GAVRETO 100mg capsules medication leaflet

GAVRETO 100 mg hard capsules

Each hard capsule contains 100 mg of pralsetinib.

For the full list of excipients, see section 6.1.

Hard capsule.

Light blue, opaque hard capsule, size 0 (22 mm long x 7 mm wide) with “BLU-667” printed on thecapsule shell body and “100 mg” on the capsule shell cap in white ink.

Gavreto is indicated as monotherapy for the treatment of adult patients with rearranged duringtransfection (RET) fusion-positive advanced non-small cell lung cancer (NSCLC) not previouslytreated with a RET inhibitor.

Therapy should be initiated by a physician experienced in the administration of anticancer medicinalproducts.

Patient selection for treatment of RET fusion-positive advanced NSCLC should be based on avalidated test method.

The recommended dose is 400 mg pralsetinib once daily on an empty stomach (see method ofadministration). Treatment should be continued until disease progression or unacceptable toxicity.

If vomiting occurs after taking a dose of pralsetinib, the patient should not take an additional dose butcontinue with the next scheduled dose.

If a dose of pralsetinib is missed, the patient should make up for the missed dose as soon as possibleon the same day. The regular daily dose schedule for pralsetinib should be resumed the next day.

Dose modifications for adverse reactions

Interruption of treatment with or without dose reduction may be considered to manage adversereactions based on severity and clinical presentation.

Patients may have their dose reduced by 100 mg decrements to a minimum dose of 100 mg once daily.

Gavreto should be permanently discontinued in patients who are unable to tolerate 100 mg orally oncedaily.

Recommended dose modifications for adverse reactions are indicated in Table 1.

Table 1. Recommended dose modifications for Gavreto for adverse reactions

Adverse reaction Severitya Dose modification

Pneumonitis/Interstitial Grade 1 or 2 Interrupt treatment with Gavreto untillung disease (ILD) resolution. Resume at a reduced dose.(see section 4.4) Permanently discontinue Gavreto for recurrentpneumonitis/ILD.

Grade 3 or 4 Permanently discontinue for pneumonitis/ILD.

Hypertension Grade 3 Interrupt treatment with Gavreto for Grade 3hypertension that persists despite optimalantihypertensive therapy. Resume at a reduceddose when hypertension is controlled.

Grade 4 Permanently discontinue Gavreto.

Transaminase elevations Grade 3 or 4 Interrupt treatment with Gavreto and monitoraspartate aminotransferase (AST) and alanineaminotransferase (ALT) once weekly untilresolution to Grade 1 or baseline.

Resume at a reduced dose.

If the transaminase elevation recurs at Grade 3or higher, permanently discontinue treatmentwith Gavreto.

Haemorrhagic events Grade 3 or 4 Interrupt treatment with Gavreto until resolutionto Grade 1.

Resume at a reduced dose.

Permanently discontinue Gavreto for life-threatening or recurrent severe haemorrhagicevents.

QT prolongation Grade 3 Interrupt treatment with Gavreto for QTcintervals >500 ms until QTc interval returns to<470 ms.

Resume at the same dose if risk factors thatcause QT prolongation are identified andcorrected.

Resume treatment at a reduced dose if other riskfactors that cause QT prolongation are notidentified.

Grade 4 Permanently discontinue Gavreto if the patienthas life-threatening arrhythmia.

Other clinically significant Grade 3 or 4 Interrupt treatment with Gavreto untiladverse reactions (see improvement to ≤Grade 2. Resume at a reducedsection 4.8) dose.

Permanently discontinue for recurrent Grade 4adverse reactions.

a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse

Events (NCI-CTCAE) version 4.03

Dose modification for use with cytochrome P-450 (CYP)3A4 and/or P-glycoprotein (P-gp) inhibitors

Concomitant use of pralsetinib with any of the following should be avoided (see section 4.4 andsection 4.5):

* Combined P-gp and strong CYP3A4 inhibitors

* Strong CYP3A4 inhibitors

* Moderate CYP3A4 inhibitors

* P-gp inhibitors

* Combined P-gp and moderate CYP3A4 inhibitors

If co-administration with any of the above inhibitors cannot be avoided, the current dose of pralsetinibshould be reduced as recommended in Table 2. After the co-administered inhibitor has beendiscontinued for 3 to 5 elimination half-lives of the inhibitor, the pralsetinib dose that was taken priorto the use of the inhibitor should be resumed.

Table 2. Recommended dose modifications for Gavreto for co-administration with CYP3A4and/or P-gp inhibitors

Current Gavreto dose Recommended Gavreto dose

* Strong CYP3A4 inhibitors;

Combined P-gp and strong * Moderate CYP3A4 inhibitors;

CYP3A4 inhibitors * P-gp inhibitors;

* Combined P-gp and moderate

CYP3A4 inhibitors400 mg orally oncedaily 200 mg orally once daily 300 mg orally once daily300 mg orally oncedaily 200 mg orally once daily 200 mg orally once daily200 mg orally oncedaily 100 mg orally once daily 100 mg orally once daily

Dose modification for use with CYP3A4 inducers

Concomitant use of pralsetinib with strong or moderate CYP3A4 inducers should be avoided (seesection 4.4 and section 4.5).

