Osimertinib

Osimertinib may increase the exposure of breast cancer resistant protein (BCRP). Based on in vitro studies, osimertinib is a competitive inhibitor of BCRP transporters.

In a clinical PK study, co-administration of osimertinib with rosuvastatin (sensitive BCRP substrate) increased the AUC and C_max of rosuvastatin by 35% and 72%, respectively. Patients taking concomitant medications with disposition dependent upon BCRP and with narrow therapeutic index should be closely monitored for signs of changed tolerability of the concomitant medication as a result of increased exposure whilst receiving osimertinib.

In a clinical PK study, co-administration of osimertinib with simvastatin (sensitive CYP3A4 substrate) decreased the AUC and C_max of simvastatin by 9% and 23% respectively. These changes are small and not likely to be of clinical significance. Clinical PK interactions with CYP3A4 substrates are unlikely. A risk for decreased exposure of hormonal contraceptives cannot be excluded.

In a clinical Pregnane X Receptor (PXR) interaction study, co-administration of osimertinib with fexofenadine (P-gp substrate) increased the AUC and C_max of fexofenadine by 56% (90% CI 35, 79) and 76% (90% CI 49, 108) after a single dose and 27% (90% CI 11, 46) and 25% (90% CI 6, 48) at steady state, respectively. Patients taking concomitant medications with disposition dependent upon P-gp and with narrow therapeutic index (e.g. digoxin, dabigatran, aliskiren) should be closely monitored for signs of changed tolerability as a result of increased exposure of the concomitant medication whilst receiving osimertinib.

Strong CYP3A4 inducers can decrease the exposure of osimertinib. In a clinical pharmacokinetic study in patients, the steady-state AUC of osimertinib was reduced by 78% when co-administered with rifampicin (600 mg daily for 21 days). Similarly, the exposure to metabolite AZ5104 decreased by 82% for the AUC and 78% for C_max. It is recommended that concomitant use of strong CYP3A inducers (e.g. Phenytoin, rifampicin and carbamazepine) with osimertinib should be avoided. Moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil) may also decrease osimertinib exposure and should be used with caution, or avoided when possible. There are no clinical data available to recommend a dose adjustment of osimertinib. Concomitant use of St. John’s Wort is contraindicated.

The safety and efficacy of this medicinal product has not been established in patients with end-stage renal disease [creatinine clearance (CLcr) less than 15 mL/min, calculated by the Cockcroft and Gault equation], or on dialysis. Caution should be exercised when treating patients with severe and end-stage renal impairment.

The safety and efficacy of this medicinal product has not been established in patients with severe hepatic impairment. Until additional data become available, use in patients with severe hepatic impairment is not recommended.

There are no data on the effect of osimertinib on human fertility. Results from animal studies have shown that osimertinib has effects on male and female reproductive organs and could impair fertility.

Across clinical trials, Left Ventricular Ejection Fraction (LVEF) decreases greater than or equal to 10% and a drop to less than 50% occurred in 3.9% (35/908) of patients treated with osimertinib who had baseline and at least one follow-up LVEF assessment. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including an assessment of LVEF at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring including LVEF assessment should be considered.

Severe, life-threatening or fatal Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g. pneumonitis) have been observed in patients treated with osimertinib in clinical studies. Most cases improved or resolved with interruption of treatment. Patients with a past medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from clinical studies.

Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g. pneumonitis) were reported in 3.9% and were fatal in 0.4% of the 1142 patients who received osimertinib in FLAURA and AURA studies. The incidence of ILD was 10.4% in patients of Japanese ethnicity, 1.8% in patients of Asian ethnicity and 2.8% in non-Asian patients.

Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude ILD. Treatment with this medicinal product should be interrupted pending investigation of these symptoms. If ILD is diagnosed, osimertinib should be discontinued and appropriate treatment initiated as necessary. Reintroduction of osimertinib should be considered only after careful consideration of the individual patient’s benefits and risk.

Case reports of Stevens-Johnson syndrome (SJS) have been reported rarely in association with osimertinib treatment. Before initiating treatment, patients should be advised of signs and symptoms of SJS. If signs and symptoms suggestive of SJS appear, osimertinib should be interrupted or discontinued immediately.

