TAGRISSO as monotherapy is indicated for:

·            the adjuvant treatment after complete tumor resection in adult patients non- small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations (see section 5.1).

·            the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations.

·            the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

TAGRISSO is indicated in combination with:

·            TAGRISSO in combination with pemetrexed and platinum-based chemotherapy is indicated for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations.

Treatment with TAGRISSO should be initiated by a physician experienced in the use of anticancer therapies.

When considering the use of TAGRISSO, EGFR mutation status (in tumour specimens for adjuvant treatment and tumor or plasma specimens for locally advanced or metastatic setting) should be determined using a validated test method (see section 4.4).

Posology

Monotherapy

The recommended dose is 80 mg Osimertinib once a day.

Combination therapy

The recommended dose of TAGRISSO is 80 mg Osimertinib once a day when taken with pemetrexed and platinum-based chemotherapy.

Refer to the Summary of Product Characteristics for pemetrexed and cisplatin or carboplatin for the respective dosing information.

Patients in the adjuvant setting should receive treatment until disease recurrence or unacceptable toxicity. Treatment duration for more than 3 years was not studied.

Patients with locally advanced or metastatic lung cancer should receive TAGRISSO treatment until disease progression or unacceptable toxicity.

If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled.

TAGRISSO can be taken with or without food at the same time each day, Tablets may be dispersed in water for patients who have difficulty swallowing, or for nasogastric tube administration.

Dose adjustments.

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 to 40 mg taken once daily.

Dose reduction guidelines for adverse reactions toxicities are provided in Table 1.

Table 1. Recommended dose modifications for TAGRISSO

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.

b        Refer to section 4.4.

ECGs: Electrocardiograms; QTc: QT interval corrected for heart rate.

Combination therapy

When TAGRISSO is administered in combination with pemetrexed and platinum-based chemotherapy, modify the dose of any one of the treatments for the management of adverse reactions, as appropriate. For TAGRISSO dose modification instructions, see Table 2. Withhold, reduce the dose or permanently discontinue pemetrexed, cisplatin or carboplatin according to their respective Prescribing Information.

Special populations

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

Hepatic impairment

No dose adjustment is recommended in patients with mild to moderate hepatic impairment (Child-Pugh A and B or total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 3 times ULN and any AST). There is no recommended dose for TAGRISSO for patients with severe hepatic impairment

(see section 5.2).

Renal impairment

No dose adjustment is recommended in patients with creatinine clearance (CLcr) 15 - 89 mL/min, as estimated by Cockcroft-Gault. There is no recommended dose of TAGRISSO for patients with end-stage renal disease (CLcr <15 mL/min)

 (see section 5.2).

Paediatric population

The safety and effectiveness of TAGRISSO in pediatric patients have not been established

Method of administration

Administer TAGRISSO 80 mg tablet orally once daily with or without food. Tablets may be dispersed in water for patients who have difficulty swallowing, or for nasogastric tube administration

If the patient is unable to swallow the tablet, Disperse tablet in 60 mL (2 ounces) of non-carbonated water only. Stir until tablet is dispersed into small pieces (the tablet will not completely dissolve) and swallow immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 120 mL to 240 mL (4 to 8 ounces) of water and immediately drink.

If administration via nasogastric tube is required, disperse the tablet as above in 15 mL of non-carbonated water, and then use an additional 15 mL of water to transfer any residues to the syringe. The resulting 30 mL liquid should be administered as per the nasogastric tube instructions with appropriate water flushes (approximately 30 mL). Repeat this step until no pieces remain in the syringe. This will help to ensure that the full prescribed dose of the TAGRISSO is given.

Assessment of EGFR mutation status

When considering the use of TAGRISSO as adjuvant treatment after complete tumour resection in patients with NSCLC, it is important that the EGFR mutation positive status (exon 19 deletions (Ex19del) or exon 21 L858R substitution mutations (L858R)) indicates treatment eligibility. A validated test should be performed in a clinical laboratory using tumour tissue DNA from biopsy or surgical specimen.

When considering the use of TAGRISSO as a treatment for locally advanced or metastatic NSCLC, it is important that the EGFR mutation positive status is determined. A validated test 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, exon 19 deletion or exon 21 (L858R) substitution mutations when TAGRISSO is given in combination

with pemetrexed and platinum-based chemotherapy 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 TAGRISSO. However, if a plasma-based ctDNA test is used and the result is negative, it is advisable to follow-up with a tissue test wherever possible due to the potential for false negative results using a plasma-based test.

Only robust, reliable and sensitive tests with demonstrated utility for the determination of EGFR mutation status should be used.

Interstitial Lung Disease (ILD)

Interstitial lung disease (ILD)/pneumonitis occurred in 4% of the 1813 TAGRISSO-treated patients; 0.4% of cases were fatal.

In the FLAURA2 study, ILD/pneumonitis occurred in 3.3% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 0.4% of cases were fatal.

Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD/pneumonitis is confirmed.

Severe Cutaneous Adverse Reactions (SCARs)

Post marketing cases consistent with erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if EMM, SJS, or TEN is suspected and permanently discontinue if confirmed.

QTc interval prolongation

Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1813 patients treated with TAGRISSO monotherapy in clinical trials, 1.1% were found to have a QTc >500 msec, and 4.3% of patients had an increase from baseline QTc >60.

Of the 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy in the FLAURA2 study, 1.8% were found to have a QTc >500 msec, and 10.5% of patients had an increase from baseline QTc >60 msec.

No QTc-related arrhythmias were reported.

Clinical trials of TAGRISSO did not enroll patients with baseline QTc of >470 msec. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia.

Cardiomyopathy

Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 3.8% of the 1813 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal.

In the FLAURA2 study, cardiomyopathy occurred in 9% of the 276 patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; 1.1% of cardiomyopathy cases were fatal.