No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinineclearance [CLCR] 30 to 89 mL/min estimated by Cockcroft-Gault). Pralsetinib has not been studied inpatients with severe renal impairment (CLCR 15 to 29 mL/min) or end-stage renal disease(CLCR <15 mL/min). Since pralsetinib elimination via the kidney is negligible, no dose adjustment isrequired in patients with severe renal impairment or end-stage renal disease (see section 5.2).

No dose adjustment is recommended for patients with mild (total bilirubin ≤ upper limit of normal[ULN] and aspartate aminotransferase [AST] > ULN or total bilirubin > 1 to 1.5 times ULN and any

AST), moderate (total bilirubin > 1.5 to 3 times ULN and any AST) or severe hepatic impairment(total bilirubin > 3 times ULN and any AST) (see section 5.2).

No dose adjustment is recommended for patients aged 65 years and above (see section 5.1).

The safety and efficacy of pralsetinib in paediatric patients below 18 years of age with RETfusion-positive advanced NSCLC have not been established. No data are available.

Gavreto is for oral use. Patients should swallow the hard capsules whole with a glass of water, on anempty stomach. They should not eat for at least two hours before and at least one hour after takingpralsetinib (see section 5.2).

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

Pneumonitis/ILD

Severe, life-threatening or fatal cases of pneumonitis/ILD have been reported in patients who receivedpralsetinib in clinical trials (see section 4.8). Patients who present with clinically symptomaticpneumonitis or ILD were excluded from clinical trials.

Patients should be advised to contact their healthcare provider immediately to report new or worseningrespiratory symptoms.

Patients who present with acute or worsening of respiratory symptoms indicative of pneumonitis/ILD(e.g., dyspnoea, cough, and fever) should be investigated to exclude other potential causes. Ifpneumonitis/ILD is considered to be related to pralsetinib, the dose of Gavreto should be interrupted,reduced or permanently discontinued based on severity of confirmed pneumonitis/ILD (seesection 4.2).

Hypertension was observed in pralsetinib-treated patients in clinical trials (see section 4.8). Treatment-related hypertension was most commonly managed with anti-hypertensive medicinal products.

Treatment with Gavreto should not be initiated in patients with uncontrolled hypertension. Pre-existing hypertension should be adequately controlled before starting Gavreto treatment. Monitoringof blood pressure is recommended after 1 week, at least monthly thereafter and as clinically indicated.

Anti-hypertensive therapy should be initiated or adjusted as appropriate. The dose should beinterrupted, reduced, or permanently discontinued based on the severity of hypertension observedduring treatment with Gavreto (see section 4.2).

Severe cases of transaminase elevations have been reported in patients who received pralsetinib inclinical trials (see section 4.8).

ALT and AST should be monitored prior to initiating Gavreto, every 2 weeks during the first3 months, then monthly thereafter and as clinically indicated. Treatment with Gavreto should beinterrupted, reduced or permanently discontinued based on severity of the transaminase elevationobserved during treatment with Gavreto (see section 4.2).

Haemorrhagic events

Severe, including fatal, haemorrhagic events can occur with Gavreto. In patients with life-threateningor recurrent severe haemorrhage, Gavreto should be permanently discontinued (see section 4.2).

Prolongation of the QT interval has been observed in patients who received Gavreto in clinical trials(see section 4.8). Therefore, before starting Gavreto treatment, patients should have a QTc interval≤470 ms and serum electrolytes within normal range. Hypokalaemia, hypomagnesaemia, andhypocalcaemia should be corrected both prior and during Gavreto treatment. Electrocardiograms(ECGs) and serum electrolytes should be monitored at the end of the first week and of the first monthof Gavreto treatment, then periodically, as clinically indicated, depending also on presence of otherrisk factors (e.g. intercurrent diarrhoea, vomiting, nausea, concomitant medications).

Pralsetinib should be used with caution in patients with medical history of cardiac arrhythmias or QTinterval prolongation, as well as in patients on strong CYP 3A4 inhibitors or on medicinal productsknown to be associated with QT/QTc prolongation.

Gavreto may require interruption, dose modification, or discontinuation (see section 4.2).

Tuberculosis, mostly extrapulmonary, has been reported in patients receiving Gavreto. Before startingtreatment, patients should be evaluated for active and inactive (“latent”) tuberculosis, as per localrecommendations. In patients with active or latent tuberculosis, standard antimycobacterial therapyshould be initiated before treatment with Gavreto is started.

Co-administration of Gavreto with combined P-gp inhibitors and strong CYP3A4 inhibitors, P-gpinhibitors, strong or moderate CYP3A4 inhibitors or combined P-gp and moderate CYP3A4 inhibitorsshould be avoided because they may increase the plasma concentration of pralsetinib (see sections 4.2and 4.5).

Co-administration of Gavreto with strong or moderate CYP3A4 inducers should be avoided becausethey may decrease the plasma concentration of pralsetinib (see section 4.2 and section 4.5).

During treatment with Gavreto and for at least 1 week after the final dose, male patients with femalepartners of childbearing potential must use effective contraception, including a barrier method (seesection 4.6).

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

Gavreto. A highly effective non-hormonal method of contraception is required for female patientsduring treatment with pralsetinib, because pralsetinib can render hormonal contraceptives ineffective.

If a hormonal method of contraception is unavoidable, then a condom must be used in combinationwith the hormonal method. Effective contraception must be continued for at least 2 weeks after thefinal dose (see section 4.6).

This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to sayessentially “sodium-free”.

