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Mechanism Of Action
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.
Absorption And Distribution
Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. Coadministration of TARCEVA with omeprazole, a proton pump inhibitor, decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61%, respectively. When TARCEVA was administered 2 hours following a 300 mg dose of ranitidine, an H2 receptor antagonist, the erlotinib AUC was reduced by 33% and Cmax by 54%. When TARCEVA 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 and Cmax decreased by 15% and 17%, respectively [see DRUG INTERACTIONS].
Metabolism And Excretion
A population pharmacokinetic analysis in 591 patients receiving the single-agent TARCEVA 2nd/3rd line regimen showed a median halflife of 36.2 hours. Time to reach steady state plasma concentration would therefore be 7 - 8 days. No significant relationships of clearance to covariates of patient age, body weight or gender were observed. Smokers had a 24% higher rate of erlotinib clearance.
An additional population pharmacokinetic analysis was conducted in 291 NSCLC patients administered single-agent erlotinib as maintenance treatment. This analysis demonstrated that covariates affecting erlotinib clearance in this patient population were similar to those seen in the prior single-agent pharmacokinetic analysis. No new covariate effects were identified.
A third population pharmacokinetic analysis was conducted that incorporated erlotinib data from 204 pancreatic cancer patients who received erlotinib plus gemcitabine. Similar results were observed 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.
In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1. 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).
Cigarette smoking reduces erlotinib exposure. In the Phase 3 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 a separate study which evaluated the single-dose pharmacokinetics of erlotinib in healthy volunteers, current smokers cleared the drug faster than former smokers or volunteers who had never smoked. The AUC0-infinity in smokers was about 1/3 to ½ of that in never/former smokers. In another study which was conducted in NSCLC patients (N=35) 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 300 mg. However, the exact dose to be recommended for patients who currently smoke is unknown [see DRUG INTERACTIONS and PATIENT INFORMATION].
Patients with Hepatic Impairment
Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with TARCEVA treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION].
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 with Renal Impairment
Less than 9% of a single dose is excreted in the urine. No clinical studies have been conducted in patients with compromised renal function.
Non-Small Cell Lung Cancer (NSCLC) – First-Line Treatment Of Patients With EGFR Mutations
The safety and efficacy of TARCEVA 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 a randomized, open-label, clinical trial conducted in Europe (Study 4). 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 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, the cobas® EGFR Mutation Test.
The baseline demographics of the overall study population were as follows: 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 histology, 66% exon 19 mutation deletions and 34% exon 21 (L858R) point mutation by a CTA.
A statistically significant improvement in investigator-determined PFS was demonstrated for patients randomized to erlotinib compared to those randomized chemotherapy (see Table 6 and Figure 1). Similar results for PFS were observed for the subgroup evaluated by an independent-review committee (approximately 75% of patients in Study 4 evaluated) and in the subgroup of 134 patients (77% of the Study 4 population) with EGFR mutations confirmed by the cobas® EGFR Mutation Test.
A protocol-specified analysis of overall survival conducted at the time of the final analysis of PFS showed no statistically significant difference between the TARCEVA 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 TARCEVA arm, 66% of patients had received at least one subsequent treatment.
Table 6: Efficacy Results (Study 4)
(N = 86)
(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, 6.0)|
|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 (17.0, 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% (9.0%, 25.3%)|
|1 Unstratified Cox regression model.|
Figure 1: Kaplan-Meier Plot of Investigator-Assessed
PFS in Study 4
In exploratory subgroup analyses based on EGFR mutation subtype, the hazard ratio (HR) for PFS was 0.27 (95% CI 0.17 to 0.43) in patients with exon 19 deletions and 0.52 (95% CI 0.29 to 0.95) in patients with exon 21 (L858R) substitution. The HR for OS was 0.94 (95% CI 0.57 to 1.54) in the exon 19 deletion subgroup and 0.99 (95% CI 0.56 to 1.76) in the exon 21 (L858R) substitution subgroup.
NSCLC - Maintenance Treatment
The efficacy and safety of TARCEVA as maintenance treatment of NSCLC were demonstrated in a randomized, double-blind, placebocontrolled trial conducted in 26 countries, in 889 patients with locally advanced or metastatic NSCLC whose disease did not progress during first-line platinum-based chemotherapy (Study 3). Patients were randomized 1:1 to receive TARCEVA 150 mg or placebo orally once daily (438 TARCEVA, 451 placebo) until disease progression or unacceptable toxicity. The primary objective of the study was to determine if the administration of TARCEVA after standard platinum-based chemotherapy in the treatment of NSCLC resulted in improved progression free survival (PFS) when compared with placebo, in all patients or in patients with EGFR immunohistochemistry (IHC) positive tumors.
Demographic characteristics were balanced between the two treatment groups.
Baseline demographics of the overall study population were as follows: male (74%), age < 65 years (66%), ECOG PS 1 (69%), ECOG PS 0 (31%), white (84%), Asian (15%), current smoker (55%), past-smoker (27%), and never smoker (17%). Disease characteristics were as follows: Stage IV (75%), Stage IIIb with effusion (25%) as classified by AJCC (6th edition) with histologic subtypes of adenocarcinoma including bronchioalveolar (45%), squamous (40%) and large cell (5%); and EGFR IHC positive (70%), negative (14%), indeterminate (4%), and missing (12%).
Table 7: Efficacy Results (Study 3): (ITT Population)
|Median in Months (95% CI)||
Hazard Ratio1 (95% CI)
|TARCEVA 150 mg
N = 438
N = 451
|Progression-Free Survival based on investigator’s assessment||2.8
|p < 0.0001|
|1 Univariate Cox regression model
2 Unstratified log-rank test.
Figure 2 depicts the Kaplan-Meier Curves for Overall Survival (ITT Population).
