Aumseqa 55 mg film-coated tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Aumseqa 55 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 55 mg of aumolertinib (as mesilate).

Excipient with known effect:

Each tablet contains 15.3 mg of anhydrous lactose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Light yellow, 7 mm round immediate release tablet debossed with “E1” on one side and plain on the reverse.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Aumseqa as monotherapy is indicated for:

• the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations.
• the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC.

4.2 Posology and method of administration

Treatment with Aumseqa should be initiated by a physician experienced in the use of anticancer medicinal products.

When considering the use of Aumseqa, EGFR mutation status in tumour or plasma specimens should be determined using a validated test method (see section 4.4).

Posology

The recommended dose of Aumseqa is 110 mg (2 tablets of 55 mg) once a day. Aumseqa should be taken at the same time each day. It can be taken with or without food.

This medicinal product should be continued until disease progression or unacceptable toxicity.

Missed dose

If a dose of Aumseqa is missed, it should be taken within the same day as soon as the patient remembers. However, if the next scheduled dose is due within 12 hours then the missed dose must be skipped.

Dose modifications for adverse reactions

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability.

If dose reduction is necessary, then the dose should be reduced from 110 mg (two tablets) to 55 mg (one tablet) taken once daily. Dose modification guidelines for adverse reactions are provided in Table 1.

If Aumseqa is withheld more than 3 weeks for toxicity and the criteria for resuming treatment are not met, Aumseqa should be discontinued permanently.

Table 1. Recommended Aumseqa dose modifications for adverse reactions

Muscular symptoms (including but not limited to): muscle pain, muscle tenderness, muscle twitches or myalgia.

CPK = creatine phosphokinase, , ECG = electrocardiogram, LVEF = left ventricular ejection fraction, QTc = corrected QT

Grade = Severity graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)

Special populations

No dose modification is required due to patient age, body weight, gender, ethnicity, or smoking status (see section 5.2).

Hepatic impairment

Based on clinical studies, no dose modification is required in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (see section 5.2).

Renal impairment

Based on clinical studies and population pharmacokinetic (PK) analysis, no dose modification is required in patients with mild or moderate renal impairment. Aumseqa has not been evaluated in patients with severe renal impairment or end-stage renal disease (creatinine clearance [CLcr] < 30 mL/min) (see section 5.2). Caution should be exercised when using Aumseqa in patients with severe or end-stage renal impairment (see section 5.2).

Paediatric population

The safety and efficacy of Aumseqa in children or adolescents aged less than 18 years have not been established. No data are available.

Method of administration

This medicinal product is for oral use.

Two 55 mg tablets should be swallowed whole with water without chewing or crushing.

Patients should be advised not to swallow the desiccant canister found in the bottle.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Strong CYP3A4 inducers and inhibitors must be avoided with aumolertinib (see section 4.5.)

4.4 Special warnings and precautions for use

Assessment of EGFR mutation status

When considering the use of Aumseqa as a treatment for patients with locally advanced or metastatic NSCLC, it is necessary to determine the mutation status of EGFR. A validated EGFR mutation test which is reliable, stable, and sensitive, should be performed using either tumour DNA derived from a tissue sample or circulating tumour DNA (ctDNA) obtained from a plasma sample.

Positive determination of EGFR mutation status (activating EGFR mutations for first-line treatment or T790M mutations following progression on or after EGFR TKI therapy) using either a tissue-based or plasma-based test indicates eligibility for treatment with Aumseqa. However, if a plasma-based ctDNA test is used and the result is negative, it is advisable to follow-up with a tumour tissue test wherever possible, as a plasma test may provide a false negative result. Only robust, reliable, and sensitive tests with demonstrated utility for the determination of EGFR mutation status should be used.

QTc interval prolongation

QTc interval prolongation has occurred in patients treated with Aumseqa (see section 4.8). QTc interval prolongation may lead to an increased risk for ventricular tachyarrhythmias (eg, torsade de pointes) or sudden death. One sudden cardiac death was reported in clinical trials with aumolertinib. Subjects with clinically important cardiac abnormalities in rhythm and conduction as measured by resting ECG, such as mean corrected QT interval (QTc) > 470 msec, complete left bundle branch block, third degree atrioventricular block, second-degree atrioventricular block, and PR interval > 250 msec were excluded from the clinical studies.

Patients with congenital long QT syndrome should avoid using Aumseqa. Patients with congestive heart failure, electrolyte abnormalities, or who are using medicines known to prolong the QT interval should have baseline electrocardiogram (ECG) and undergo regular ECG and electrolyte monitoring.

Coadministration of moderate or strong CYP3A inhibitors and medications known to prolong QTc interval with Aumseqa should be avoided (see section 4.3 and 4.5). Dose modification is recommended in patients with a confirmed QTc interval > 500 ms (see section 4.2). Patients with prolonged QTc intervals who develop symptoms or signs of severe arrhythmia including, but not limited to torsades de pointes and ventricular tachycardia should permanently discontinue treatment with Aumseqa and be immediately treated as per standard of care.

