomitinib and its metabolite O-desmethyl dacomitinib have a low potential to inhibit theactivities of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevantconcentrations. In vitro, dacomitinib has a low potential to induce CYP1A2, CYP2B6, or CYP3A4 atclinically relevant concentrations.

Effect of dacomitinib on drug transporters

In vitro, dacomitinib has a low potential to inhibit the activities of drug transporters P-gp(systemically), organic anion transporters (OAT)1 and OAT3, OCT2, organic anion transportingpolypeptide (OATP)1B1, and OATP1B3, but may inhibit the activity of P-gp (in the GI tract), BCRP(systemically and GI tract), and OCT1 at clinically relevant concentrations.

Effect of dacomitinib on UGT Enzymes

In vitro, dacomitinib has a low potential to inhibit uridine-diphosphate glucuronosyltransferase(UGT)1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15.

The plasma half-life of dacomitinib ranges from 54 to 80 hours. Dacomitinib showed a clearance of20.0 L/hr with an inter-individual variability of 32% (CV%). In 6 healthy male subjects given asingle-oral dose of [14C] radiolabeled dacomitinib, a median of 82% of the total administeredradioactivity was recovered in 552 hours; faeces (79% of dose) was the major route of excretion, with3% of the dose recovered in urine, of which < 1% of the administered dose was unchangeddacomitinib.

Age, race, gender, body weight

Based on population pharmacokinetic analyses, patient age, race (Asian and non-Asian), gender, andbody weight do not have a clinically relevant effect on predicted steady-state exposure of dacomitinib.

Approximately 90% of patients included in this analysis were Asian or White.

In a dedicated hepatic impairment study, following a single-oral dose of 30 mg Vizimpro, dacomitinibexposure (AUCinf and Cmax) was unchanged in mild hepatic impairment (Child-Pugh class A; N=8) anddecreased by 15% and 20%, respectively in moderate hepatic impairment (Child-Pugh class B; N=9)when compared to subjects with normal hepatic function (N=8). In a second dedicated hepaticimpairment study, following a single-oral dose of 30 mg Vizimpro, dacomitinib exposure wasunchanged for AUCinf and increased by 31% for Cmax in subjects with severe hepatic impairment(Child-Pugh class C; N=8), when compared to subjects with normal hepatic function (N=8). Inaddition, based on a population pharmacokinetic analysis using data from 1381 patients, that included158 patients with mild hepatic impairment defined by National Cancer Institute (NCI) criteria [totalbilirubin ≤ Upper Limit of Normal (ULN) and Aspartate Aminotransferase (AST) > ULN, or totalbilirubin > 1.0 to 1.5 × ULN and any AST; N=158], mild hepatic impairment had no effect on thepharmacokinetics of dacomitinib. From the small number of patients in the moderate group [totalbilirubin > 1.5 to 3 × ULN and any AST; N=5], there is no evidence for a change in dacomitinibpharmacokinetics.

No clinical studies have been conducted in patients with impaired renal function. Based on populationpharmacokinetic analyses, mild (60 mL/min ≤ CrCl < 90 mL/min; N=590) and moderate(30 mL/min ≤ CrCl < 60 mL/min; N=218) renal impairment, did not alter dacomitinibpharmacokinetics, relative to subjects with normal (CrCl ≥ 90 mL/min; N=567) renal function.

Limited pharmacokinetic data are available in patients with severe renal impairment(CrCl < 30 mL/min) (N=4). The pharmacokinetics in patients requiring haemodialysis have not beenstudied.

Exposure response relationships

No clear relationship between dacomitinib exposure and efficacy could be characterised over theexposure range studied. Significant exposure-safety relationship was defined for Grade ≥ 3rash/dermatitis acneiform, other skin toxicities, diarrhoea and Grade ≥ 1 stomatitis.

