Tagrisso (Osimertinib)
osimertinib mesylate
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Adjuvant therapy — resected EGFRm NSCLC | Adults, post-tumor resection (Stage IB–IIIA per AJCC 7th ed.) | Monotherapy | FDA Approved |
| Unresectable Stage III EGFRm NSCLC — post-chemoradiation | Adults, disease not progressed during/after platinum-based CRT | Monotherapy (consolidation) | FDA Approved |
| First-line metastatic EGFRm NSCLC | Adults, EGFR exon 19del or L858R | Monotherapy | FDA Approved |
| First-line locally advanced/metastatic EGFRm NSCLC — with chemotherapy | Adults, EGFR exon 19del or L858R | Combination (+ pemetrexed/platinum) | FDA Approved |
| Previously treated T790M-positive metastatic NSCLC | Adults, progressed on/after prior EGFR TKI | Monotherapy | FDA Approved |
Osimertinib is indicated exclusively for NSCLC harboring specific EGFR mutations. For all indications except T790M-positive disease, tumors must carry exon 19 deletions or exon 21 L858R substitutions confirmed by an FDA-approved companion diagnostic test. Tissue-based testing is preferred; plasma-based (ctDNA) testing is acceptable for metastatic settings, but negative plasma results should be followed by tissue biopsy when feasible. The drug has demonstrated activity across disease stages — from post-surgical adjuvant therapy (ADAURA) through unresectable locally advanced disease after chemoradiation (LAURA), first-line metastatic treatment both as monotherapy (FLAURA) and in combination with platinum-pemetrexed (FLAURA2), and second-line use after prior EGFR TKI failure with confirmed T790M resistance (AURA3).
EGFR uncommon mutations (e.g., G719X, S768I, L861Q): Limited data from single-arm studies and case series suggest activity; not included in the approved labeling. Evidence quality: Low.
Leptomeningeal metastases from EGFRm NSCLC: Several prospective studies (BLOOM, AURA) have reported intracranial responses with osimertinib 160 mg daily; not a labeled indication. Evidence quality: Moderate.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Adjuvant — post-resection (stage IB–IIIA) | 80 mg PO once daily | 80 mg PO once daily | 80 mg/day | Continue for up to 3 years or until recurrence/unacceptable toxicity With or without prior adjuvant chemotherapy |
| Stage III unresectable — consolidation post-CRT | 80 mg PO once daily | 80 mg PO once daily | 80 mg/day | Initiate within 42 days of completing CRT; continue until progression or unacceptable toxicity |
| First-line metastatic EGFRm NSCLC — monotherapy | 80 mg PO once daily | 80 mg PO once daily | 80 mg/day | Continue until progression or unacceptable toxicity No food restriction |
| First-line metastatic — osimertinib + pemetrexed/platinum | 80 mg PO once daily | 80 mg PO once daily + pemetrexed 500 mg/m² q3w | 80 mg/day | Platinum (cisplatin 75 mg/m² or carboplatin AUC5) for 4 cycles, then osimertinib + pemetrexed maintenance |
| Second-line — T790M-positive after prior EGFR TKI | 80 mg PO once daily | 80 mg PO once daily | 80 mg/day | Confirm T790M by tissue or plasma; continue until progression Negative ctDNA warrants tissue rebiopsy |
| Co-administration with strong CYP3A4 inducer | 160 mg PO once daily | 160 mg PO once daily | 160 mg/day | Resume 80 mg 3 weeks after stopping the inducer Avoid strong CYP3A inducers if possible |
Dose Modifications for Adverse Reactions
| Adverse Reaction | Action |
|---|---|
| ILD/Pneumonitis | Permanently discontinue osimertinib |
| QTc >500 msec on ≥2 ECGs | Withhold until QTc <481 msec; resume at 40 mg daily |
| QTc prolongation with life-threatening arrhythmia | Permanently discontinue |
| Symptomatic congestive heart failure | Permanently discontinue |
| Suspected SJS/TEN or aplastic anemia | Withhold; permanently discontinue if confirmed |
| Grade ≥3 other adverse reaction | Withhold up to 3 weeks; if improves to grade 0–2, resume at 80 mg or 40 mg; if no improvement, permanently discontinue |
Tablets may be dispersed in 60 mL of non-carbonated water for patients who cannot swallow solids; the resulting suspension should be administered immediately. Nasogastric tube administration is also possible using 15 mL of water for dispersion with a 15 mL rinse (total 30 mL), administered within 30 minutes of preparation.