A decline in left ventricular ejection fraction (LVEF) ≥10 percentage points from baseline and to less than 50% LVEF occurred in 4.2% of 1557 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of patients treated with TAGRISSO experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. In the FLAURA2 study, 8% (21/262) of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, who had baseline and at least one follow-up LVEF assessment, experienced LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%.

For patients who will be receiving TAGRISSO monotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors.

For patients who will be receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in all patients.

Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO

Keratitis

Keratitis was reported in 0.6% (n=10) of the 1813 patients treated with TAGRISSO monotherapy in the Clinical 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 (see section 4.2 Table 1).

Aplastic Anemia

Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.06% of 1813) and post marketing. Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO (see section 4.2).

Sodium

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

Pharmacokinetic interactions

Effect of Other Drugs on TAGRISSO in Clinical Pharmacokinetic Studies Strong CYP3A Inducers: The steady-state AUC of osimertinib was reduced by 78% in patients when co-administered with rifampin (600 mg daily for 21 days) [see Drug Interactions (7.1)].

Strong CYP3A Inhibitors: Co-administering TAGRISSO with 200 mg itraconazole twice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on the exposure of osimertinib (AUC increased by 24% and Cmax decreased by 20%).

Effect of gastric acid reducing active substances on osimertinib

The exposure of osimertinib was not affected by concurrent administration of a single 80 mg TAGRISSO tablet following 40 mg omeprazole administration for 5 days..

Active substances whose plasma concentrations may be altered by TAGRISSO

Based on in vitro studies, osimertinib is a competitive inhibitor of BCRP transporters.

In a clinical PK study, co-administration of TAGRISSO with rosuvastatin (sensitive BCRP substrate) increased the AUC and Cmax of rosuvastatin by 35% and 72%, respectively. Patients taking concomitant medicinal products 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 TAGRISSO (see section 5.2).

In a clinical PK study, co-administration of TAGRISSO with simvastatin (sensitive CYP3A4 substrate) decreased the AUC and Cmax 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 TAGRISSO with fexofenadine (P-gp substrate) increased the AUC and Cmax 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 TAGRISSO (see section 5.2).

Based on animal data, TAGRISSO can cause malformations, embryo lethality, and postnatal death at doses resulting in exposures 1.5 times or less the human exposure at the clinical dose of 80 mg daily [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating TAGRISSO.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose [see Use in Specific Populations (8.1)].

Males

Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of TAGRISSO [see Nonclinical Toxicology (13.1)].

Infertility

Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential. The effects on female fertility showed a trend toward reversibility. It is not known whether the effects on male fertility are reversible Adjuvant Treatment of EGFR Mutation-Positive NSCLC – Monotherapy

The safety of TAGRISSO was evaluated in ADAURA, a randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy. At time of DFS analysis, the median duration of exposure to TAGRISSO was 22.5 months.

Serious adverse reactions were reported in 16% of patients treated with TAGRISSO. The most common serious adverse reaction (≥1%) was pneumonia (1.5%). Adverse reactions leading to dose reductions occurred in 9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were diarrhea (4.5%), stomatitis (3.9%), nail toxicity (1.8%) and rash (1.8%). Adverse reactions leading to permanent discontinuation occurred in 11% of patients treated with TAGRISSO. The most frequent adverse reactions leading to discontinuation of TAGRISSO were interstitial lung disease (2.7%), and rash (1.2%).

Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities which occurred in ADAURA.

Table 3. Adverse Reactions (Numbers in the table are adverse events with no causality established to the Investigational Medicinal Product) Occurring in ≥10% of Patients Receiving TAGRISSO in ADAURA

^bbNCI CTCAE v4.0.

^†All events were grade 3.

^*Includes diarrhea, colitis, enterocolitis, enteritis.

^‡Includes aphthous ulcer, cheilitis, gingival ulceration, glossitis, tongue ulceration, stomatitis and mouth ulceration.

^**Includes abdominal discomfort, abdominal pain, abdominal lower pain, abdominal upper pain, epigastric discomfort, hepatic pain.

^§Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, eczema asteatotic, lichen planus, skin erosion, pustule.

^¶Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.

^§§Includes dry skin, skin fissures, xerosis, eczema, xeroderma.

^#Includes pruritus, pruritus generalized, eyelid pruritus.

^þIncludes cough, productive cough, upper-airway cough syndrome.

^††Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.

^¶¶Includes cystitis, urinary tract infection, and urinary tract infection bacterial.

^bIncludes asthenia, fatigue.

^##Includes dizziness, vertigo, and vertigo positional.

^‡Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis, acneiform dermatitis, pustule.

^§ Includes dry skin, eczema, skin fissures, xerosis.

^¶Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, paronychia.

^#Includes pruritus, pruritus generalized, eyelid pruritus.

^þIncludes fatigue, asthenia.

Clinically relevant adverse reactions in AURA3 in <10% of patients receiving TAGRISSO were epistaxis (5%), interstitial lung disease (3.9%), alopecia (3.6%), urticaria (2.9%), palmar-plantar erythrodysesthesia syndrome (1.8%), QTc interval prolongation (1.4%), keratitis (1.1%), and erythema multiforme (0.7%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

Table 10. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3

NA=not applicable

^*NCI CTCAE v4.0

^†Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 279, Chemotherapy comparator 131)

^‡Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 270, Chemotherapy 5; fasting glucose was not a protocol requirement for patients in the chemotherapy arm)

Clinically relevant laboratory abnormalities in AURA3 that occurred in <20% of patients receiving TAGRISSO included increased blood creatinine (7%).

Other Clinical Trials Experience

The following adverse reaction has been reported following administration of TAGRISSO: increased blood creatine phosphokinase.

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

Adjuvant Treatment of EGFR Mutation-Positive NSCLC – Monotherapy

The safety of TAGRISSO was evaluated in ADAURA, a randomized, double-blind, placebo-controlled trial for the adjuvant treatment of patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy. At time of DFS analysis, the median duration of exposure to TAGRISSO was 22.5 months.

