TUKYSA 150mg film-coated tablets medication leaflet

TUKYSA 50 mg film-coated tablets

TUKYSA 150 mg film-coated tablets

TUKYSA 50 mg film-coated tablets

Each film-coated tablet contains 50 mg of tucatinib.

TUKYSA 150 mg film-coated tablets

Each film-coated tablet contains 150 mg of tucatinib.

Each 150 mg film-coated tablet contains 27.64 mg of sodium and 30.29 mg of potassium.

A 300 mg dose of TUKYSA contains 55.3 mg of sodium and 60.6 mg of potassium.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

TUKYSA 50 mg film-coated tablets

Round, yellow, film-coated tablet, debossed with “TUC” on one side and “50” on the other side. The50 mg tablet has a diameter of approximately 8 mm.

TUKYSA 150 mg film-coated tablets

Oval-shaped, yellow, film-coated tablet, debossed with “TUC” on one side and “150” on the otherside. The 150 mg tablet is approximately 17 mm in length and 7 mm in width.

TUKYSA is indicated in combination with trastuzumab and capecitabine for the treatment of adultpatients with HER2-positive locally advanced or metastatic breast cancer who have received at least2 prior anti-HER2 treatment regimens.

Treatment with TUKYSA should be initiated and supervised by a physician experienced in theadministration of anti-cancer medicinal products.

The recommended dose is 300 mg tucatinib (two 150 mg tablets) taken twice daily continuously incombination with trastuzumab and capecitabine, at doses described in Table 1. Refer to the summaryof product characteristics (SmPC) for co-administered trastuzumab and capecitabine for additionalinformation. The treatment components can be administered in any order.

Table 1: Recommended dosing

Timing relative to

Treatment Dose Treatment days food intake300 mg orally With or without a

Tucatinib Continuouslytwice daily meal1 000 mg/m2 orally Days 1 to 14 every Within 30 minutes

Capecitabinetwice daily 21 days after a meal

Trastuzumab

Intravenous dosing

Initial dose 8 mg/kg intravenously Day 1

Subsequent doses 6 mg/kg intravenously Every 21 days Not applicable

OR

Subcutaneous dosing 600 mg subcutaneously Every 21 days

Treatment with TUKYSA should be continued until disease progression or unacceptable toxicity.

In the case of a missed dose, the patient should take their next dose at the regularly scheduled time.

The recommended tucatinib dose modifications for patients with adverse reactions (see section 4.8)are provided in Tables 2 and 3. Refer to the SmPC for co-administered trastuzumab and capecitabinefor dose modifications for toxicities suspected to be caused by those therapies.

Table 2: Recommended tucatinib dose reductions for adverse reactions

Dose level Tucatinib dose

Recommended starting dose 300 mg twice daily

First dose reduction 250 mg twice daily

Second dose reduction 200 mg twice daily

Third dose reduction 150 mg twice daily11. TUKYSA should be permanently discontinued in patients unable to tolerate 150 mg orally twice daily.

Table 3: Recommended tucatinib dose modifications for adverse reactions

Adverse

Severity1

Tucatinib dosage modificationreaction

Diarrhoea Grade 1 and 2 No dose modification is required.

Grade 3 without antidiarrheal Initiate or intensify appropriate medicaltreatment therapy. Interrupt tucatinib until recovery to≤ Grade 1, then resume tucatinib at the samedose level.

Grade 3 with antidiarrheal Initiate or intensify appropriate medicaltreatment therapy. Interrupt tucatinib until recovery to≤ Grade 1, then resume tucatinib at the nextlower dose level.

Grade 4 Permanently discontinue tucatinib.

Increased ALT, Grade 1 bilirubin No dose modification is required.

AST or total (> ULN to 1.5 × ULN)bilirubin2

Grade 2 bilirubin (> 1.5 to Interrupt tucatinib until recovery to ≤ Grade 1,3 × ULN) then resume tucatinib at the same dose level.

Grade 3 ALT or AST Interrupt tucatinib until recovery to ≤ Grade 1,(> 5 to 20 × ULN) then resume tucatinib at the next lower doselevel.

OR

Grade 3 bilirubin(> 3 to 10 × ULN)

Grade 4 ALT or AST Permanently discontinue tucatinib.

(> 20 × ULN)

OR

Grade 4 bilirubin (> 10 × ULN)

ALT or AST > 3 × ULN Permanently discontinue tucatinib.