CYP3A4 and/or P-gp inhibitors

P-gp inhibitors: Co-administration of a single 200 mg dose of pralsetinib with cyclosporine single600 mg dose (a P-gp and weak-moderate CYP3A4 inhibitor) in healthy subjects increased pralsetinib

AUC0-∞ by 81% and Cmax by 48%, relative to a 200 mg dose of pralsetinib administered alone.

Combined P-gp and strong CYP3A4 inhibitors: Co-administration of 200 mg pralsetinib once dailywith itraconazole 200 mg once daily (a P-gp inhibitor and strong CYP3A4) increased pralsetinib

AUC0-∞ by 251% and Cmax by 84% , compared to pralsetinib administered alone.

Co-administration of pralsetinib with P-gp and/or strong or moderate CYP3A4 inhibitors may increasepralsetinib plasma concentrations, which may increase the risk of adverse reactions of pralsetinib. Co-administration of pralsetinib with the following should be avoided (see section 4.4):

* combined P-gp and strong CYP3A4 inhibitors (including, but not limited to, ketoconazole,itraconazole, cobicistat, clarithromycin, ritonavir, or saquinavir)

* strong CYP3A4 inhibitors (including, but not limited to, telithromycin, troleandomycin,voriconazole, ceritinib, idelalisib, nefazodone, nelfinavir, or grapefruit juice)

* moderate CYP3A4 inhibitors (including, but not limited to, aprepitant, ciprofloxacin,conivaptan, crizotinib, fluconazole, fluvoxamine, imatinib, isavuconazole, or tofisopam)

* P-gp inhibitors (including, but not limited to, cyclosporine, carvedilol or quinidine)

* combined P-gp and moderate CYP3A4 inhibitors (including, but not limited to, dronedarone,diltiazem, erythromycin, verapamil)

If co-administration with any of the above inhibitors cannot be avoided, reduce the current dose ofpralsetinib (section 4.2).

Co-administration of pralsetinib with strong CYP3A4 inducers can decrease pralsetinib plasmaconcentrations, which may decrease the efficacy of pralsetinib. Co-administration of 400 mgpralsetinib as a single dose with rifampin 600 mg once daily (a strong CYP3A4 inducer) decreasedpralsetinib AUC0-∞ by 68% and Cmax by 30%. Therefore, co-administration of pralsetinib with strong

CYP3A4 inducers (including, but not limited to, carbamazepine, phenytoin, rifabutin, rifampicin and

St. John’s Wort [Hypericum perforatum]) should be avoided (see section 4.4).

Sensitive substrates of CYP3A4, CYP2C8, CYP2C9, P-gp, BCRP, OATP1B1, OATP1B3, OAT1,

MATE1 and MATE2-K with narrow therapeutic index

Co-administration of pralsetinib can alter the exposure of sensitive substrates of CYP enzymes(CYP3A4, CYP2C9 and CYP2C8) and transporters (P-gp, BCRP, OATP1B1, OATP1B3, OAT1,

MATE1 and MATE2-K). Substrate drugs of these CYP enzymes and transporters with narrowtherapeutic index (including, but not limited to cyclosporine, paclitaxel and warfarin) should beavoided.

Women of childbearing potential/Contraception in females and males

Women of childbearing potential should be informed that pralsetinib may cause foetal harm (seesection 5.3).

The pregnancy status of women of childbearing potential should be verified prior to initiating Gavretotreatment.

Women of childbearing potential have to use highly effective non-hormonal contraception duringtreatment and for at least 2 weeks following the last dose of Gavreto (see section 4.4).

Males with female partners of childbearing potential must use effective contraception, including abarrier method, during treatment with Gavreto and for at least 1 week following the last dose of

Gavreto.

Patients should be advised to contact their healthcare provider immediately if they become pregnant,or if pregnancy is suspected, while taking Gavreto.

There are no data from the use of pralsetinib in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3).

Based on its mechanism of action and findings in animals, pralsetinib may cause foetal harm whenadministered to pregnant women.

Gavreto should not be used during pregnancy unless the clinical condition of the woman requirestreatment with pralsetinib.

It is unknown whether pralsetinib or its metabolites are excreted in human milk.

A risk to the breast-fed child cannot be excluded.

Breast-feeding should be discontinued during treatment with Gavreto and for 1 week following thefinal dose.

There is no clinical data on the effects of pralsetinib on fertility.

Based on non-clinical safety findings, fertility may be compromised during treatment with pralsetinib(see section 5.3). Men and women should seek advice on effective fertility preservation beforetreatment.

Gavreto has minor influence on the ability to drive and use machines. Caution should be exercisedwhen driving or operating machines as patients may experience fatigue while taking Gavreto (seesection 4.8).

The most common adverse reactions were anaemia (53.0%), aspartate aminotransferase increased(49.1%), neutropenia (46.7%), musculoskeletal pain (44.4%), constipation (43.9%), fatigue (42.2%),alanine aminotransferase increased (37.0%), leukopenia (37.0%), and hypertension (35.0%).

The most common serious adverse reactions were pneumonia (15.6%), pneumonitis (5.7%) andanaemia (5.2%).

The most common severe adverse reactions were anaemia (22.4%), neutropenia (21.1%), hypertension(17.6%), pneumonia (15.4%), and lymphopenia (17.4%).

