Osimertinib mesylate, a third-generation inhibitor of receptor tyrosine kinases, is an antineoplastic agent.1, 4, 5, 6, 7
Osimertinib mesylate is used in the treatment of adults with non-small cell lung cancer (NSCLC), including as adjuvant therapy after tumor resection when tumors have epidermal growth factor receptor ( EGFR ) exon 19 deletions or exon 21 L858R mutations; as treatment of locally advanced, unresectable (stage III) NSCLC that has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and when tumors have EGFR exon 19 deletions or exon 21 L858R mutations; as first-line treatment of metastatic NSCLC when tumors have EGFR exon 19 deletions or exon 21 L858R mutations; in combination with pemetrexed and platinum-based chemotherapy as first-line treatment of locally advanced or metastatic NSCLC when tumors have EGFR exon 19 deletions or exon 21 L858R mutations; and as treatment of metastatic EGFR T790M mutation-positive NSCLC that has progressed on or after EGFR tyrosine kinase inhibitor therapy.1 Osimertinib has been designated an orphan drug by FDA for the treatment of EGFR mutation-positive NSCLC.13 Information on FDA-approved companion diagnostic tests for the detection of EGFR mutations in NSCLC is available at [Web].1
Adjuvant Treatment of EGFR Mutation-positive Non-small Cell Lung Cancer
Osimertinib mesylate is used for adjuvant treatment after tumor resection in patients with NSCLC harboring EGFR exon 19 deletions (del19) or exon 21 (L858R) substitution mutations as detected by an FDA-approved diagnostic test.1, 20 Disease-free survival benefit has been observed in adults receiving osimertinib in the adjuvant setting compared with those receiving placebo.1, 30
The current indication for osimertinib as adjuvant treatment of early stage (IB-IIIA) EGFR mutation-positive NSCLC following complete tumor resection is based principally on the results of an ongoing randomized, multicenter, double-blind, placebo-controlled phase 3 study (ADAURA).1, 30 In this study, 682 patients were randomized (stratified by disease stage, EGFR mutation, and Asian or non-Asian race) in a 1:1 ratio to receive either osimertinib 80 mg daily or placebo following recovery from surgery or standard adjuvant chemotherapy.1 Patients were randomized within 10 or 26 weeks of surgery based on receipt of adjuvant chemotherapy.1 Therapy was continued for 3 years or until disease recurrence or unacceptable toxicity occurred.1, 30 The primary measure of efficacy was disease-free survival (as evaluated by the investigator) in patients with stage II to IIIA NSCLC; additional measures of efficacy were disease-free survival in the overall population and overall survival in patients with stage II to IIIA disease.1, 30 Preoperative, postoperative, or planned radiation therapy was not permitted.30 The median age of patients was 63 years (range: 30-86 years); approximately 72% had never smoked, 70% were female, 64% were of Asian ancestry, and 60% had received adjuvant chemotherapy.1, 30 All enrolled patients had a World Health Organization (WHO) performance status of 0 or 1; 55% of patients had an EGFR del19 mutation, 45% had exon 21 (L858R) substitution mutations, and 1% had T790M mutations.1, 30 At the time of an interim analysis, enrollment was complete and enrolled patients had been followed for at least 1 year; at the time of this analysis, the independent data monitoring committee recommended unblinding the treatment groups because of evidence of benefit.30
At the time of the interim analysis, the median follow-up for disease-free survival in 470 patients with stage II to IIIA disease was 22.1 or 14.9 months in patients receiving osimertinib or placebo, respectively.30 Median disease-free survival had not been reached in patients receiving osimertinib, but was 19.6 months in those receiving placebo.1, 30 At 24 months, osimertinib decreased the risk of disease progression or death by 83% in the subgroup of patients with stage II to IIIA disease.30 In the overall study population, median disease-free survival had not been reached in patients receiving osimertinib, but was 27.5 months in those receiving placebo.1, 30 At 24 months, osimertinib decreased the risk of disease progression or death by 80% in the overall study population.30 Results of subgroup analyses (based on age, gender, race, smoking status, EGFR mutation, disease stage, or use of adjuvant chemotherapy) suggested that the effect of osimertinib on disease-free survival was consistent across all subgroups.30 Overall survival data were immature at the time of the interim analysis.30 In an exploratory analysis, 5 osimertinib-treated patients and 34 placebo-recipients had CNS involvement at the time of disease recurrence.1
Locally Advanced, Unresectable (Stage III) EGFR Mutation-positive Non-small Cell Lung Cancer
Osimertinib is used for the treatment of adults with locally advanced, unresectable (stage III) NSCLC whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations as detected by an FDA-approved diagnostic test.1 A significantly improved progression-free survival benefit was observed with osimertinib as compared to placebo in patients with unresectable stage III EGFR -mutated NSCLC.1, 35
The current indication for osimertinib is based principally on the results of a randomized, multicenter, double-blind, placebo-controlled, phase 3 study (LAURA) in adults with locally advanced, unresectable, stage III NSCLC, with an EGFR exon 19 deletion or exon 21 L858R mutation and a World Health Organization (WHO) performance status score of 0 or 1.35 Patients eligible for enrollment completed concurrent or sequential platinum-based chemoradiotherapy within 6 weeks prior to randomization and did not have disease progression during or after definitive chemoradiotherapy.35 In this study, 216 patients were randomized in a 2:1 ratio to receive either osimertinib (80 mg orally once daily) or placebo until disease progression (as seen by objective radiologic confirmation) or until fulfillment of another criteria for discontinuation.35 The primary end point was progression-free survival.35 The median age of patients was 63 years (range: 36-84 years); 70% had never smoked, 61% were female, 82% were of Asian ancestry, and the baseline WHO performance status was 0 (51%) or 1 (49%).1 In addition, 54% of patients had exon 19 deletions and 45% had exon 21 L858R mutations.1