Repeated-dose toxicity

In oral repeated-dose toxicity studies for up to 6 months in rats and 9 months in dogs, the primarytoxicities were identified in the skin/hair (dermal changes in rats and dogs, atrophy/dysplasia of hairfollicles in rats), kidney (papillary necrosis often accompanied by tubular degeneration, regeneration,dilatation and/or atrophy and changes in urinary markers indicative of renal injury in rats, erosion orulceration of the pelvic epithelium with associated inflammation without changes indicative of renaldysfunction in dogs), eye (cornea epithelial atrophy in rats and dogs, corneal ulcers/erosions withred/swollen conjunctiva(e), conjunctivitis, elevated third eyelid, increased squinting, partially closedeyes, lacrimation, and/or ocular discharge in dogs), and digestive system (enteropathy in rats and dogs,erosions/ulcers of the mouth with reddened mucous membranes in dogs), and atrophy of epithelialcells of other organs in rats. In addition, hepatocellular necrosis with transaminase increases andhepatocellular vacuolation were observed in rats only. These effects were reversible with the exceptionof hair follicles and kidney changes. All effects occurred at systemic exposure below that in humans atthe recommended dose of 45 mg once daily.

Dacomitinib was tested using a series of genetic toxicology assays. Dacomitinib was not mutagenic ina bacterial reverse mutation (Ames) assay, and not clastogenic or aneugenic in the in vivo bonemarrow micronucleus assay in male and female rats. Dacomitinib was clastogenic in the in vitrohuman lymphocyte chromosome aberration assay at cytotoxic concentrations. Dacomitinib is notdirectly reactive toward DNA as evidenced by the negative response in the bacterial reverse mutationassay and did not induce chromosome damage in a bone marrow micronucleus assay at concentrationsup to approximately 60-70 times the unbound AUC or Cmax at the recommended human dose. Thus,dacomitinib is not expected to be genotoxic at clinically relevant exposure concentrations.

Carcinogenicity studies have not been performed with dacomitinib.

Fertility studies have not been performed with dacomitinib. In repeat-dose toxicity studies withdacomitinib, effects on reproductive organs were observed in female rats given approximately0.3 times the unbound AUC at the recommended human dose (for 6 months) and were limited toreversible epithelial atrophy in the cervix and vagina. There was no effect on reproductive organs inmale rats given ≤ 2 mg/kg/day for 6 months (approximately 1.1 times the unbound AUC at therecommended human dose), or in dogs given ≤ 1 mg/kg/day for 9 months (approximately 0.3 times theunbound AUC at the recommended human dose).

Developmental toxicity

In embryo-foetal development studies in rats and rabbits, pregnant animals received oral doses up toapproximately 2.4 times and 0.3 times, respectively, the unbound AUC at the recommended humandose during the period of organogenesis. Maternal body weight gain and food intake were lower inpregnant rats and rabbits. The maternally toxic dose was foetotoxic in rats, resulting in reduced foetalbody weights and higher incidence of unossified metatarsals.

A phototoxicity study with dacomitinib in pigmented rats showed no phototoxicity potential.

Environmental risk assessment studies have shown that dacomitinib has the potential to be verypersistent, bioaccumulative and toxic to the environment (see section 6.6).

Lactose monohydrate

Microcrystalline cellulose

Sodium starch glycolate

Magnesium stearate

Opadry II Blue 85F30716 containing:

Polyvinyl alcohol - partially hydrolysed (E1203)

Talc (E553b)

Titanium dioxide (E171)

Macrogol (E1521)

Indigo carmine aluminium lake (E132)

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

Aluminium/aluminium blister containing 10 film-coated tablets. Each pack contains 30 film-coatedtablets.

Dacomitinib has the potential to be a very persistent, bioaccumulative and toxic substance (seesection 5.3). Any unused medicinal product or waste material should be disposed of in accordancewith local requirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/19/1354/001

EU/1/19/1354/002

EU/1/19/1354/003

Date of first authorisation: 02 April 2019

Date of latest renewal: 07 December 2023

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

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