AND

Bilirubin > 2 × ULN

Other adverse Grade 1 and 2 No dose modification is required.

reactions

Grade 3 Interrupt tucatinib until recovery to ≤ Grade 1,then resume tucatinib at the next lower doselevel.

Grade 4 Permanently discontinue tucatinib.

1. Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events

Version 4.032. Abbreviations: ULN=upper limit of normal; ALT=alanine aminotransferase; AST=aspartateaminotransferase

Co-administration with CYP2C8 inhibitors

Concomitant use with strong CYP2C8 inhibitors should be avoided. If co-administration with a strong

CYP2C8 inhibitor cannot be avoided, the starting tucatinib dose should be reduced to 100 mg orallytwice daily. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, thetucatinib dose that was taken prior to initiating the inhibitor should be resumed (see section 4.4 andsection 4.5). Monitoring for TUKYSA toxicity should be increased when administered with moderate

No dose adjustment is required in patients aged ≥ 65 years (see section 5.2). Tucatinib has not beeninvestigated in patients above the age of 80 years.

No dose adjustment is required in patients with mild, moderate, or severe renal impairment (seesection 5.2).

No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2).

For patients with severe hepatic impairment (Child-Pugh C), a reduced starting dose of 200 mg orallytwice daily is recommended.

The safety and efficacy of TUKYSA in paediatric patients have not been established. No data areavailable.

TUKYSA is for oral use. The tablets should be swallowed whole and should not be chewed, crushed,or split prior to swallowing (see section 5.2).

TUKYSA should be taken approximately 12 hours apart, at the same time every day, with or without ameal. TUKYSA may be taken at the same time with capecitabine.

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

Increased ALT, AST, and bilirubin

Increased ALT, AST, and bilirubin have been reported during treatment with tucatinib (seesection 4.8). ALT, AST, and total bilirubin should be monitored every three weeks or as clinicallyindicated. Based on the severity of the adverse reaction, treatment with tucatinib should be interrupted,then dose reduced or permanently discontinued (see section 4.2).

Increased creatinine without impaired renal function

Increase in serum creatinine (30% mean increase) has been observed due to inhibition of renal tubulartransport of creatinine without affecting glomerular function (see section 4.8). Alternative markerssuch as BUN, cystatin C, or calculated glomerular filtration rate (GFR), which are not based oncreatinine, may be considered to determine whether renal function is impaired.

Diarrhoea, including severe events such as dehydration, hypotension, acute kidney injury and death,has been reported during treatment with tucatinib (see section 4.8). If diarrhoea occurs, antidiarrhealsshould be administered as clinically indicated. For Grade ≥ 3 diarrhoea, treatment with tucatinibshould be interrupted, then dose reduced or permanently discontinued (see section 4.2). Promptmedical management should also be instituted in the event of persistence of concomitant Grade 2diarrhoea with concomitant Grade ≥ 2 nausea and/or vomiting. Diagnostic tests should be performedas clinically indicated to exclude infectious causes of Grade 3 or 4 diarrhoea or diarrhoea of any gradewith complicating features (dehydration, fever, neutropenia).

Embryo-foetal toxicity

Based on findings from animal studies and its mechanism of action, tucatinib may cause harmfuleffects to the foetus when administered to a pregnant woman. In animal reproduction studies,administration of tucatinib to pregnant rabbits during organogenesis caused foetal abnormalities inrabbits at maternal exposures similar to the clinical exposures at the recommended dose.

Pregnant women should be advised of the potential risk to a foetus. Women of childbearing potentialshould be advised to use effective contraception during and up to at least 1 week after the last dose oftreatment (see section 4.6). Male patients with female partners of childbearing potential should also beadvised to use an effective method of contraception during and up to at least 1 week after the last doseof treatment.

Sensitive CYP3A substrates

Tucatinib is a strong CYP3A inhibitor. Thus, tucatinib has the potential to interact with medicinalproducts that are metabolised by CYP3A, which may lead to increased plasma concentrations of theother product (see section 4.5). When tucatinib is co-administered with other medicinal products, the

SmPC for the other product should be consulted for the recommendations regarding co-administrationwith CYP3A inhibitors. Concomitant treatment of tucatinib with CYP3A substrates when minimalconcentration changes may lead to serious or life-threatening adverse reactions should be avoided. Ifconcomitant use is unavoidable, the CYP3A substrate dosage should be reduced in accordance withthe concomitant medicinal product SmPC.