Based on the data from clinical trials, exposure-response relationships for any Grade 3 or 4 adversereaction were observed at higher exposures, with a faster time to onset for adverse reactions withincreasing pralsetinib exposure.

Dose reductions due to adverse reactions occurred in 46.7% of patients treated with Gavreto. The mostcommon adverse reactions resulting in dose reductions were neutropenia (15.6%), anaemia (10.6%),lymphopenia (7.2%), pneumonitis (5.7%), blood creatine phosphokinase increased (5.2%),hypertension (4.8%), leukopenia (4.6%), and fatigue (4.1%).

Permanent discontinuation due to adverse reactions occurred in 10.6% of patients treated with

Gavreto. The most common adverse reactions that led to permanent discontinuation of Gavreto werepneumonia and pneumonitis (2.6% and 2.2%, respectively).

The safety population includes a total of 540 patients, including 281 patients with advanced NCSLC,as well as patients with other solid tumours (including RET fusion thyroid cancer and RET mutationmedullary thyroid cancer), who received pralsetinib at a starting dose of 400 mg, see section 5.1. Noclinically relevant differences in the safety profile across indications have been observed.

Adverse reactions reported in patients treated with Gavreto in the ARROW trial are listed below(Table 3), according to the MedDRA System Organ Class and frequency.

Frequencies are defined using the following convention: 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), and notknown (cannot be estimated from the available data).

Within each system organ class, adverse reactions are presented in order of decreasing frequency andseverity.

Table 3. Adverse reactions reported in all patients treated with 400 mg Gavreto in the

ARROW trial (N=540)

System organ class/ All

Adverse reactions Frequency Grades 3-4category grades% %

Pneumonia1 Very common 22.4 13.1

Urinary tract infection 14.8 4.4

Tuberculosis2 Uncommon 0.7 0.4

Anaemia3 53.0 22.4

Neutropenia4 46.7 21.1

Leukopenia5 Very common 37.0 8.9

Lymphopenia6 26.9 17.4

Thrombocytopenia7 19.6 4.8

Hypocalcaemia 23.1 3.9

Hyperphosphataemia 17.4 0.2

Hypoalbuminaemia Very common 14.8 -

Hypophosphataemia 13.0 6.7

Hyponatraemia 12.2 4.4

Headache8 18.0 0.6

Taste disorder9 Very common 16.7 -

Hypertension10

Haemorrhage11 Very common 35.0 17.620.6 3.9

Cough12 28.1 0.6

Dyspnoea Very common 20.4 2.0

Pneumonitis13 12.2 3.3

Constipation 43.9 0.6

Diarrhoea 33.1 3.1

Nausea Very common 19.6 0.2

Abdominal pain14 17.8 1.5

Dry mouth 16.5 -

Vomiting 14.8 1.1

Stomatitis15 Common 6.9 1.3

Aspartate aminotransferase increased* 49.1 6.9

Alanine aminotransferase increased* Very common 37.0 4.8

Hyperbilirubinaemia16 14.4 1.7

Rash17 Very common 19.1 -

Musculoskeletal pain18 44.4 2.6

Blood creatine phosphokinase increased Very common 16.7 7.6

Fatigue19 42.2 4.1

Oedema20 Very common 31.5 0.2

Pyrexia 27.8 1.5

QT prolongation21 Common 5.2 0.4

Blood creatinine increased Very common 25.4 0.6

Blood alkaline phosphatase increased Very common 12.0 1.51 includes pneumonia, pneumocystis jirovecii pneumonia, pneumonia cytomegaloviral, atypical pneumonia,lung infection, pneumonia bacterial, pneumonia haemophilus, pneumonia influenzal, pneumoniastreptococcal, pneumonia moraxella, pneumonia staphylococcal, pneumonia pseudomonal, atypicalmycobacterial pneumonia, pneumonia legionella2 most of the cases reported extrapulmonary tuberculosis such as lymph node tuberculosis, peritonealtuberculosis or renal tuberculosis3 includes anaemia, haematocrit decreased, red blood cell count decreased, haemoglobin decreased, aplasticanaemia4 includes neutrophil count decreased, neutropenia5 includes white blood cell count decreased, leukopenia6 includes lymphopenia, lymphocyte count decreased7 includes thrombocytopenia, platelet count decreased8 includes headache, tension headache9 includes ageusia, dysgeusia10 includes hypertension, blood pressure increased11 includes 39 preferred terms from the SMQ Haemorrhage (excl laboratory terms) narrow, with the exclusionof terms related to invasive drug administration, terms related to rupture, disseminated intravascularcoagulopathy, terms related to traumatic haemorrhages, and haemorrhagic terms related to pregnancy, birthor neonatal12 includes cough, productive cough13 includes pneumonitis, interstitial lung disease14 includes abdominal pain, abdominal pain upper15 includes stomatitis, aphthous ulcer16 includes blood bilirubin increased, hyperbilirubinaemia, bilirubin conjugated increased, blood bilirubinunconjugated increased17 includes rash, rash maculo-papular, dermatitis acneiform, erythema, rash generalised, rash papular, rashpustular, rash macular, rash erythematous18 includes musculoskeletal chest pain, myalgia, arthralgia, pain in extremity, neck pain, musculoskeletal pain,back pain, bone pain, spinal pain, musculoskeletal stiffness19 includes asthenia, fatigue20 includes oedema, swelling face, peripheral swelling, oedema peripheral, face oedema, periorbital oedema,eyelid oedema, generalised oedema, swelling, localised oedema21 includes electrocardiogram QT prolonged, long QT syndrome

* additionally, transaminases increased were reported in 3.7% (0.6% Grades 3-4)

Pneumonitis/ILD

Pneumonitis and ILD occurred in 12.2% of 540 patients with NSCLC or other solid tumours, enrolledin the ARROW Study who received Gavreto (see section 4.4). Among the patients who hadpneumonitis/ILD, the median time to onset was 16.1 weeks.

