Aumolertinib

Aumolertinib is an irreversible, small molecule tyrosine kinase inhibitor (TKI) of EGFR with inhibitory activity against EGFR TKI sensitising mutations (EGFR exon 19 [Ex19Del] deletion and EGFR L858R, respectively) and EGFR TKI resistance mutation (EGFR T790M). The major active metabolite of aumolertinib, HAS-719, showed a similar activity profile to aumolertinib.

Anti-proliferation activity

In vitro studies demonstrated that aumolertinib potently inhibited proliferation of EGFR T790M mutant cancer cell lines including NCI-H1975 (T790M/L858R) and PC9-GR (T790M/Del19), with IC50s of 3.3nM and 2.7nM, respectively. Aumolertinib also potently inhibited proliferation of EGFR activating mutant cancer cell lines including HCC827 (EGFR Del19) and PC9 (EGFR Del19), with IC50s of 3.3nM and 4.1nM, respectively. Aumolertinib only weakly inhibited proliferation of the EGFR wild type cancer cell line A431, with an IC50 of 596.6nM.

In vivo, aumolertinib lead to tumour shrinkage in EGFR T790M/L858R and EGFR activating mutant xenograft models in mice. In contrast, aumolertinib showed minimal tumour growth inhibition in the A431 xenograft model with the WT EGFR.

Effects on QTc interval duration

The QTc interval prolongation potential of aumolertinib was assessed in 49 subjects who received aumolertinib. Serial ECGs were collected at baseline and following a single dose and at steady-state to evaluate the effect of aumolertinib on QTc intervals. A concentration-QT analysis predicted a QTc interval prolongation at 110 mg of 9.06 msec with an upper bound of 11.01 msec (90% confidence interval [CI]).

Absorption

Following oral administration, aumolertinib was absorbed quickly and its median peak plasma concentration was 4 to 6 hours after single and multiple dosing. The median peak plasma concentrations of its primary active metabolite HAS-719 were observed at 4 to 6 hours post dose after multiple dosing. Aumolertinib and HAS-719 exposures (AUC) and C_max increased in a slightly less-than-proportional manner across the 55 to 220 mg dose range. Steady-state concentrations of aumolertinib were achieved in 8 days with approximately 1.8-fold accumulation in AUC after once daily administration. Steady-state concentrations of HAS-719 were achieved in15 days, with approximately 4.6-fold accumulation in AUC after once daily dosing of aumolertinib.

The multiple dose PK parameters of aumolertinib and HAS-719 are provided in the following table.

Multiple dose PK parameters of aumolertinib and HAS-719 following oral administration of aumolertinib 110 mg in adults with NSCLC:

^* Based on non-compartmental analysis from part 3, dose extension part, of the phase ½ study
AUC_tau = area under the plasma concentration-time curve from time zero to the endo the dosing interval, C_max = maximum concentration, C_min = lowest concentration, CV = coefficient of variation

Food effects

Based on a clinical PK study, food does not alter aumolertinib bioavailability to a clinically meaningful extent (AUC increased by 20% [90% CI: 10, 30] with no change in C_max).

Distribution

Based on population pharmacokinetic analysis, the apparent volume of aumolertinib distribution in subjects with NSCLC at steady-state was 875 L. In vitro plasma protein binding of aumolertinib and HAS-719 is high (≥99.5%). Aumolertinib was shown to bind both albumin and α-acidic glycoprotein with no concentration dependence at clinically relevant concentrations in vitro. The blood/plasma ratio of aumolertinib in humans was <1, indicating limited partitioning into red blood cells.

Biotransformation

Aumolertinib is primarily metabolised by cytochrome P450 isozyme CYP3A4, with smaller contributions from CYP3A5, CYP1A2, and CYP2A6. HAS-719 is an active major circulating metabolite that is formed via N-demethylation.

Elimination

Following a single oral administration of a 110 mg dose of aumolertinib in humans, approximately 85% of the administered dose was eliminated in faeces as aumolertinib and its metabolites, while approximately 5% of the dose was eliminated in urine. The mean terminal half-lives of aumolertinib and HAS-719 were approximately 31 and 55 hours, respectively.

Other information on drug-drug interactions (DDI)

Interactions with transporter proteins

In vitro studies have shown that aumolertinib is not a substrate of OATP1B1, OATP1B3, OAT1, OAT3, OCT2, and MATE2-K.

Based on in vitro studies, aumolertinib did not inhibit OATP1B3, OAT3, MATE2-K, or bile salt export pump (BSEP). Aumolertinib is a weak inhibitor of organic anion transporting polypeptide (OATP)1B1, organic anion transporter (OAT)1, and OCT2 in vitro. Considering the C_max for aumolertinib following a 110 mg once daily dose, drug-drug interactions between aumolertinib and OATP1B1, OAT1, and OCT2 substrates are not anticipated to be clinically relevant.

Based on in vitro studies, aumolertinib is a substrate of P-gp and breast-cancer resistance proteins (BCRP).

Based on in vitro studies, aumolertinib is an inhibitor of BCRP, however, drug-drug interactions between aumolertinib and BCRP substrates are not anticipated to be clinically relevant based on a physiologically based pharmacokinetic (PBPK) analysis.