At a median follow-up of 22 or 5.6 months in patients receiving osimertinib or placebo, respectively, patients receiving osimertinib had a significantly longer median progression-free survival than those receiving placebo (39.1 versus 5.6 months).35 The 36-month overall survival was 84% for those patients administered osimertinib and 74% with placebo.35 The objective response rate in osimertinib-treated patients was 57% compared with 33% in those receiving placebo.35 Patients receiving osimertinib had a longer median duration of response (36.9 versus 6.5 months) compared with those receiving placebo.35
First-line Therapy for EGFR Mutation-positive Metastatic Non-small Cell Lung Cancer
Osimertinib mesylate is used for the first-line treatment of metastatic NSCLC in patients whose tumors harbor EGFR exon 19 deletions (del19) or exon 21 (L858R) substitution mutations as detected by an FDA-approved diagnostic test.1, 21 A progression-free survival benefit has been observed in adults with previously untreated EGFR mutation-positive metastatic NSCLC receiving osimertinib compared with patients receiving erlotinib or gefitinib.1, 21
The current indication for osimertinib in the first-line treatment of metastatic NSCLC is based principally on the results of a randomized, multicenter, double-blind phase 3 study (FLAURA) in adults with previously untreated locally advanced or metastatic NSCLC.1, 21 In this study, 556 patients were randomized (stratified by race and EGFR mutation) in a 1:1 ratio to receive either osimertinib (80 mg orally once daily) or investigator's choice of gefitinib (250 mg orally once daily) or erlotinib (150 mg orally once daily) until disease progression or unacceptable toxicity occurred.1, 21 The primary measure of efficacy was progression-free survival (as evaluated by the investigator).1 Patients with CNS metastases not requiring corticosteroid therapy and whose condition was neurologically stable for at least 2 weeks following completion of surgery or radiation therapy were eligible for this study.1, 21 The median age of patients was 64 years (range: 26-93 years); most patients (95%) had metastatic disease, 64% had never smoked, 63% were female, 62% were of Asian ancestry, and 7% had received prior adjuvant or neoadjuvant chemotherapy.1, 21 All enrolled patients had a WHO performance status of 0 or 1 and were required to have evidence of an EGFR mutation (confirmed by the cobas® EGFR Mutation Test or a clinical trial assay); 63% of patients had exon 19 deletions, 37% had exon 21 (L858R) substitution mutations, and less than 1% also had T790M mutations.1 Approximately 20% of the patients randomized to investigator's choice of erlotinib or gefitinib received osimertinib therapy following disease progression.1
At a median follow-up of 15 or 9.7 months in patients receiving osimertinib or investigator's choice of erlotinib or gefitinib, respectively, patients receiving osimertinib had a longer median progression-free survival than those receiving erlotinib or gefitinib (18.9 versus 10.2 months; hazard ratio of 0.46).1, 21 Effects of osimertinib on investigator-assessed progression-free survival and progression-free survival as assessed by a blinded independent central review committee (BICR) were comparable.1, 21 The objective response rate in osimertinib-treated patients was 77% compared with 69% in those receiving erlotinib or gefitinib; complete responses were achieved in 2 or 1% of patients, respectively.1 Patients receiving osimertinib had a longer median duration of response (17.6 versus 9.6 months) compared with those receiving erlotinib or gefitinib.1 Results of subgroup analyses (based on age, gender, WHO performance status, race, smoking status, EGFR mutation, or presence of brain metastases) suggested that the effect of osimertinib on progression-free survival was consistent across all subgroups.21, 22, 23 In the subgroup of 41 patients with baseline measurable CNS metastases, BICR-assessed CNS objective response rates were 77 or 63% in the osimertinib or investigator's choice of EGFR tyrosine kinase inhibitor groups, respectively, with durable responses of 6 months or more in 47 or 33% of patients, respectively, or 12 months or more in 47 or 33% of patients, respectively; complete responses were achieved in 18% of patients receiving osimertinib and none of those receiving erlotinib or gefitinib.1 At a median duration of follow-up of 35.8 or 27 months in patients receiving osimertinib or investigator's choice of an EGFR tyrosine kinase inhibitor, respectively, median overall survival was prolonged in patients receiving osimertinib compared with those receiving erlotinib or gefitinib (38.6 versus 31.8 months; hazard ratio of 0.80).1, 31 Results of subgroup analyses (based on age, gender, WHO performance status, race, smoking status, EGFR mutation, or presence of brain metastases) suggested that the effect of osimertinib on overall survival was consistent across subgroups.31
First-line Therapy for EGFR-mutation Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer
Osimertinib is used in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of adults with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations as detected by an FDA-approved diagnostic test.1 A significantly improved progression-free survival benefit was observed with osimertinib in combination with chemotherapy as compared to osimertinib monotherapy in patients with EGFR -mutated advanced NSCLC.1, 36