Serious adverse reactions were reported in 16% of patients treated with TAGRISSO. The most common serious adverse reaction (≥1%) was pneumonia (1.5%). Adverse reactions leading to dose reductions occurred in 9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were diarrhea (4.5%), stomatitis (3.9%), nail toxicity (1.8%) and rash (1.8%). Adverse reactions leading to permanent discontinuation occurred in 11% of patients treated with TAGRISSO. The most frequent adverse reactions leading to discontinuation of TAGRISSO were interstitial lung disease (2.7%), and rash (1.2%).

Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities which occurred in ADAURA.

Table 3. Adverse Reactions (Numbers in the table are adverse events with no causality established to the Investigational Medicinal Product) Occurring in ≥10% of Patients Receiving TAGRISSO in ADAURA^bb

^bbNCI CTCAE v4.0.

^†All events were grade 3.

^*Includes diarrhea, colitis, enterocolitis, enteritis.

^‡Includes aphthous ulcer, cheilitis, gingival ulceration, glossitis, tongue ulceration, stomatitis and mouth ulceration.

^**Includes abdominal discomfort, abdominal pain, abdominal lower pain, abdominal upper pain, epigastric discomfort, hepatic pain.

^§Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic, rash vesicular, rash follicular, erythema, folliculitis, acne, dermatitis, dermatitis acneiform, dermatitis bullous, dermatitis exfoliative generalized, drug eruption, eczema, eczema asteatotic, lichen planus, skin erosion, pustule.

^¶Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.

^§§Includes dry skin, skin fissures, xerosis, eczema, xeroderma.

^#Includes pruritus, pruritus generalized, eyelid pruritus.

^þIncludes cough, productive cough, upper-airway cough syndrome.

^††Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain.

^¶¶Includes cystitis, urinary tract infection, and urinary tract infection bacterial.

^bIncludes asthenia, fatigue.

^##Includes dizziness, vertigo, and vertigo positional.

Clinically relevant adverse reactions in ADAURA in <10% of patients receiving TAGRISSO were alopecia (6%), epistaxis (6%), interstitial lung disease (3%), palmar-plantar erythrodysesthesia syndrome (1.8%), skin hyperpigmentation (1.8%),  urticaria (1.5%), keratitis (0.6%), QTc interval prolongation (0.6%), and erythema multiforme (0.3%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

Table 4. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in ADAURA

^*NCI CTCAE v4.0

^†Based on the number of patients with available follow-up laboratory data.

Laboratory abnormalities in ADAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (10%).

Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer – Monotherapy

The safety of TAGRISSO was evaluated in FLAURA, a multicenter international double-blind randomized (1:1) active-controlled trial conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO was 16.2 months.

Serious adverse reactions were reported in 4% of patients treated with TAGRISSO; the most common serious adverse reactions (≥1%) were pneumonia (2.9%), ILD/pneumonitis (2.1%), and pulmonary embolism (1.8%). Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (4.3%), diarrhea (2.5%), and lymphopenia (1.1%). Adverse reactions leading to permanent discontinuation occurred in 13% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3.9%).

Tables 5 and 6 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA.

Table 5. Adverse Reactions (numbers in the table are adverse events with no causality established to the Investigational Medicinal Product) Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA*

^*NCI CTCAE v4.0

^†One grade 5 (fatal) event was reported (diarrhea) for EGFR TKI comparator.

^‖Includes stomatitis and mouth ulceration.

^‡Includes rash, rash generalized, 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, pustule.

^§Includes dry skin, skin fissures, xerosis, eczema, xeroderma.

^¶Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.

^#Includes pruritus, pruritus generalized, eyelid pruritus.

^þIncludes fatigue, asthenia.

^b Includes prolonged QT interval reported as adverse reaction.

Clinically relevant adverse reactions in FLAURA in <10% of patients receiving TAGRISSO were alopecia (7%), epistaxis (6%), interstitial lung disease (3.9%), urticaria (2.2%), palmar-plantar erythrodysesthesia syndrome (1.4%) and skin hyperpigmentation (0.4%). , QTc interval prolongation (1.1%), and keratitis (0.4%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

Table 6. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA

^*NCI CTCAE v4.0

^†Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO range: 267 - 273 and EGFR TKI comparator range: 256 - 268).

^‡Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: TAGRISSO (179) and EGFR comparator (191).

Clinically relevant laboratory abnormalities in FLAURA that occurred in <20% of patients receiving TAGRISSO was increased blood creatinine (9%).

Previously Untreated EGFR Mutation-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer – TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy

The safety of TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was evaluated in FLAURA2, a multicenter international open-label, randomized (1:1), active-controlled trial conducted in 557 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, locally advanced or metastatic NSCLC who had not received previous systemic treatment for advanced disease. The median duration of exposure to TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was 22.3 months and the median duration of exposure to TAGRISSO monotherapy was 19.3 months.

Serious adverse reactions were reported in 38% of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy; the most frequently reported serious adverse reactions (≥2%) in the combination arm were anemia (3.3%), COVID-19 (2.5%), pneumonia (2.5%), febrile neutropenia (2.2%), thrombocytopenia (2.2%), and pulmonary embolism (2.2%). Fatal adverse reactions occurred in 7% of patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapy including pulmonary embolism (1.1%), pneumonia (1.1%) and cardiomyopathy (1.1%).

Dosage interruptions of TAGRISSO, when given with pemetrexed and platinum-based chemotherapy, due to an adverse reaction occurred in 44% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included anemia (4.7%), neutropenia (4.3%), diarrhea (3.6%), febrile neutropenia (3.3%) and thrombocytopenia (2.9%).