Pharmacology
Mechanism of Action
Osimertinib is a third-generation, irreversible EGFR tyrosine kinase inhibitor that covalently binds to the cysteine-797 residue within the ATP-binding site of the EGFR kinase domain via a reactive acrylamide warhead. It selectively targets activating EGFR mutations (exon 19 deletions and L858R) and the T790M resistance mutation at approximately 9-fold lower concentrations than needed to inhibit wild-type EGFR, conferring a wider therapeutic window and reduced toxicity compared to earlier-generation agents. Osimertinib also inhibits HER2, HER3, HER4, ACK1, and BLK at clinically relevant concentrations. Two circulating active metabolites, AZ5104 and AZ7550, each reach approximately 10% of parent drug exposure. AZ5104 demonstrates roughly 8-fold greater potency against T790M/exon 19 deletion mutants than the parent compound. Importantly, osimertinib achieves brain-to-plasma AUC ratios of approximately 2:1, supporting its established activity against CNS metastases.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral bioavailability ~70%; Tmax 6 h (range 3–24 h); food has no clinically significant effect on exposure | No food restriction simplifies dosing; slow absorption supports once-daily schedule |
| Distribution | Vss/F = 918 L; protein binding 95%; brain:plasma AUC ratio ~2:1 | Extensive tissue penetration including CNS; supports efficacy against brain metastases |
| Metabolism | Primarily CYP3A4/3A5 (oxidation, dealkylation); active metabolites AZ5104 and AZ7550 (~10% each of parent exposure) | Strong CYP3A inducers reduce exposure by ~78%; strong inhibitors have no clinically significant effect (~24% AUC increase) |
| Elimination | t½ 48 h; CL/F 14.3 L/h; feces 68%, urine 14%; unchanged drug ~2% of total elimination; steady state by day 15 | Long half-life supports once-daily dosing with 3-fold accumulation at steady state; minimal renal excretion of parent drug |
Side Effects
Adverse reaction data below are drawn from the pooled monotherapy safety population (N=1,813) and the pivotal trials ADAURA (adjuvant, N=337), FLAURA (first-line metastatic, N=279), FLAURA2 (combination, N=276), and AURA3 (second-line, N=279) from the FDA prescribing information.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea | 58% | Usually mild-moderate; only 2.2% grade ≥3; dose interruption needed in 2.5% |
| Rash (grouped term) | 58% | Includes acneiform, maculopapular, erythematous forms; grade ≥3 in 1.1%; less severe than with 1st-gen TKIs |
| Dry skin | 36% | Includes xerosis and skin fissures; emollients recommended from treatment start |
| Nail toxicity | 35% | Paronychia, onycholysis, nail discoloration; rarely grade ≥3 (0.4%) |
| Stomatitis | 32% | Includes aphthous ulcers and mouth ulceration; grade ≥3 in 0.7% |
| Fatigue | 21% | Grade ≥3 in 1.4%; may limit physical activity |
| Decreased appetite | 20% | Nutritional support if weight loss >5% |
| Musculoskeletal pain | 18% (ADAURA); 38% (pooled) | Back, joint, and extremity pain; pooled monotherapy rate across trials is higher |
| Cough | 17% | Important to differentiate from ILD/pneumonitis onset |
| Pruritus | 17% | Generalized or localized; topical antipruritics helpful |
| Nausea | 14% | More common in combination regimen (43%) |
| Constipation | 15% | More frequent in combination setting (29%) |
| Headache | 12% | Usually self-limiting; evaluate for CNS progression if new or worsening |
| Vomiting | 11% | More frequent in combination and second-line settings |