Cardiac failure

Life threatening and fatal cardiac failure occurred in 2 patients (0.4%) treated with Aumseqa (see section 4.8). For patients with known cardiovascular risk factors and conditions which may affect left ventricular ejection fraction (LVEF), cardiac function should be monitored, such as measuring LVEF at baseline and during treatment with Aumseqa. For patients who develop symptomatic congestive heart failure during treatment, Aumseqa should be discontinued (see section 4.2).

Interstitial Lung Disease (ILD)

ILD has been reported in patients treated with Aumseqa (see section 4.8). Patients with acute episodes and/or exacerbations of pulmonary symptoms (eg, dyspnoea, cough, or fever) with no clear cause should be investigated for possible ILD during treatment with Aumseqa. Treatment should be interrupted while conducting investigation of these symptoms. If ILD is confirmed, Aumseqa should be permanently discontinued (see section 4.2), and appropriate treatment for ILD initiated.

Increased blood creatine phosphokinase (CPK)

In clinical studies at the recommended dose, increased blood CPK has been reported. Increased blood CPK was asymptomatic in most cases and did not lead to discontinuation.

Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. Dose modification may be required in the event of ≥ Grade 3 CPK elevation (see section 4.2).

Avoid concomitant administration of Aumseqa with medicinal products that can increase blood CPK eg, strong CYP3A4 inhibitors, as they may increase the risk of blood CPK increase and/or muscular symptoms (see section 4.5). Obtain serum CPK prior to initiating aumolertinib, and periodically during treatment as clinically indicated.

Venous thromboembolic events

Thromboembolic events, including deep vein thrombosis and pulmonary embolism, have been reported in subjects treated with Aumseqa. If clinical signs and symptoms of thromboembolic events occur or are suspected, patients should be evaluated promptly, followed by appropriate treatment. Aumseqa should be withheld, and the patient stabilised before resuming therapy.

Lactose

Aumseqa contains anhydrous lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicine contains < 1 mmol sodium (23.3 mg) per 110 mg dose (2 tablets of 55 mg), that is to say essentially ‘sodium-free’.

Routine monitoring

Liver function

Liver function test abnormalities (including increases in alanine aminotransferase [ALT] aspartate aminotransferase [AST], and blood bilirubin levels) have been observed during treatment with aumolertinib, including rarely reported drug-induced liver injury (DILI). Monitor liver function prior to initiating Aumseqa, and periodically during treatment: typically every 3 weeks during the first 5 months of treatment, and every 6 weeks thereafter. The frequency of monitoring may be adjusted according to the severity of liver function abnormalities or symptoms.

Renal function

Increased blood CPK (see above) can be associated with acute renal impairment. No such events were reported in clinical studies. As a precautionary measure, monitor renal function prior to initiating Aumseqa, and periodically during treatment as clinically indicated.

Electrolyte disturbances

Electrolyte disturbances including hyponatraemia and hypokalaemia have been observed in clinical trials with Aumseqa and were mostly mild in severity. Monitor prior to initiating Aumseqa, and periodically during treatment as clinically indicated.

4.5 Interaction with other medicinal products and other forms of interaction

Active substances that may increase aumolertinib plasma concentrations

CYP3A4 inhibitors

Aumolertinib is mainly metabolized by CYP3A4 enzymes. In a drug-drug interaction study, coadministration of aumolertinib with a strong CYP3A4 inhibitor (itraconazole) significantly increased aumolertinib exposure (area under the plasma concentration-time curve [AUC] increased 3.7-fold). Coadministration of Aumseqa with strong CYP3A4 inhibitors (eg, clarithromycin, itraconazole, and lopinavir) must be avoided (see section 4.3). Moderate CYP3A4 inhibitors (eg, verapamil and fluconazole) may also increase aumolertinib exposure and should be avoided.

Grapefruit juice is a strong CYP3A4 inhibitor and must be avoided.

Active substances that may decrease aumolertinib plasma concentrations

CYP3A4 inducers

In a drug-drug interaction study, coadministration of aumolertinib with a strong CYP3A4 inducer (rifampicin) significantly decreased aumolertinib exposure (AUC decreased by approximately 90%). Coadministration of Aumseqa with strong CYP3A4 inducers (eg, rifampicin, carbamazepine, phenytoin sodium and St. John’s wort) must be avoided (see section 4.3). Moderate CYP3A4 inducers (eg, bosentan or efavirenz) may also decrease aumolertinib exposure and should be avoided.

Potential for aumolertinib to affect the exposure to other medicinal products

Substrates of drug transporter

Based on in vitro studies, aumolertinib is an inhibitor of organic anion transporting polypeptide (OATP)1B1, organic anion transporter (OAT)1, OCT2, and multidrug and toxin extrusion (MATE)1. However, considering the average steady-state C_max for aumolertinib following a 110 mg once daily dose, drug-drug interactions between Aumseqa and substrates of OATP1B1, OAT1 and OCT2 are not anticipated to be clinically relevant.

Based on in vitro studies, aumolertinib is a weak inhibitor of breast cancer resistance protein (BCRP). Based on PBPK modelling, minimal interactions (eg, with rosuvastatin) are expected.