Permanent discontinuation of TAGRISSO when given in combination with pemetrexed and platinum-based chemotherapy due to an adverse reaction occurred in 11% of patients. Adverse reactions which resulted in permanent discontinuation of TAGRISSO in ≥1% of patients included ILD/pneumonitis (2.9%), pneumonia (1.4%), and decreased ejection fraction (1.1%).

Adverse reactions leading to dose reduction of TAGRISSO occurred in 10% of patients treated with TAGRISSO in combination with pemetrexed and platinum-based chemotherapy. The most frequently reported adverse reactions leading to dose reduction of TAGRISSO in the combination arm in ≥1% of patients were diarrhea (1.1%) and rash (1.1%).

Tables 7 and 8 summarize common adverse reactions and laboratory abnormalities which occurred in FLAURA2.

Table 7. Adverse Reactions (numbers in the table are adverse events with no causality established to the Investigational Medicinal Product) Occurring in ≥10% of Patients Receiving TAGRISSO in FLAURA2*

^*NCI CTCAE v5.0

^†Includes stomatitis and mouth ulceration.

^‡Includes rash, 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, pustule.

^¶Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail pigmentation, nail disorder, nail toxicity, nail dystrophy, nail infection, nail ridging, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomalacia, paronychia.

^§Includes dry skin, skin fissures, xerosis, eczema, xeroderma.

^#Includes pruritus, eyelid pruritus.

Clinically relevant adverse reactions in FLAURA2 in <10% of patients receiving TAGRISSO in combination with pemetrexed and platinum-based chemotherapy were alopecia (9%), epistaxis (7%), palmar-plantar erythrodysesthesia syndrome (5%), interstitial lung disease (3.3%) skin hyperpigmentation (2.5%), , QTc interval prolongation (1.8%), erythema multiforme (1.4%), urticaria (1.4%), and keratitis (0.7%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

Table 8. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in FLAURA2*^,†

^*NCI CTCAE v5.0

^†Findings based on test results presented as CTCAE grade shifts.

^‡Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO with pemetrexed and platinum-based chemotherapy arm: 275 and TAGRISSO monotherapy arm: 275).

Previously Treated EGFR T790M Mutation-Positive Metastatic Non-Small Cell Lung Cancer – Monotherapy

The safety of TAGRISSO was evaluated in AURA3, a multicenter international open label randomized (2:1) controlled trial conducted in 419 patients with unresectable or metastatic EGFR T790M mutation-positive NSCLC who had progressive disease following first line EGFR TKI treatment. A total of 279 patients received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment. A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after 4 cycles of chemotherapy could continue maintenance pemetrexed until disease progression, unacceptable toxicity, or investigator determination that the patient was no longer benefiting from treatment. Left Ventricular Ejection Fraction (LVEF) was evaluated at screening and every 12 weeks. The median duration of treatment was 8.1 months for patients treated with TAGRISSO and 4.2 months for chemotherapy-treated patients. The trial population characteristics were: median age 62 years, age less than 65 (58%), female (64%), Asian (65%), never smokers (68%), and ECOG PS 0 or 1 (100%).

Serious adverse reactions were reported in 18% of patients treated with TAGRISSO and 26% in the chemotherapy group. No single serious adverse reaction was reported in 2% or more patients treated with TAGRISSO. One patient (0.4%) treated with TAGRISSO experienced a fatal adverse reaction (ILD/pneumonitis).

Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The most frequent adverse reactions leading to dose reductions or interruptions were prolongation of the QT interval as assessed by ECG (1.8%), neutropenia (1.1%), and diarrhea (1.1%). Adverse reactions resulting in permanent discontinuation of TAGRISSO occurred in 7% of patients treated with TAGRISSO. The most frequent adverse reaction leading to discontinuation of TAGRISSO was ILD/pneumonitis (3%).

Tables 9 and 10 summarize common adverse reactions and laboratory abnormalities which occurred in TAGRISSO-treated patients in AURA3.

Table 9. Adverse Reactions (Numbers in the table are adverse events with no causality established to the Investigational Medicinal Product) Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3^*

^*NCI CTCAE v4.0.

^†No grade 4 events were reported.

^‖Includes stomatitis and mouth ulceration.

^‡Includes rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis, acneiform dermatitis, pustule.

^§ Includes dry skin, eczema, skin fissures, xerosis.

^¶Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis, onychomadesis, paronychia.

^#Includes pruritus, pruritus generalized, eyelid pruritus.

^þIncludes fatigue, asthenia.

Clinically relevant adverse reactions in AURA3 in <10% of patients receiving TAGRISSO were epistaxis (5%), interstitial lung disease (3.9%), alopecia (3.6%), urticaria (2.9%), palmar-plantar erythrodysesthesia syndrome (1.8%), QTc interval prolongation (1.4%), keratitis (1.1%),erythema multiforme (0.7%) and skin hyperpigmentation (0.4%). QTc interval prolongation represents the incidence of patients who had a QTcF prolongation >500 msec.

Table 10. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3

NA=not applicable

^*NCI CTCAE v4.0

^†Each test incidence, except for hyperglycemia, is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 279, Chemotherapy comparator 131)

^‡Hyperglycemia is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (TAGRISSO 270, Chemotherapy 5; fasting glucose was not a protocol requirement for patients in the chemotherapy arm)

Clinically relevant laboratory abnormalities in AURA3 that occurred in <20% of patients receiving TAGRISSO included increased blood creatinine (7%).

Other Clinical Trials Experience

The following adverse reaction has been reported following administration of TAGRISSO: increased blood creatine phosphokinase.

Post marketing Experience 

The following adverse reactions have been identified during post-approval use of TAGRISSO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

·       Skin and subcutaneous tissue: Erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), cutaneous vasculitis, erythema dyschromicum perstans

·       Blood and lymphatic system disorders: Aplastic anemia

To report any side effect(s):

·       Saudi Arabia:

·       Other GCC States:

-       Please contact the relevant competent authority.