Figure 2: Kaplan - Meier Curve for Overall Survival of
Patients by Treatment Group in Study 3
The PFS and OS Hazard Ratios, respectively, in patients with EGFR IHC-positive tumors were 0.69 (95% CI: 0.58, 0.82) and 0.77 (95% CI: 0.64, 0.93). The PFS and OS Hazard Ratios in patients with IHC-negative tumors were 0.77 (95% CI: 0.51, 1.14) and 0.91 (95% CI: 0.59, 1.38), respectively.
Patients with adenocarcinoma had an OS Hazard Ratio of 0.77 (95% CI: 0.61, 0.97) and patients with squamous histology had an OS Hazard Ratio of 0.86 (95% CI: 0.68, 1.10).
NSCLC –Second/Third Line Treatment
The efficacy and safety of single-agent TARCEVA was assessed in a randomized, double blind, placebo-controlled trial in 731 patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen (Study 1). Patients were randomized 2:1 to receive TARCEVA 150 mg or placebo (488 TARCEVA, 243 placebo) orally once daily until disease progression or unacceptable toxicity. Study endpoints included overall survival, response rate, and progression-free survival (PFS). Duration of response was also examined. The primary endpoint was survival. The study was conducted in 17 countries.
Baseline demographics of the overall study population were as follows: male (65%), white (78%), Asian (12%), black (4%), age < 65 years (62%), ECOG PS 1 (53%), ECOG PS 0 (13%), ECOG PS 2 (25%), ECOG PS 3 (9%), current or ex-smoker (75%), never smoker (20%), and exposure to prior platinum therapy (93%). Tumor characteristics were as follows: adenocarcinoma (50%), squamous (30%), undifferentiated large cell (9%), and mixed non-small cell (2%).
The results of the study are shown in Table 8.
Table 8: Efficacy Results (Study 1): (ITT Population)
|TARCEVA||Placebo||Hazard Ratio 1||95% CI||p-value|
|Survival||Median 6.7 mo||Median 4.7 mo||0.73||0.61 - 0.86||< 0.001 2|
|Progression-Free Survival||Median 9.9 wk||Median 7.9 wk||0.59||0.50 - 0.70||< 0.001 2|
|Tumor Response (CR+PR)||8.9%||0.9%||< 0.001 3|
|Response Duration||Median 34.3 wk||Median 15.9 wk|
|1 Cox regression model with the following
covariates: ECOG performance status, number of prior regimens, prior platinum,
best response to prior chemotherapy.
2 Two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.
3 Two-sided Fisher's exact test.
Survival was evaluated in the intent-to-treat population. Figure 3 depicts the Kaplan-Meier curves for overall survival. The primary survival and PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.
Figure 3: Kaplan - Meier Curve for Overall Survival of
Patients by Treatment Group in Study 1
Note: HR is from Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. P-value is from two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy.
NSCLC – Lack Of Efficacy Of TARCEVA Administered Concurrently With Chemotherapy
Results from two, multicenter, placebo-controlled, randomized, trials in over 1000 patients conducted in first-line patients with locally advanced or metastatic NSCLC showed no clinical benefit with the concurrent administration of TARCEVA with platinum-based chemotherapy [carboplatin and paclitaxel (TARCEVA, N = 526) or gemcitabine and cisplatin (TARCEVA, N = 580)].
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 (Study 2). 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 [the approved dose and schedule for pancreatic cancer, see the gemcitabine package insert]). TARCEVA or placebo was taken orally once daily until disease progression or unacceptable toxicity. The primary endpoint was survival. Secondary endpoints included response rate, and progression-free survival (PFS). Duration of response was also examined. The study was conducted in 18 countries. 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 patients were treated in the 150 mg cohort to draw conclusions.
In the 100 mg cohort, baseline demographics of the overall study population were as follows: male (52%), white (88%), Asian (7%), black (2%), age < 65 years (53%), ECOG PS 1 (51%), ECOG PS 0 (32%), and ECOG PS 2 (17%). There was 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. The majority of the patients (76%) had distant metastases at baseline and 24% had locally advanced disease.
The results of the study are shown in Table 9.
Table 9: Efficacy Results: 100 mg Cohort (Study 2)
|TARCEVA + Gemcitabine||Placebo + Gemcitabine||Hazard Ratio1||95% CI||p-value|
|Survival||Median 6.4 mo 250 deaths||Median 6.0 mo 254 deaths||0.81||0.68 - 0.97||0.0282|
|Progression-Free Survival||Median 3.8 mo 225 events||Median 3.5 mo 232 events||0.76||0.64 - 0.92||0.0062|
|Tumor Response (CR+PR)||8.6%||7.9%||0.873|
|Response Duration||Median 23.9 wk||Median 23.3 wk|
|1 Cox regression model with the following
covariates: ECOG performance status, and extent of disease.
2 Two-sided Log-Rank test stratified by ECOG performance status and extent of disease.
3 Two-sided Fisher's exact test.
Survival was evaluated in the intent-to-treat population. Figure 4 depicts the Kaplan-Meier curves for overall survival in the 100 mg cohort. The primary survival and PFS analyses were two-sided Log-Rank tests stratified by ECOG performance status and extent of disease.
Figure 4: Kaplan - Meier Curve for Overall Survival:
100 mg Cohort in Study 2
Note: HR is from Cox regression model with the following covariates: ECOG performance status and extent of disease. The p-value is from two-sided Log-Rank test stratified by ECOG performance status and extent of disease.
Last reviewed on RxList: 3/24/2016
This monograph has been modified to include the generic and brand name in many instances.
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