Concomitant use of tucatinib with a P-gp substrate increased the plasma concentrations of P-gpsubstrate, which may increase the toxicity associated with a P-gp substrate. Dose reduction of P-gpsubstrates (including sensitive intestinal substrate such as dabigatran) should be considered inaccordance with the concomitant medicine SmPC and P-gp substrates should be administered withcaution when minimal concentration changes may lead to serious or life-threatening toxicities.

Strong CYP3A/moderate CYP2C8 inducers

Concomitant use of tucatinib with a strong CYP3A or moderate CYP2C8 inducer decreased tucatinibconcentrations, which may reduce tucatinib activity. Concomitant use with a strong CYP3A inducer ormoderate CYP2C8 inducer should be avoided.

Strong/moderate CYP2C8 inhibitors

Concomitant use of tucatinib with a strong CYP2C8 inhibitor increased tucatinib concentrations,which may increase the risk of tucatinib toxicity. Concomitant use with strong CYP2C8 inhibitorsshould be avoided (see section 4.2).

There are no clinical data on the impact of concomitant use of moderate CYP2C8 inhibitors ontucatinib concentrations. Monitoring for tucatinib toxicity should be increased with moderate CYP2C8inhibitors.

This medicinal product contains 55.3 mg sodium per 300 mg dose. This is equivalent to 2.75% of therecommended maximum daily dietary intake of sodium for an adult.

This medicinal product contains 60.6 mg potassium per 300 mg dose. This should be taken intoconsideration for patients who have impaired kidney function or are on a controlled potassium diet(diet with low potassium content).

Tucatinib is primarily metabolised by CYP2C8. Tucatinib is a metabolism-based inactivator of

CYP3A and inhibits renal transporters of metformin and creatinine. Tucatinib is a substrate of P-gp.

Effects of other medicinal products on tucatinib

CYP3A/CYP2C8 inducers

A clinical drug interaction study found that co-administration of a single dose of 300 mg tucatinib withrifampicin (a strong CYP3A and moderate CYP2C8 inducer) resulted in a reduction in tucatinibconcentrations (0.6-fold Cmax (90% CI: 0.5, 0.8) and 0.5-fold AUC (90% CI: 0.4, 0.6)).

Co-administration of tucatinib with strong CYP3A or moderate CYP2C8 inducers such as rifampicin,phenytoin, St. John's wort, or carbamazepine should be avoided as this may result in decreased activityof tucatinib (see section 4.4).

A clinical drug interaction study found that co-administration of a single dose of 300 mg tucatinib withgemfibrozil (a strong CYP2C8 inhibitor) resulted in an increase in tucatinib concentrations (1.6-fold

Cmax (90% CI: 1.5, 1.8) and 3.0-fold AUC (90% CI: 2.7, 3.5)). Co-administration of tucatinib withstrong CYP2C8 inhibitors such as gemfibrozil should be avoided as this may result in increased risk oftucatinib toxicity (see section 4.4).

A clinical drug interaction study found that co-administration of a single dose of 300 mg tucatinib withitraconazole (a strong CYP3A inhibitor) resulted in an increase in tucatinib concentrations (1.3-fold

Cmax (90% CI: 1.2, 1.4) and 1.3-fold AUC (90% CI: 1.3, 1.4)). No dose adjustment is required.

Based on clinical drug interaction studies conducted with tucatinib, no drug interactions were observedwhen tucatinib is combined with omeprazole (a proton pump inhibitor). No dose adjustment isrequired.

Effects of tucatinib on other medicinal products

Tucatinib is a strong CYP3A inhibitor. A clinical drug interaction study found that co-administrationof tucatinib with midazolam (a sensitive CYP3A substrate) resulted in an increase in midazolamconcentrations (3.0-fold Cmax (90% CI: 2.6, 3.4) and 5.7-fold AUC (90% CI: 5.0, 6.5)).

Co-administration of tucatinib with sensitive CYP3A substrates such as alfentanil, avanafil, buspirone,darifenacin, darunavir, ebastine, everolimus, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol,saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, and vardenafil may increase theirsystemic exposures which may increase the toxicity associated with a CYP3A substrate. Concomitantuse of tucatinib with CYP3A substrates, when minimal concentration changes may lead to serious orlife-threatening toxicities, should be avoided. If concomitant use is unavoidable, the CYP3A substratedosage should be decreased in accordance with the concomitant medicinal product SmPC.

