Gavreto - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

GAVRETO 100 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 100 mg of pralsetinib.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

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

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

4.2 Posology and method of administration

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

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

Posology

The recommended dose is 400 mg pralsetinib once daily on an empty stomach (see method of administration). 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 but continue with the next scheduled dose.

Missed doses

If a dose of pralsetinib is missed, the patient should make up for the missed dose as soon as possible on 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 adverse reactions 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 once daily.

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

Table 1. Recommended dose modifications for Gavreto for adverse 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 strong cytochrome P-450 (CYP)3A4 inhibitors or combined P-glycoprotein (P-gp) and strong CYP3A4 inhibitors

Concomitant use of pralsetinib with known strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors should be avoided (see section 4.4 and section 4.5). If co-administration with a strong CYP3A4 inhibitor or combined P-gp and strong CYP3A4 inhibitor cannot be avoided, the current dose of pralsetinib should be reduced as recommended in Table 2. After the strong CYP3A4 inhibitor or combined P-gp and strong CYP3A4 inhibitor have been discontinued for 3 to 5 elimination half-lives, the pralsetinib dose that was taken prior to the use of the inhibitor should be resumed.

Table 2. Recommended dose modifications for Gavreto for co-administration with strong CYP3A4 inhibitors or combined P -gp and strong CYP3A4 inhibitors

Dose modification for use with strong CYP3A4 inducers

Concomitant use of pralsetinib with strong CYP3A4 inducers should be avoided (see section 4.4 and section 4.5). If concomitant use with a strong CYP3A4 inducer cannot be avoided, the dose of pralsetinib should be increased to double the current pralsetinib dose starting on Day 7 of co-administration of pralsetinib with the strong CYP3A4 inducer. After the strong CYP3A4 inducer has been discontinued for at least 14 days, the pralsetinib dose that was taken prior to the use of the inducer should be resumed.

Special populations

Renal impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLCR] 30 to 89 mL/min estimated by Cockcroft-Gault). Pralsetinib has not been studied in patients 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 is required in patients with severe renal impairment or end-stage renal disease (see section 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin < upper limit of normal [ULN] and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST). Pralsetinib has not been studied in patients with moderate or severe hepatic impairment, therefore its use in patients with moderate or severe hepatic impairment is not recommended (see section 5.2).

Elderly

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

Paediatric population

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

Method of administration

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Pneumonitis/ILD

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

Patients should be advised to contact their healthcare provider immediately to report new or worsening respiratory 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. If pneumonitis/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 (see section 4.2).

Hypertension

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. Preexisting hypertension should be adequately controlled before starting Gavreto treatment. Monitoring of 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 be interrupted, reduced, or permanently discontinued based on the severity of hypertension observed during treatment with Gavreto (see section 4.2).

Transaminase elevations

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

ALT and AST should be monitored prior to initiating Gavreto, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Treatment with Gavreto should be interrupted, reduced or permanently discontinued based on severity of the transaminase elevation observed during treatment with Gavreto (see section 4.2).

Haemorrhagic events

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

QT prolongation

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, and hypocalcaemia 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 month of Gavreto treatment, then periodically, as clinically indicated, depending also on presence of other risk factors (e.g. intercurrent diarrhoea, vomiting, nausea, concomitant medications).

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

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

Drug interactions

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

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

Fertility and pregnancy

During treatment with Gavreto and for at least 1 week after the final dose, male patients with female partners of childbearing potential must use effective contraception (see section 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 patients during 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 combination with the hormonal method. Effective contraception must be continued for at least 2 weeks after the final dose (see section 4.6).

Sodium content

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

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

In vitro data indicate that pralsetinib is primarily metabolised by CYP3A4 and transported by P-gp. Therefore, inducers and inhibitors of CYP3A4 and P-gp may alter the plasma concentrations of pralsetinib.

Active substances that may have an effect on pralsetinib

Strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors

Co-administration of pralsetinib with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors can increase pralsetinib plasma concentrations, which may increase the incidence and severity of adverse reactions of pralsetinib. Co-administration of 200 mg pralsetinib once daily with itraconazole 200 mg once daily (a strong CYP3A4 and P-gp inhibitor) increased pralsetinib Cmax by 84% and AUCo-æ by 251%, compared to pralsetinib administered alone.

Therefore, co-administration of pralsetinib with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors (including, but not limited to, ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole nefazodone, grapefruit or Seville oranges) should be avoided (see section 4.4). If co-administration with strong CYP3A4 inhibitors or combined P-gp and strong CYP3A4 inhibitors cannot be avoided, reduce the current dose of pralsetinib (section 4.2).