Concomitant use of aumolertinib may increase exposure to MATE1 substrates. Caution is recommended when aumolertinib is coadministered with MATE1 substrates with a narrow therapeutic index.

In a clinical drug-drug interaction study, aumolertinib increased the C_max and AUC of fexofenadine, a sensitive P-glycoprotein (P-gp) substrate by 86% and 67%, respectively. Caution should be used when administering Aumseqa with medicinal products that are sensitive P-gp substrates with narrow therapeutic window (eg, digoxin, dabigatran).

Substrates of cytochrome P450 enzymes

The enzymatic activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (2 substrates) did not change significantly at any aumolertinib concentration evaluated. Based on these in vitro results, aumolertinib does not

appear to be an inhibitor of the major human CYPs and has little potential to cause drug-drug interactions which could result from inhibition of these major CYP enzymes.

Effect of gastric acid reducing active substances on aumolertinib

No clinically relevant changes in aumolertinib exposure are anticipated with gastric acid reducing agents such as famotidine or omeprazole. Aumseqa may be coadministered with gastric acid reducing agents without dose adjustment.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving Aumseqa. All patients should be advised to use highly effective contraception during treatment and for 4 weeks after completion of treatment with Aumseqa.

Pregnancy

There are no or limited amount of data from the use of Aumseqa in pregnant women. Aumseqa is not recommended during pregnancy and in women of childbearing potential not using contraception.

were observed (see section 5.3).

Breast-feeding

It is unknown whether aumolertinib or metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Aumseqa and for 4 weeks after completion of treatment with Aumseqa.

Fertility

There is no clinical data on the effect of Aumseqa on human fertility. In animal studies, no effects were observed regarding male fertility, but fertility effects were observed in females (see section 5.3).

4.7 Effects on ability to drive and use machines

Aumseqa may have a minor influence on the ability to drive and use machines. In some patients, fatigue and dizziness have been reported following administration with aumolertinib. The patient should be advised not to drive or use machines until fatigue and/or dizziness resolve.

4.8 Undesirable effects

Summary of the safety profile

The data described below reflect exposure to Aumseqa in 538 patients with EGFR mutation-positive NSCLC. These patients received Aumseqa at the recommended dose of 110 mg once a day in two multicentre pivotal studies: one Phase 3 study in the first-line setting (AENEAS) and one Phase 1/2 study in pre-treated patients (see section 5.1).

The most frequently reported adverse reactions (≥ 20%, all Grades) in patients treated with Aumseqa were increased AST (37.9%, hyponatraemia (33.1%), increased ALT, 30.9%), decreased white blood cell (WBC) count (27.9%), increased blood CPK (26.6%), decreased platelet count (26.0%), and rash (22.7%). The most frequently reported Grade ≥ 3 adverse reaction (≥ 5%) was elevated blood CPK (6.1%).

Serious adverse reactions occurred in 3.3% of patients. The most common serious adverse reaction was pulmonary embolism in 1.1% of patients.

Treatment discontinuation due to adverse reactions occurred in 1.3% of patients. The most common adverse reactions leading to treatment discontinuation were interstitial lung disease (ILD) and cough, occurring in 0.4% of patients each.

Treatment interruption and dose reduction due to adverse reactions occurred in 9.3% and 2.2% of patients, respectively. The most common adverse reaction leading to interruption or dose reduction was increased blood CPK, occurring in 5.4% and 1.7% of patients, respectively.

Patients with a medical history of ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from the studies. Patients with clinically important cardiac abnormalities in rhythm and conduction as measured by resting ECG (eg, QTc interval greater than 470 ms) were also excluded from the studies. Patients were required to have LVEF > 40% to enrol in the studies.

Tabulated list of adverse reactions

Adverse reactions reported are presented in Table 2 and listed by system organ class, preferred term and frequency with the most frequent reactions listed first.

The following definitions apply to the frequency terminology used hereafter: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 2. Adverse reactions reported in patients treated with Aumseqa^a

Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The severity of adverse reactions was assessed based on the CTCAE, defining Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life threatening, and Grade 5=death.

^a Data is pooled from Phase 1/2 Study and AENEAS Study; only patients receiving 110 mg dose of Aumseqa are summarized.

^b Includes: neutropenia, neutrophil count decreased, white blood cell count decreased* ^c Includes: platelet count decreased*, thrombocytopenia

^d Includes: blood sodium decreased, hyponatraemia*

^e Includes: blood potassium decreased, hypokalaemia*

^f Includes: conjunctival haemorrhage, conjunctivitis, dry eye, eye discharge, eye haemorrhage, eye pain, lacrimation increased, photophobia, visual impairment ^g Includes: cardio-respiratory arrest, electrocardiogram QT prolonged, sudden cardiac death, syncope, ventricular arrhythmia. Grade 5 cardio-respiratory arrest and sudden cardiac death occurred in one patient each.

^h Includes: cardiac failure, cardiac failure chronic, pulmonary oedema. Grade 5 pulmonary oedema was reported in one patient.

