Antineoplastic agent. ATC code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Erlotinib potently inhibits the intracellular phosphorylation of HER1/EGFR receptor. HER1/EGFR receptor is expressed on the cell surface of normal cells and cancer cells. In non-clinical models, inhibition of EGFR phosphotyrosine results in cell stasis and/or death.
Non-small cell lung cancer (Tarceva administered as monotherapy): First-line therapy for patients with EGFR activating mutations: The efficacy of Tarceva in first-line treatment of patients with EGFR activating mutations in NSCLC was demonstrated in a phase III, randomized, open-label trial (ML20650, EURTAC). This study was conducted in Caucasian patients with metastatic or locally advanced NSCLC (stage IIIB and IV) who have not received previous chemotherapy or any systemic antitumour therapy for their advanced disease and who present mutations in the tyrosine kinase domain of the EGFR (exon 19 deletion or exon 21 mutation). Patients were randomized 1:1 to receive Tarceva 150 mg or platinum based doublet chemotherapy.
The primary endpoint of investigator assessed progression free survival (PFS), was determined at a pre-planned interim analysis (n=153, hazard ratio (HR)=0.42, 95% Cl, 0.27 to 0.64; p<0.0001 for the Tarceva group (n=77) relative to the chemotherapy group (n=0.76)). A 58% reduction in the risk of disease progression or death was observed. In the Tarceva versus chemotherapy arms respectively, median PFS was 9.4 and 5.2 months and objective response rate (ORR) was 54.5% and 10.5%. PFS results were confirmed by an independent review of the scans, median PFS was 10.4 months in the Tarceva group compared with 5.4 months in the chemotherapy group (HR=0.47, 95%Cl, 0.27 to 0.78; p=0.003). The overall survival data were immature at the time of interim analysis (HR=0.80, 95% Cl, 0.47 to 1.37, p=0.4170).
At an updated analysis with 62% of OS maturity, OS HR was 0.93 (95 % CI, 0.64 to 1.36, p=0.7149). A high crossover was observed with 82% of the patients in the chemotherapy arm receiving subsequent therapy with an EGFR tyrosine kinase inhibitor and all but 2 of those patients had subsequent Tarceva. In the updated analysis, PFS results remained consistent with the interim analysis results. Median PFS assessed by the investigators was 10.4 and 5.1 months in the Tarceva and chemotherapy arms respectively (HR=0.34, 95 % CI, 0.23 to 0.49, p<0.0001).
Additional published data: In a prospective analysis of patients with advanced NSCLC having tumours with activating mutations in the EGFR TK domain, the median PFS for the 113 patients treated with first-line Tarceva was 14 months (95% Cl, 9.7 to 18.3 months) and the median overall survival was 28.0 months (95% Cl, 22.7 to 33 months).
A pooled analysis of published data from NSCLC patients showed that patients having tumours with EGFR activating mutations and receiving Tarceva as predominantly first-line therapy (n=70, 12.5 months, 95%Cl [10.6-16.0]) had a longer median PFS compared to those receiving chemotherapy (n=359, 6.0 months, 95%Cl [5.4-6.7]).
First-line maintenance therapy: The efficacy and safety of Tarceva as first-line maintenance therapy of NSCLC was demonstrated in a randomized, double-blind, placebo-controlled trial BO18192 (SATURN). This study was conducted in 889 patients with locally advanced or metastatic NSCLC who did not progress during 4 cycles of platinum-based doublet chemotherapy. Patients were randomized 1:1 to receive Tarceva 150 mg or placebo orally once daily. The primary end-point of the study was PFS in all patients and in patients with an EGFR IHC positive tumour. Baseline demographic and disease characteristics were well balanced between the two treatment arms.
In this study BO18192 (SATURN), the overall population showed a benefit for the primary PFS end-point (HR=0.71 p<0.0001) and the secondary OS end-point (HR=0.81 p=0.0088). However the largest benefit was observed in a predefine exploratory analysis in patients with EGFR activating mutations (n= 49) demonstrating a substantial PFS benefit (HR=0.10, 95% CI, 0.04 to 0.25; p<0.0001) and an overall survival HR of 0.83 (95% CI, 0.34 to 2.02). 67% of placebo patients in the EGFR mutation positive subgroup received second or further line treatment with EGFR-TKIs. In patients with EGFR wild type tumors (n=388), the PFS HR was 0.78 (95% CI, 0.63 to 0.96; p=0.0185) and the overall survival HR was 0.77 (95% CI, 0.61 to 0.97; p=0.0243).
