CLINICAL PHARMACOLOGY
Mechanism of Action and Pharmacodynamics
The mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.
Pharmacokinetics
Erlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Its half-life is about 36 hours and it is cleared predominantly by CYP3A4 metabolism and to a lesser extent by CYP1A2.
Absorption and Distribution
Bioavailability of erlotinib following a 150 mg oral dose of TARCEVA is about 60% and peak plasma levels occur 4 hrs after dosing. Food increases bioavailability substantially, to almost 100%.
Following absorption, erlotinib is approximately 93% protein bound to albumin and alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume of distribution of 232 liters.
Metabolism and Elimination
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).
A population pharmacokinetic analysis in 591 patients receiving single-agent TARCEVA showed a median half-life 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 (see Interactions section).
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.
Special Populations
Patients with Hepatic Impairment
Erlotinib is cleared predominantly by the liver. No data are currently available regarding the influence of hepatic dysfunction and/or hepatic metastases on the pharmacokinetics of erlotinib (see PRECAUTIONS - Patients with Hepatic Impairment, Adverse Reactions and DOSAGE AND ADMINISTRATION - Dose Modifications sections).
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.
Interactions
Erlotinib is metabolized predominantly by CYP3A4, and inhibitors of CYP3A4 would be expected to increase exposure. Co-treatment with the potent CYP3A4 inhibitor ketoconazole increased erlotinib AUC by 2/3 (see PRECAUTIONS - Drug interactions and DOSAGE AND ADMINISTRATION - Dose Modifications sections).
Pretreatment with the CYP3A4 inducer rifampicin for 7 days prior to TARCEVA administration increased erlotinib clearance by 3-fold and reduced AUC by 2/3. In a separate study, treatment with rifampicin for 11 days, with coadministration of a single 450 mg dose of TARCEVA on day 8 resulted in a mean erlotinib exposure (AUC) that was 57.6% of that observed following a single 150 mg TARCEVA dose in the absence of rifampicin treatment (see PRECAUTIONS - Drug interactions and DOSAGE AND ADMINISTRATION - Dose Modifications sections).
Pretreatment and coadministration of TARCEVA decreased the AUC of CYP3A4 substrate, midazolam, by 24%. The mechanism is not clear.
In a Phase Ib study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.
In the pivotal Phase III NSCLC trial, current smokers achieved erlotinib trough plasma concentrations that 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. When the single dose pharmacokinetics of erlotinib were evaluated in healthy volunteers, current smokers cleared the drug significantly faster than former smoker or volunteers who had never smoked. The AUC0-infinity in smokers is about 1/3 of that in never/former smokers. This reduced exposure in current smokers is presumably due to induction of CYP1A1 in lung and CYP1A2 in the liver. (see PRECAUTIONS – Information for Patients section).
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CLINICAL STUDIES
Non-Small Cell Lung Cancer (NSCLC) - TARCEVA Administered as a Single Agent
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. 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. About half the patients (326) had EGFR expression status characterized.
Table 1 summarizes the demographic and disease characteristics of the study population. Demographic characteristics were well balanced between the two treatment groups. About two-thirds of the patients were male. Approximately one-fourth had a baseline ECOG performance status (PS) of 2, and 9% had a baseline ECOG PS of 3. Fifty percent of the patients had received only one prior regimen of chemotherapy. About three quarters of these patients were known to have smoked at some time.
Table 1: Demographic and Disease Characteristics | TARCEVA
(N = 488) | Placebo
(N = 243) |
| Characteristics | N | (%) | N | (%) |
| Gender | | | | |
| Female | 173 | (35) | 83 | (34) |
| Male | 315 | (65) | 160 | (66) |
| Age (years) | | | | |
| < 65 | 299 | (61) | 153 | (63) |
| ≥ 65 | 189 | (39) | 90 | (37) |
| Race | | | | |
| Caucasian | 379 | (78) | 188 | (77) |
| Black | 18 | (4) | 12 | (5) |
| Asian | 63 | (13) | 28 | (12) |
| Other | 28 | (6) | 15 | (6) |
| ECOG Performance Status at BaselineStratification factor as documented at baseline; distribution differs slightly from values reported at time of randomization. | | | | |
| 0 | 64 | (13) | 34 | (14) |
| 1 | 256 | (52) | 132 | (54) |
| 2 | 126 | (26) | 56 | (23) |
| 3 | 42 | (9) | 21 | (9) |
| Weight Loss in Previous 6 Months | | | | |
| < 5% | 320 | (66) | 166 | (68) |
| 5 – 10% | 96 | (20) | 36 | (15) |
| > 10% | 52 | (11) | 29 | (12) |
| Unknown | 20 | (4) | 12 | (5) |
| Smoking History | | | | |
| Never Smoked | 104 | (21) | 42 | (17) |
| Current or Ex-smoker | 358 | (73) | 187 | (77) |
| Unknown | 26 | (5) | 14 | (6) |
| Histological Classification | | | | |
| Adenocarcinoma | 246 | (50) | 119 | (49) |
| Squamous | 144 | (30) | 78 | (32) |
| Undifferentiated Large Cell | 41 | (8) | 23 | (9) |
| Mixed Non-Small Cell | 11 | (2) | 2 | (<1) |
| Other | 46 | (9) | 21 | (9) |
| Time from Initial Diagnosis to Randomization (Months) | | | | |
| < 6 | 63 | (13) | 34 | (14) |
| 6 – 12 | 157 | (32) | 85 | (35) |
| > 12 | 268 | (55) | 124 | (51) |
| Best Response to Prior Therapy at Baseline | | | | |
| CR/PR | 196 | (40) | 96 | (40) |
| PD | 101 | (21) | 51 | (21) |
| SD | 191 | (39) | 96 | (40) |
| Number of Prior Regimens at Baseline | | | | |
| 1 | 243 | (50) | 121 | (50) |
| 2 | 238 | (49) | 119 | (49) |
| 3 | 7 | (1) | 3 | (1) |
| Exposure to Prior Platinum at Baseline | | | | |
| Yes | 454 | (93) | 224 | (92) |
| No | 34 | (7) | 19 | (8) |
The results of the study are shown in Table 2.
