Epidermal growth factor receptor (EGFR) is expressed on the cell surface of both normal and cancer cells. In some tumor cells signaling through this receptor plays a role in tumor cell survival and proliferation irrespective of EGFR mutation status. Erlotinib reversibly inhibits the kinase activity of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor and thereby inhibiting further downstream signaling. Erlotinib binding affinity for EGFR exon 19 deletion or exon 21 (L858R) mutations is higher than its affinity for the wild type receptor. Erlotinib inhibition of other tyrosine kinase receptors has not been fully characterized.
Erlotinib is about 60% absorbed after oral administration. Peak plasma levels occur 4 hours after dosing.
Effect of Food
Food increased the bioavailability of erlotinib to approximately 100%.
Erlotinib is 93% protein bound to plasma albumin and alpha-1 acid glycoprotein (AAG).
Erlotinib has an apparent volume of distribution of 232 liters.
Erlotinib is eliminated with a median half-life of 36.2 hours in patients receiving the single-agent erlotinib 2nd /3rd line regimen. Time to reach steady state plasma concentration would therefore be 7 to 8 days.
Erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1, in vitro.
Following a 100 mg oral dose, 91% of the dose was recovered: 83% in feces (1% of the dose as intact parent) and 8% in urine (0.3% of the dose as intact parent).
Neither age, body weight, nor gender had a clinically significant effect on the systemic exposure of erlotinib in NSCLC patients receiving single-agent erlotinib for 2nd /3rd line treatment or for maintenance treatment, and in pancreatic cancer patients who received erlotinib plus gemcitabine. The pharmacokinetics of erlotinib in patients with compromised renal function is unknown.
Patients with Hepatic Impairment
In vitro and in vivo evidence suggest that erlotinib is cleared primarily by the liver. However, erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh B) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.
Patients That Smoke Tobacco Cigarettes
In a single-dose pharmacokinetics trial in healthy volunteers, cigarette smoking (moderate CYP1A2 inducer) increased erlotinib clearance and decreased erlotinib AUC0-inf by 64% (95% CI, 46 to 76%) in current smokers compared with former/never smokers. In a NSCLC trial, current smokers achieved erlotinib steady-state trough plasma concentrations which were approximately 2-fold less than the former smokers or patients who had never smoked. This effect was accompanied by a 24% increase in apparent erlotinib plasma clearance. In another study which was conducted in NSCLC patients who were current smokers, pharmacokinetic analyses at steady-state indicated a dose-proportional increase in erlotinib exposure when the erlotinib dose was increased from 150 mg to 300 mg. [see Dosage and Administration (2.4), Drug Interactions (7) and Patient Counseling Information (17)].
Drug Interaction Studies
Co-administration of gemcitabine had no effect on erlotinib plasma clearance.
Co-administration with a strong CYP3A4 inhibitor, ketoconazole, increased erlotinib AUC by 67%. Co-administration with a combined CYP3A4 and CYP1A2 inhibitor, ciprofloxacin, increased erlotinib exposure [AUC] by 39%, and increased erlotinib maximum concentration [Cmax ] by 17%. [see Dose Modifications (2.4), Drug Interactions (7)].
Pre-treatment with the CYP3A4 inducer rifampicin, for 7 to 11 days prior to erlotinib, decreased erlotinib AUC by 58% to 80% [see Dose Modifications (2.4), Drug Interactions (7)].
CYP1A2 Inducers or Smoking Tobacco
See Specific Populations Section [see Dose Modifications (2.4), Drug Interactions (7)].
Drugs that Increase Gastric pH
Erlotinib solubility is pH dependent and decreases as pH increases. When a proton pump inhibitor (omeprazole) was co-administered with erlotinib the erlotinib exposure [AUC] was decreased by 46% and the erlotinib maximum concentration [Cmax ] was decreased by 61%. When erlotinib was administered 2 hours following a 300 mg dose of an H-2 receptor antagonist (ranitidine), the erlotinib AUC was reduced by 33% and the erlotinib Cmax was reduced by 54%. When erlotinib was administered with ranitidine 150 mg twice daily (at least 10 h after the previous ranitidine evening dose and 2 h before the ranitidine morning dose), the erlotinib AUC was decreased by 15% and the erlotinib Cmax was decreased by 17% [see Dose Modifications (2.4), Drug Interactions (7)].