The BO25460 (IUNO) study was conducted in 643 patients with advanced NSCLC whose tumors did not harbor an EGFR-activating mutation (exon 19 deletion or exon 21 L858R mutation) and who had not experienced disease progression after four cycles of platinum-based chemotherapy.
The objective of the study was to compare the overall survival of first line maintenance therapy with erlotinib versus erlotinib administered at the time of disease progression. The study did not meet its primary endpoint. OS of Tarceva in first line maintenance was not superior to Tarceva as second line treatment in patients whose tumor did not harbor an EGFR-activating mutation (HR=1.02, 95% CI, 0.85 to 1.22, p=0.82). The secondary endpoint of PFS showed no difference between Tarceva and placebo in maintenance treatment (HR=0.94, 95 % CI, 0.80 to 1.11; p=0.48).
Based on the data from the BO25460 (IUNO) study, Tarceva use is not recommended for first-line maintenance treatment in patients without an EGFR activating mutation.
Second/Third-line therapy: The efficacy and safety of Tarceva in second/third-line therapy of NSCLC was demonstrated in a randomized, double-blind, placebo-controlled trial (BR.21). This study was conducted in 17 countries, in 731 patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen. Patients were randomized 2:1 to receive Tarceva 150 mg or placebo orally once daily. Study end points included overall survival, time to deterioration of lung cancer-related symptoms (cough, dyspnea and pain), response rate, duration of response, PFS, and safety. The primary end-point was survival.
Due to the 2:1 randomization, 488 patients were randomized to Tarceva and 243 patients to placebo. Patients were not selected for HER1/EGFR status, gender, race, smoking history and histological classification.
Demographic characteristics were well balanced between the two treatment arms. About two-thirds of the patients were male and approximately one-third had a baseline ECOG performance status (PS) of 2 and 9% had a baseline ECOG of 3. Ninety-three percent and 92% of all patients in the Tarceva and placebo groups, respectively, had received a prior platinum-containing regimen and 36% and 37% of all patients, respectively, had received a prior taxane therapy. Fifty percent of the patients had received only one prior regimen of chemotherapy.
Survival was evaluated in the intent-to-treat population. The median overall survival improved by 42.5% and was 6.7 months in the Tarceva group (95% CI, 5.5 - 7.8 months) compared with 4.7 months in the placebo group (95% CI, 4.1 to 6.3 months). The primary survival analysis was adjusted for the stratification factors as reported at the time of randomization (ECOG PS, best response to prior therapy, number of prior regimens, and exposure to prior platinum) and HER1/EGFR status. In this primary analysis, the adjusted hazard ratio for death in the Tarceva group relative to the placebo group was 0.73 (95% CI, 0.60 to 0.87) (p = 0.001). The percentage of patients alive at 12 months was 31.2% and 21.5%, respectively.
The survival benefit with Tarceva treatment was seen across most subsets. A series of subsets of patients formed by the values of the stratification factors at randomization and at baseline, HER1/EGFR status, prior exposure to taxanes, smoking history, gender, age, histology, prior weight loss, time between initial diagnosis and randomization, and geographic location were examined in exploratory univariate analyses to assess the robustness of the overall survival result. Nearly all of the hazard ratios in the Tarceva group relative to the placebo group were less than 1.0, suggesting that the survival benefit from Tarceva was robust across subsets. Of note, the survival benefit of Tarceva was comparable in patients with a baseline ECOG PS of 2-3 (HR = 0.77) or a PS of 0-1 (HR = 0.73) and patients who had received one chemotherapy regimen (HR= 0.76) or two or more regimens (HR=0.76).