A clinical drug interaction study found that co-administration of tucatinib with digoxin (a sensitive

P-gp substrate) resulted in an increase in digoxin concentrations (2.4-fold Cmax (90% CI: 1.9, 2.9) and1.5-fold AUC (90% CI: 1.3, 1.7)). Concomitant use of tucatinib with a P-gp substrate may increase theplasma concentrations of the P-gp substrate, which may increase the toxicity associated with the P-gpsubstrate. Dose reduction of P-gp substrates (including sensitive intestinal substrate such asdabigatran) should be considered in accordance with the concomitant medicine SmPC and P-gpsubstrates should be administered with caution when minimal concentration changes may lead toserious or life-threatening toxicities (see section 4.4).

CYP2C8 substrates

A clinical drug interaction study found that co-administration of tucatinib with repaglinide (a CYP2C8substrate) resulted in an increase in repaglinide concentrations (1.7-fold Cmax (90% CI: 1.4, 2.1) and1.7-fold AUC (90% CI: 1.5, 1.9)). No dose adjustment is required.

MATE1/2K substrates

A clinical drug interaction study found that co-administration of tucatinib with metformin (a

MATE1/2-K substrate) resulted in an increase in metformin concentrations (1.1-fold Cmax (90% CI:

1.0, 1.2) and 1.4-fold AUC (90% CI: 1.2, 1.5)). Tucatinib reduced the renal clearance of metforminwithout any effect on GFR as measured by iohexol clearance and serum cystatin C. No doseadjustment is required.

Based on clinical drug interaction studies conducted with tucatinib, no drug interactions were observedwhen tucatinib is combined with tolbutamide (a sensitive CYP2C9 substrate). No dose adjustment isrequired.

Based on findings in animals, tucatinib may cause harmful pharmacological effects when administeredto women during pregnancy and/or on the foetus/newborn child. Women of childbearing potentialshould be advised to avoid becoming pregnant and to use effective contraception during and up to atleast 1 week after treatment. Male patients with female partners of childbearing potential should alsobe advised to use effective contraception during and up to at least 1 week after treatment (see section4.4).

Please also refer to section 4.6 of the prescribing information for trastuzumab and capecitabine.

There are no data from the use of tucatinib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). TUKYSA should not be used during pregnancy unless theclinical condition of the woman requires treatment with tucatinib. The pregnancy status of women ofchildbearing potential should be verified prior to initiating treatment with tucatinib. If the patientbecomes pregnant during treatment, the potential hazard to the foetus/newborn child must beexplained to the patient.

It is unknown whether tucatinib/metabolites are excreted in human milk. A risk to thenewborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with

TUKYSA. Breast-feeding may be resumed 1 week after treatment.

No fertility studies in men or women have been conducted. Based on findings from animal studies,tucatinib may impair fertility in females of reproductive potential (see section 5.3).

TUKYSA has no or negligible influence on the ability to drive and use machines. The clinical status ofthe patient should be considered when assessing the patient’s ability to perform tasks that requirejudgment, motor, or cognitive skills.

The most commonly reported Grade 3 and 4 adverse reactions (≥ 5%) during treatment are diarrhoea(13%), ALT increased (6%) and AST increased (5%).

Serious adverse reactions occurred in 29% of patients treated with tucatinib, and include diarrhoea(4%), vomiting (3%), and nausea (2%).

Adverse reactions leading to discontinuation of TUKYSA occurred in 6% of patients; the mostcommon adverse reactions leading to discontinuation were diarrhoea (1%) and ALT increased (1%).

Adverse reactions leading to dose reduction of TUKYSA occurred in 23% of patients; the mostcommon adverse reactions leading to dose reduction were diarrhoea (6%), ALT increased (5%), and

AST increased (4%).

The data summarised in this section reflect exposure to TUKYSA in 431 patients with locallyadvanced unresectable or metastatic HER2-positive breast cancer who received TUKYSA incombination with trastuzumab and capecitabine across two studies, HER2CLIMB and ONT-380-005(see section 5.1). The median duration of exposure to TUKYSA across these studies was 7.4 months(range, < 0.1, 43.6).

The adverse reactions observed during treatment are listed in this section by frequency category.

Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10);uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known(cannot be estimated from the available data).