Two-year carcinogenicity studies were conducted in mice and rats with erlotinib at oral doses of up to 60 mg/kg/day in mice, 5 mg/kg/day in female rats, and 10 mg/kg/day in male rats. The studies were negative for carcinogenic findings. Exposure in mice at the highest dose tested was approximately 10 times the exposure in humans at the erlotinib dose of 150 mg/day. The highest dose evaluated in male rats resulted in exposures that were twice those in humans and exposures at the highest tested dose in female rats were slightly lower than those in humans.
Erlotinib did not cause genetic damage in a series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration and mammalian cell mutation) and in the in vivo mouse bone marrow micronucleus test.
Erlotinib did not impair fertility in either male or female rats.
The safety and efficacy of erlotinib as monotherapy for the first-line treatment of patients with metastatic NSCLC containing EGFR exon 19 deletions or exon 21 (L858R) substitution mutations was demonstrated in Study 1, a randomized, open-label, clinical trial conducted in Europe. One hundred seventy-four (174) White patients were randomized 1:1 to receive erlotinib 150 mg once daily until disease progression (n = 86) or four cycles of a standard platinum-based doublet chemotherapy (n = 88); standard chemotherapy regimens were cisplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin plus gemcitabine, and carboplatin plus docetaxel. The main efficacy outcome measure was progression-free survival (PFS) as assessed by the investigator. Randomization was stratified by EGFR mutation (exon 19 deletion or exon 21 (L858R) substitution) and Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 vs. 1 vs. 2). EGFR mutation status for screening and enrollment of patients was determined by a clinical trials assay (CTA). Tumor samples from 134 patients (69 patients from the erlotinib arm and 65 patients from the chemotherapy arm) were tested retrospectively by the FDA-approved companion diagnostic, cobas® EGFR Mutation Test.
Baseline demographics of the overall study population were: female (72%), White (99%), age ≥65 years (51%), ECOG PS 1 (53%), with ECOG PS 0 (33%), and ECOG PS 2 (14%), current smoker (11%), past-smoker (20%), and never smoker (69%). The disease characteristics were 93% Stage IV and 7% Stage IIIb with pleural effusion as classified by the American Joint Commission on Cancer (AJCC, 6th edition), 93% adenocarcinoma, 66% exon 19 mutation deletions and 34% exon 21 (L858R) point mutation by CTA.
A statistically significant improvement in investigator-determined PFS (based on RECIST 1 or clinical progression) was demonstrated for patients randomized to erlotinib compared to those randomized to chemotherapy (see Table 6 and Figure 1). Similar results for PFS (based on RECIST 1) were observed for the subgroup evaluated by an independent-review committee (approximately 75% of patients evaluated in Study 1) and in the subgroup of 134 patients (77% of Study 1 population) with EGFR mutations confirmed by the cobas® EGFR Mutation Test.
A protocol-specified analysis of overall survival (OS) conducted at the time of the final analysis of PFS showed no statistically significant difference between the erlotinib and chemotherapy arms. At the time of the data cut-off, 84% of patients in the chemotherapy arm had received at least one subsequent treatment, of whom 97% received an EGFR-tyrosine kinase inhibitor. In the erlotinib arm, 66% of patients had received at least one subsequent treatment.
Table 6: Efficacy Results (Study 1)
|Efficacy Parameter||Erlotinib (N = 86)||Chemotherapy (N = 88)|
|Number of Progressions or Deaths||71 (83%)||63 (72%)|
|Median PFS in Months (95% CI)||10.4 (8.7, 12.9)||5.2 (4.6, 6)|
|Hazard Ratio (95% CI) (1)||0.34 (0.23, 0.49)|
|p-value (unstratified log-rank test)||< 0.001|
|Number of Deaths (%)||55 (64%)||54 (61%)|
|Median OS in Months (95% CI)||22.9 (17, 26.8)||19.5 (17.3, 28.4)|
|Hazard Ratio (95% CI)1||0.93 (0.64, 1.35)|
|Objective Response Rate (95% CI)||65% (54.1%, 75.1%)||16% (9%, 25.3%)|
(1) Unstratified Cox regression model.
Figure 1: Kaplan-Meier Curves of Investigator-Assessed PFS in Study 1
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