A survival benefit of Tarceva was also observed in patients who did not achieve an objective tumor response (by RECIST). This was evidenced by a hazard ratio for death of 0.83 among patients whose best response was stable disease and 0.85 among patients whose best response was progressive disease.
Table 1 summarizes the results for the study, including survival, time to deterioration of lung cancer-related symptoms, and progression-free survival (PFS). (See Table 1.)
Click on icon to see table/diagram/image
Symptom deterioration was measured using the EORTC QLQ-C30 and QLQ-LC13 quality of life questionnaires. Baseline scores of cough, dyspnea and pain were similar in the two treatment groups. Tarceva resulted in symptom benefits by significantly prolonging time to deterioration in cough (HR =0.75), dyspnea (HR=0.72) and pain (HR=0.77), versus placebo. These symptom benefits were not due to an increased use of palliative radiotherapy or concomitant medication in the Tarceva group.
The median PFS was 9.7 weeks in the Tarceva group (95% CI, 8.4 - 12.4 weeks) compared with 8.0 weeks in the placebo group (95% CI, 7.9 to 8.1 weeks). The HR for progression, adjusted for stratification factors and HER1/EGFR status, was 0.61 (95% CI, 0.51 to 0.73) (p < 0.001). The percent of PFS at 6 months was 24.5% and 9.3%, respectively, for the Tarceva and placebo arms.
The objective response rate by RECIST in the Tarceva group was 8.9% (95% CI, 6.4 to 12.0%). The median duration of response was 34.3 weeks, ranging from 9.7 to 57.6+ weeks. Two responses (0.9%, 95% CI, 0.1 to 3.4) were reported in the placebo group. The proportion of patients who experienced complete response, partial response or stable disease was 44.0% and 27.5%, respectively, for the Tarceva and placebo groups (p=0.004).
In a double-blind, randomized phase III study (MO22162, CURRENTS) comparing two doses of Tarceva (300 mg versus 150 mg) in current smokers (mean of 38 pack years) with locally advanced or metastatic NSCLC in the second-line setting after failure on chemotherapy, the 300 mg dose of Tarceva demonstrated no PFS benefit over the recommended dose (7.00 vs 6.86 weeks, respectively). Patients in this study were not selected based on EGFR mutation status.
Pancreatic Cancer (Tarceva administered concurrently with gemcitabine): The efficacy and safety of Tarceva in combination with gemcitabine as a first line treatment was assessed in a randomized, double blind, placebo-controlled trial in 569 patients with locally advanced, unresectable or metastatic pancreatic cancer. Patients were randomized 1:1 to receive Tarceva (100 mg or 150 mg) or placebo once daily on a continuous schedule plus gemcitabine IV (1000 mg/m2
, Cycle 1 - Days 1, 8, 15, 22, 29, 36 and 43 of an 8 week cycle; Cycle 2 and subsequent cycles - Days 1, 8 and 15 of a 4 week cycle [approved dose and schedule for pancreatic cancer, see the gemcitabine SPC]). Tarceva or placebo was taken orally once daily until disease progression or unacceptable toxicity. Study end points included overall survival, response rate and PFS. Duration of response was also examined. The primary endpoint was survival. A total of 285 patients were randomized to receive gemcitabine plus Tarceva (261 patients in the 100 mg cohort and 24 patients in the 150 mg cohort) and 284 patients were randomized to receive gemcitabine plus placebo (260 patients in the 100 mg cohort and 24 patients in the 150 mg cohort). Too few observations were made for the 150 mg cohort to draw conclusions.
Baseline demographic and disease characteristics of the patients were similar between the 2 treatment groups, 100 mg Tarceva plus gemcitabine or placebo plus gemcitabine, except for a slightly larger proportion of females in the Tarceva arm (51%) compared with the placebo arm (44%). The median time from initial diagnosis to randomization was approximately 1.0 month. Approximately half of the patients had a baseline ECOG performance status (PS) of 1, and 17 % had a baseline ECOG PS of 2. Most patients presented with metastatic disease at study entry as the initial manifestation of pancreatic cancer (77% in the Tarceva arm, 76% in the placebo arm).
