Aumolertinib

Aumolertinib has not been evaluated in patients with severe renal impairment (creatinine clearance [CLc] <30 mL/min) or end-stage renal disease. Caution should be exercised when using aumolertinib in patients with severe or end-stage renal impairment.

In animal studies, impacts on fertility effects were observed in females. There are no clinical data on the effect of aumolertinib on human fertility.

There are no data from the use of aumolertinib in pregnant women. Studies in animals have shown reproductive and developmental toxicity. Mechanistically, all EGFR targeting medicinal products have the potential to cause foetal harm. Based on its mechanism of action and preclinical data, aumolertinib should not be used during pregnancy.

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

Women of childbearing potential/Contraception

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

Aumolertinib may decrease the efficacy of hormonal contraceptives. Advise patients to avoid concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring). Females using hormonal contraceptives should be counselled to use an alternative contraceptive method (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during concomitant use and for 4 weeks after discontinuation of aumolertinib.

Fertility

In animal studies, impacts on fertility effects were observed in females. There are no clinical data on the effect of aumolertinib on human fertility.

Aumolertinib has minor influence on the ability to drive and use machines. Fatigue and dizziness have been reported in some patients following administration with aumolertinib. Patients experiencing these symptoms should be advised not to drive or use machines until these symptoms resolve.

Summary of the safety profile

The most frequently reported adverse reactions in subjects treated with aumolertinib were aspartate aminotransferase (AST) increased (40.4%), hyponatraemia (37.2%), alanine aminotransferase (ALT) increased (33%), blood CPK increased (31.7%), white blood cell (WBC) count decreased (30.6%), platelet count decreased (29.4%), upper respiratory tract infections (23.3%), and rash (22.8%). The most frequently reported Grade ≥ 3 adverse reaction was blood CPK increased (7.5%).

The most common serious adverse reactions were venous thromboembolism (4.2%), lower respiratory tract and lung infections (2.8%), and urinary tract infection (1.1%).

Treatment discontinuation due to adverse reactions occurred in 2.2% of subjects. The most common adverse reaction leading to treatment discontinuation was ILD, occurring in 0.4% of subjects.

Treatment interruption and dose reduction due to adverse reactions occurred in 12.1% and 3.1% of subjects, respectively. The most common adverse reaction leading to interruption or dose reduction was blood CPK increased (occurring in 6.1% and 2.0% of subjects, respectively); dose interruption due to ALT increased occurred in 1.8% of subjects.

Tabulated list of adverse reactions

The data described in this section reflect exposure to aumolertinib in subjects with EGFR mutation-positive NSCLC. 545 subjects received aumolertinib at the recommended dose of 110 mg once a day in 2 multicentre pivotal studies: 1 phase 3 study in the first-line setting (HS-10296-03-01, AENEAS) and 1 phase ½ study in pre-treated subjects (HS-10296-12-01, APOLLO).

Adverse reactions reported are presented in the table below and listed by system organ class, MedDRA 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, <1/1 000); very rare (<1/10 000); not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse reactions reported in subjects treated with aumolertinib:

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 Includes: acute sinusitis, laryngopharyngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, and upper respiratory tract infection.
^b Includes: cystitis, pyelonephritis acute, urethritis, and urinary tract infection.
^c Includes: atypical pneumonia, bronchitis, pneumonia, and sputum purulent.
^d Includes: conjunctivitis and conjunctivitis allergic.
^e Includes: blood sodium decreased, hyponatraemia*.
^f Includes: blood potassium decreased, hypokalaemia*.
^g Includes: dry eye and xerophthalmia.
^h Includes: visual impairment and blurred vision.
ⁱ Includes: eye pain, and ocular discomfort.
^j Includes: ocular hyperaemia, conjunctival haemorrhage, and eye haemorrhage.
^k Includes: abnormal sensation in eye, and foreign body sensation in eyes.
^l Includes: corneal exfoliation and corneal opacity.
^m Includes: eyelid oedema and swelling of eyelid.
ⁿ Includes: cardiac failure, cardiac failure chronic, ejection fraction decreased, and pulmonary oedema.
° Includes: blood pressure increased, hypertension.
^p Includes: deep vein thrombosis, pulmonary embolism, venous thrombosis limb, cerebral infarction and cerebral thrombosis.
^q Includes: cough, productive cough, and upper-airway cough syndrome.
^r Includes: bronchiolitis, interstitial lung disease, and pneumonitis.
^s Includes: aphthous ulcer, dry mouth, glossodynia, mouth ulceration, oral pain, stomatitis, and tongue ulceration.
^t Includes: drug eruption, papule, macule, rash, rash maculo-papular, rash papular, rash pruritic, rash pustular, and urticaria.
^u Includes: dermatitis and dermatitis acneiform.
^v Includes: erythema and erythema nodosum.
^w Includes: neutropenia, neutrophil count decreased, and white blood cell count decreased*.
^x Includes: platelet count decreased*, and thrombocytopenia.
^y Includes: blood bilirubin increased, and hyperbilirubinemia.
^* Represent incidence of laboratory findings, not of adverse events

Description of selected adverse reactions

Interstitial lung disease (ILD)

In clinical studies (N=545), ILD was reported in 16 subjects (2.9%) treated with aumolertinib 110 mg. One fatal case of ILD was reported. The median time-to-onset of ILD was 124 days (range: 2 days – 932 days). The median time-to-resolution of ILD was 41 days (range: 14 days - 702 days).