ⁱ Includes: blood pressure increased, hypertension

^j Includes: cough, productive cough, upper-airway cough syndrome

^k Includes: bronchiolitis, interstitial lung disease, pneumonitis

^l Includes: aphthous ulcer, dry mouth, glossodynia, mouth ulceration, oral pain, stomatitis, tongue ulceration

^m Includes: dermatitis, dermatitis acneiform, drug eruption, erythema, erythema nodosum, folliculitis, macule, palmar-plantar erythrodysaesthesia syndrome, papule, photosensitivity reaction, rash, rash maculo-papular, rash papular, rash pruritic, rash pustular, urticaria * Represent incidence of laboratory findings, not of adverse events

Description of selected adverse reactions

The below information discusses the Phase 1/2 study for aumolertinib 110 mg and the Phase 3 AENEAS study, where patients were randomized 1:1 to receive aumolertinib (110 mg once daily, n = 214) or gefitinib (250 mg once daily, n = 215).

Interstitial lung disease (ILD)

In the AENEAS study, ILD was reported in 10 patients (4.7%) in the aumolertinib arm; 1 patient experienced pneumonitis Grade ≥ 3. In the gefitinib arm, ILD was reported for 12 patients (5.6%); 2 patients (0.9%) experienced Grade ≥ 3 pneumonitis. No ILD was reported in patients who received aumolertinib 110 mg in the Phase 1/2 Study.

In all patients treated with aumolertinib the median time-to-onset of ILD was 97 days (range: 2-571 days). The median time-to-resolution was 32 days (range: 14-457 days). The median time-to-onset of Grade ≥ 3 ILD was 40 days, and the time-to-resolution was 14 days.

Cardiac failure

In the AENEAS study, cardiac failure was reported in 1 patient in each of the aumolertinib and gefitinib arms. The event reported in the aumolertinib arm had a fatal outcome.

In the Phase 1/2 study, 1 patient (0.4%) developed Grade 4 cardiac failure that improved to Grade 1 following discontinuation of treatment with aumolertinib.

In all patients treated with aumolertinib the median time-to-onset of cardiac failure was 232.5 days (range: 84-381 days). The median time-to-resolution was 98 days (range: 36-160 days). The median time-to-onset of Grade ≥ 3 cardiac failure was 293 days, and the time-to-resolution was 26 days.

In the AENEAS study, 1 patient (0.2%) in the aumolertinib arm had a decline in LVEF of ≥ 10% to an absolute value < 50% and 8 patients (3.7%) had a decline in LVEF ≥ 15% from baseline and remained ≥ 50%. In the gefitinib arm, 2 patients (0.9%) had a decline in LVEF of ≥ 10% to an absolute value of LVEF < 50% and 2 patients (0.9%) had a decline in LVEF ≥ 15% from baseline and remained ≥ 50%.

In the Phase 1/2 study, none of the patients experienced a decline in LVEF of ≥ 10% to an absolute value < 50% and 3 patients (1.1%) had a decline in LVEF ≥ 15% from the baseline and remained ≥ 50%.

QT prolongation

In the AENEAS study, the number of patients (incidence) and severity of QT prolongation were similar in the aumolertinib and gefitinib arms, occurring in 25 (11.7%) and 20 (9.3%) of the patients, respectively. QT prolongation Grade ≥ 3 was reported in 4 patients (1.9%) and 5 patients (2.3%) in the aumolertinib and gefitinib arms, respectively. Two patients in the aumolertinib arm had events with fatal outcome (1 patient had cardio-respiratory arrest and 1 had sudden cardiac death).

QTc interval greater than 500 ms was reported in 2 patients (0.9%) and 6 patients (2.8%) in the aumolertinib and gefitinib arms, respectively. An increase of ≥ 60 ms from baseline occurred in 13 patients (6.1%) and 11 patients (5.1%) in the aumolertinib and gefitinib arms, respectively.

In the Phase 1/2 study, QT prolongation was reported in 14 patients (4.9%); 1 patient (0.4%) had Grade ≥ 3 event (syncope). No patients had QTc interval greater than 500 ms and 5 patients (1.8%) experienced increase of ≥ 60 ms from baseline.

In all patients treated with aumolertinib the median time-to-onset of QT prolongation was 22 days (range: 1-625 days). The median time-to-resolution was 86 days (range: 1-655 days).

The median time-to-onset of Grade ≥ 3 QT prolongation was 267 days, and the time-to-resolution was 1 day.

Elevated blood creatine phosphokinase (CPK)

In the AENEAS study, events of elevated CPKs were reported in 103 patients (48.1%) and 46 patients (21.4%) in the aumolertinib and gefitinib arms, respectively. Most of the events were Grade 1 to 2 in severity and not associated with muscular symptoms. Grade ≥ 3 events of CPK elevation were reported in 15 patients (7.0%) and 1 patient (0.5%) in the aumolertinib and gefitinib arms, respectively.

In the Phase 1/2 Study, events of elevated CPK were reported in 77 patients (27.2%), and 16 patients (5.7%) had elevated CPK of Grade ≥ 3.

Across both studies, there were no treatment discontinuations due to events of elevated CPK.