Interactions with drug metabolising enzymes

Based on in vitro studies, aumolertinib did not inhibit the major human cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 [2 substrates]).

In vitro, aumolertinib induced CYP1A2 expression, however this effect is not anticipated to be clinically relevant. In vitro, aumolertinib induced CYP3A4 expression and was a time-dependent inhibitor of CYP3A. Aumolertinib decreased the exposure of midazolam (a sensitive CYP3A substrate) by approximately 27% in a clinical study, and is therefore considered a weak inducer of CYP3A.

Aumolertinib was found to be an inhibitor of UGT1A1 and UGT2B7 in vitro. Considering the steady-state C_max concentrations after 110 mg daily dose, this is not likely to be clinically relevant. Intestinal interactions cannot be ruled out, however, the clinical impact is unknown.

Special population

Age, gender, body weight, and ethnicity

In a population PK analysis, no clinically significant relationships were identified between steady-state exposure (AUC_ss) and patient's age (range: 27 to 89 years), gender (60% female), ethnicity, and body weight (range: 37 to 106 kg).

The majority of healthy volunteers and subjects in studies to date have been of a Han Chinese ethnic background. However, data from a single dose PK bridging study in healthy volunteers found no clinically meaningful differences in aumolertinib PK between Chinese and non-Chinese subjects (including Caucasian, Black/African American and Hispanic/Latino subjects). An additional steady-state PK study in European subject with NSCLC found no clinically meaningful PK differences of aumolertinib and its metabolite HAS-719 between Chinese and non-Chinese (Caucasian) subjects.

Hepatic impairment

Hepatic metabolism is the principal route of aumolertinib clearance, and CYP3A4 is the major enzyme catalysing the biotransformation of aumolertinib. In clinical studies, C_max and AUC were reduced by up to 54% and 31% in subjects with moderate hepatic impairment, and by approximately 64% and 50% in subjects with severe hepatic impairment, respectively, compared to healthy controls. However, no clinically relevant changes in the exposure of unbound aumolertinib were observed in subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.

Based on a population PK analysis, no effect of hepatic function (as assessed by markers of liver function AST, ALT, albumin, total bilirubin, and by National Cancer Institute Organ Dysfunction Working Group [NCI-ODWG] hepatic impairment category) was identified on aumolertinib exposure.

Renal impairment

Data from the clinical studies indicate that renal clearance of aumolertinib is negligible. Consequently, it is not anticipated that aumolertinib PK will be altered by reduced renal function.

In a population PK analysis, aumolertinib and HAS-719 exposures were similar in subjects with mild renal impairment (60 ≤ CLcr < 90 mL/min), subjects with moderate renal impairment (30 ≤ CLcr ≤ 60 mL/min), and patients with normal renal function (CLcr ≥ 90 mL/min). Aumolertinib has not been evaluated in subjects with severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease.

The main findings observed in repeat dose toxicity studies in rats and/or dogs comprised effects in the skin, gastrointestinal tract, mouth, eyes, male mammary gland, liver, and lungs, which were consistentwith the pharmacology of EGFR inhibition. The observed findings provided no safety margins in relation to clinically relevant exposure. Target organ toxicities at tolerated doses were generally either completely or partially recovered during or at the end of the recovery phase of the chronic toxicity.

Non-clinical data indicate that aumolertinib and its metabolite (HAS-719) inhibit the h-ERG channel, and QTc prolonging effects cannot be excluded.

Carcinogenicity studies have not been conducted with aumolertinib. In vitro study results showed that aumolertinib is not expected to be phototoxic.

Reproductive toxicity

In a rat fertility study wherein dosing was initiated prior to implantation, decreases in mean numbers of corpora lutea, implantation sites, live fetuses were observed at 100 mg/kg along with an increase in postimplantation loss. No treatment-related changes were noted on sperm parameters. Considering also some published data reporting subfertility of mice lacking Egfr expression, female fertility may be impaired by treatment with aumolertinib. Exposure levels at the dose of 30 mg/kg shown to be devoid of effects on rat fertility is comparable to that reached in patients at the maximum recommended dose.

In an embryo-foetal development study in rats, there were no aumolertinib-related effects on embryo-foetal development at doses up to 100 mg/kg (corresponding to 3.4-fold clinical exposure at the maximum recommended human dose)

In an embryo-foetal development study in rabbits, animals received doses ranging from 5 to 30 mg/k/day which corresponded to exposure levels below (0.1- to 0.6-fold) those reached in patients at the maximum recommended dose. Maternal toxicity was observed at all dose levels. In particular, maternal death and spontaneous abortion were observed at ≥15 mg/kg and premature delivery occurred at 30 mg/kg. Fetal lethality was noted at all dose levels, with a decrease in the number of live fetuses at 30 mg/kg. Examination of fetuses showed treatment-related effects on fetal sternum development (decreased ossification rate at all doses and decreased number of sternebrae at ≥15 mg/kg), as well as an increase in an abnormality of artery arborization (at all doses).