The current indication for osimertinib is based principally on the results of a randomized, multicenter, open-label, phase 3 study (FLAURA2) in adults with locally advanced or metastatic NSCLC who had not previously received systemic treatment for advanced disease.36 Patients eligible for enrollment also had a WHO performance status score of 0 or 1 and completed any prior radiation or chemoradiation or glucocorticoid therapy at least 2 weeks before initiation of study treatment.36 In this study, 557 patients were randomized in a 1:1 ratio to receive either osimertinib 80 mg once daily in combination with chemotherapy (pemetrexed and a platinum-based agent) administered IV on day 1 of 21-day cycles for 4 cycles followed by osimertinib 80 mg once daily plus pemetrexed maintenance therapy every 3 weeks or osimertinib 80 mg once daily.36 The primary end point was progression-free survival.36 The median age of patients was 61 years (range: 26-85 years); 66% had never smoked, 61% were female, 64% were of Asian ancestry, and the baseline WHO performance status was 0 (37%) or 1 (63%).1 The majority of patients had metastatic disease (96%).1 In addition, 61% of patients had exon 19 deletions and 38% had exon 21 L858R mutations.1
At a median follow-up of 19.5 or 16.5 months in patients receiving osimertinib-chemotherapy therapy or osimertinib monotherapy, respectively, patients receiving osimertinib-chemotherapy had a significantly longer median progression-free survival than those receiving osimertinib monotherapy (25.5 versus 16.7 months).36 The 24-month overall survival was 79% for those patients administered osimertinib-chemotherapy and 73% with osimertinib monotherapy.36 An objective response, as determined by investigator assessment, was 83% in the osimertinib-chemotherapy group compared to 76% in osimertinib monotherapy group.36 Patients receiving osimertinib-chemotherapy had a longer median duration of response according to investigator assessment (24 vs 15. 3 months).36
Previously Treated EGFR T790M Mutation-positive Metastatic Non-small Cell Lung Cancer
Osimertinib mesylate is used for the treatment of metastatic NSCLC in patients with the EGFR T790M mutation (as detected by an FDA-approved diagnostic test) who experienced disease progression during or following EGFR tyrosine kinase inhibitor therapy.1, 17
The current indication for osimertinib in the treatment of metastatic NSCLC following failure of prior EGFR tyrosine kinase inhibitor therapy is based principally on the results of a randomized, multicenter, open-label, active-controlled study (AURA3) in 419 adults with metastatic EGFR T790M mutation-positive NSCLC (confirmed by the cobas® EGFR Mutation Test) whose disease had progressed while receiving prior systemic therapy, including a first-line EGFR tyrosine kinase inhibitor (e.g., gefitinib, erlotinib, afatinib).1, 19 Patients were randomized in a 2:1 ratio to receive osimertinib (80 mg orally once daily) or platinum-based chemotherapy (pemetrexed 500 mg/m2 in combination with either cisplatin 75 mg/m2 or carboplatin dosed to a target area under the plasma concentration-time curve [AUC] of 5 mg/mL per minute by IV infusion once every 3 weeks for a maximum of 6 cycles); patients receiving platinum-based chemotherapy whose disease had not progressed after 4 cycles were permitted to receive maintenance pemetrexed therapy.1, 19 Treatment was continued until disease progression, unacceptable toxicity, or study withdrawal occurred.1, 19 The primary efficacy end point of the study was progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1); secondary end points included objective response rate, duration of response, and overall survival.1, 19 The median age of patients was 62 years; the majority of patients were female (64%), of Asian ancestry (65%), had never smoked (68%), and had adenocarcinoma histology (84%).1, 19 Thirty-four percent of the patients had CNS metastases at baseline, among which 11% had measurable disease.1, 19
At a median follow-up of 8.3 months, patients receiving osimertinib in the AURA3 study had a longer median investigator-assessed progression-free survival compared with patients receiving platinum-based chemotherapy (10.1 versus 4.4 months).1, 19 Analysis of progression-free survival according to BICR resulted in similar findings as the investigator assessment.1, 19 Patients receiving osimertinib also had a higher objective response rate (65 versus 29%) and a longer median duration of response (11 versus 4.2 months) compared with those receiving platinum-based chemotherapy.1 Complete response was achieved in 1% of patients in both treatment groups.1 In the subgroup of patients with baseline measurable CNS metastases, BICR-assessed CNS objective response rates were 57 or 25% in the osimertinib or platinum-based chemotherapy groups, respectively, with durable responses of 6 months or more in 47 or 0% of patients receiving these respective treatments, or 9 months or more in 12 or 0% of patients receiving these respective treatments; complete responses were achieved in 7% of patients receiving osimertinib and none of those receiving platinum-based chemotherapy.1 At a median follow-up 23.5 or 20.3 months in patients receiving osimertinib or platinum-based chemotherapy, respectively, no substantial difference in median overall survival was observed between the treatment groups (26.8 versus 22.5 months; hazard ratio 0.87).1, 32
EGFR -activating mutations are present in approximately 30% of NSCLC cases and observed at a higher rate in Asian compared with Western populations, in nonsmokers compared with smokers, and in patients with adenocarcinoma histology.27, 29, 37 The majority of EGFR mutations are exon 19 deletions or an L858R substitution in exon 21, which together account for about 90% of EGFR mutations in patients with NSCLC.29