Survival was evaluated in the intent-to-treat population based on follow-up survival data including 551 deaths. Results are presented for the 100 mg dose cohort (504 deaths). The adjusted hazard ratio for death in the Tarceva group relative to the placebo group was 0.82 (95 % CI, 0.69 to 0.98) (p = 0.028). The percent of patients alive at 12 months was 23.8 % in the Tarceva group compared to 19.4% in the placebo group. The median overall survival was 6.4 months in the Tarceva group compared with 6 months in the placebo group. Table 4 summarizes the results of the study. (See Table 2.)
Click on icon to see table/diagram/image
The median PFS was 3.81 months (16.5 weeks) in the Tarceva group (95 % CI, 3.58 to 4.93 months) compared with 3.55 months (15.2 weeks) in the placebo group (95 % CI, 3.29 to 3.75 months) (p = 0.006).
The median duration of response was 23.9 weeks, ranging from 3.71 to 56+ weeks. The objective response rate (complete response and partial response) was 8.6 % in the Tarceva group and 7.9% in the placebo group. The proportion of patients who experienced complete response, partial response or stable disease was 59 % and 49.4 %, respectively, for the Tarceva and placebo groups (p = 0.036).
Exposure: Following a 150 mg oral dose of Tarceva, at steady state, the median time to reach maximum plasma concentrations is approximately 4.0 hours with median maximum plasma concentrations achieved of 1,995 ng/ml. Prior to the next dose at 24 hours, the median minimum plasma concentrations are 1,238 ng/ml. Median AUC achieved during the dosing interval at steady state are 41.300 mcg*hr/ml.
Oral erlotinib is well absorbed and has an extended absorption phase, with mean peak plasma levels occurring at 4 hours after oral dosing. A study in normal healthy volunteers provided an estimate of bioavailability of 59%. The exposure after an oral dose may be increased by food.
Following absorption, erlotinib is highly bound in blood, with approximately 95% bound to blood components, primarily to plasma proteins (i.e. albumin and alpha-1 acid glycoprotein [AAG]), with a free fraction of approximately 5%.
Erlotinib has a mean apparent volume of distribution of 232 L and distributes into tumor tissue of humans. In a study of 4 patients (3 NSCLC, and 1 with laryngeal cancer) receiving 150 mg daily oral doses of Tarceva, tumor samples from surgical excisions on Day 9 of treatment revealed tumor concentrations of erlotinib that averaged 1,185 ng/g of tissue. This corresponded to an overall average of 63% of the steady state observed peak plasma concentrations. The primary active metabolites were present in tumor at concentrations averaging 160 ng/g tissue, which corresponded to an overall average of 113% of the observed steady state peak plasma concentrations. Tissue distribution studies using whole body autoradiography following oral administration with [14
C] labeled erlotinib in athymic nude mice with HN5 tumor xenografts have shown rapid and extensive tissue distribution with maximum concentrations of radiolabeled drug (approximately 73% of that in plasma) observed at 1 hour.
Erlotinib is metabolised in humans by hepatic cytochrome P450 enzymes, primarily by CYP3A4 and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and CYP1B1 in tumour tissue potentially contribute to the metabolic clearance of erlotinib. In vitro
studies indicate approximately 80-95% of erlotinib metabolism by the CYP3A4 enzyme. There are three main metabolic pathways identified: 1) O-demethylation of either side chain or both, followed by oxidation to the carboxylic acids; 2) oxidation of the acetylene moiety followed by hydrolysis to the aryl carboxylic acid; and 3) aromatic hydroxylation of the phenyl-acetylene moiety. The primary metabolites of erlotinib produced by O-demethylation of either side chain have comparable potency to erlotinib in nonclinical in vitro
assays and in vivo
tumor models. They are present in plasma at levels that are <10% of erlotinib and display similar pharmacokinetics as erlotinib.
The metabolites and trace amounts of erlotinib are excreted predominantly via the feces (>90%), with renal elimination accounting for only a small amount of an oral dose.
Clearance: A population pharmacokinetic analysis in 591 patients receiving single agent Tarceva show a mean apparent clearance of 4.47 L/hour with a median half-life of 36.2 hours. Therefore, the time to reach steady state plasma concentration would be expected to occur in approximately 7-8 days. No significant relationships between predicted apparent clearance and patient age, body weight, gender, and ethnicity were observed.