Serious adverse reactions of pneumonitis/ILD were reported for 5.7% of patients, including Grade 3events (2.8%), Grade 4 (0.6%) and one fatal (Grade 5) event (0.2%).

In clinical trials, the majority of the patients with Grade 1 or Grade 2 pneumonitis were able tocontinue treatment without recurrent pneumonitis/ILD following dose interruption and dose reduction.

Dose interruption occurred in 8.9%, dose reduction in 5.7% and permanent dose discontinuation in2.2% of patients due to ILD/pneumonitis. The median time to resolution was 4.3 weeks.

Hypertension (including blood pressure increased) occurred in 35.0% of 540 patients with NSCLC orother solid tumours, including Grade ≤2 events in 17.4% and Grade 3 in 17.6% of patients. No

Grade 4 or Grade 5 events were reported. Among the patients who had hypertension, the median timeto onset was 2.1 weeks.

Serious adverse reactions of hypertension were reported in 1.3% of all patients (all Grade 3 events).

Dose interruption occurred in 8.0% of patients, dose reduction in 4.8% and one patient (0.2%)required permanent dose discontinuation. The median time to resolution was 4.0 weeks.

Increased AST occurred in 49.1% of 540 patients, including Grade 3 or 4 in 6.9% of patients.

Increased ALT occurred in 37.0% of patients, including Grade 3 or 4 events in 4.8% of patients. Themedian time to first onset for increased AST was 2.1 weeks and increased ALT was 3.5 weeks.

Serious adverse reactions of increased AST and ALT were reported in 0.7% and 0.6% of patients,respectively.

Dose interruption due to increased AST or ALT occurred in 5.0% and 3.9% of patients, respectivelyand dose reduction in 2.0% and 1.5%, respectively. No patients required permanent dosediscontinuation. The median time to resolution was 6.0 and 5.1 weeks for increased AST and ALT,respectively.

Haemorrhagic events

Haemorrhagic events occurred in 20.6% of the 540 patients, including Grade 3 events in 3.7% ofpatients and a Grade 4 or fatal (Grade 5) event each occurred in one patient (0.2%).

Serious adverse reactions of haemorrhage were reported for 3.9% of patients.

Seventeen patients (3.1%) required dose interruption. Dose reduction or permanent dosediscontinuation due to haemorrhage occurred in 0.4% and 0.2% of patients, respectively.

QT prolongation occurred in 5.2% of 540 patients with NSCLC or other solid tumours. In 2 patients(0.4%) the event was assessed as serious. The majority of patients experienced non-severe events - i.e.

Grade 1, in 21 (3.9%) and Grade 2, in 5 patients (0.9%). Two patients (0.4%) experienced Grade 3events of Electrocardiogram QT prolonged, which both resolved. There was no life-threatening orfatal QT prolongation. Three patients (0.6%) had an event that remained unresolved by time of datacut-off. Dose reductions or interruptions were required by two Electrocardiogram QT prolongedpatients, each. No QT prolongation event led to permanent discontinuation of pralsetinib.

Infections were commonly experienced by 66.1% of 540 patients during the median treatment time of15.9 months. Most frequently (>10%), pneumonia and urinary tract infection were reported (22.4%and 14.8%, respectively). The majority of infections were mild (Grade 1 or 2) and resolved; severeinfection (Grade ≥3) occurred in 30.4% patients (with fatal events reported for 4.1%).

Infections reported as serious occurred for 18.5% of patients. The most common (>2%) seriousinfection was pneumonia (15.6%), followed by urinary tract infection (3.7%) and sepsis (3.7%). Themajority of patients experiencing sepsis had concurrent pneumonia or urinary tract infection reported.

Dose interruption due to infection occurred in 12.8% of patients (mainly due to pneumonia [10.9%]and urinary tract infection [2.6%]). Dose was reduced due to infections in 3.7% of patients (mainlydue to pneumonia [3.5%]). Permanent treatment discontinuation was required by 2.6% of patients dueto infections (mainly due to pneumonia [2.6%]).

In ARROW (N=540), 30.9% of patients were 65 years of age and older. Compared with youngerpatients (<65), more patients of ≥65 years old reported adverse reactions that led to permanent dosediscontinuation (29.3% versus 18.8%). Of the commonly reported events with higher incidence inelderly patients (≥65), hypertension has the greatest difference in comparison with patients <65 yearsof age. However, hypertension is also expected to occur more frequently in the elderly population.

Older patients reported more Grade 3 or higher adverse reactions compared to younger patients(89.8% versus 78.3%).

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.

No cases of overdose have been reported in clinical trials with pralsetinib. The maximum dose ofpralsetinib studied clinically is 600 mg orally once daily. Adverse reactions observed at this dose wereconsistent with the safety profile at 400 mg once daily (see section 4.8).