Table 4: Adverse reactions

System organ class Frequency Adverse reaction

Respiratory, thoracic and Very common Epistaxismediastinal disorders

Gastrointestinal disorders Very common Diarrhoea, Nausea, Vomiting, Stomatitis1

Skin and subcutaneous tissue Very common Rash2disorders

Musculoskeletal and connective Very common Arthralgiatissue disorders

Investigations Very common AST increase, ALT increase, Blood bilirubinincreased3, weight decrease1. Stomatitis includes stomatitis, oropharyngeal pain, mouth ulceration, oral pain, lip ulceration, glossodynia, tongueblistering, lip blister, oral dysaesthesia, tongue ulceration, aphthous ulcer2. Rash includes rash maculo-papular, rash, dermatitis acneiform, erythema, rash macular, rash papular, rash pustular, rashpruritic, rash erythematous, skin exfoliation, urticaria, dermatitis allergic, palmar erythema, plantar erythema and skintoxicity3. Blood bilirubin increased also includes hyperbilirubinemia

Increased ALT, AST, or bilirubin

In HER2CLIMB, increased ALT, AST or bilirubin occurred in 41% of patients treated with tucatinibin combination with trastuzumab and capecitabine. Grade 3 and above events occurred in 9% ofpatients. Increased ALT, AST or bilirubin led to dose reduction in 9% of patients and treatmentdiscontinuation in 1.5% of patients. The median time to onset of any grade increased ALT, AST, orbilirubin was 37 days; 84% of events resolved, with a median time to resolution of 22 days.

Monitoring and dose modification (including discontinuation) should be considered (see section 4.4).

In HER2CLIMB, diarrhoea occurred in 82% of patients treated with tucatinib in combination withtrastuzumab and capecitabine. Grade 3 and above diarrhoea events occurred in 13% of patients. Twopatients who developed Grade 4 diarrhoea subsequently died, with diarrhoea as a contributor to death.

Diarrhoea led to dose reduction in 6% of the patients and treatment discontinuation in 1% of thepatients. The median time to onset of any grade diarrhoea was 12 days; 81% of diarrhoea eventsresolved, with a median time to resolution of 8 days. Prophylactic use of antidiarrheals was notrequired. Antidiarrheal medicinal products were used in less than half of the treatment cycles wherediarrhoea events were reported. The median duration of antidiarrheal use was 3 days per cycle (seesection 4.4).

Increased creatinine without impaired renal function

Increase in serum creatinine has been observed in patients treated with tucatinib due to inhibition ofrenal tubular transport of creatinine without affecting glomerular function. In clinical studies, increasesin serum creatinine (30% mean increase) occurred within the first cycle of tucatinib, remained elevatedbut stable throughout treatment and were reversible upon treatment discontinuation.

In the HER2CLIMB study, 82 patients who received tucatinib were ≥ 65 years, of whom 8 patientswere ≥ 75 years. The incidence of serious adverse reactions was 34% in patients ≥ 65 years comparedto 28% in patients < 65 years. There were too few patients ≥ 75 years to assess differences in safety.

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 specific antidote, and the benefit of haemodialysis in the treatment of tucatinib overdose isunknown. In the event of an overdose, treatment with tucatinib should be withheld and generalsupportive measures should be applied.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EH03.

Tucatinib is a reversible, potent and selective tyrosine kinase inhibitor of HER2. In cellular signallingassays, tucatinib is > 1 000-fold more selective for HER2 compared to epidermal growth factorreceptor. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition ofdownstream cell signalling and cell proliferation, and induces death in HER2 driven tumour cells. Invivo, tucatinib inhibits the growth of HER2 driven tumours and the combination of tucatinib andtrastuzumab showed enhanced anti-tumour activity in vitro and in vivo compared to either medicinalproduct alone.

Multiple doses of tucatinib 300 mg twice a day did not have an effect on the QTc interval in a TQTstudy in healthy subjects.

The efficacy of tucatinib in combination with trastuzumab and capecitabine was evaluated in arandomised, double-blind, placebo-controlled, active comparator, global study (HER2CLIMB).

Patients enrolled had locally advanced unresectable or metastatic HER2-positive breast cancer, with orwithout brain metastases, and had prior treatment with trastuzumab, pertuzumab, and trastuzumabemtansine (T-DM1) separately or in combination, in the neoadjuvant, adjuvant or metastatic setting.

HER2 overexpression or amplification was confirmed by central laboratory analysis.

Patients with brain metastases, including those with untreated or progressing lesions, were eligible toenrol provided they were neurologically stable and did not require immediate brain radiation orsurgery. Patients who required immediate local intervention could receive local therapy and besubsequently enrolled. The study included patients with untreated brain metastases and patients withtreated brain metastases that were either stable or progressing since last brain radiation or surgery.

