Table 1.

Pharmacological properties of osimertinib in advanced NSCLC with activating EGFR mutations

Pharmacodynamic properties

Binds irreversibly to clinically relevant mutant EGFR kinase forms (e.g. L858R, ex19del, T790M) to selectively inhibit mutant EGFR kinase activity [7, 19, 20]; potently inhibits EGFR phosphorylation in EGFR-TKI-sensitizing mutant and T790M mutant NSCLC cell lines, exhibiting less activity against wild-type cell lines [7, 20]

Produces two pharmacologically active metabolites; AZ7550 is similar to osimertinib in potency and selectivity, while AZ5104 is more potent in inhibiting both mutant EGFR and wild-type EGFR (smaller selectivity margin than osimertinib) [7, 19]

Dose-dependently induced profound and sustained tumour regression in xenograft and transgenic models of EGFR-mutant lung cancer (including those of CNS metastases) in vivo [7, 30]; exhibited potent anti-tumour activity against both L858R and L858R/T790M EGFR-mutant tumours (unlike afatinib, which was only effective against the former) in transgenic mice [7]

Exhibited anti-tumour effects in pts with NSCLC harbouring various EGFR mutations (common and uncommon) in clinical trials [10, 11, 27]; inhibited growth of CNS metastases in pts with EGFR mutation-positive NSCLC [13, 31]

Resistance to osimertinib eventually develops in pts, with various mechanisms underlying acquired resistance [32]; in a subset of pts in the phase III FLAURA trial (Sect. 2), the most common acquired resistance mechanisms identified in osimertinib recipients who experienced clinical progression and/or discontinued treatment were MET amplification (15%; 14/91) and the EGFR C797S mutation (7%; 6/91) [33]

Potential for QTc prolongation and changes in cardiac contractility [18–20]; a concentration-dependent QTc interval prolongation of 14 ms is predicted at the recommended dosage [19, 20]; in a pooled analysis of data from clinical trials (n = 1479 treated with osimertinib), a QTc increase from baseline of > 60 ms and a QTc > 500 ms occurred in 3.1% and 0.8% of pts, respectively, while an LVEF decline of ≥ 10% from baseline and to < 50% LVEF occurred in 3.2% of pts who had baseline data and ≥ 1 follow-up assessment (n = 1233) [19, 20]

Pharmacokinetic properties

Linear pharmacokinetics with dose-proportional increases in exposure (Cmax and AUC; dose range 20–240 mg) [19, 20, 34]

Slow absorption after oral administration (median Tmax 6 h) [19, 20, 34]; no clinically meaningful effects of food on osimertinib exposure in pts with EGFR mutation-positive advanced NSCLC or of omeprazole-induced gastric pH elevations on exposure in healthy volunteers [35]

Steady-state exposures reached after 15 days of once-daily administration (drug accumulation ≈ 3-fold) [19]

Extensively distributed in tissues (mean Vd 918 L at steady state) [19, 20]; high blood-brain barrier penetrance and brain exposure relative to other EGFR-TKIs in preclinical studies (brain to plasma AUC ratios ≈ 2 with oral dosing in animal models [19]) [30, 36]; achieved rapid, high and uniform brain exposure in a phase I trial in adults with EGFR mutation-positive advanced NSCLC and CNS metastases (n = 4) [31]

Main metabolic pathways are oxidation (primarily by CYP3A) and dealkylation, with two pharmacologically active metabolites found in plasma after oral administration (AZ7550 and AZ5104; each had a geometric mean exposure ≈ 10% that of osimertinib at steady state) [19, 20, 34]

Low to moderate clearance (14.2 L/h at steady state) and long half-life (≈ 50 h after single dose) in pts with advanced NSCLC [34]

Eliminated primarily in faeces (68%) and less so in urine (14%); unchanged drug represented ≈ 2% of the elimination [19, 20]

Pharmacokinetics in pts with CLcr < 15 mL/min or severe hepatic impairment (TBil 3–10 × ULN and any AST) unknown [19, 20]; in the EU, caution is required in pts with CLcr < 30 mL/min and use in pts with severe hepatic impairment is not recommended [20]

Drug interactions

Concomitant use of strong CYP3A inducers may decrease osimertinib exposure and should be avoided in the EU [20] and, if possible, in the USA (dosage adjustments required if concomitant use is unavoidable) [19]; in the EU, the co-administration of osimertinib and moderate CYP3A4 inducers should be approached with caution or, if possible, avoided [20]

In the EU, pts concomitantly using drugs with disposition dependent upon BCRP or P-gp and narrow therapeutic indices should be closely monitored for tolerability of the concomitant drug (exposure potentially increased) [20]; in the USA, pts concomitantly using BCRP or P-gp substrates should be monitored for adverse reactions of the BCRP or P-gp substrate (unless instructed otherwise in approved labelling) [19]

Effect of use with drugs known to prolong QTc interval is unknown; in the USA, co-administration of osimertinib and drugs known to prolong the QTc interval with known risk of Torsades de pointes should be avoided if feasible (or periodic ECG monitoring conducted if not) [19]

AST aspartate aminotransferase, AUC area under the plasma concentration-time curve, BCRP breast cancer resistance protein, CL_cr creatinine clearance, C_max peak plasma concentration, CNS central nervous system, EGFR epidermal growth factor receptor, ex19del exon 19 deletion, LVEF left ventricular ejection fraction, NSCLC non-small cell lung cancer, P-gp P-glycoprotein, pts patients, TBil total bilirubin, TKI tyrosine kinase inhibitor, T_max time to peak plasma concentration, ULN upper limit of normal, V_d volume of distribution