In TAGRISSO clinical studies a limited number of patients were treated with daily doses of up to 240 mg without dose limiting toxicities. In these studies, patients who were treated with TAGRISSO daily doses of 160 mg and 240 mg experienced an increase in the frequency and severity of a number of typical EGFR TKI-induced AEs (primarily diarrhoea and skin rash) compared to the 80 mg dose. There is limited experience with accidental overdoses in humans. All cases were isolated incidents of patients taking an additional daily dose of TAGRISSO in error, without any resulting clinical consequences.

There is no specific treatment in the event of TAGRISSO overdose. In case of suspected overdose, TAGRISSO should be withheld and symptomatic treatment initiated.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors; ATC code: L01EB04. Mechanism of action

Osimertinib is a Tyrosine Kinase Inhibitor (TKI). It is an irreversible inhibitor of EGFRs harboring sensitising-mutations (EGFRm) and TKI-resistance mutation T790M.

Pharmacodynamic effects

In vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against EGFR across a range of all clinically relevant EGFR sensitising-mutant and T790M mutant NSCLC cell lines (apparent IC50s from 6 nM to 54 nM against phospho-EGFR). This leads to inhibition of cell growth, while showing significantly less activity against EGFR in wild-type cell lines (apparent IC50s from 480 nM to 1.8 μM against phospho-EGFR). In vivo oral administration of osimertinib lead to tumour shrinkage in both EGFRm and T790M NSCLC xenograft and transgenic mouse lung tumour models.

Cardiac electrophysiology

The QTc interval prolongation potential of TAGRISSO was assessed in 210 patients who received osimertinib 80 mg daily in AURA2. Serial ECGs were collected following a single dose and at steady- state to evaluate the effect of osimertinib on QTc intervals. A pharmacokinetic/pharmacodynamic analysis predicted a drug-related QTc interval prolongation at 80 mg of 14 msec with an upper bound of 16 msec (90% CI).

Clinical efficacy and safety

Adjuvant Treatment of Early-Stage EGFR Mutation-Positive Non-Small Cell Lung Cancer (NSCLC)

The efficacy of TAGRISSO was demonstrated in a randomized, double-blind, placebo-controlled trial (ADAURA [NCT02511106]) for the adjuvant treatment of patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive NSCLC who had complete tumor resection, with or without prior adjuvant chemotherapy. Eligible patients with resectable tumors (stage IB – IIIA according to American Joint Commission on Cancer [AJCC] 7^th edition) were required to have predominantly non-squamous histology and EGFR exon 19 deletions or exon 21 L858R mutations identified prospectively from tumor tissue in a central laboratory by the cobas^® EGFR Mutation Test. Patients with clinically significant uncontrolled cardiac disease, prior history of ILD/pneumonitis, or who received treatment with any EGFR kinase inhibitor were not eligible for the study.

Patients were randomized (1:1) to receive TAGRISSO 80 mg orally once daily or placebo following recovery from surgery and standard adjuvant chemotherapy if given. Patients who did not receive adjuvant chemotherapy were randomized within 10 weeks and patients who received adjuvant chemotherapy were randomized within 26 weeks following surgery. Randomization was stratified by mutation type (exon 19 deletions or exon 21 L858R mutations), race (Asian or non-Asian) and pTNM staging (IB or II or IIIA) according to AJCC 7^th edition. Treatment was given for 3 years or until disease recurrence, or unacceptable toxicity.

The major efficacy outcome measure was disease-free survival (DFS, defined as reduction in the risk of disease recurrence or death) in patients with stage II – IIIA NSCLC determined by investigator assessment. Additional efficacy outcome measures included DFS in the overall population (patients with stage IB – IIIA NSCLC), and overall survival (OS) in patients with stage II – IIIA NSCLC and in the overall population.

A total of 682 patients were randomized to TAGRISSO (n=339) or placebo (n=343). The median age was 63 years (range 30-86 years); 70% were female; 64% were Asian and 72% were never smokers. Baseline World Health Organization (WHO) performance status was 0 (64%) or 1 (36%); 31% had stage IB, 35% II, and 34% IIIA. With regard to EGFR mutation status, 55% were exon 19 deletions and 45% were exon 21 L858R mutations. The majority (60%) of patients received adjuvant chemotherapy prior to randomization (27% IB; 70% II, 79% IIIA).

ADAURA demonstrated a statistically significant difference in DFS for patients treated with TAGRISSO compared to patients treated with placebo. The final analysis of OS demonstrated a statistically significant improvement in OS for patients treated with TAGRISSO compared to patients treated with placebo. Median OS was not reached in either arm. In the overall population (IB-IIIA), the median follow-up time was 61.5 months in both treatment arms. Efficacy results from ADAURA are summarized in Table 11 and Figures 1 and 2, respectively.

Table 11. Efficacy Results in ADAURA according to Investigator Assessment

DFS results based on investigator assessment.

CI=Confidence Interval; NE=Not Estimable; NR=Not Reached

^‡Stratified by race (Asian vs non-Asian), mutation status (Ex19del vs L858R), and pTNM staging

^§Pike estimator

^‖Stratified log-rank test

Figure 1. Kaplan-Meier Curves of Disease-Free Survival (Overall Population) by Investigator Assessment in ADAURA

Figure 2. Kaplan-Meier Curves of Overall Survival (Overall Population) in ADAURA

In an exploratory analysis of site(s) of relapse, the proportion of patients with CNS involvement at the time of disease recurrence was 5 patients (1.5%) on the TAGRISSO arm and 34 patients (10%) on the placebo arm.