Patients were excluded from the study if they received systemic corticosteroids (≥ 2 mg total daily ofdexamethasone or equivalent) for control of symptoms of CNS metastases < 28 days prior to the firstdose of study treatment. The study also excluded patients with leptomeningeal disease. Patients whohad previously been treated with HER2 tyrosine kinase inhibitors were excluded with the exception ofpatients who received lapatinib for ≤ 21 days and was discontinued for reasons other than diseaseprogression or severe toxicity. For patients with hormone receptor-positive tumours, endocrine therapywas not permitted as concomitant therapy, with the exception of gonadotropin-releasing hormoneagonists used for ovarian suppression in premenopausal women.

A total of 612 patients were randomised 2:1 to receive tucatinib in combination with trastuzumab andcapecitabine (N=410) or placebo in combination with trastuzumab and capecitabine (N=202).

Randomisation was stratified by the presence or history of brain metastases (yes vs. no), Eastern

Cooperative Oncology Group (ECOG) performance status (0 vs. 1), and region (U.S., Canada, or restof world).

Patient demographics were balanced between treatment arms. The median age was 54 years(range, 25 to 82); 116 (19%) patients were aged 65 years or older. 444 patients were white (73%) and607 were female (99%). 314 patients (51%) had an ECOG performance status of 1 and 298 patients(49%) had an ECOG performance status of 0. Sixty percent had oestrogen and/or progesteronereceptor-positive disease. Forty-eight percent of patients had a presence or history of brain metastases;of these, 23% had untreated brain metastases, 40% had treated but stable brain metastases, and 37%had treated but radiographically progressing brain metastases. Additionally, 49% of patients had lungmetastases, 35% had liver metastases, and 14% had skin metastases. Patients had a median of 4 (range,2 to 17) prior lines of systemic therapy and a median of 3 (range, 1 to 14) prior lines of systemictherapy in the metastatic setting. All patients received prior trastuzumab-based treatments andtrastuzumab emtansine, while all but two patients had prior pertuzumab-based treatment.

Tucatinib or placebo, 300 mg orally twice per day, was administered until disease progression orunacceptable toxicity. Trastuzumab was administered intravenously as a loading dose of 8 mg/kg on

Day 1 of Cycle 1, followed by a maintenance dose of 6 mg/kg on Day 1 of each subsequent 21-daycycle. An alternate dosing option for trastuzumab was a fixed dose of 600 mg administeredsubcutaneously on Day 1 of each 21-day cycle. Capecitabine, 1 000 mg/m2 orally twice per day, wasadministered on Days 1 through 14 of each 21-day cycle.

The primary endpoint was progression-free survival (PFS) by blinded independent central review(BICR) in the first 480 randomised patients. In this population, the median duration of exposure totucatinib was 7.3 months (range < 0.1, 35.1) for patients on the tucatinib + trastuzumab + capecitabinearm compared to 4.4 months (range < 0.1, 24.0) of placebo for patients on the placebo + trastuzumab +capecitabine arm. Similar differences in exposure to trastuzumab and capecitabine were observed.

Secondary endpoints were evaluated in all randomised patients (N=612) and included overall survival(OS), PFS among patients with a history or presence of brain metastases (PFSBrainMets) and confirmedobjective response rate (ORR).

Primary and key secondary endpoint results were consistent across pre-specified subgroups: hormonereceptor status, presence or history of brain metastases, ECOG status, and region. PFS as determinedby the investigator was consistent with PFS as assessed by BICR.

Efficacy results from the primary analysis are summarised in Table 5 and Figures 1 and 2.

Table 5: Efficacy results from the HER2CLIMB study (primary analysis)

Tucatinib + Trastuzumab + Placebo + Trastuzumab +

Capecitabine Capecitabine

PFS1 N=320 N=160

Number of events (%) 178 (56) 97 (61)

Hazard ratio (95% CI)2 0.54 (0.42, 0.71)

P-value3 < 0.00001

Median (months) (95% CI) 7.8 (7.5, 9.6) 5.6 (4.2, 7.1)

OS N=410 N=202

Number of deaths, n (%) 130 (32) 85 (42)

Hazard ratio (95% CI)2 0.66 (0.50, 0.87)

P-value3 0.00480

Median OS, months (95% CI) 21.9 (18.3, 31.0) 17.4 (13.6, 19.9)

PFS 4

BrainMets N=198 N=93

Number of events (%) 106 (53.5) 51 (54.8)

Hazard ratio (95% CI)2 0.48 (0.34, 0.69)