The American Society of Clinical Oncology (ASCO) has published a guideline addressing the treatment of stage IV NSCLC harboring driver alterations such as EGFR mutations.38 The guideline strongly recommends osimertinib as a first-line treatment option for patients with EGFR exon 19 deletions or exon 21 L858R substitution mutations.38 Clinicians may consider combining osimertinib with platinum doublet chemotherapy or offering the combination of amivantamab plus lazertinib as alternative first-line approaches.38
Osimertinib is administered orally once daily without regard to meals.1 The tablets should be swallowed whole and should not be crushed.1
For patients unable to swallow solids, osimertinib tablets may be dispersed in a container with 60 mL (2 ounces) of noncarbonated water and immediately swallowed; no other liquids should be used.1 When preparing the drug dispersion, the water should be stirred (without crushing, heating, or ultrasonicating) until the tablet is dispersed (the tablet will not completely dissolve).1 Following administration, the container should be rinsed with an additional 120-240 mL (4-8 ounces) of water and the contents swallowed immediately to ensure that the full dose is given.1
Alternatively, if administration through a nasogastric tube is required, the tablet should be dispersed in a container with 15 mL of noncarbonated water and drawn into a syrin the container should then be rinsed with an additional 15 mL of water to transfer any residue to the syringe.1 The resulting 30-mL drug dispersion should be administered through the nasogastric tube, and the tube should be flushed with appropriate volumes of water (approximately 30 mL).1 This step should be repeated until no tablet pieces remain in the syringe.1 The dispersion and residues should be administered within 30 minutes of the addition of the tablet to water.1
If a dose of osimertinib is missed, the next dose should be taken at the regularly scheduled time; the missed dose should not be taken.1
Dosage of osimertinib mesylate is expressed in terms of osimertinib.1
Adjuvant Treatment of EGFR Mutation-positive Non-small Cell Lung Cancer
The recommended adult dosage of osimertinib for adjuvant therapy of EGFR del19 or L858R mutation-positive non-small cell lung cancer (NSCLC) after tumor resection is 80 mg once daily.1 Osimertinib therapy should be continued for up to 3 years or until disease recurrence or unacceptable toxicity occurs.1
Locally Advanced, Unresectable (Stage III) EGFR Mutation-positive Non-small Cell Lung Cancer
The recommended adult dosage of osimertinib for treatment of locally advanced, unresectable (stage III) EGFR del19 or L858R mutation-positive NSCLC following platinum-based chemoradiation therapy is 80 mg once daily.1 Osimertinib therapy should be continued until disease progression or unacceptable toxicity occurs.1
First-line Therapy for EGFR Mutation-positive Metastatic Non-small Cell Lung Cancer
The recommended adult dosage of osimertinib for the initial treatment of EGFR del19 or L858R mutation-positive metastatic NSCLC is 80 mg once daily.1 Osimertinib therapy should be continued until disease progression or unacceptable toxicity occurs.1
First-line Therapy for EGFR Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer
The recommended adult dosage of osimertinib for the initial treatment of EGFR del19 or L858R mutation-positive locally advanced or metastatic NSCLC is 80 mg once daily in combination with pemetrexed and platinum-based chemotherapy.1 Therapy should be continued until disease progression or unacceptable toxicity occurs due to osimertinib.1
Clinicians should refer to the pemetrexed and cisplatin or carboplatin prescribing information for dosing information for these agents.1
Previously Treated EGFR T790M Mutation-positive Metastatic Non-small Cell Lung Cancer
The recommended adult dosage of osimertinib for the treatment of EGFR T790M mutation-positive metastatic NSCLC following failure of prior EGFR tyrosine kinase inhibitor therapy is 80 mg once daily.1 Osimertinib therapy should be continued until disease progression or unacceptable toxicity occurs.1
If any grade of ILD or pneumonitis occurs in patients who have not received recent definitive platinum-based chemoradiation therapy, osimertinib therapy should be permanently discontinued.1
If grade 1 ILD/pneumonitis occurs in patients who have received recent definitive platinum-based chemoradiation therapy, osimertinib should be withheld or continued, as clinically indicated.1 If grade ≥2 ILD/pneumonitis occurs in these patients, osimertinib should be permanently discontinued.1
If corrected QT (QTc) interval exceeds 500 msec on at least 2 separate ECGs, osimertinib therapy should be withheld until the QTc interval is less than 481 msec or returns to baseline (if baseline QTc interval is 481 msec or more).1 Osimertinib therapy may then be resumed at a reduced dosage of 40 mg daily.1 If QTc-interval prolongation is accompanied by signs and/or symptoms of life-threatening arrhythmia, the drug should be permanently discontinued.1
If symptomatic congestive heart failure occurs, osimertinib should be permanently discontinued.1
If Stevens-Johnson syndrome, toxic epidermal necrolysis, or erythema multiforme major is suspected, osimertinib therapy should be withheld.1 Permanently discontinue osimertinib therapy if Stevens-Johnson syndrome, toxic epidermal necrolysis, or erythema multiforme major is confirmed.1
If cutaneous vasculitis is suspected, osimertinib should be withheld and the patient should be evaluated for systemic involvement; consider consultation with a dermatologist.1 Consider permanent discontinuance of osimertinib based on severity when no other etiology is identified.1
Blood and Bone Marrow Toxicity
If aplastic anemia is suspected, withhold osimertinib therapy.1 Osimertinib should be permanently discontinued if aplastic anemia is confirmed.1