Strong CYP3A4 inducers

Co-administration of pralsetinib with strong CYP3A4 inducers can decrease pralsetinib plasma concentrations, which may decrease the efficacy of pralsetinib. Co-administration of 400 mg pralsetinib as a single dose with rifampin 600 mg once daily (a strong CYP3A4 inducer) decreased pralsetinib Cmax by 30% and AUCo-vby 68%. Based on a population PK analysis, CYP3A4 weak inducers decreased pralsetinib exposures, but were not clinically significant in patients with NSCLC. Therefore, co-administration of pralsetinib with strong CYP3A4 inducers (including, but not limited to, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin and St. John’s Wort [Hypericum perforatum ]) should be avoided (see section 4.4). If co-administration cannot be avoided, increase the pralsetinib dose (see section 4.2).

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 narrow therapeutic index (including, but not limited to cyclosporine, paclitaxel and warfarin) should be avoided.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Con­traception in females and males

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

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

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

Males with female partners of childbearing potential have to use effective contraception 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.

Pregnancy

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

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

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

Breast-feeding

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 the final dose.

Fertility

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 before treatment.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most common adverse reactions were anaemia (47.2%), aspartate aminotransferase increased (46.0%), neutropenia (43.9%), constipation (41.9%), musculoskeletal pain (39.8%), fatigue (37.3%), leukopenia (35.4%), alanine aminotransferase increased (33.9%), and hypertension (33.0%). The most common serious adverse reactions were pneumonia (11.7%), pneumonitis (5.3%) and anaemia (3.8%).

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

Dose reductions due to adverse reactions occurred in 41.5% of patients treated with Gavreto. The most common adverse reactions resulting in dose reductions were neutropenia (14.0%), anaemia (8.5%), lymphopenia (5.3%), pneumonitis (5.3%), leukopenia (4.2%), blood creatine phosphokinase increased (4.0%), hypertension (4.0%), and fatigue (3.8%).

Permanent discontinuation due to adverse reactions occurred in 8.1% of patients treated with Gavreto. The most common adverse reactions that led to permanent discontinuation of Gavreto were pneumonia and pneumonitis (1.9% for each).

Tabulated list of adverse reactions

The safety population includes a total of 528 patients, including 281 patients with advanced NCSLC, as well as patients with other solid tumours (including RET fusion thyroid cancer and RET mutation medullary thyroid cancer), who received pralsetinib at a starting dose of 400 mg, see section 5.1. No clinically 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 not known (cannot be estimated from the available data).

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

Table 3. Adverse reactions reported in all patients treated with 400 mg Gavreto in the ARROW trial (N=528)

1 includes pneumonia, pneumocystis jirovecii pneumonia, pneumonia cytomegaloviral, atypical pneumonia,

lung infection, pneumonia bacterial, pneumonia haemophilus, pneumonia influenzal, pneumonia streptococcal, pneumonia moraxella, pneumonia staphylococcal, pneumonia pseudomonal, atypical mycobacterial pneumonia, pneumonia legionella

• 2 includes anaemia, haematocrit decreased, red blood cell count decreased, haemoglobin decreased, aplastic anaemia

• 3 includes neutrophil count decreased, neutropenia

• 4 includes white blood cell count decreased, leukopenia

• 5 includes lymphopenia, lymphocyte count decreased

• 6 includes thrombocytopenia, platelet count decreased

• 7 includes ageusia, dysgeusia

• 8 includes headache, tension headache

• 9 includes hypertension, blood pressure increased

• 10 includes 39 preferred terms from the SMQ Haemorrhage (excl laboratory terms) narrow, with the exclusion of terms related to invasive drug administration, terms related to rupture, disseminated intravascular coagulopathy, terms related to traumatic haemorrhages, and haemorrhagic terms related to pregnancy, birth or neonatal

• 11 includes cough, productive cough

• 12 includes pneumonitis, interstitial lung disease

• 13 includes abdominal pain, abdominal pain upper

• 14 includes stomatitis, aphthous ulcer

• 15 includes blood bilirubin increased, hyperbilirubi­naemia, bilirubin conjugated increased, blood bilirubin unconjugated increased

• 16 includes rash, rash maculo-papular, dermatitis acneiform, erythema, rash generalised, rash papular, rash pustular, rash macular, rash erythematous