P-value3 < 0.00001

Median (months) (95% CI) 7.6 (6.2, 9.5) 5.4 (4.1, 5.7)

Confirmed ORR for Patients with

N=340 N=171

Measurable Disease

ORR (95% CI)5 40.6 (35.3, 46.0) 22.8 (16.7, 29.8)

P-value6 0.00008

CR (%) 3 (0.9) 2 (1.2)

PR (%) 135 (39.7) 37 (21.6)

DOR

Median DOR in months (95% CI)7 8.3 (6.2, 9.7) 6.3 (5.8, 8.9)

BICR=blinded independent central review; CI=confidence interval; PFS=progression-free survival; OS=overall survival;

ORR=objective response rate; CR=complete response; PR=partial response; DOR=duration of response.

1. Primary PFS analysis conducted in first 480 randomised patients. PFS based on Kaplan-Meier analyses.

2. Hazard ratio and 95% confidence intervals are based on stratified Cox proportional hazards regression model controllingfor stratification factors (presence or history of brain metastases, Eastern Cooperative Oncology Group (ECOG) status,and region of world)3. Two-sided p-value based on re-randomisation procedure controlling for stratification factors4. Analysis includes patients with history or presence of parenchymal brain metastases at baseline, including target andnon-target lesions. Does not include patients with dural lesions only.

5. Two-sided 95% exact confidence interval, computed using the Clopper-Pearson method6. Cochran-Mantel-Haenszel test controlling for stratification factors (presence or history of brain metastases, Eastern

Cooperative Oncology Group (ECOG) status, and region of world)7. Calculated using the complementary log-log transformation method

Figure 1. Kaplan-Meier curves of progression-free survival (per BICR)

TUC+Tras+Cape

Pbo+Tras+Cape

Patients at risk Months since randomisation

TUC+Tras+Cape

Pbo+Tras+Cape

Figure 2. Kaplan-Meier curves of progression-free survival (per BICR) in patients with brainmetastases

Pbo+Tras+Cape TUC+Tras+Cape

Months since randomisation

Patients at risk

TUC+Tras+Cape

Pbo+Tras+Cape

As planned per protocol, approximately two years after last patient randomised, the final OS analysiswas performed based on 370 events, which corresponded to a median follow-up of 29.6 months.

Median OS was 24.7 months (95% CI: 21.6, 28.9) for patients on the tucatinib + trastuzumab +

Progression free survival

Progression free survivalcapecitabine arm compared to 19.2 months (95% CI: 16.4, 21.4) for patients on the placebo +trastuzumab + capecitabine arm (HR=0.725; 95% CI: 0.585, 0.898). The final OS analysis is present in

Figure 3.

Figure 3. Kaplan-Meier curves of overall survival (final analysis)

TUC+Tras+Cape

Pbo+Tras+Cape

Patients at risk Months since randomisation

TUC+Tras+Cape

Pbo+Tras+Cape

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

TUKYSA in all subsets of the paediatric population in malignant breast neoplasms (see section 4.2 forinformation on paediatric use).

Plasma tucatinib exposure (AUCinf and Cmax) demonstrated dose proportional increases at oral dosesfrom 50 to 300 mg (0.17 to 1 time the recommended dose). Tucatinib exhibited 1.7-fold accumulationfor AUC and 1.5-fold accumulation for Cmax following administration of 300 mg tucatinib twice dailyfor 14 days. Time to steady-state was approximately 4 days.

Following a single oral dose of 300 mg tucatinib, the median time to peak plasma concentration wasapproximately 2.0 hours (range 1.0 to 4.0 hours).

Following administration of a single dose of tucatinib in 11 subjects after a high-fat meal(approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUCinf increased by 1.5-fold,the Tmax shifted from 1.5 hours to 4.0 hours, and Cmax was unaltered. The effect of food on the

Overall survivalpharmacokinetics of tucatinib was not clinically meaningful, thus tucatinib may be administeredwithout regard to food.

The apparent volume of distribution of tucatinib was approximately 1670 L in healthy subjects after asingle dose of 300 mg. The plasma protein binding was 97.1% at clinically relevant concentrations.

Tucatinib is metabolised primarily by CYP2C8 and to a lesser extent via CYP3A and aldehydeoxidase.

In vitro drug interaction studies

Tucatinib is a substrate of CYP2C8 and CYP3A.

Tucatinib is a reversible inhibitor of CYP2C8 and CYP3A and a time-dependent inhibitor of CYP3A,at clinically relevant concentrations.