There is no known antidote for Gavreto overdose. In the event of suspected overdose, Gavreto shouldbe interrupted and supportive care instituted. Based on the large volume of distribution of pralsetiniband extensive protein binding, dialysis is unlikely to result in significant removal of pralsetinib.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EX23.

Pralsetinib is a potent protein kinase inhibitor that selectively targets oncogenic RET fusions (KIF5B-

RET and CCDC6-RET). In NSCLC, RET fusions are one of the main oncogenic drivers. In vitro,pralsetinib inhibited several oncogenic RET fusions more potently than off-target kinases at clinicallyrelevant concentrations (e.g. 81-fold selectivity over VEGFR2). Pralsetinib exhibited anti-tumouractivity in cultured cells and animal tumour implantation models representing multiple tumour typesharbouring oncogenic RET fusions (KIF5B-RET, CCDC6-RET).

The QT interval prolongation potential of pralsetinib was assessed in 34 patients with RET fusion-positive solid tumours administered at 400 mg once daily in a formal ECG sub-study.

In patients receiving pralsetinib in the ARROW study, QT prolongation was reported (see section 4.8).

Therefore, dose interruption or modification may be required in patients treated with pralsetinib (seesections 4.2 and 4.4).

The efficacy of Gavreto was studied in patients with RET fusion-positive advanced NSCLC in Study

BLU-667-1101 (ARROW), a multicenter, non-randomised, open-label, multi-cohort phase I/II clinicaltrial. The study enrolled, in separate cohorts, patients with RET fusion-positive advanced NSCLC whohad progressed on platinum-based chemotherapy as well as patients that progressed on prior therapyother than platinum based therapy or were systemic treatment-naïve. The study was ongoing at thetime of approval.

All NSCLC patients were required to have locally advanced or metastatic disease with measurabledisease by Response Evaluable Criteria in Solid Tumours (RECIST) version 1.1. (v1.1) and have a

RET fusion as determined by local testing (Next Generation Sequencing (NGS), fluorescence in situhybridization (FISH), other). Patients with asymptomatic central nervous system (CNS) metastases,including patients with stable or decreasing steroid use within 2 weeks prior to study entry, wereenrolled. The protocol excluded patients with a known primary driver alteration other than RETfusions, patients with a history of prolonged QT syndrome or Torsades de pointes or a familial historyof prolonged QT syndrome, clinically symptomatic pneumonitis, and any prior or ongoing clinicallysignificant medical condition that could affect patient's safety.

The primary efficacy outcome measure was overall response rate (ORR) according to RECIST v1.1 asevaluated by a Blinded Independent Central Review (BICR). Secondary efficacy outcomes includedduration of response (DOR), progression free survival (PFS) and overall survival (OS).

Overall RET fusion-positive NSCLC population

The efficacy population consisted of 281 patients with RET fusion-positive advanced NSCLC whowere treated at a starting dose of 400 mg orally once daily, including 116 who were treatment-naïveand 141 who previously received platinum-based chemotherapy. As of the last data cut-off date (4

March 2022), the median follow-up was 24.1 months.

The demographic characteristics across the 281 patients were: 54.1% female, 46.3% White,45.6% Asian, 3.6% Hispanic/Latino, and the median age was 60.0 years (range: 26 to 87) with37.4% ≥65 years of age. The majority of patients had an ECOG performance status at baseline of0 (29.5%) or 1 (68.0%), had metastatic disease (98.6%), had never smoked (62.6%) or were formersmokers (33.1%) and had adenocarcinoma (96.8%). A history of brain metastases was seen in 34.5%of patients. Patients previously treated with platinum-based chemotherapy (N=141), received a medianof 2 prior lines of therapy (range: 1-8). In addition to platinum-based chemotherapy, 40.4% received

PD-1/PD-L1 inhibitors, 27.7% received multikinase inhibitors (MKIs) and 48.9% received priorradiation therapy. 15.5% of systemic treatment-naïve patients (N=116) received prior radiationtherapy. RET fusions were detected in 75.8% of patients using NGS (36.7% tissue samples; 15.7%plasma samples, 23.5% unknown), 15.3% using FISH, 6.0% unknown, and 2.8% using other methods.

The most common RET fusion partners were KIF5B (70.1%) and CCD6 (17.8%).

Efficacy results are summarised in Table 4. The median time to first response was 1.8 months for theoverall population (range: 0.9-20.5 months), as well as for patients previously treated with platinumchemotherapy (range: 1.3-11.4 months) and treatment-naïve patients (range: 0.9-20.5 months).

Table 4: Efficacy results for RET fusion-positive advanced NSCLC (ARROW) (efficacypopulation)

Previously Previouslytreated with

Efficacy Overall treated with non-platinum Treatment-naïveparameter (N =281) platinumchemotherapy systemic (N=116)(N=141) treatment(N=24)

Overall responserate (ORR)a 65.8% 59.6% 70.8% 72.4%(95% CI) (60.0%, 71.4%) (51.0%, 67.7%) (48.9%, 87.4%) (63.3%, 80.3%)

Completeresponse, n (%) 18 (6.4) 10 (7.1) 0 8 (6.9)

Partial response, n(%) 167 (59.4) 74 (52.5) 17 (70.8) 76 (65.5)

Duration ofresponse (DOR) N=185 N=84 N=17 N=84

DOR, median(95% CI) in 19.1 (14.5, 27.3) 23.4 (14.8,39.4) 20.4 (9.3, NR) 13.4 (9.4, 23.1)months

Patients with DOR≥ 6-monthsb, % 79.5% 81.0% 94.1% 75.0%

NR= Not reacheda Confirmed overall response rate assessed by BICRb Calculated using the proportion of responders with an observed duration of response at least 6 months orgreater

No clinically relevant difference in efficacy was seen in patients with a KIF5B or CCDC6 fusionpartner. BICR response rates were: ORR= 68.5% (95% CI: 61.5, 74.9) in 197 patients with a KIF5Bfusion partner; and ORR= 72.0% (95% CI: 57.5, 83.8) in 50 patients with a CCDC6 fusion partner.