If any other grade 3 or higher adverse reaction occurs, osimertinib therapy should be interrupted for up to 3 weeks.1 If the adverse reaction improves to grade 2 or less within this time period, the drug may be resumed at the original dosage or at a reduced dosage of 40 mg daily.1 If there is no improvement within 3 weeks of withholding osimertinib, the drug should be permanently discontinued.1
Concomitant Use with CYP3A4 Inducers
Concomitant use of osimertinib with strong cytochrome P-450 (CYP) isoenzyme 3A4 inducers should be avoided.1 If concomitant use is unavoidable, osimertinib dosage should be increased to 160 mg daily.1 The usual dosage of 80 mg daily should be resumed 3 weeks after the strong CYP3A4 inducer is discontinued.1
Combination Therapy with Pemetrexed and Platinum-based Chemotherapy
When osimertinib is concomitantly administered with pemetrexed and platinum-based chemotherapy, the dose of any one of the treatments should be modified for the management of adverse reactions, as appropriate.1 For dosage modifications for osimertinib specifically, please refer to information above under Dosage Modifications.1 The dosage of pemetrexed, cisplatin, or carboplatin may be withheld, reduced, or permanently discontinued according to their respective prescribing information.1
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B; total bilirubin concentration not exceeding the upper limit of normal [ULN] with AST concentration exceeding the ULN; or total bilirubin concentration 1-3 times the ULN with any AST concentration).1 Insufficient data are available to provide dosage recommendations for patients with severe hepatic impairment.1
No dosage adjustment is necessary in patients with mild to severe renal impairment (creatinine clearance 15-89 mL/minute).1 Insufficient data are available to provide dosage recommendations for patients with end-stage renal disease (creatinine clearance less than 15 mL/minute).1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Interstitial Lung Disease/Pneumonitis
Severe or fatal interstitial lung disease (ILD)/pneumonitis may occur in patients receiving osimertinib.1 Across all clinical studies, ILD/pneumonitis occurred in 4% of 1813 patients who received osimertinib as monotherapy without recent definitive chemoradiation therapy and was fatal in 0.4% of patients receiving the drug.1 In patients administered osimertinib in combination with pemetrexed and platinum-based chemotherapy, ILD/pneumonitis was reported in 3.3% of 276 patients, with 0.4% of cases fatal in nature.1
Following definitive platinum-based chemoradiation therapy, ILD/pneumonitis (including radiation pneumonitis) occurred in 80 (56%) of 143 patients administered osimertinib monotherapy and 28 (38%) of 73 patients given placebo in a clinical study.1 Among the patients receiving osimertinib, a single fatality related to ILD/pneumonitis occurred; 3.5% of patients experienced grade 3 adverse reactions of ILD/pneumonitis and 52% experienced grade 1 or 2 reactions.1 Discontinuation of osimertinib therapy due to ILD/pneumonitis occurred in 7% of patients with dosage interruptions occurring in 35% of patients.1 Rechallenge with osimertinib occurred in 46 patients and 11% of these patients experienced recurrence of ILD/pneumonitis.1 Of the 80 patients with ILD/pneumonitis during osimertinib monotherapy, 40% experienced resolution, 1.3% had resolution with sequelae, 16% were in the process of resolution, 41% did not experience resolution, and 1.3% expired.1
For patients administered osimertinib who have not received recent definitive platinum-based chemoradiation therapy, osimertinib should be withheld and clinicians should promptly investigate for ILD in patients who present with worsening or respiratory symptoms suggestive of ILD (e.g., dyspnea, couth, fever).1 If a diagnosis of ILD is confirmed, the drug should be permanently discontinued.1
For patients administered recent definitive platinum-based chemoradiation therapy with grade 1 ILD/pneumonitis, osimertinib therapy should be continued or interrupted and restarted, as appropriate.1 Osimertinib should be permanently discontinued in patients with grade ≥2 ILD/pneumonitis.1
Prolongation of the corrected QT (QTc) interval has been reported in patients receiving osimertinib.1 Across all clinical studies of osimertinib monotherapy, QTc-interval prolongation exceeding 500 msec or an increase from baseline QTc interval of greater than 60 msec occurred in 1.1 or 4.3%, respectively, of 1813 osimertinib-treated patients.1 In a clinical study of osimertinib in combination with pemetrexed and platinum-based chemotherapy in 276 patients, QTc-interval prolongation exceeding 500 msec or an increase from baseline QTc interval of greater than 60 msec occurred in 1.8 or 10.5% of patients, respectively.1
No QTc-related arrhythmias were reported with osimertinib and clinical trials did not enroll patients with a baseline QTc >470 msec.1 The manufacturer recommends periodic monitoring of ECG and serum electrolytes during osimertinib therapy in patients at risk for QT-interval prolongation, including those with congenital long QT syndrome, congestive heart failure, or electrolyte abnormalities, and in those receiving concomitant drugs known to prolong the QT interval with known risk of torsades de pointes.1 If QT-interval prolongation occurs, dosage reduction, temporary interruption, or permanent discontinuance of therapy may be necessary.1 If QTc-interval prolongation is accompanied by signs and/or symptoms of life-threatening arrhythmia, osimertinib therapy should be permanently discontinued.1
Cardiomyopathy has been reported in patients receiving osimertinib.1 Across all clinical studies of osimertinib monotherapy, cardiomyopathy (defined as cardiac failure, congestive heart failure, pulmonary edema, or decreased ejection fraction) was reported in 3.8% of 1813 patients; fatal cardiomyopathy occurred in 0.1% of patients receiving the drug.1 Additionally, decreases in left ventricular ejection fraction (LVEF) to less than 50% with a decline of ≥10% from baseline was reported in 4.2% of 1557 osimertinib-treated patients who had baseline and follow-up LVEF assessments.1 In the primary clinical study evaluating osimertinib for the adjuvant treatment of NSCLC, decreases in LVEF of ≥10% and to <50% were reported in 1.5% of 325 osimertinib-treated patients.1