Table 2: Efficacy Results | TARCEVA | Placebo | Hazard
Ratio Cox regression model with the following covariates: ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. | 95% CI | p-value |
| Survival |
Median
6.7 mo |
Median
4.7 mo | 0.73 | 0.61 – 0.86 | <0.001 Two-sided Log-Rank test stratified by ECOG performance status, number of prior regimens, prior platinum, best response to prior chemotherapy. |
| 1-year Survival | 31.2% | 21.5% | | | |
| Progression-Free Survival |
Median
9.9 wk |
Median
7.9 wk | 0.59 | 0.50 – 0.70 | <0.001 |
| Tumor Response (CR+PR) | 8.9% | 0.9% | | | <0.001 Two-sided Fisher’s exact test |
| Response Duration | Median
34.3 wk | Median 15.9 wk | | | |
Survival was evaluated in the intent-to-treat population. Figure 1 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.
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.
A series of subsets of patients were examined in exploratory univariate analyses. The results of these analyses are shown in Figure 2.The effect of TARCEVA on survival was similar across most subsets. An apparently larger effect, however, was observed in two subsets: patients with EGFR positive tumors (HR = 0.68) and patients who never smoked (HR = 0.42). These subsets are considered further below.
  
NSCLC - 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. 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 and the role of EGFR tumor expression in survival were 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.
Table 3 summarizes the demographic and disease characteristics of the study population that was randomized to receive 100 mg of TARCEVA plus gemcitabine or placebo plus gemcitabine. Baseline demographic and disease characteristics of the patients were similar between the 2 treatment groups, 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. Most patients presented with metastatic disease at study entry as the initial manifestation of pancreatic cancer. About 1/4 of the patients (136/521) had EGFR expression status characterized.
Table 3: Demographic and Disease Characteristics: 100 mg Cohort | TARCEVA+ Gemcitabine
(N=261) | Placebo + Gemcitabine
(N=260) |
| Characteristics | N | (%) | N | (%) |
| Gender | | | | |
| Female | 134 | (51) | 114 | (44) |
| Male | 127 | (49) | 146 | (56) |
| Age (Years) | | | | |
| <65 | 136 | (52) | 138 | (53) |
| ≥65 | 125 | (48) | 122 | (47) |
| Race | | | | |
| Caucasian | 225 | (86) | 231 | (89) |
| Black | 8 | (3) | 5 | (2) |
| Asian | 20 | (8) | 14 | (5) |
| Other | 8 | (3) | 10 | (3) |
| ECOG Performance StatusUnknown includes responses of 'Unknown' and missing. | | | | |
| 0 | 82 | (31) | 83 | (32) |
| 1 | 134 | (51) | 132 | (51) |
| 2 | 44 | (17) | 45 | (17) |
| Unknown | 1 | (<1) | 0 | (0) |
| Disease Status at BaselineStratification factor as documented at baseline; distribution differs slightly from values reported at time of randomization. | | | | |
| Locally Advanced | 61 | (23) | 63 | (24) |
| Distant Metastasis | 200 | (77) | 197 | (76) |
The results of the study are shown in Table 4.
Table 4: Efficacy Results: 100 mg Cohort | TARCEVA + Gemcitabine | Placebo+ Gemcitabine | Hazard
Ratio Cox regression model with the following covariates: ECOG performance status, and extent of disease. | 95% CI | p-value |
| Survival |
Median
6.4 mo
250 deaths |
Median
6.0 mo
254 deaths | 0.81 | 0.68 – 0.97 | 0.028 Two-sided Log-Rank test stratified by ECOG performance status and extent of disease. |
| 1-year Survival | 23.8% | 19.4% | | | |
| Progression-Free Survival |
Median
3.8 mo
225 events |
Median
3.5 mo
232 events | 0.76 | 0.64 – 0.92 | 0.006 |
| Tumor Response (CR+PR) | 8.6% | 7.9% | | | 0.87 Two-sided Fisher’s exact test. |
| Response Duration |
Median
23.9 wk |
Median
23.3 wk | | | |
Survival was evaluated in the intent-to-treat population. Figure 6 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.
Note: HR is from Cox regression model with the following covariates: ECOG performance status and extent of disease. P-value is from two-sided Log-Rank test stratified by ECOG performance status and extent of disease.
In a series of exploratory univariate subset analyses (the stratification factors at randomization and at baseline, as well as pain intensity by visual analog score, EGFR status, gender, age, race, and any prior chemotherapy), all of the HRs in the TARCEVA plus gemcitabine arm relative to the placebo plus gemcitabine arm were less than or equal to 1.0 suggesting consistency across all patient subsets. However, in patients with pain intensity score >20, female, locally advanced, age ≥65 years, or performance status 0 or 1, the benefit of erlotinib was uncertain.
  
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