In all patients treated with aumolertinib the median time-to-onset of elevated CPK was 43 days (range: 1-636 days). The median time-to-resolution was 105 days (range: 1-724 days). The median time-to-onset of Grade ≥ 3 elevated CPK was 43.5 days, and the time-to-resolution was 14.5 days.

Elevated liver enzymes

In the AENEAS study, ALT elevations were reported in 63 patients (29.4%) and 120 patients (55.8%) in the aumolertinib and gefitinib arms, respectively. AST elevations were reported in 64 patients (29.9%) and 116 patients (54.0%) in the aumolertinib and gefitinib arms, respectively. Most events were Grades 1 to 2. Grade ≥ 3 ALT elevations were reported in 6 patients (2.8%) and 26 patients (12.1%) in the aumolertinib and gefitinib arms, respectively. Grade ≥ 3 AST elevations were reported in 3 patients (1.4%) and 20 patients (9.3%) in the aumolertinib and gefitinib arms, respectively. DILI was reported in 1 patient (0.5%) and 4 patients (1.9%) in the aumolertinib and gefitinib arms, respectively.

In the Phase 1/2 study, ALT and AST elevations were reported in 31 patients (11%) and 36 patients (12.7%), respectively. Grade ≥ 3 ALT and AST elevations were reported in 5 patients (1.7%) and 1 patient (0.4%), respectively. No events of DILI were reported. One patient met the criteria for Hy’s law.

In all patients treated with aumolertinib the median time-to-onset of ALT and AST elevations was 43 days (range: 1-553 days) and 43 days (range: 1-562 days), respectively. The median time-to-resolution was 36 days (range: 1-652 days) and 43 days (range: 2-702 days), respectively. The median time-to-onset of Grade ≥ 3 ALT and AST elevations was 63 days and 19.5 days, respectively; and the time-to-resolution was 8 days and 10 days.

Ocular toxicity

In the AENEAS Study, ocular toxicity was reported in 10 patients (4.7%) in the aumolertinib arm and 15 patients (7.0%) in the gefitinib arm. These events were Grades 1 to 2. Conjunctivitis was the most frequently reported eye disorder; 4 patients (1.9%) in the aumolertinib arm and 8 patients (3.7%) in the gefitinib arm.

In the Phase 1/2 study, ocular toxicity was reported in 27 patients (9.5%). Conjunctivitis and dry eye were the most common eye disorder events reported in 11 patients (3.9%).

No Grade ≥ 3 events of ocular toxicity were observed across studies.

In all patients treated with aumolertinib the median time-to-onset of ocular toxicity was 43 days (range: 2-444 days). The median time-to-resolution was 63 days (range: 2-279 days).

Haematological events

In AENEAS study, the most frequently reported events were decreased WBC in 52 patients (24.3%) in the aumolertinib arm and 34 patients (15.8%) in the gefitinib arm, decreased platelet count in 49 patients (22.9%) in the aumolertinib arm and 17 patients (7.9%) in the gefitinib arm, and anaemia in 43 patients (20.1%) in the aumolertinib arm and 22 patients (10.2%) in the gefitinib arm. Most reported events were Grades 1 to 2. Events that were Grade ≥ 3 were decreased WBC in 6 patients (2.8%) in aumolertinib arm and none in gefitinib arm, decreased platelets count in 4 patients (1.9%) in the aumolertinib arm and 2 patients (0.9%) in the gefitinib arm, and anaemia in 2 patients (0.9%) in the aumolertinib arm and none in gefitinib arm.

In the Phase 1/2 study, decreased WBC was the most common haematological adverse reaction reported in 36 patients (12.7%) followed by anaemia in 32 patients (11.3%) and decreased platelet count in 19 patients (6.7%). Anaemia was the most frequently reported Grade ≥ 3 haematological event, reported in 4 patients (1.4%).

No fatal haematological events were reported across the studies.

In all patients treated with aumolertinib the median time-to-onset of decreased WBC and decreased platelet count was 43 days (range: 1-631 days) and 46.5 days (range: 8-629 days), respectively. The median time-to-resolution was 102 days (range: 4-645 days) and 110 days (range: 4-734 days), respectively. The median time-to-onset of Grade ≥ 3 decreased WBC and decreased platelet count was 210 days and 81 days, respectively; and the time-to-resolution was 5.5 days and 11 days.

In all patients treated with aumolertinib the median time-to-onset of anaemia was 41 days (range: 1-553 days). The median time-to-resolution was 43 days (range: 3-701 days). The median time-to-onset of Grade ≥ 3 anaemia was 62 days, and the time-to-resolution was 16 days.

Hyponatraemia

In the AENEAS study, hyponatraemia was reported in 16 patients (7.5%) and 17 patients (7.9%) in the aumolertinib and gefitinib arms, respectively. Grade ≥ 3 hyponatraemia was reported in 2 patients (0.9%) and 1 patient (0.5%) in the aumolertinib and gefitinib arms, respectively.

In the Phase 1/2 Study, hyponatraemia was reported in 10 patients (3.5%). Grade > 3 hyponatraemia was reported in 4 patients (1.4%).