| Prolonged QTc interval | 10% | QTc >500 msec in 1.1% of monotherapy patients; concentration-dependent effect (~14 msec mean change at 80 mg) |
| Upper respiratory infection | 10% | Standard management; monitor for pneumonitis overlap |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Alopecia | 6–7% | Typically non-total; cosmetically distressing to some patients |
| Epistaxis | 5–6% | Usually mild; check platelet count if recurrent |
| ILD/Pneumonitis | 3–4% | Potentially fatal (0.4%); see Serious tier for management |
| Cardiomyopathy (decreased LVEF) | 3.8% | LVEF decline ≥10 points to <50% in 4.2% of monitored patients; higher with combination (9%) |
| Urticaria | 1.5–2.9% | May indicate hypersensitivity; re-evaluate if recurrent |
| Palmar-plantar erythrodysesthesia | 1.4–1.8% | Hand-foot skin reaction; moisturizers and dose modification if severe |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Interstitial lung disease / Pneumonitis | 4% | Any time during treatment | Withhold immediately; CT chest + pulmonology consult; permanently discontinue if confirmed. Fatal in 0.4%. |
| QTc prolongation (>500 msec) | 1.1% | Any time; concentration-dependent | Withhold until QTc <481 msec; resume at 40 mg. Permanently discontinue if life-threatening arrhythmia. |
| Cardiomyopathy / Heart failure | 3.8% (mono); 9% (combo) | Variable; monitor throughout | LVEF monitoring at baseline + during treatment; permanently discontinue for symptomatic CHF. Fatal in 0.1%. |
| Stevens-Johnson syndrome / Toxic epidermal necrolysis | Rare (postmarketing) | Any time | Withhold if suspected; permanently discontinue if confirmed. Dermatology and supportive care. |
| Aplastic anemia | 0.06% | Variable | Withhold if suspected; CBC with differential; hematology consult; permanently discontinue if confirmed. Some fatal cases reported. |
| Keratitis | 0.6% | Any time | Prompt ophthalmology referral for eye pain, photophobia, blurred vision, or redness. |
| Cutaneous vasculitis | Rare (postmarketing) | Any time | Withhold; evaluate for systemic involvement; dermatology consult; consider permanent discontinuation. |
| Setting | Discontinuation Rate | Most Common Reason |
|---|---|---|
| Monotherapy — 1st-line metastatic (FLAURA) | 13% | ILD/pneumonitis (3.9%) |
| Adjuvant (ADAURA) | 11% | ILD (2.7%), rash (1.2%) |
| Combination — 1st-line (FLAURA2) | 11% | ILD/pneumonitis (2.9%), pneumonia (1.4%), decreased EF (1.1%) |
| 2nd-line T790M+ (AURA3) | 7% | ILD/pneumonitis (3%) |
ILD/pneumonitis is the most clinically significant toxicity of osimertinib, occurring in approximately 4% of patients with a 0.4% fatality rate. New or worsening dyspnea, cough, or fever should prompt immediate osimertinib interruption and urgent high-resolution CT imaging. Differential diagnosis includes radiation pneumonitis (especially in the LAURA population), infection, and disease progression. Once ILD is confirmed, osimertinib must be permanently discontinued. Corticosteroids are typically used for management, though evidence for their efficacy is limited to case series.
Drug Interactions
Osimertinib is metabolized primarily by CYP3A4/3A5. It is a substrate of P-glycoprotein and BCRP, and an inhibitor of BCRP. Notably, strong CYP3A4 inhibitors (e.g., itraconazole) do not meaningfully increase osimertinib exposure, and gastric acid-reducing agents (e.g., omeprazole) do not affect its pharmacokinetics. The most clinically relevant interactions involve strong CYP3A4 inducers, BCRP/P-gp substrates, and QTc-prolonging agents.
