U.S. Food & Drug Administration (FDA) Clinical Pharmacology Corner Update: FDA Approves TAGRISSO (osimertinib)

FDA Approves TAGRISSO^® (osimertinib) for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy

On November 13, 2015, the United States Food and Drug Administration (FDA) approved TAGRISSO (osimertinib) for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. The approved recommended dosage of TAGRISSO tablets for oral administration is 80 mg once daily with or without food.

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Osimertinib

• MOA: Osimertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR), which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at approximately 9-fold lower concentrations than wild-type.
• Dose proportionality: Exhibited dose-proportional increases in systemic exposure over the dose range of 20 to 240 mg (i.e., 0.25 to 3 times the approved recommended dosage).
• Accumulation: Approximately 3-fold accumulation.
• Plasma protein binding: Plasma protein binding of osimertinib was not determined due to instability. It is likely to be high based on its physiochemical properties. 
• Terminal half-life (mean): Approximately 48 hours in patients.
• Metabolism: Primarily metabolized by CYP3A. 
• Excretion: Approximately 68% of the total recovered radio-labeled osimertinib dose was eliminated in the feces and 14% was eliminated in the urine. Unchanged osimertinib accounted for approximately 2% of the elimination.
• Exposure-safety: The probability of patient experiencing all grades of rash or diarrhea increased with exposure at steady state. However, the incidences of grade 3 or higher rash or diarrhea were less than 1%. A pharmacokinetic/pharmacodynamic analysis suggests a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at the 80 mg dose of osimertinib.

Drug Interaction Potential

Drug interaction studies with inhibitors, inducers or substrates of CYP enzymes and transporters have not been conducted with TAGRISSO.

• Avoid concomitant administration of TAGRISSO with strong CYP3A inhibitors, including macrolide antibiotics (e.g., telithromycin), antifungals (e.g., itraconazole), antivirals (e.g., ritonavir), nefazodone, as concomitant use of strong CYP3A inhibitors may increase osimertinib plasma concentrations. If no other alternative exists, monitor patients more closely for adverse reactions of TAGRISSO. 
• Avoid concomitant administration of TAGRISSO with strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine) or St. John’s Wort as strong CYP3A inducers and St. Johns’ wort may decrease osimertinib plasma concentrations.

Use in Specific Populations

No clinically significant differences in the PK of osimertinib were observed based on age, sex, ethnicity, body weight, smoking status, mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment, or mild hepatic impairment (total bilirubin

Safety and Efficacy

Clinical effectiveness and safety of TAGRISSO were demonstrated at the recommended dose in two multicenter, single-arm, open-label clinical trials, AURA extension (n=201) and AURA2 (n=210), in patients with metastatic EGFR T790M mutation-positive NSCLC who had progressed on prior systemic therapy, including an EGFR TKI. The objective response rate was 57% for AURA extension study and 61% for AURA2 study. The most common adverse events (AEs) were diarrhea, rash, dry skin, and nail toxicity. Dose interruptions, dose reductions and treatment discontinuations with TAGRISSO 80 mg due to AEs were reported for 18.7%, 4.4%, and 5.6% of patients, respectively.

---

Full prescribing information is available at http://go.usa.gov/c2Zu5.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (http://go.usa.gov/c2Zhm). 

We always welcome your thoughts regarding the format, content, and utility of information you receive via this Burst email initiative. Comments may be sent via email to ocp@fda.hhs.gov.

This burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.