Tarceva (Erlotinib) - Description and Clinical Pharmacology

DESCRIPTION

TARCEVA (erlotinib), a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. TARCEVA contains erlotinib as the hydrochloride salt that has the following structural formula:

Erlotinib hydrochloride has the molecular formula C₂₂H₂₃N₃O₄.HCl and a molecular weight of 429.90. The molecule has a pK_a of 5.42 at 25^oC. Erlotinib hydrochloride is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.

Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased solubility at a pH of less than 5 due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2.

TARCEVA tablets for oral administration are available in three dosage strengths containing erlotinib hydrochloride (27.3 mg, 109.3 mg and 163.9 mg) equivalent to 25 mg, 100 mg and 150 mg erlotinib and the following inactive ingredients: lactose monohydrate, hypromellose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate and titanium dioxide. The tablets also contain trace amounts of color additives, including FD&C Yellow #6 (25 mg only) for product identification.

CLINICAL PHARMACOLOGY

Mechanism of Action

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

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. Co-administration of TARCEVA with omeprazole, a proton pump inhibitor, decreased the erlotinib exposure [AUC] and maximum concentration [C_max] by 46% and 61% respectively [see Drug Interactions (7)].

Following absorption, erlotinib is approximately 93% protein bound to plasma albumin and alpha-1 acid glycoprotein (AAG). Erlotinib has an apparent volume of distribution of 232 liters.

Metabolism and Excretion:

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.

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.

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 was 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 AUC_0-infinity in smokers was about 1/3 to 1/2 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 Counseling Information ].   

Special Populations:

Patients with Hepatic Impairment

Patients with hepatic impairment (total bilirubin > ULN or Child Pugh A, B and C) should be closely monitored during therapy with TARCEVA. Treatment with TARCEVA should be used with extra caution in patients with total bilirubin > 3 x ULN [see Warnings and Precautions (5.2), Adverse Reactions (6.3), and Dosage and Administration (2.3) ].

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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Erlotinib has not been tested for carcinogenicity.

Erlotinib has been tested for genotoxicity in a series of in vitro   assays (bacterial mutation, human lymphocyte chromosome aberration, and mammalian cell mutation) and an in vivo mouse bone marrow micronucleus test and did not cause genetic damage.

Erlotinib did not impair fertility in either male or female rats.

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.

Table 4 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 4: Demographic and Disease Characteristics

* Stratification factor as documented at baseline; distribution differs slightly from values reported at time of randomization.
	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 Baseline*
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 5.

Table 5: Efficacy Results

	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)
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 ( 3)
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.

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 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.

Table 6 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.

Table 6: Demographic and Disease Characteristics: 100 mg Cohort

*Unknown includes responses of 'Unknown' and missing. **Stratification factor as documented at baseline; distribution differs slightly from values reported at time of randomization.
	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 Status*
0	82	(31)	83	(32)
1	134	(51)	132	(51)
2	44	(17)	45	(17)
Unknown*	1	(<1)	0	(0)
Disease Status at Baseline**
Locally Advanced	61	(23)	63	(24)
Distant Metastasis	200	(77)	197	(76)

The results of the study are shown in Table 7. 

Table 7: Efficacy Results: 100 mg Cohort

	TARCEVA + Gemcitabine	Placebo+ Gemcitabine	Hazard Ratio ( 1)	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 ( 2)
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 ( 3)
Response Duration	Median 23.9 wk	Median 23.3 wk

Survival was evaluated in the intent-to-treat population. Figure 2 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.