Previously Untreated EGFR Mutation-Positive Metastatic NSCLC

FLAURA – TAGRISSO Monotherapy

The efficacy of TAGRISSO was demonstrated in a randomized, multicenter, double-blind, active-controlled trial (FLAURA [NCT02296125]) in patients with EGFR exon 19 deletions or exon 21 L858R mutation-positive, metastatic NSCLC, who had not received previous systemic treatment for metastatic disease. Patients were required to have measurable disease per RECIST v1.1, a WHO performance status of 0-1, and EGFR exon 19 deletions or exon 21 L858R mutation in tumor prospectively identified by the cobas^® EGFR Mutation Test in a central laboratory or by an investigational assay at a CLIA-certified or accredited laboratory. Patients with CNS metastases not requiring steroids and with stable neurologic status for at least two weeks after completion of definitive surgery or radiotherapy were eligible. Patients were assessed at the investigator’s discretion for CNS metastases if they had a history of, or suspected, CNS metastases at study entry.

Patients were randomized (1:1) to receive TAGRISSO 80 mg orally once daily or to receive gefitinib 250 mg orally once daily or erlotinib 150 mg orally once daily until disease progression or unacceptable toxicity. Randomization was stratified by EGFR mutation type (exon 19 deletions or exon 21 L858R mutation) and ethnicity (Asian or non-Asian). Patients randomized to the control arm were offered TAGRISSO at the time of disease progression if tumor samples tested positive for the EGFR T790M mutation. The major efficacy outcome measure was progression-free survival (PFS), as assessed by investigator. Additional efficacy outcome measures included OS and overall response rate (ORR).

A total of 556 patients were randomized to TAGRISSO (n=279) or to control (gefitinib n=183; erlotinib n=94). The median age was 64 years (range 26-93 years); 54% were <65 years of age; 63% were female; 62% were Asian and 64% were never smokers. Baseline WHO performance status was 0 (41%) or 1 (59%); 5% had Stage IIIb and 95% had Stage IV; and 7% received prior systemic cytotoxic chemotherapy as neoadjuvant or adjuvant therapy. With regard to EGFR tumor testing, 63% were exon 19 deletions and 37% were exon 21 L858R; 5 patients (<1%) also had a concomitant de novo T790M mutation. EGFR mutation status was confirmed centrally using the cobas^® EGFR Mutation Test in 90% of patients. At the time of the final data cut-off, of those randomized to TAGRISSO and to investigator’s choice erlotinib or gefitinib arm, 133 (48%) and 180 (65%) patients had received at least one subsequent treatment, respectively. Out of the 180 patients randomized to erlotinib or gefitinib who received subsequent treatment, 85 (47%) patients received TAGRISSO as first subsequent therapy.

FLAURA demonstrated a statistically significant improvement in PFS for patients randomized to TAGRISSO as compared to erlotinib or gefitinib (see Table 12 and Figure 3). The final analysis of overall survival demonstrated a statistically significant improvement in overall survival in patients randomized to TAGRISSO compared to erlotinib or gefitinib (see Table 12 and Figure 4).

Table 12. Efficacy Results in FLAURA according to Investigator Assessment

^*Without documented radiological disease progression

^†Stratified by ethnicity (Asian vs non-Asian) and mutation status (Ex19del vs L858R)

^‡Pike estimator

^§Stratified log-rank test

^¶Confirmed responses

Figure 3. Kaplan-Meier Curves of PFS by Investigator Assessment in FLAURA

In a supportive analysis of PFS according to blinded independent central review (BICR), median PFS was 17.7 months in the TAGRISSO arm compared to 9.7 months in the EGFR TKI comparator arm (HR=0.45; 95% CI: 0.36, 0.57).

Figure 4. Kaplan-Meier Curves of Overall Survival in FLAURA

Of 556 patients, 200 patients (36%) had baseline brain scans reviewed by BICR; this included 106 patients in the TAGRISSO arm and 94 patients in the investigator choice of EGFR TKI arm. Of these 200 patients, 41 had measurable CNS lesions per RECIST v1.1. Results of pre-specified exploratory analyses of CNS ORR and duration of response (DoR) by BICR in the subset of patients with measurable CNS lesions at baseline are summarized in Table 13.

Table 13. CNS ORR and DOR by BICR in Patients with Measurable CNS Lesions at Baseline in FLAURA

^*According to RECIST v1.1.

^†Based on confirmed response.

^‡Based on patients with response only; DoR defined as the time from the date of first documented response (complete response or partial response) until progression or death event.

Previously Untreated EGFR Mutation-Positive Locally Advanced or Metastatic NSCLC

FLAURA2 – TAGRISSO in Combination with Pemetrexed and Platinum-based Chemotherapy

The efficacy of TAGRISSO in combination with pemetrexed and platinum-based chemotherapy was demonstrated in a randomized, multicenter, open-label trial (FLAURA2 [NCT04035486]) in patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive locally advanced or metastatic NSCLC, who had not received previous systemic treatment for advanced disease. Patients were required to have measurable disease per RECIST v1.1, a WHO performance status of 0-1, and EGFR exon 19 deletions or exon 21 L858R mutations as identified by the cobas^® EGFR Mutation Test v2 performed prospectively in tissue samples in a central laboratory or by a local test performed in a CLIA-certified or accredited laboratory.

Patients were randomized (1:1) to one of the following treatment arms:

·       TAGRISSO (80 mg) orally once daily with pemetrexed (500 mg/m²) and investigator’s choice of cisplatin (75 mg/m²) or carboplatin (AUC5) administered intravenously on Day 1 of 21-day cycles for 4 cycles, followed by TAGRISSO (80 mg) orally once daily and pemetrexed (500 mg/m²) administered intravenously every 3 weeks

·       TAGRISSO (80 mg) orally once daily

Randomization was stratified by race (Chinese/Asian, non-Chinese/Asian or non-Asian), WHO performance status (0 or 1), and method for tissue testing (central or local). Patients received study therapy until intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit.