In the efficacy population, the CNS ORR by central assessment (per RECIST v1.1) was 53.3% (95%

CI: 26.6, 78.7); 3 patients (20.0%) had a CR and 5 patients (33.3%) had a PR.

In ARROW (N=540), 30.9% of patients were 65 years of age and older. No overall differences inpharmacokinetic, safety or efficacy were observed in comparison with younger patients.

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

Gavreto in all subsets of the paediatric population in the treatment of lung cancer (small cell andnon-small cell lung cancer) (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.

Pralsetinib Cmax and AUC in patients increased inconsistently over the dose range of 60 mg to 600 mgonce daily (0.15 to 1.5 times the recommended dose); pharmacokinetics was linear in the dose rangeof 200 and 400 mg in healthy volunteers. Pralsetinib plasma concentrations reached steady state by 3to 5 days.

At the recommended dose of 400 mg once daily under fasting conditions, the mean steady state Cmaxof pralsetinib was 2840 ng/mL and the mean steady state area under the concentration-time curve(AUC0-24h) was 40100 h*ng/mL. The mean accumulation ratio was ~2-fold after repeated dosing.

The median time to peak concentration (Tmax) ranged from 2.0 to 4.0 hours following single doses ofpralsetinib 60 mg to 600 mg (0.15 to 1.5 times the approved recommended dose). The absolutebioavailability of pralsetinib has not been determined.

Following administration of a single dose of 200 mg Gavreto with a high-fat meal (approximately 800to 1000 calories with 50 to 60% of calories from fat), the mean (90% CI) Cmax of pralsetinib wasincreased by 104% (65%, 153%), the mean (90% CI) AUC0-∞ was increased by 122% (96%, 152%),and the median Tmax was delayed from 4 to 8.5 hours, compared to the fasted state.

The steady state mean apparent volume of distribution of pralsetinib is 255 L. Plasma protein bindingof pralsetinib is 97.1% and is independent of concentration. The blood-to-plasma ratio is 0.6 to 0.7.

Pralsetinib is primarily metabolised by CYP3A4 and UGT1A4, and to a lesser extent by CYP2D6 and

CYP1A2 in vitro.

Following a single oral dose of approximately 310 mg of radiolabelled pralsetinib to healthy subjects,pralsetinib metabolites from oxidation (M531, M453, M549b) and glucuronidation (M709) weredetected in small to trace amounts (~ 5%).

The mean plasma elimination half-life of pralsetinib was 13.4 hours following a single dose of 400 mg(the recommended dose) pralsetinib and 17.9 hours following multiple doses of 400 mg pralsetinib.

The steady state mean apparent oral clearance of pralsetinib (CL/F) is 9.9 L/h.

Following a single oral dose of radiolabelled pralsetinib to healthy subjects, 72.5% of the radioactivedose was recovered in faeces (66% as unchanged) and 6.1% in urine (4.8% as unchanged).

In vitro studies with CYP substrates

In vitro studies indicate that pralsetinib is a time-dependent inhibitor of CYP3A4/5 at clinicallyrelevant concentrations. Pralsetinib may have the potential to inhibit or induce CYP2C8, CYP2C9, and

CYP3A4/5 at clinically relevant concentrations.

In vitro studies with drug transporters

In vitro studies indicate that pralsetinib may have the potential to inhibit P-gp, BCRP, OATP1B1,

OATP1B3, OAT1, MATE1, and MATE2-K at clinically relevant concentrations. In vitro studies alsoindicate that pralsetinib may be a potential substrate of P-gp at clinically relevant concentrations (seesection 4.5).

Based on the population PK model, no clinically relevant differences in the pharmacokinetics ofpralsetinib were observed based on age (19 to 87 years), sex, race (White, Black, or Asian), bodyweight (34.9 to 128 kg), mild hepatic impairment, or mild to moderate renal impairment (CLCR 30 to89 mL/min estimated by Cockcroft-Gault). Hence, no dose modifications are needed in the above-mentioned special populations. The effect of severe renal impairment (CLCR 15 to 29 mL/min), end-stage renal disease (CLCR < 15 mL/min) on the pharmacokinetics of pralsetinib is unknown (seesection 4.2).