Patient factors, which correlate with erlotinib pharmacokinetics, are serum total bilirubin, AAG concentrations and current smoking. Increased serum concentrations of total bilirubin and AAG concentrations were associated with a slower rate of erlotinib clearance. Smokers had a higher rate of erlotinib clearance (See 2.8, Interactions with other medicinal products and other forms of interaction).
A second population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204 pancreatic cancer patients who received erlotinib plus gemcitabine. This analysis demonstrated that covariates affecting erlotinib clearance in patients from the pancreatic study were very similar to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified. Co-administration of gemcitabine had no effect on erlotinib plasma clearance.
Pharmacokinetics in Special Populations:
There have been no specific studies in pediatric or elderly patients.
Hepatic impairment: Erlotinib is mainly cleared by the liver. Erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh score 7-9) compared with patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases.
Renal impairment: Erlotinib and its metabolites are not significantly excreted by the kidneys, as less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.
Smokers: A pharmacokinetic study in nonsmoking and currently cigarette smoking healthy subjects has shown that cigarette smoking leads to increased clearance of, and decreased exposure to, erlotinib. The AUC0-infinity
in smokers was about 1/3 of that in never/former smokers (n=16 in each of smoker and never/former smoker arms). This reduced exposure in current smokers is presumably due to induction of CYP1A1 in lung and CYP1A2 in the liver.
In the pivotal Phase III NSCLC trial, current smokers achieved erlotinib steady state trough plasma concentration of 0.65 μg/mL (n=16) which was approximately 2-fold less than the former smokers or patients who had never smoked (1.28 μg/mL, n=108). This effect was accompanied by a 24% increase in apparent erlotinib plasma clearance.
In a phase I dose escalation study in NSCLC patients who were current smokers, pharmacokinetic analyses at steady-state indicated a dose proportional increase in erlotinib exposure when the Tarceva dose was increased from 150 mg to the maximum tolerated dose of 300 mg. Steady-state trough plasma concentrations at a 300mg dose in current smokers in this study was 1.22 μg/mL (n=17) (See Special Dosage Instructions under Dosage & Administration, Interactions).
Toxicology: Nonclinical Safety:
Carcinogenicity: Evidence for a carcinogenic potential was not seen in nonclinical studies. Erlotinib was neither genotoxic nor clastogenic in genetic toxicity studies. Two year carcinogenicity studies with erlotinib conducted in rats and mice at exposures exceeding human therapeutic exposure were negative.
Genotoxicity: Erlotinib was negative in the standard battery of genotoxicity assays.
Impairment of Fertility: Impairment of fertility was not observed in studies with male and female rats at doses near the MTD levels.
Reproductive Toxicity: Data from reproductive toxicology tests in rats and rabbits indicate that, following exposure to erlotinib at doses near the MTD and/or doses that were maternally toxic, there was embryotoxicity, but there was no evidence of teratogenicity, or abnormal preor postnatal physical or behavioral development. Maternal toxicity in both rats and rabbits in these studies occurred at plasma exposure levels that were similar to those in humans following a 150 mg dose of erlotinib.
Other: Chronic dosing effects observed in at least 1 animal species or study included effects on the cornea (atrophy, ulceration), skin (follicular degeneration and inflammation, redness, and alopecia), ovary (atrophy), liver (liver necrosis), kidney (renal papillary necrosis and tubular dilatation), and gastrointestinal tract (delayed gastric emptying and diarrhea). Red blood cell (RBC) counts, hematocrit and hemoglobin were decreased and reticulocytes were increased. White blood cells (WBCs), primarily neutrophils, were increased. There were treatment-related increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin.
studies of erlotinib showed inhibition of hERG channels at concentrations at least 20 times higher than the free drug concentration in humans at therapeutic doses. Studies in dogs did not show QT-prolongation. A systematic centralized review of ECG data from 152 individuals from seven studies with healthy volunteers found no evidence of QT prolongation, and clinical studies have found no evidence of arrhythmias, associated with QT prolongation.