Cardiomyopathy was reported in 9% of 276 patients administered osimertinib in combination with pemetrexed and platinum-based chemotherapy; 1.1% of these cases were fatal.1 Additionally, 21 (8%) of 162 patients treated with osimertinib in combination with pemetrexed and platinum-based chemotherapy, who had baseline and follow-up LVEF assessments, experienced decreases in LVEF to less than 50% with a decline of ≥10% from baseline.1
Following platinum-based chemoradiation therapy, decreases in LVEF to less than 50% with a decline of ≥10% from baseline was reported in 3% of 135 osimertinib-treated patients and no patients administered placebo.1
In patients administered osimertinib monotherapy, cardiac monitoring (including LVEF) should be assessed prior to initiating osimertinib and periodically during therapy in patients with cardiac risk factors.1
In patients administered osimertinib in combination with pemetrexed and platinum-based chemotherapy, cardiac monitoring (including LVEF) should be assessed prior to initiating osimertinib and periodically during therapy in all patients.1
LVEF should be assessed in any patient who develops relevant cardiac signs or symptoms during osimertinib therapy.1 Osimertinib should be permanently discontinued in patients who develop symptomatic congestive heart failure.1
Keratitis has been reported in 0.6% of 1813 patients receiving osimertinib monotherapy in clinical studies.1
Patients who develop manifestations suggestive of keratitis (e.g., eye inflammation, lacrimation, photosensitivity, blurred vision, eye pain, red eye) should be referred promptly to an ophthalmologist for evaluation.1
Erythema Multiforme, Toxic Epidermal Necrolysis, and Stevens-Johnson Syndrome
In postmarketing surveillance, erythema multiforme major, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported in patients receiving osimertinib.1
Osimertinib should be withheld if erythema multiforme major, toxic epidermal necrolysis, or Stevens-Johnson syndrome is suspected; if diagnosis is confirmed, permanently discontinue osimertinib.1
In postmarketing surveillance, cutaneous vasculitis (e.g., leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis) have been reported in patients receiving osimertinib.1
If cutaneous vasculitis is suspected, osimertinib should be withheld and the patient should be evaluated for systemic involvement; consultation with a dermatologist should be considered.1 Permanent discontinuation of osimertinib should be considered based on severity when no other etiology is identified.1
Aplastic anemia has been reported in patients receiving osimertinib in clinical trials (0.06% of 1813) and in postmarketing surveillance; some cases have resulted in fatal outcomes.1 Patients should be advised of the signs and symptoms of aplastic anemia (e.g., new or persistent fevers, bruising, bleeding, pallor).1 If aplastic anemia is suspected, osimertinib should be withheld and a hematology consultation should be obtained.1 If an aplastic anemia diagnosis is confirmed, permanently discontinue osimertinib.1 Perform a complete blood count with differential before initiating therapy, periodically throughout treatment, and more frequently if indicated.1
Fetal/Neonatal Morbidity and Mortality
Osimertinib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 Embryofetal toxicity (e.g., postimplantation loss, early embryonic death, decreased fetal weight) has been demonstrated in animals at exposures approximately 1.5 times those observed in humans at the recommended dosage.1 There are no adequate and well-controlled studies in pregnant women.1
Pregnancy should be avoided during therapy.1 The manufacturer states that pregnancy status should be verified prior to initiation of osimertinib therapy in females of reproductive potential and that such females should be advised to use effective contraception during osimertinib therapy and for 6 weeks after the drug is discontinued.1 In addition, males with female partners of reproductive potential should use effective methods of contraception while receiving the drug and for 4 months after the drug is discontinued.1
Although there are no available data in pregnant women, animal studies suggest that osimertinib may cause fetal harm.1 If osimertinib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1
It is not known whether osimertinib is distributed into human milk or if the drug has any effect on milk production or the nursing infant.1 Adverse effects (e.g., reduced growth rates, neonatal deaths) have been observed in the offspring of rats administered osimertinib during gestation and early lactation.1 Because of the potential for serious adverse reactions to osimertinib in nursing infants, women should be advised to discontinue nursing while receiving the drug and for 2 weeks after the drug is discontinued.1
Females and Males of Reproductive Potential
Pregnancy status should be verified prior to initiation of osimertinib therapy in females of reproductive potential and such females should be advised to use effective contraception during osimertinib therapy and for 6 weeks after the drug is discontinued.1 In addition, males with female partners of reproductive potential should use effective methods of contraception while receiving the drug and for 4 months after the drug is discontinued.1