• 17 includes musculoskeletal chest pain, myalgia, arthralgia, pain in extremity, neck pain, musculoskeletal pain, back pain, bone pain, spinal pain, musculoskeletal stiffness

• 18 includes asthenia, fatigue

• 19 includes oedema, swelling face, peripheral swelling, oedema peripheral, face oedema, periorbital oedema, eyelid oedema, generalised oedema, swelling, localised oedema

• 20 includes electrocardiogram QT prolonged, long QT syndrome

• * additionally, 3.0% transaminases increased were reported (0.6% Grades 3–4)

4.9 Overdose

Symptoms

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

Management

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

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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

Mechanism of action

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 clinically relevant concentrations (e.g. 81-fold selectivity over VEGFR2). Pralsetinib exhibited anti-tumour activity in cultured cells and animal tumour implantation models representing multiple tumour types harbouring oncogenic RET fusions (KIF5B-RET, CCDC6-RET).

Pharmacodynamic effects

Cardiac electrophysiology

The QT interval prolongation potential of pralsetinib was assessed in 34 patients with RET fusionpositive 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 (see sections 4.2 and 4.4).

Clinical efficacy and safety

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 clinical trial. The study enrolled, in separate cohorts, patients with RET fusion-positive advanced NSCLC who had progressed on platinum-based chemotherapy as well as patients that progressed on prior therapy other than platinum based therapy or were systemic treatment-naive. The study was ongoing at the time of approval.

All NSCLC patients were required to have locally advanced or metastatic disease with measurable disease 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 situ hybridization (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, were enrolled. The protocol excluded patients with a known primary driver alteration other than RET fusions, patients with a history of prolonged QT syndrome or Torsades de pointes or a familial history of prolonged QT syndrome, clinically symptomatic pneumonitis, and any prior or ongoing clinically significant medical condition that could affect patient's safety.

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

Overall RET fusion-positive NSCLC population

The efficacy population consisted of 233 patients with RET fusion-positive advanced NSCLC who were treated at a starting dose of 400 mg orally once daily, including 75 who were treatment-naive and 136 who previously received platinum-based chemotherapy. As of the last data cut-off date, the median follow-up was 17.1 months.

The demographic characteristics across the 233 patients were: 52.4% female, 51.9% White, 39.5% Asian, 3.9% Hispanic/Latino, and the median age was 60.0 years (range: 26 to 87) with 37.8% >65 years of age. The majority of patients had an ECOG performance status at baseline of 0 (33.5%) or 1 (63.9%), had metastatic disease (97.4%), had never smoked (62.2%) or were former smokers (33.5%) and had adenocarcinoma (96.1%). A history of brain metastases was seen in 37.3% of patients. Patients previously treated with platinum-based chemotherapy (N=136), received a median of 2 prior lines of therapy (range: 1–8). In addition to platinum-based chemotherapy, 40.4% received PD-1/PD-L1 inhibitors, 27.9% received multikinase inhibitors (MKIs) and 47.8% received prior radiation therapy. 21.3% of systemic treatment-naive patients (N=75) received prior radiation therapy. RET fusions were detected in 79.4% of patients using NGS (42.9% tumour samples; 15.9% blood or plasma samples, 20.6% unknown), 18.0% using FISH, and 2.6% using other methods. The most common RET fusion partners were KIF5B (70.4%) and CCD6 (17.6%).

Efficacy results are summarised in Table 4. The median time to first response was 1.8 months for the overall population (range: 0.9–11.4 months), as well as for patients previously treated with platinum chemotherapy (range: 1.3–11.4 months) and treatment-naive patients (range: 0.9–6.1 months).

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

population)

NR= Not reached

a Confirmed overall response rate assessed by BICR

b Calculated using the proportion of responders with an observed duration of response at least 6 months or

greater

ORR and median DOR for the 233 patients with RET fusion-positive advanced NSCLC in the efficacy population was 64.4% (95% CI: 57.9, 70.5) and 22.3 months (95% CI: 14.7, NR), respectively.

No clinically relevant difference in efficacy was seen in patients with a KIF5B or CCDC6 fusion partner. BICR response rates were: ORR= 67.7% (95% CI: 59.9, 74.8) in 164 patients with a KIF5B fusion partner; and ORR= 68.3% (95% CI: 51.9, 81.9) in 41 patients with a CCDC6 fusion partner.

The intracranial ORR assessed by BICR was 70.0% (95% CI: 34.8, 93.3) in 10 response evaluable patients with brain metastases at baseline, including 3 patients with a complete response. All patients had target brain lesion shrinkage with pralsetinib treatment.