Keratitis was reported in 0.7% (n=8) of the 1142 patients treated with osimertinib in the FLAURA and AURA studies. Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist.

QTc interval prolongation occurs in patients treated with osimertinib. QTc interval prolongation may lead to an increased risk for ventricular tachyarrhythmias (e.g. torsade de pointes) or sudden death. No arrhythmic events were reported in FLAURA or AURA studies. Patients with clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram (ECG) (e.g. QTc interval greater than 470 ms) were excluded from these studies.

When possible, the use of osimertinib in patients with congenital long QT syndrome should be avoided. Periodic monitoring with electrocardiograms (ECGs) and electrolytes should be considered in patients with congestive heart failure, electrolyte abnormalities, or those who are taking medicinal products that are known to prolong the QTc interval. Treatment should be withheld in patients who develop a QTc interval greater than 500 msec on at least 2 separate ECGs until the QTc interval is less than 481 msec or recovery to baseline if the QTc interval is greater than or equal to 481 msec, then resume osimertinib at a reduced dose as described in the table below. Osimertinib should be permanently discontinued in patients who develop QTc interval prolongation in combination with any of the following: Torsade de pointes, polymorphic ventricular tachycardia, signs/symptoms of serious arrhythmia.

Recommended dose modifications for osimertinib:

^a Note: The intensity of clinical adverse events graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
ECGs: Electrocardiograms; QTc: QT interval corrected for heart rate

There are no or limited amount of data from the use of osimertinib in pregnant women. Studies in animals have shown reproductive toxicity (embryolethality, reduced foetal growth, and neonatal death). Based on its mechanism of action and preclinical data, osimertinib may cause foetal harm when administered to a pregnant woman. Osimertinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with osimertinib.

It is not known whether osimertinib or its metabolites are excreted in human milk. There is insufficient information on the excretion of osimertinib or its metabolites in animal milk. However, osimertinib and its metabolites were detected in the suckling pups and there were adverse effects on pup growth and survival. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with osimertinib.

Contraception in males and females

Women of childbearing potential should be advised to avoid becoming pregnant while receiving osimertinib. Patients should be advised to use effective contraception for the following periods after completion of treatment with this medicinal product: at least 2 months for females and 4 months for males. A risk for decreased exposure of hormonal contraceptives cannot be excluded.

Fertility

There are no data on the effect of osimertinib on human fertility. Results from animal studies have shown that osimertinib has effects on male and female reproductive organs and could impair fertility.

Osimertinib has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Studies in EGFR mutation-positive NSCLC patients

The data described below reflect exposure to osimertinib in 1142 patients with EGFR mutationpositive non-small cell lung cancer. These patients received osimertinib at a dose of 80 mg daily in two randomised Phase 3 studies (FLAURA, first line and AURA3, second line only), two single-arm studies (AURAex and AURA2, second line or greater) and one Phase 1 study (AURA1, first-line or greater). Most adverse reactions were Grade 1 or 2 in severity. The most commonly reported adverse drug reactions (ADRs) were diarrhoea (49%) and rash (47%). Grade 3 and Grade 4 adverse reactions across both studies were 9.7% and 0.9%, respectively. In patients treated with osimertinib 80 mg once daily, dose reductions due to adverse reactions occurred in 2.1% of the patients. Discontinuation due to adverse reactions was 4.3%.

Patients with a medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from clinical studies. Patients with clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram (ECG) (e.g. QTc interval greater than 470 ms) were excluded from these studies. Patients were evaluated for LVEF at screening and every 12 weeks thereafter.

Tabulated list of adverse reactions

Adverse reactions have been assigned to the frequency categories in Table 2 where possible based on the incidence of comparable adverse event reports in a pooled dataset from the 1142 EGFR mutation positive NSCLC patients who received osimertinib at a dose of 80 mg daily in the FLAURA, AURA3, AURAex, AURA 2 and AURA1 studies.

Adverse reactions are listed according to system organ class (SOC) in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse reaction is based on the CIOMS III convention and is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).