Results of animal studies suggest that osimertinib may impair female and male fertility.1 In female rats, administration of osimertinib at a dosage of 20 mg/kg daily (producing peak plasma osimertinib concentrations approximately 1.5 times those observed with the recommended human dosage) from 2 weeks before mating to pregnancy day 8 had no effect on estrus cycles or pregnancy rates, but caused early embryonic deaths; the effects of osimertinib on fertility appeared to be reversible when female rats were mated 1 month after discontinuance of the drug.1
Increased preimplantation embryonic loss was observed in untreated female rats mated to osimertinib-treated male rats; it is not known whether these effects are reversible.1
Safety and efficacy of osimertinib have not been established in pediatric patients.1
In clinical trials of osimertinib monotherapy involving 1813 patients, 770 patients were ≥65 years of age and 207 patients were ≥75 years of age.1 Although no overall differences in efficacy or safety were observed between patients ≥65 years of age and younger patients, exploratory analysis suggested an increased incidence of ≥grade 3 adverse reactions (43% versus 33%) and more frequent dosage modifications for adverse reactions (34% versus 23%) in patients ≥65 years of age.1
In a clinical study of osimertinib following definitive platinum-based chemoradiation therapy involving 142 patients, 62 patients were ≥65 years of age and 13 patients were ≥75 years of age.1 No overall differences in efficacy or safety were observed between patients ≥65 years of age and younger patients.1
In a clinical study of osimertinib in combination with pemetrexed and platinum-based chemotherapy involving 276 patients, 104 patients were ≥65 years of age and 23 patients were ≥75 years of age.1 Clinical studies of combination therapy did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients; however, exploratory analysis suggested an increased incidence of ≥grade 3 adverse reactions (68% versus 61%) and more frequent dosage modifications for adverse reactions (55% versus 43%) in patients ≥65 years of age.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of osimertinib are not substantially altered in patients with mild to moderate hepatic impairment (Child-Pugh class A or B; total bilirubin concentration not exceeding the upper limit of normal [ULN] with AST concentration exceeding the ULN; or total bilirubin concentration 1-3 times the ULN with any AST concentration).1 The drug has not been studied in patients with severe (total bilirubin concentration 3-10 times the ULN with any AST concentration) hepatic impairment.1
Population pharmacokinetic analysis suggests that the pharmacokinetics of osimertinib are not substantially altered in patients with mild to severe renal impairment (creatinine clearance of 15-89 mL/minute).1 The drug has not been studied in patients with end-stage renal disease (creatinine clearance less than 15 mL/minute).1
Adverse effects reported in more than 20% of patients receiving osimertinib as monotherapy include leukopenia, lymphophenia, anemia, diarrhea, rash, musculoskeletal pain, neutropenia, nail toxicity, dry skin, stomatitis, and fatigue.1
Adverse effects reported in more than 20% of patients receiving osimertinib following platinum-based chemoradiation therapy include lymphopenia, leukopenia, ILD/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough, and COVID-19.1
Adverse effects reported in more than 20% of patients receiving osimertinib in combination with pemetrexed and platinum-based chemotherapy include leukopenia, thrombocytopenia, neutropenia, lymphophenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, and increased creatinine.1
Osimertinib mesylate is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A.1, 12 In vitro studies indicate that osimertinib induces CYP1A2; the drug does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1.1
Osimertinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate of organic anion transport protein (OATP) 1B1 or OATP1B3.1 Osimertinib inhibits BCRP but does not inhibit organic anion transporter (OAT) 1, OAT3, OATP1B1, OATP1B3, multidrug and toxin extrusion transporter (MATE) 1, MATE2K, or organic cation transporter (OCT) 2.1
Drugs Affecting Hepatic Microsomal Enzymes
When the strong CYP3A4 inhibitor itraconazole (200 mg twice daily) was administered concomitantly with osimertinib, peak plasma concentrations of osimertinib decreased by 20% and area under the plasma concentration-time curve (AUC) increased by 24%; however, these changes were not considered to be clinically important.1
Concomitant use of osimertinib with strong inducers of CYP3A4 may decrease plasma concentrations of osimertinib.1 When the strong CYP3A4 inducer rifampin (600 mg daily for 21 days) was administered concomitantly with osimertinib (80 mg once daily) in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC), peak plasma concentrations and AUC of osimertinib decreased by 73 and 78%, respectively.1, 15 Because of the potential for reduced efficacy of osimertinib, concomitant administration of osimertinib and strong CYP3A4 inducers (e.g., rifampin) should be avoided.1 If concomitant use cannot be avoided, dosage of osimertinib should be increased.1
Drugs Metabolized by Hepatic Microsomal Enzymes
When the CYP3A4 substrate simvastatin (single 40-mg dose) was administered concomitantly with osimertinib (80 mg daily) in patients with EGFR mutation-positive NSCLC, peak plasma concentrations and (AUC) of simvastatin were not substantially affected.1, 16
Drugs Transported by Breast Cancer Resistance Protein
Concomitant use of osimertinib and drugs that are substrates of BCRP (e.g., rosuvastatin) may increase exposure and toxicity of the BCRP substrate.1 When the BCRP substrate rosuvastatin (single 20-mg dose) was administered concomitantly with osimertinib (80 mg daily) in patients with EGFR mutation-positive NSCLC, peak plasma concentrations and AUC of rosuvastatin were increased by 72 and 35%, respectively.1, 16 Patients receiving BCRP substrates concomitantly with osimertinib should be monitored for adverse effects of the substrate drug, unless otherwise specified in the manufacturer's labeling for the substrate.1