Monitoring
-
EGFR Mutation Status
Before initiation
Routine Confirm exon 19del, L858R, or T790M by FDA-approved companion diagnostic (tissue preferred; ctDNA acceptable for metastatic). Negative plasma results warrant tissue biopsy. -
Pregnancy Test
Before initiation
Routine Verify pregnancy status in females of reproductive potential prior to starting osimertinib due to embryo-fetal toxicity risk. -
CBC with Differential
Baseline, then periodically
Routine Monitor for cytopenias including neutropenia, thrombocytopenia, lymphopenia, and aplastic anemia. Increase frequency if clinically indicated (e.g., new fevers, bruising, pallor). -
ECG
Baseline, then periodically
Routine Assess QTc interval at baseline and during treatment. Essential in patients with cardiac history, electrolyte abnormalities, or concomitant QTc-prolonging medications. QTc >500 msec requires dose modification. -
LVEF / Echocardiogram
Baseline + during treatment
Routine Conduct in patients with cardiac risk factors (monotherapy) or in all patients (combination with chemotherapy). Repeat if cardiac symptoms develop. LVEF decline ≥10 points to <50% occurred in 4.2% of monitored patients. -
Electrolytes
Baseline, then periodically
Routine Potassium, magnesium, sodium, calcium. Correct abnormalities before and during treatment to reduce QTc prolongation risk. -
Respiratory Symptoms
Every visit
Trigger-based New or worsening dyspnea, cough, or fever should trigger immediate evaluation for ILD/pneumonitis with high-resolution CT. Withhold osimertinib pending results. -
Dermatologic Assessment
Every visit
Trigger-based Evaluate for rash, nail toxicity, and skin reactions. Suspect SJS/TEN if target lesions, mucosal involvement, or severe blistering. Dermatology referral for grade ≥3 reactions or suspected vasculitis. -
Ophthalmologic Assessment
If symptoms arise
Trigger-based Prompt referral to ophthalmology for eye pain, blurred vision, photophobia, or redness suggestive of keratitis (0.6% incidence).
Contraindications & Cautions
Absolute Contraindications
- The FDA prescribing information lists no formal absolute contraindications. However, the following clinical scenarios should be considered as effective contraindications based on the warnings and precautions framework.
- Confirmed ILD/pneumonitis during prior osimertinib exposure — permanent discontinuation is mandated; rechallenge is not recommended.
- Confirmed aplastic anemia during prior osimertinib exposure — permanent discontinuation required.
Relative Contraindications (Specialist Input Recommended)
- Baseline QTc >470 msec — patients with prolonged baseline QTc were excluded from clinical trials. If treatment is considered, cardiology co-management and serial ECG monitoring are essential.
- Congenital long QT syndrome — enhanced cardiac monitoring required; risk-benefit assessment with cardiology.
- Symptomatic heart failure or LVEF <40% — cardiomyopathy risk is increased; cardio-oncology consultation recommended.
- Prior SJS/TEN with any EGFR TKI — cross-reactivity risk unclear; specialist dermatology input recommended.
- Severe hepatic impairment (Child-Pugh C) — no dosing data available; pharmacokinetics in this population are unknown.
- End-stage renal disease (CLcr <15 mL/min) — no dosing data available.
Use with Caution
- Concurrent use of strong CYP3A4 inducers — reduces osimertinib exposure by ~78%; dose increase to 160 mg required if unavoidable.
- Concurrent P-gp or BCRP substrate medications with narrow therapeutic index (e.g., digoxin, dabigatran) — monitor for increased substrate toxicity.
- Elderly patients (≥65 years) — exploratory analysis suggests higher rates of grade ≥3 adverse events (43% vs 33%) and more frequent dose modifications.
- Patients with prior radiation to the chest (LAURA population) — overlapping ILD risk; careful differentiation between radiation and drug-induced pneumonitis is critical.
- Active or prior interstitial lung disease requiring steroids — excluded from clinical trials; use with heightened vigilance if benefit outweighs risk.
Although osimertinib does not carry a formal boxed warning, the FDA prescribing information includes a prominent embryo-fetal toxicity warning. Animal studies demonstrated post-implantation loss, embryonic death, and fetal malformations at exposures near clinical levels. Females of reproductive potential must use effective contraception during treatment and for 6 weeks after the final dose. Males with female partners of reproductive potential must use effective contraception for 4 months after the final dose. Pregnancy status must be verified before initiation.