Tucatinib has low potential to inhibit CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and

UGT1A1 at clinically relevant concentrations.

Tucatinib is a substrate of P-gp and BCRP. Tucatinib is not a substrate of OAT1, OAT3, OCT1,

OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, and BSEP.

Tucatinib inhibits MATE1/MATE2-K-mediated transport of metformin and OCT2/MATE1-mediatedtransport of creatinine. The observed serum creatinine increase in clinical studies with tucatinib is dueto inhibition of tubular secretion of creatinine via OCT2 and MATE1.

Following a single oral dose of 300 mg, tucatinib is cleared from plasma with a geometric meanhalf-life of approximately 8.5 hours and apparent clearance of 148 L/h in healthy subjects.

Excretion

Tucatinib is predominantly eliminated by the hepatobiliary route and is not appreciably renallyeliminated. Following a single oral dose of 300 mg 14C-tucatinib, approximately 85.8% of the totalradiolabelled dose was recovered in faeces (15.9% of the administered dose as unchanged tucatinib)and 4.1% in urine with an overall total recovery of 89.9% within 312 hours post-dose. In plasma,approximately 75.6% of the plasma radioactivity was unchanged, 19% was attributed to identifiedmetabolites, and approximately 5% was unassigned.

Based on population pharmacokinetic analysis according to demographic characteristics, age(< 65 years (N=211); ≥ 65 years (N=27)), albumin (25.0 to 52.0 g/L), creatinine clearance (CLcr 60 to89 mL/min (N=89); CLcr 30 to 59 mL/min (N=5)), body weight (40.7 to 138.0 kg), and race (White(N=168), Black (N=53), or Asian (N=10)) did not have a clinically meaningful effect on tucatinibexposure. There are no data for subjects with severely impaired renal function.

The pharmacokinetics of tucatinib have not been evaluated in a dedicated renal impairment study.

Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment had no clinically relevanteffect on tucatinib exposure. Tucatinib AUCinf was increased by 1.6-fold in subjects with severe(Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function. There are nodata for breast cancer patients with severely impaired hepatic function.

Carcinogenicity studies have not been conducted with tucatinib.

Tucatinib was not clastogenic or mutagenic in the standard battery of genotoxicity assays.

In repeat-dose toxicity studies in rats, decreased corpora lutea/corpus luteum cyst, increased interstitialcells of the ovary, atrophy of the uterus, and mucification of the vagina were observed at doses of≥ 6 mg/kg/day administered twice daily, equivalent to 0.09 times the human exposure based on

AUC0-12 at the recommended dose. No histological effects were observed on male or femalereproductive tracts in cynomolgus monkeys or on male reproductive tracts in rats at doses resulting inexposures up to 8 times (in monkey) or 13 times (in rat) the human exposure at the recommended dosebased on AUC0-12.

Embryo-foetal development studies were conducted in rabbits and rats. In pregnant rabbits, increasedresorptions, decreased percentages of live foetuses, and skeletal, visceral, and external malformationswere observed in foetuses at ≥ 90 mg/kg/day; at this dose, maternal exposure is approximatelyequivalent to the human exposure at the recommended dose based on AUC. In pregnant rats,decreased maternal body weight and body weight gain were observed at doses of ≥ 90 mg/kg/day.

Foetal effects of decreased weights and delayed ossification were observed at ≥ 120 mg/kg/day; at thisdose, maternal exposure is approximately 6-fold higher than human exposure at the recommendeddose based on AUC.

Copovidone (E1208)

Crospovidone (E1202)

Sodium chloride

Potassium chloride (E508)

Sodium hydrogen carbonate (E500)

Silica, colloidal anhydrous (E551)

Magnesium stearate

Microcrystalline cellulose

Poly(vinyl alcohol) (E1203)

Titanium dioxide (E171)

Macrogol 4000 (E1521)

Talc (E553b)

Yellow iron oxide (E172)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

OPA/ALU/PVC blister sealed with aluminium foil.

TUKYSA 50 mg film-coated tablets

Each carton contains 88 film-coated tablets (11 blisters with 8 tablets each).

TUKYSA 150 mg film-coated tablets

Each carton contains 84 film-coated tablets (21 blisters with 4 tablets each).

Not all pack sizes may be marketed.

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

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

TUKYSA 50 mg film-coated tablets: EU/1/20/1526/001

TUKYSA 150 mg film-coated tablets: EU/1/20/1526/002

Date of first authorisation: 11 February 2021

Date of latest renewal: 17 September 2025

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

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