In all patients treated with aumolertinib the median time-to-onset of hyponatraemia was 106 days (range: 8-619 days). The median time-to-resolution was 36 days (range: 1-446 days). The median time-to-onset of Grade ≥ 3 hyponatraemia was 43 days, and the time-to-resolution was 4 days.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

In the Phase 1/2 clinical study, patients were given Aumseqa daily doses of 220 mg (39 patients) and 260 mg (6 patients). The frequency and severity of blood CPK elevation were higher in patients receiving 220 mg of Aumseqa compared with patients receiving the daily recommended dose of 110 mg.

There is no specific treatment for Aumseqa overdose. In the event of an overdose or suspected overdose, the patient should be closely monitored, Aumseqa treatment should be withheld and symptomatic treatment should be provided as clinically required.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EB11.

Mechanism of action

Aumolertinib is a third generation, irreversible, small molecule tyrosine kinase inhibitor (TKI) of EGFR with potent inhibitory activity against EGFR TKI sensitizing mutations (EGFR exon 19 [Ex19Del] deletion and EGFR L858R, respectively) and EGFR TKI resistance mutation (EGFR T790M). The major active metabolite of aumolertinib, HAS-719, showed a similar activity profile to aumolertinib.

In cell culture experiments and xenograft tumour models in mice, aumolertinib showed anti-tumour activity against NSCLC cell lines harbouring EGFR mutations and, to a lesser extent in wild-type EGFR and EGFR-amplification.

Pharmacodynamic effects

Effects on QT interval duration

Aumolertinib inhibited the hERG-mediated potassium current in HEK 293 cells in vitro with an IC₅₀ of 2.96 μM but had no apparent effect on cardiovascular functions in nonclinical studies. The QTc interval prolongation potential of Aumseqa was assessed in 49 patients who received Aumseqa. Serial ECGs were collected at baseline, following a single dose, and at steady state to evaluate the effect of Aumseqa on QTc intervals. A concentration-QT analysis predicted a drug-related QTc interval prolongation at 110 mg of 8.6 ms with an upper bound of 10.5 ms (90% confidence interval [CI]).

Clinical efficacy and safety

Previously untreated EGFR mutation positive locally advanced or metastatic NSCLC in the Phase 3 (AENEAS Study)

The efficacy and safety of Aumseqa for the treatment of patients with locally advanced or metastatic NSCLC harbouring EGFR TKI-sensitizing mutations, who had not received any

systemic treatment, was demonstrated in a randomised, double-blind, active-controlled, multicentre Phase 3 clinical study in China. Patient tumour tissue samples were required to have 1of the 2 common EGFR mutations known to be associated with EGFR TKI sensitivity (exon19 deletion and/or L858R).

A total of 429 Asian patients were randomised 1:1 to receive Aumseqa (110 mg once daily, n = 214) or gefitinib (250 mg once daily, n = 215). Each treatment cycle was 21 days with no gap between cycles (i.e., continuous dosing). Patients continued treatment until disease progression or other study termination criteria were met. Treatment beyond the point of disease progression was allowed as long as there was continued clinical benefit, as judged by the Investigator.

The primary efficacy endpoint was progression-free survival (PFS) as assessed by the Investigator. The evaluation by the independent review committee (IRC) was used for the sensitivity analysis. Additional endpoints included overall survival (OS), objective response rate (ORR), depth of response (DepOR), duration of response (DoR), and disease control rate (DCR).

Table 3. Baseline demographics and disease characteristics for the FAS population in the AENEAS Study

* ECOG PS score (0 or 1)

Aumseqa demonstrated a statistically significant improvement in Investigator assessed PFS with a 54% lower risk of disease progression or death. The results of sensitivity analyses of the primary endpoint of PFS shows consistent with those from the primary analysis. Aumolertinib treatment resulted in improved PFS across all

predefined subgroups regardless of EGFR mutation type (exon 19 deletion versus L858R), brain metastasis status (present versus absent at baseline), sex, age (< 65 versus ≥ 65 years), smoking history, and ECOG PS score (0 versus 1). Similar improvement was also seen for independent central review (ICR)-assessed PFS. The median OS for both treatment arms was not yet reached at the data cut-off date.

Table 4. Efficacy results for aumolertinib versus gefitinib from the AENEAS Study

* Full analysis set (FAS)

Note: [1] Stratified Cox Proportional Hazards model. [2] Stratified log-rank test. CI: confidence interval, DoR: duration of response, HR: hazard ratio, IRC: independent central review, NA: not available, ORR: objective response rate, PFS: progression-free survival

*Stratified by EGFR mutations (exon 19deletion or L858R) and the presence of baseline brain metastasis status (yes or no).

Figure 1 presents a Kaplan-Meier plot of Investigator -assessed PFS.

Figure 1. Kaplan-Meier estimates of Investigator-assessed progression-free survival

(PFS) in the AENEAS Study^*

CI: confidence interval; mPFS: median progression-free survival.

*Full analysis set (FAS)

Previously treated EGFR mutation positive locally advanced or metastatic NSCLC patients in the Phase 1/2 Study

The safety and efficacy of oral, once daily administration of Aumseqa in patients with locally advanced or metastatic NSCLC who had progressed after previous treatment with EGFR TKIs was demonstrated in an open-label, multicentre Phase ½ study. The study had 3 parts: part 1 dose-escalation, part 2 dose-expansion, and part 3 dose-extension (APOLLO Study). Aumolertinib doses evaluated ranged from 55 mg to 260 mg administered once daily.