Hepatic Impairment

Following a single oral dose of 200 mg pralsetinib, peak pralsetinib exposure was similar in subjectswith moderate hepatic impairment (as defined by Child-Pugh criteria) compared to subjects withnormal hepatic function, with geometric mean ratios (GMR) (90% CI) of 98.6% (59.7, 163) for Cmaxand 112% (65.4, 193) for AUC0-∞. In subjects with severe hepatic impairment (as defined by Child-

Pugh criteria), AUC0-∞ was also similar compared to subjects with normal hepatic function (85.8%[51.1, 144]). Cmax was slightly lower in subjects with severe hepatic impairment compared to subjectswith normal hepatic function, with a Cmax GMR of 67.9% (35.3, 131). Unbound Cmax (Cmax,u) and

AUC0-∞ (AUC0-∞,u) were slightly higher in subjects with severe hepatic impairment (as defined by

Child-Pugh criteria) compared to subjects with normal hepatic function, with a Cmax,u GMR of 129%(70.4, 236) and AUC0-∞,u GMR of 163% (98.7, 268). There was no clear relationship between Cmax or

AUC0-∞ and Child-Pugh total score or the components of the Child-Pugh score. Similar PK resultswere obtained when hepatic impairment subjects were classified by NCI-ODWG criteria.

Therefore, no dose adjustment is needed in patients with hepatic impairment.

In studies of up to 13 weeks duration in rats and cynomolgus monkeys, the primary findings atexposures similar to steady state human exposures (AUC) at 400 mg once daily in patients withadvanced NSCLC included physeal dysplasia in the rat (2 times margin) and haematological effects (1times margin) in both species. Additional adverse findings at higher exposures include degenerativechanges in male and female reproductive organs (2 times margin) and increases in blood phosphoruswith corresponding mineralization in soft tissues in rats (≥2 times margin), and myocardialhaemorrhage in rats (4.4 times margin). Increased blood pressure was observed in rats after a singledose of 25 mg/kg (2 times). The No-Observed-Adverse-Effect-Level (NOAEL) of pralsetinib in the13-week studies was 10 mg/kg/day in both species, corresponding to exposure (AUC) margins of1 times relative to the human exposures.

Regarding local exposure and toxicity, there was no evidence of gastrointestinal disturbance in eitherspecies up to the NOAEL dose of 10 mg/kg (0.9 times human margin). At higher doses in monkeys,gastrointestinal ulcerations and haemorrhage were observed.

Embryotoxicity/Teratogenicity

In an embryo-fetal development study, administration of pralsetinib to rats during the period oforganogenesis was teratogenic and embryotoxic at exposures below the steady-state human clinicalexposure (AUC) at 400 mg once daily dose. Malformations, including visceral (primarily kidney andureter) and skeletal (vertebral, rib, costal cartilage, and vertebral central anomalies) were observed atapproximately 0.2-fold of the human exposure. Postimplantation loss occurred at 0.5-fold of thehuman exposure, and increased to 100% incidence at 1.5-fold of human exposure.

In a dedicated fertility and early embryonic development study conducted in treated male rats mated totreated female rats pralsetinib did not have an effect on male or female mating performance or abilityto become pregnant. However, consistent with the findings of the embryofetal development toxicologystudy there was post-implantation loss at doses as low as 5 mg/kg (approximately 0.3 times the humanexposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rattoxicology study). At the 20 mg/kg dose level (approximately 2.5-3.6 times the human exposure) 82%of female rats had totally resorbed litters, with 92% post-implantation loss (early resorptions). In aseparate fertility and early embryonic development study in which male rats administered pralsetinibwere mated with untreated female rats, intrauterine survival of the embryos (mean litter proportions ofpost-implantation loss and mean numbers and litter proportions of viable embryos) were unaffected bypralsetinib administration to males at the 20 mg/kg dose level (approximately 1.4 times the humanexposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data collected in this study). Inaddition, no pralsetinib-related effects on male reproductive performance (mating, fertility, andpregnancy indices) were observed in this study.

In a 13-week repeat-dose toxicology study, male rats exhibited microscopic evidence of tubulardegeneration/atrophy in the testis with secondary cellular debris and reduced sperm in the lumen of theepididymis, which correlated with lower mean testis and epididymis weights and gross observations ofsoft and small testis. Female rats exhibited degeneration of the corpus luteum in the ovary. For bothsexes, these effects were observed at pralsetinib doses ≥10 mg/kg/day, approximately 0.9 times thehuman exposure based on AUC at the clinical dose of 400 mg.

No findings were noted in the reproductive organs in a 13-week repeated-dose toxicology study inmonkeys at dose levels up to 10 mg/kg/day (approximately 1 times the human exposure at the 400 mgonce daily dose).

Pralsetinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was negativein both in vitro human lymphocyte chromosome aberration assay and in vivo rat bone marrowmicronucleus tests.

Carcinogenicity studies with pralsetinib have not been conducted.

Hypromellose

Cellulose microcrystalline

Starch, pregelatinised

Sodium hydrogen carbonate

Citric acid

Magnesium stearate

Brilliant blue FCF (E133)

Hypromellose

Titanium dioxide (E171)

Shellac

Propylene glycol (E1520)

Potassium hydroxide

Titanium dioxide (E171)

Not applicable.

3 years.

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

Store in the original package in order to protect from moisture.

High density polyethylene (HDPE) bottle with child-resistant closure (polypropylene) and foiledinduction seal liner and desiccant sachet (silica gel)

Pack sizes: 60, 90 or 120 capsules.

Not all pack sizes may be marketed.

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

Blueprint Medicines (Netherlands) B.V.

Gustav Mahlerplein 21082 MA Amsterdam

Netherlands

EU/1/21/1555/001

EU/1/21/1555/002

EU/1/21/1555/003

Date of first authorisation: 18 November 2021

Date of latest renewal: 15 September 2023

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

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