Cardiac failure

In clinical studies (N=545), cardiac failure was reported in 4 subjects (0.7%). Two subjects (0.4%) reported cardiac failure of Grade ≥ 3. The median time-to-onset of any Grade cardiac failure was 249 days (range: 84 days – 381 days), and the median time-to-resolution was 35 days (range: 22 days – 160 days). One subject with cardiac failure died due to pulmonary oedema and upper gastrointestinal haemorrhage. Four subjects (0.7%) had a decline in LVEF of ≥ 10% to an absolute value < 50%. Nineteen subjects (3.5%) had a decline in LVEF of ≥ 15% but the absolute LVEF remained ≥ 50% in these subjects.

QTc prolongation

In clinical studies (N=545), QT prolongation was reported in 51 subjects (9.4%) treated with aumolertinib 110 mg. In 4 subjects (0.7%) the events were Grade ≥ 3. The median time-to-onset of any Grade QT prolongation was 22 days (range: 1 day – 839 days) and the median time-to-resolution was 100 days (1 day – 1,068 days). Seven subjects (1.3%) had symptomatic events, 4 (0.7%) of which were Grade ≥ 3. The reported symptomatic events were cardiac arrest, cardio-respiratory arrest, sudden cardiac death, syncope (n=2), and ventricular arrhythmia (n=2 The median time-to-onset of syncope and ventricular arrhythmia was 204 days and 252 days, respectively. Two subjects with QT prolongation died: 1 due to sudden cardiac death and 1 due to cardio-respiratory arrest. 5 subjects (0.9%) had a maximum absolute QTcF interval > 500 msec and 23 subjects (4.2%) had a maximum change in QTcF from baseline > 60 msec.

Diarrhoea

In clinical studies (N=545), diarrhoea was reported in 72 subjects (13.2%) treated with aumolertinib 110 mg. In 4 subjects (0.7%) the events were Grade ≥ 3. The median time-to-onset of any Grade diarrhoea was 27 days (range: 1 day – 1,046 days) and the median time-to-resolution was 13 days (1 day – 846 days). Three subjects (0.6%) experienced SAEs of diarrhoea. 1 subject reported potassium imbalance. Six subjects reported hypokalaemia of Grade 3.

Elevated blood creatinine phosphokinase (CPK) and rhabdomyolysis

In clinical studies (N=545), elevated blood CPK was reported in 173 subjects (31.7%) treated with aumolertinib 110 mg. In 41 subjects (7.5%), the events were Grade ≥ 3. The median time-to-onset of any Grade blood CPK increased was 64 days (range: 1 day – 926 days) and the median time-to-resolution was 215 days (4 days – 1,156 days). Elevated blood CPK led to treatment discontinuation in 1 subject (0.2%). Events of elevated Blood CPK were considered rhabdomyolysis if they were Grade 3 with muscle related symptoms or Grade 4 with or without muscle related symptoms. In total, 14 subjects (2.6%) treated with aumolertinib 110 mg were considered to have experienced rhabdomyolysis.

Hepatic dysfunction

In clinical studies (N=545), hepatic dysfunction was reported in 204 subjects (37.4%) treated with aumolertinib 110 mg. In 20 (3.7%) of these subjects the events were Grade ≥ 3. The median time-to-onset of any Grade hepatic dysfunction was 44 days (range: 1 day – 841 days) and the median time-to-resolution was 62 days (2 days – 1,036 days). AST and ALT elevations were reported in 118 (21.7%) and 110 (20.2%) subjects, respectively. Thirteen subjects (2.4%) reported AST increased of Grade ≥ 3 and 5 subjects (0.9%) reported ALT increased of Grade ≥ 3. One subject (0.2%) reported drug-induced liver injury of Grade ≥ 3 with a time-to-onset of 8 days and a time-to-resolution of 6 days.

Venous thromboembolism (VTE)

In clinical studies (N=545), VTE (including deep vein thrombosis, pulmonary embolism, and venous thrombosis limb) was reported in 39 subjects (7.2%) treated with aumolertinib 110 mg. In 17 subjects (3.1%) the events were Grade ≥ 3. The median time-to-onset of any Grade VTE was 229 days (range: 8 days – 1,087 days) and the median time-to-resolution was 142 days (7 days – 830 days). Pulmonary embolism was reported by 21 subjects (3.9%), with 15 (2.8%) of the events being Grade ≥ 3. Venous thrombosis limb was reported by 16 subjects (2.9%), with 2 (0.4%) of the events being Grade ≥ 3. Deep vein thrombosis was reported by 9 subjects (1.7%), with 1 (0.2%) of the events being Grade ≥ 3. In addition, cerebral infarction and cerebral thrombosis were respectively reported in 4 (0.7%) and 1 (0.2%) subjects, with 3 (0.6%) of the events being Grade ≥ 3.