Table 2. Adverse reactions reported in FLAURA and AURA studies^a:

^a Data is cumulative from FLAURA and AURA (AURA3, AURAex, AURA 2 and AURA1) studies; only events for patients receiving at least one dose of osimertinib as their randomised treatment are summarised.
^b National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.
^c Includes cases reported within the clustered terms: Interstitial lung disease, pneumonitis.
^d 5 CTCAE grade 5 events (fatal) were reported.
^e Includes cases reported within the clustered terms: Keratitis, punctate keratitis, corneal erosion, corneal epithelium defect.
^f Includes cases reported within the clustered terms for rash AEs: Rash, rash generalised, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, drug eruption, skin erosion.
^g Includes cases reported within the clustered terms: Dry skin, skin fissures, xerosis, eczema, xeroderma.
^h Includes casesreported within the clustered terms: Nail bed disorder, nail bed inflammation, nail bed infection, nail discolouration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.
ⁱ Includes cases reported within the clustered terms: pruritus, pruritus generalised, eyelid pruritus.
^j One event was reported in a post-marketing study, and the frequency has been derived from the FLAURA and AURA studies and the post-marketing study (N=4720).
^k Representsthe incidence of patients who had a QTcF prolongation >500msec.
^l Represents the incidence of laboratory findings, not of reported adverse events.

Safety findings in the single-arm Phase 2 AURAex and AURA2 studies were generally consistent with those observed in the AURA3 osimertinib arm. No additional or unexpected toxicity has been observed and adverse events have been aligned in type, severity and frequency.

Description of selected adverse reactions

Interstitial lung disease (ILD)

In the FLAURA and AURA studies, the incidence of ILD was 10.4% in patients of Japanese ethnicity, 1.8% in patients of non-Japanese Asian ethnicity and 2.8% in non-Asian patients. The median time to onset of ILD or ILD-like adverse reactions was 85 days.

QTc interval prolongation

Of the 1142 patients in FLAURA and AURA studies treated with osimertinib 80 mg, 0.9% of patients (n=10) were found to have a QTc greater than 500 msec, and 3.6% of patients (n=41) had an increase from baseline QTc greater than 60 msec. A pharmacokinetic/pharmacodynamic analysis with osimertinib predicted a concentration-dependent increase in QTc interval prolongation. No QTcrelated arrhythmias were reported in the FLAURA or AURA studies.

Gastrointestinal effects

In the FLAURA and AURA studies, diarrhoea was reported in 49% of patients of which 39% were Grade 1 events, 8.0% Grade 2 and 1.2% were Grade 3; no Grade 4 or 5 events were reported. Dose reduction was required in 0.2% of patients and dose interruption in 1.4%. One event (0.1%) led to discontinuation. In FLAURA and AURA3 the median time to onset was 19 days and 22 days, respectively, and the median duration of the Grade 2 events was 19 days and 6 days, respectively.

Haematological events

Early reductions in the median laboratory counts of leukocytes, lymphocytes, neutrophils and platelets have been observed in patients treated with osimertinib, which stabilised over time and then remained above the lower limit of normal. Adverse events of leukopenia, lymphopenia, neutropenia and thrombocytopenia have been reported, most of which were mild or moderate in severity and did not lead to dose interruptions.

Elderly

In FLAURA and AURA3 (N=1142), 43% of patients were 65 years of age and older, and 13% were 75 years of age and older. Compared with younger subjects (<65), more subjects ≥65 years old had reported adverse reactions that led to study drug dose modifications (interruptions or reductions) (13.4% versus 7.6%). The types of adverse events reported were similar regardless of age. Older patients reported more Grade 3 or higher adverse reactions compared to younger patients (13.4% versus 9.3%). No overall differences in efficacy were observed between these subjects and younger subjects. A consistent pattern in safety and efficacy results was observed in the analysis of AURA Phase 2 studies.

Low body weight

Patients receiving osimertinib 80 mg with low body weight (<50 kg) reported higher frequencies of Grade ≥3 adverse events (52% versus 35%) and QTc prolongation (14% versus 4%) than patients with higher body weight (≥50 kg).