Drugs Affected by the P-glycoprotein Transport System
Concomitant use of osimertinib and drugs that are substrates of P-gp (e.g., fexofenadine) may increase exposure and toxicity of the P-gp substrate.1 When the P-gp substrate fexofenadine was administered concomitantly with osimertinib, peak plasma concentrations and AUC of fexofenadine were increased by 76 and 56%, respectively, following a single dose, and by 25 and 27%, respectively, at steady state.1 Patients receiving P-gp substrates concomitantly with osimertinib should be monitored for adverse effects of the substrate drug, unless otherwise specified in the manufacturer's labeling for the substrate drug.1
Drugs that Prolong the QT Interval
Concomitant use of osimertinib and drugs that prolong the QT interval may result in additive effects on QT-interval prolongation. 1 Concomitant use of drugs known to prolong the QT interval with known risk of torsades de pointes should be avoided when possible.1 If concomitant use of drugs known to prolong the QT interval with known risk of torsades de pointes cannot be avoided, the manufacturer recommends periodic monitoring of ECG and electrolytes.1
Drugs Affecting Gastric Acidity
Concomitant administration of a single 80-mg dose of osimertinib with omeprazole (40 mg daily for 5 days) did not affect systemic exposure to osimertinib.1
Osimertinib mesylate, a third-generation inhibitor of receptor tyrosine kinases, is an antineoplastic agent.1, 4, 5, 6, 7 The drug binds irreversibly and selectively to certain mutant forms of the epidermal growth factor receptor (EGFR), including EGFR-sensitizing mutations (e.g., exon 19 deletion [del19], exon 21 substitution [L858R]) and the secondary T790M mutation. 1, 4, 5, 6, 7, 10, 11
Although first- and second-generation EGFR tyrosine kinase inhibitors (e.g., afatinib, erlotinib, gefitinib) have demonstrated improved outcomes in patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations (e.g., del19, L858R), secondary resistance eventually develops following approximately 9-13 months of treatment.4, 6, 7, 8, 9, 10, 11 Clinical resistance to EGFR tyrosine kinase inhibitors has been attributed to the development of a secondary mutation, EGFR T790M, in approximately 50-60% of cases;4, 5, 6, 8, 9, 10, 11 this mutation results in production of a bulky methionine side chain in the receptor kinase domain of EGFR that is thought to sterically hinder the binding of first-generation (reversible) EGFR tyrosine kinase inhibitors to EGFR.6, 7, 8 Second-generation (irreversible) EGFR tyrosine kinase inhibitors (e.g., afatinib, dacomitinib) were developed to overcome this resistance; however, their clinical use has been limited by dose-limiting toxicities (e.g., skin rash, GI toxicity) possibly due to activity against wild-type EGFR.4, 5, 6, 7, 8, 9, 10, 24, 25, 26 Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, exhibits approximately ninefold greater affinity for mutant forms of EGFR than wild-type EGFR.1, 10 In vitro studies and studies in animal tumor xenograft models indicate that the drug has antitumor activity against NSCLC cell lines expressing EGFR mutations L858R/T790M, L858R, T790M/del19, and del19 and, to a lesser extent, wild-type EGFR.1 Osimertinib also inhibits the activity of HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, ACK1, and BLK at clinically relevant concentrations in vitro.1
Following oral administration, median time to peak plasma osimertinib concentrations is approximately 6 hours (range 3-24 hours) with steady-state concentrations achieved within approximately 15 days.1, 11, 12 Dose-proportional increases in area under the plasma concentration-time curve (AUC) and peak plasma concentration of osimertinib are observed over a dose range of 20-240 mg.1, 4, 11 Administration of osimertinib with a high-fat meal slightly increased the AUC and peak plasma concentration of the drug by 19 and 14%, respectively, compared with the fasted state.1, 11 Limited data in animals suggest that osimertinib distributes into the brain.1 Osimertinib is predominantly metabolized by the cytochrome P-450 (CYP) isoenzyme 3A.1, 12 Two active metabolites (AZ7550 and AZ5104) have been identified, each accounting for approximately 10% of total drug exposure; AZ7550 has a similar potency to osimertinib, but AZ5104 exhibits higher potency against mutant EGFR and wild-type EGFR.1, 10, 11 Osimertinib is 95% bound to plasma proteins.1 Osimertinib is principally eliminated in feces (68%) and to a lesser extent in urine (14%); approximately 2% of an administered dose is eliminated as unchanged drug.1, 12 The mean elimination half-life of osimertinib is 48 hours.1
The pharmacokinetics of osimertinib do not appear to be affected by age, gender, or race (Asian versus non-Asian), body weight, baseline albumin concentration, line of therapy, or smoking status.1, 11 In addition, the pharmacokinetics of osimertinib in patients receiving combination therapy with pemetrexed and platinum-based chemotherapy are similar to that seen with osimertinib monotherapy.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Osimertinib mesylate can only be obtained through a limited network of specialty distributors.14 Consult manufacturer's website for additional information.14
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 40 mg (of osimertinib) | ||
80 mg (of osimertinib) | Tagrisso® | AstraZeneca |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions January 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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16. Harvey RD, Isambert N, Rafii S, et al. Effect of multiple-dose osimertinib (AZD9291) on the pharmacokinetics (PK) of simvastatin and rosuvastatin. Abstract e14098 (published in conjunction with the 2016 ASCO meeting). Chicago, IL.
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