Patient Counselling
Purpose of Therapy
Osimertinib is a targeted therapy that works specifically against cancer cells carrying certain EGFR gene mutations. It blocks a protein that drives lung cancer growth while having less effect on normal cells, which is why its side effects differ from traditional chemotherapy. The duration of treatment depends on the disease stage: up to 3 years for post-surgical adjuvant therapy, and until disease progression or intolerable side effects for advanced or metastatic disease.
How to Take
Take one tablet at the same time each day, with or without food. Swallow whole with water. If swallowing is difficult, the tablet can be dissolved in a small amount of non-carbonated water and should be taken immediately once mixed. Do not crush, heat, or use fizzy drinks to dissolve the tablet. If a dose is missed, skip the missed dose and take the next dose at the usual time — do not double up.
Sources
- TAGRISSO (osimertinib) [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; revised February 2024. FDA Label Primary source for all dosing, adverse reaction incidence rates, pharmacokinetics, warnings, and dose modification guidance.
- FDA approves osimertinib with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA News Release, February 16, 2024. FDA.gov Official FDA announcement of the FLAURA2-based combination indication approval.
- FDA approves osimertinib for locally advanced, unresectable (stage III) non-small cell lung cancer following chemoradiation therapy. FDA News Release, September 25, 2024. FDA.gov Official FDA announcement of the LAURA-based consolidation indication for unresectable stage III disease.
- Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137 FLAURA primary analysis: established osimertinib as first-line standard with median PFS 18.9 vs 10.2 months.
- Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi:10.1056/NEJMoa1913662 FLAURA overall survival analysis: median OS 38.6 vs 31.8 months, confirming survival benefit.
- Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071 ADAURA primary analysis: established adjuvant osimertinib with DFS HR 0.20 for stage IB-IIIA disease.
- Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-1948. doi:10.1056/NEJMoa2306434 FLAURA2 primary PFS analysis: osimertinib + platinum-pemetrexed improved median PFS to 25.5 vs 16.7 months.
- Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674 AURA3 trial: established osimertinib superiority over chemotherapy in T790M-positive NSCLC with PFS HR 0.30.
- Ramalingam SS, Kato T, Dong X, et al. Osimertinib after definitive chemoradiotherapy in patients with unresectable stage III EGFRm NSCLC: LAURA trial. J Clin Oncol. 2024;42(suppl 17):LBA4. doi:10.1200/JCO.2024.42.17_suppl.LBA4 LAURA trial primary results: PFS HR 0.16 (39.1 vs 5.6 months), establishing osimertinib consolidation after CRT.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 1.2025. NCCN.org Positions osimertinib as preferred first-line therapy for EGFRm NSCLC across adjuvant, unresectable, and metastatic settings.
- Finlay MRV, Anderton M, Ashton S, et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem. 2014;57(20):8249-8267. doi:10.1021/jm500973a Describes the structure-driven drug design of osimertinib and its selective binding to mutant EGFR with ~9-fold selectivity over wild-type.
- Dickinson PA, Cantarini MV, Collier J, et al. Metabolic disposition of osimertinib in rats, dogs, and humans. Drug Metab Dispos. 2016;44(8):1201-1212. doi:10.1124/dmd.115.069179 Characterizes the ADME profile of osimertinib and its active metabolites AZ5104 and AZ7550 across species.
- Vishwanathan K, Dickinson PA, So K, et al. Absolute bioavailability of osimertinib in healthy adults. Clin Pharmacol Ther. 2019;105(5):1198-1205. doi:10.1002/cpt.1064 Phase 1 study establishing absolute oral bioavailability of osimertinib at 70% using IV microtracer methodology.
- Brown K, Comisar C, Witjes H, et al. Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer. Br J Clin Pharmacol. 2017;83(6):1216-1226. doi:10.1111/bcp.13223 Describes osimertinib population PK supporting fixed 80 mg dosing across age, weight, ethnicity, and organ function subgroups.
- Planchard D, Brown KH, Kim DW, et al. Osimertinib Western and Asian clinical pharmacokinetics in patients and healthy volunteers. Cancer Chemother Pharmacol. 2016;77(4):767-776. doi:10.1007/s00280-016-2992-z Confirms consistent PK across Western and Asian populations, supporting the same dose for all ethnicities with once-daily administration.