The APOLLO Study assessed the safety and efficacy of Aumseqa at the recommended dose of 110 mg once daily in patients positive for the T790M mutation. Patients were required to be positive for the T790M mutation by central laboratory testing using a biopsy sample taken after disease progression following the most recent EGFR TKI treatment. The primary efficacy endpoint was ORR as assessed by ICR. Key secondary endpoints included assessment of additional efficacy endpoints, including DCR, PFS, DoR, DepOR, and OS.

Patients (n = 244) aged 27 to 87 years (mean 60.8 years) received 110 mg Aumseqa once daily. Of these, 142 (58.2%) were female and 102 (41.8%) were male; 178 (73.0%) had never smoked; 4 were active smokers (1.6%), and 62 (25.4%) were ex-smokers. As required by the protocol, all the patients’ tumours had the T790M mutation, including the 155 patients (63.5%) with an exon 19 deletion, 85 patients (34.8%) with an L858R mutation, and 4 patients (1.6%) with other EGFR mutations. Eighty-five patients (34.8%) had an ECOG PS score of 0 and 159 (65.2%) had a score of 1. Ninety-one patients (37.3%) had brain metastases.

ORR assessed by ICR was 65.6% (95% CI: 59.2, 71.5) and DCR was 93.4% (95% CI: 89.6, 96.2). The lower limit of the 95% CI of ORR exceeded the prespecified value of 30%.

Long-term analyses (median follow-up time: 33.7 months) reported a median PFS of 12.4 months (assessed by ICR), median DoR of 15.1 months per ICR, and a median OS of 31.5 months.

Paediatric population

The Medicines and Healthcare product Regulatory Agency (MHRA) has waived the obligation to submit the results of studies with aumolertinib in all subsets of the paediatric population in NSCLC, see section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Absorption

Following oral administration, aumolertinib was absorbed quickly and its median peak plasma concentration was 4 hours after single and multiple dosing. The median peak plasma concentrations of its primary active metabolite HAS-719 were observed at 4 to 8 hours post dose after multiple dosing. Aumolertinib and HAS-719 exposures (AUC) and C_max increased in an approximately dose proportional manner across the 55 to 220 mg dose range. Steady-state concentrations of aumolertinib were achieved in 8 days with approximately 1.8-fold accumulation in AUC after once daily administration. Steady-state concentrations of HAS-719 were achieved after 8 days with approximately 4.6-fold accumulation in AUC after once daily dosing of aumolertinib.

Food effects

There were no clinically relevant differences in exposures when aumolertinib was administered with a high-fat meal as compared to a fasted state. Aumolertinib can be administered with or without food.

The multiple dose PK parameters of aumolertinib and HAS-719 are provided in Table 5.

Table 5. Multiple dose PK parameters of aumolertinib and HAS-719 following oral administration of aumolertinib 110 mg in adults with NSCLC

^*Based on non-compartmental analysis from part 3, dose extension part, of the Phase 1/2 study

AUC_tau = area under the plasma concentration-time curve from time zero to the end of the dosing interval, C_max = maximum plasma concentration, C_min = minimum plasma concentration, CV = coefficient of variation

Distribution

Aumolertinib and HAS-719 binding to human plasma proteins is high (≥ 99.5%). The blood/plasma ratio of aumolertinib in rats was approximately 1.5, indicating that the drug partitions to red blood cells.

In rats, following oral dosing at 20 mg/kg aumolertinib was rapidly and extensively distributed into various tissues with peak tissue concentrations occurring at 2 hours post-dose (first sampling time point). Relatively high concentrations of HAS-719 were observed in tissues that exhibited high concentrations of aumolertinib.

Biotransformation

Aumolertinib is primarily metabolized by cytochrome P450 isozyme CYP3A4, with smaller contributions from CYP3A5, CYP1A2, and CYP2A6. HAS-719 is an active major circulating metabolite that is formed via an N-demethylation pathway. HAS-719 is approximately 2 to 3-fold less potent against EGFR-mutants than the parent compound.

Elimination

Following a single oral administration of a 110 mg dose of aumolertinib in humans, approximately 85% of the administered dose was eliminated in faeces as aumolertinib and its metabolites, while approximately 5% of the dose was eliminated in urine. The mean terminal half-lives of aumolertinib and HAS-719 were approximately 31 and 55 hours, respectively.

Special population

Age, gender, body weight, and ethnicity

In a population PK analysis, no clinically significant relationships were identified between steady-state exposure (AUC_ss) and patient’s age (range: 27 to 89 years), gender (60% female), ethnicity, and body weight (range: 37 to 100 kg).

The majority of healthy volunteers and patients in studies to date have been of a Han Chinese ethnic background. However, data from a PK bridging study in healthy volunteers found no differences in aumolertinib PK between Chinese and non-Chinese patients (including Caucasian, Black/African American and Hispanic/Latino participants).