Progression-free survival, as assessed by investigator per RECIST 1.1 was the primary efficacy outcome measure. Overall survival was a key secondary outcome measure. Additional efficacy outcome measures included ORR and DoR.

A total of 557 patients were randomized to either TAGRISSO in combination with pemetrexed and platinum-based chemotherapy (n=279) or TAGRISSO monotherapy (n=278). The median age was 61 years (range 26-85 years); 39% were ≥65 years and 8% were ≥75 years of age; 61% were female; 64% were Asian and 66% were never smokers. Baseline WHO PS was 0 (37%) or 1 (63%); 4% had locally advanced and 96% had metastatic NSCLC; and 1.8% received prior systemic cytotoxic chemotherapy as neoadjuvant or adjuvant therapy. With regard to EGFR tumor testing, 61% of tumors had exon 19 deletions and 38% had exon 21 L858R mutations; 0.7% of patients had tumors with both exon 19 deletions and exon 21 L858R. EGFR mutation status was centrally confirmed using the cobas^® EGFR Mutation Test v2 in 96% of patients.

FLAURA2 demonstrated a statistically significant improvement in PFS for patients randomized to TAGRISSO in combination with pemetrexed and platinum-based chemotherapy as compared to TAGRISSO monotherapy (see Table 14 and Figure 5). While OS results were immature at the current analysis, with 45% of pre-specified deaths for the final analysis reported, no trend towards a detriment was observed.

Table 14. Efficacy Results in FLAURA2 according to Investigator Assessment

NE=Not Estimable; NR=Not Reached

^#PFS and ORR results by BICR were consistent with those reported via investigator assessment.

^*Without documented radiological disease progression.

^†Stratified by race (Chinese/Asian, non-Chinese/Asian vs non-Asian), WHO performance status (0 or 1) and method of tissue testing (central or local).

^‡Pike estimator.

^§Stratified log-rank test.

^¶Confirmed responses.

Figure 5. Kaplan-Meier Curves of PFS by Investigator Assessment in FLAURA2

All patients had available baseline brain scans reviewed by BICR using modified RECIST; 78/557 (14%) patients had CNS measurable lesions. Results of pre-specified exploratory analyses of CNS ORR and DoR by BICR are summarized in Table 15.

Table 15. Exploratory Analysis – CNS Efficacy by BICR in Patients with CNS Metastases on a Baseline Brain Scan in FLAURA2

^*According to RECIST v1.1.

^†Based on confirmed response.

^‡Based on patients with response only; DoR defined as the time from the date of first documented response (complete response or partial response) until progression or death event.

Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC

The efficacy of TAGRISSO was demonstrated in a randomized, multicenter open-label, active-controlled trial in patients with metastatic EGFR T790M mutation-positive NSCLC who had progressed on prior systemic therapy, including an EGFR TKI (AURA3). All patients were required to have EGFR T790M mutation-positive NSCLC identified by the cobas^® EGFR Mutation Test performed in a central laboratory prior to randomization.

A total of 419 patients were randomized 2:1 to receive TAGRISSO (n=279) or platinum-based doublet chemotherapy (n=140). Randomization was stratified by ethnicity (Asian vs non-Asian). Patients in the TAGRISSO arm received TAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, or investigator determination that the patient was no longer benefiting from treatment. Patients in the chemotherapy arm received pemetrexed 500 mg/m² with carboplatin AUC5 or pemetrexed 500 mg/m² with cisplatin 75 mg/m² on Day 1 of every 21-day cycle for up to 6 cycles. Patients whose disease had not progressed after four cycles of platinum-based chemotherapy could have received pemetrexed maintenance therapy (pemetrexed 500 mg/m² on Day 1 of every 21-day cycle).

The major efficacy outcome measure was PFS according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) by investigator assessment. Additional efficacy outcome measures included ORR, DoR, and OS. Patients randomized to the chemotherapy arm who had radiological progression according to both investigator and BICR were permitted to cross over to receive treatment with TAGRISSO.

The baseline demographic and disease characteristics of the overall trial population were: median age 62 years (range: 20-90 years), ≥75 years old (15%), female (64%), White (32%), Asian (65%), never smoker (68%), WHO performance status 0 or 1 (100%). Fifty-four percent (54%) of patients had extra-thoracic visceral metastases, including 34% with central nervous system (CNS) metastases (including 11% with measurable CNS metastases) and 23% with liver metastases. Forty-two percent (42%) of patients had metastatic bone disease.

In AURA3, there was a statistically significant improvement in PFS in the patients randomized to TAGRISSO compared to chemotherapy (see Table 16 and Figure 6). No statistically significant difference was observed between the treatment arms at final OS analysis. At the time of the final OS analysis, 99 patients (71%) randomized to chemotherapy had crossed over to TAGRISSO treatment.

Table 16. Efficacy Results According to Investigator Assessment in AURA3

^*Without documented radiological disease progression

^†Stratified by ethnicity (Asian vs non-Asian)

^‡Pike estimator

^§Stratified log-rank test

^¶Confirmed Responses

^#Logistic regression analysis

Figure 6. Kaplan-Meier Curves of PFS by Investigator Assessment in AURA3

In a supportive analysis of PFS according to BICR, median PFS was 11 months in the TAGRISSO arm compared to 4.2 months in the chemotherapy arm (HR 0.28; 95% CI: 0.20, 0.38).

Of 419 patients, 205 (49%) had baseline brain scans reviewed by BICR; this included 134 (48%) patients in the TAGRISSO arm and 71 (51%) patients in the chemotherapy arm. Assessment of CNS efficacy by RECIST v1.1 was performed in the subgroup of 46/419 (11%) patients identified by BICR to have measurable CNS lesions on a baseline brain scan. Results are summarized in Table 17.

Table 17. CNS ORR and DoR by BICR in Patients with Measurable CNS Lesions at Baseline in AURA3

^*According to RECIST v1.1.

^†Based on confirmed response.