Elderly population

In ARROW (N=528), 37.8% of patients were 65 years of age and older. No overall differences in pharmacokinetic, safety or efficacy were observed in comparison with younger patients.

Paediatric population

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 and non-small cell lung cancer) (see section 4.2 for information on paediatric use).

Conditional approval

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

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

5.2 Pharmacokinetic properties

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

At the recommended dose of 400 mg once daily under fasting conditions, the mean steady state Cmax of pralsetinib was 2830 ng/mL and the mean steady state area under the concentration-time curve (AUCo-24h) was 43900 Ivng/mL. The mean accumulation ratio was ~2-fold after repeated dosing.

Absorption

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

Effect of food

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

Distribution

The mean apparent volume of distribution of pralsetinib is 3.8 L/kg (268 L). Plasma protein binding of pralsetinib is 97.1% and is independent of concentration. The blood-to-plasma ratio is 0.6 to 0.7.

Biotransformation

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) were detected in small to trace amounts (~ 5%).

Elimination

The mean plasma elimination half-life of pralsetinib was 14.7 hours following a single dose of 400 mg (the recommended dose) pralsetinib and 22.2 hours following multiple doses of 400 mg pralsetinib.

The steady state mean apparent oral clearance of pralsetinib (CL/F) is 9.1 L/h.

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

Interactions with CYP substrates

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

Interactions with transport proteins

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. Pralsetinib is a substrate of P-gp. (see section 4.5).

In vitro studies with drug transporters

In vitro studies indicate that pralsetinib may be a potential substrate of P-glycoprotein (P-gp) and BCRP at clinically relevant concentrations.

Special populations

No clinically relevant differences in the pharmacokinetics of pralsetinib were observed based on age (19 to 87 years), sex, race (White, Black, or Asian), body weight (34.9 to 128 kg), mild to moderate (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild hepatic impairment (total bilirubin < ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST). The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease (CLcr < 15 mL/min), or moderate to severe hepatic impairment (total bilirubin > 1.5 times ULN and any AST) on the pharmacokinetics of pralsetinib is unknown (see section 4.2). Hence, no dose modifications are needed in the above mentioned special populations.

5.3 Preclinical safety data

Repeat-dose toxicity studies

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

Regarding local exposure and toxicity, there was no evidence of gastrointestinal disturbance in either species 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 of organogenesis was teratogenic and embryotoxic at exposures below the steady-state human clinical exposure (AUC) at 400 mg once daily dose. Malformations, including visceral (primarily kidney and ureter) and skeletal (vertebral, rib, costal cartilage, and vertebral central anomalies) were observed at approximately 0.2-fold of the human exposure. Postimplantation loss occurred at 0.5-fold of the human exposure, and increased to 100% incidence at 1.5-fold of human exposure.

Reproductive toxicity

In a dedicated fertility and early embryonic development study conducted in treated male rats mated to treated female rats pralsetinib did not have an effect on male or female mating performance or ability to become pregnant. However, consistent with the findings of the embryofetal development toxicology study there was post-implantation loss at doses as low as 5 mg/kg (approximately 0.3 times the human exposure (AUC) at the clinical dose of 400 mg based on toxicokinetic data from the 13-week rat toxicology 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 a 13-week repeat-dose toxicology study, male rats exhibited microscopic evidence of tubular degeneration/a­trophy in the testis with secondary cellular debris and reduced sperm in the lumen of the epididymis, which correlated with lower mean testis and epididymis weights and gross observations of soft and small testis. Female rats exhibited degeneration of the corpus luteum in the ovary. For both sexes, these effects were observed at pralsetinib doses >10 mg/kg/day, approximately 0.9 times the human 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 in monkeys at dose levels up to 10 mg/kg/day (approximately 1 times the human exposure at the 400 mg once daily dose).

Genotoxicity and carcinogenicity

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

Carcinogenicity studies with pralsetinib have not been conducted.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule content

Hypromellose

Cellulose microcrystalline

Starch, pregelatinised

Sodium hydrogen carbonate

Citric acid

Magnesium stearate

Capsule shell

Brilliant blue FCF (E133)

Hypromellose

Titanium dioxide (E171)

Printing ink

Shellac

Propylene glycol (E1520)

Potassium hydroxide

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

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

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

6.5 Nature and contents of container

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

Pack sizes: 60, 90 or 120 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/21/1555/001

EU/1/21/1555/002

EU/1/21/1555/003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18 November 2021