Hepatic impairment

Hepatic metabolism is the principal route of aumolertinib clearance, and CYP3A4 is the major enzyme catalysing the biotransformation of aumolertinib. In clinical studies, no clinically relevant changes in the exposure of unbound aumolertinib were observed in patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. Based on a population PK analysis, no effect of hepatic function (as assessed by markers of liver function AST, ALT, albumin, total bilirubin, and by National Cancer Institute - Organ Dysfunction Working Group (NCI-ODWG) hepatic impairment category) was identified on aumolertinib exposure.

Renal impairment

Data from the clinical studies indicate that renal clearance of aumolertinib is negligible. Consequently, it is not anticipated that aumolertinib PK will be altered by reduced renal function. In a population PK analysis, aumolertinib and HAS-719 exposures were similar in patients with mild renal impairment (60 ≤ CLcr < 90 mL/min), patients with moderate renal impairment (30 ≤ CLcr < 60 mL/min), and patients with normal renal function (CLcr ≥ 90 mL/min). Aumolertinib has not been evaluated in patients with severe renal impairment or end-stage renal disease (CLcr < 30 mL/min).

5.3 Preclinical safety data

The main finding observed in repeat dose toxicity studies in rats and dogs comprised effects in the skin, gastrointestinal tract, mouth, eyes, liver, and lungs, which were consistent with the pharmacology of EGFR inhibition or the condition of the animal. Target organ toxicities at tolerated doses were generally either completely or partially recovered during or at the end of the recovery phase of the chronic toxicity.

In vitro and in vivo genotoxicity studies conducted with aumolertinib, suggests that neither aumolertinib nor its impurities are genotoxic at relevant concentrations.

Carcinogenicity studies have not been conducted with aumolertinib. In vitro study results showed that aumolertinib is not expected to be phototoxic.

Reproductive toxicity

The effects of aumolertinib on the fertility and early embryonic development in rats and on embryo-foetal development in rats and rabbits were evaluated.

In a fertility and early embryonic development study in rats, statistically significant decreases in gravid uterus weight, mean numbers of corpora lutea, implantation sites, live foetuses, and the mean live foetus index were seen, along with increases in the post-implantation loss, the mean number of resorptions, and the resorption index at 100 mg/kg. Exposure (based on

AUC₂₄ at steady state) in nonpregnant female rats given 100 mg/kg/day was 25,322 ng·hr/mL, which resulted in an exposure ratio of 3.8 as compared to humans given 110 mg (6602 ng·hr/mL). No aumolertinib-related changes were noted in sperm counts, motility, sperm morphology examinations. There were no effects in fertility up to 100 mg/kg in males, or 30 mg/kg in females.

In an embryo-foetal development study in rats, decreases in maternal body weight, body weight gain, and food consumption were noted at 100 mg/kg but there were no aumolertinib-related toxic effects in embryo-foetal development or in foetal external, visceral, or skeletal development. Exposure (based on AUC₂₄ on gestational day 15) in pregnant rats given 100 mg/kg/day was 22,756 ng·hr/mL, which resulted in an exposure ratio of 3.4 as compared to humans given 110 mg (6602 ng·hr/mL).

In an embryo-foetal development study in New Zealand white rabbits reduced food consumption, decreased body weight, reduced or no faecal output with oliguria or anuria, miscarriage, and/or premature delivery were seen. In addition, at 15 and 30 mg/kg, maternal death and spontaneous abortion was observed, and at 30 mg/kg, premature delivery. Sternum development of the foetus was slightly delayed (at 5, 15 and 30 mg/kg the ossification rate of sternum decreased; at 15 and 30 mg/kg the sternum number of foetuses was slightly reduced), and the number of live foetuses at 30 mg/kg was slightly reduced. A dose-responsive increase in the incidence of abnormal arterial arborisation (abnormal opening of the left common carotid artery) in foetuses was observed across the doses tested (5, 15 and 30 mg/kg).

Exposure (based on AUC₂₄ on gestational day 19) in pregnant rabbits given 5 mg/kg/day was 347 ng·hr/mL, which resulted in an exposure ratio < 1 as compared to humans given 110 mg (6602 ng·hr/mL). No teratogenicity was observed with aumolertinib up to 100 mg/kg in rats and 30 mg/kg in rabbits.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Microcrystalline cellulose

Sodium starch glycolate

Anhydrous lactose

Sodium stearyl fumarate

Magnesium stearate

Tablet coating:

Opadry (85F12300 Yellow) components include:

Polyvinyl alcohol

Titanium dioxide

Polyethylene glycol

Talc

Iron oxide yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 30°C.

Store in the original bottle in order to protect from moisture. Do not swallow desiccant.

Do not remove desiccant from bottle.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with an aluminium heat-induction sealed child-resistant closure, and a silica gel desiccant cannister inside.

Each bottle contains 60 tablets.

Each carton contains one bottle.

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

SFL Pharmaceuticals Deutschland GmbH

Marie-Curie-Strasse 8

79539 Loerrach

Germany

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 54280/0002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

03/06/2025

10 DATE OF REVISION OF THE TEXT

03/06/2025