^‡Based on patients with response only; DoR defined as the time from the date of first documented response (complete response or partial response) until progression or death event.

The area under the plasma concentration-time curve (AUC) and maximal plasma concentration (Cmax) of osimertinib increased dose proportionally over 20 to 240 mg dose range (i.e., 0.25 to 3 times the recommended dosage) after oral administration and exhibited linear pharmacokinetics (PK). Administration of TAGRISSO orally once daily resulted in approximately 3-fold accumulation with steady-state exposures achieved after 15 days of dosing. At steady state, the Cmax to Cmin (minimal concentration) ratio was 1.6-fold.

The pharmacokinetics in patients treated with osimertinib in combination with pemetrexed and platinum-based chemotherapy are similar to those in patients treated with osimertinib monotherapy.

Absorption

The median time to Cmax of osimertinib was 6 hours (range 3-24 hours).

Following administration of a 20 mg TAGRISSO tablet with a high-fat, high-calorie meal (containing approximately 58 grams of fat and 1000 calories), the Cmax and AUC of osimertinib were comparable to that under fasting conditions.

Distribution

The mean volume of distribution at steady-state (Vss/F) of osimertinib was 918 L. Plasma protein binding of osimertinib was 95%. PET brain imaging studies in healthy volunteers and in patients with brain metastases show that osimertinib is distributed to the brain following intravenous injection of a micro dose of 11C-labeled osimertinib.

Elimination

Osimertinib plasma concentrations decreased with time and a population estimated mean half-life of osimertinib was 48 hours, and oral clearance (CL/F) was 14.3 (L/h).

Metabolism

The main metabolic pathways of osimertinib were oxidation (predominantly CYP3A) and dealkylation in vitro. Two pharmacologically active metabolites (AZ7550 and AZ5104) have been identified in the plasma after TAGRISSO oral administration. The geometric mean exposure (AUC) of each metabolite (AZ5104 and AZ7550) was approximately 10% of the exposure of osimertinib at steady-state.

Excretion

Osimertinib is primarily eliminated in the feces (68%) and to a lesser extent in the urine (14%). Unchanged osimertinib accounted for approximately 2% of the elimination.

Specific Populations

No clinically significant differences in the pharmacokinetics of osimertinib were observed based on age, sex, ethnicity, body weight, baseline albumin, line of therapy, smoking status, renal function (creatinine clearance (CLcr) ≥15 mL/min by Cockcroft-Gault), or hepatic impairment (Child-Pugh A and B, or total bilirubin ≤ ULN and AST > ULN or total bilirubin between 1 to 3 times ULN and any AST). The pharmacokinetics of osimertinib in patients with end-stage renal disease (CLcr <15 mL/min) or severe hepatic impairment (total bilirubin 3 to 10 times ULN and any AST) are unknown [see Use in Specific Populations (8.6) and (8.7)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year carcinogenicity was conducted in male and female rats at oral osimertinib doses of 1, 3, and 10 mg/kg/day. Osimertinib increased the incidences of hemangioma and combined hemangioma/hemangiosarcoma in the mesenteric lymph node and whole body at 10 mg/kg/day (0.2 times the human exposure based on AUC at the clinical dose of 80 mg once daily). Administration of osimertinib to male and female rasH2 transgenic mice by oral gavage daily for 26 weeks did not result in an increased incidence of neoplasms at doses up to 10 mg/kg/day.

Osimertinib did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in mouse lymphoma cells or in the rat in vivo micronucleus assay.

Based on studies in animals, male fertility may be impaired by treatment with TAGRISSO. Degenerative changes were present in the testes in rats and dogs exposed to osimertinib for 1 month or more with evidence of reversibility in the rat. Following administration of osimertinib to rats for approximately 10 weeks at a dose of 40 mg/kg, at exposures 0.5 times the AUC observed at the recommended clinical dose of 80 mg once daily, there was a reduction in male fertility, demonstrated by increased pre-implantation loss in untreated females mated to treated males.

Based on studies in animals, female fertility may be impaired by treatment with TAGRISSO. In repeat dose toxicity studies, histological evidence of anestrus, corpora lutea degeneration in the ovaries and epithelial thinning in the uterus and vagina were seen in rats exposed to osimertinib for 1 month or more at exposures 0.3 times the AUC observed at the recommended clinical dose of 80 mg once daily. Findings in the ovaries seen following 1 month of dosing exhibited evidence of reversibility. In a female fertility study in rats, administration of osimertinib from 2 weeks prior to mating through Day 8 of gestation at a dose of 20 mg/kg/day (approximately 1.5 times the Cmax at the recommended dose of 80 mg once daily) had no effects on estrous cycling or the number of females becoming pregnant, but caused early embryonic deaths. These findings showed evidence of reversibility when females were mated 1 month after treatment discontinuation.

Animal Toxicology and/or Pharmacology

Administration of osimertinib resulted in histological findings of lens fiber degeneration in the 2-year rat carcinogenicity study at ≥3 mg/kg/day (exposures 0.2 times the human exposure based on AUC). These findings were consistent with the ophthalmoscopic observation of lens opacities, which were first noted from week 52 and showed a gradual increase in incidence and severity with increased duration of dosing.

Tablet core

Mannitol Microcrystalline cellulose

Low-substituted hydroxypropyl cellulose Sodium stearyl fumarate

Tablet coating

Polyvinyl alcohol Titanium dioxide (E 171) Macrogol 3350

Talc

Yellow iron oxide (E 172)

Red iron oxide (E 172)

Black iron oxide (E 172)

Not applicable.

This medicinal product does not require any special storage conditions.

Al/Al perforated unit dose blisters. Cartons of 30 x 1 tablets (3 blisters).

Al/Al perforated unit dose blisters. Cartons of 28 x 1 tablets (4 blisters).

Not all pack sizes may be marketed.

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