"The U.S. Food and Drug Administration today granted accelerated approval to Zykadia (ceritinib) for patients with a certain type of late-stage (metastatic) non-small cell lung cancer (NSCLC).
Zykadia is an anaplastic lymphoma kinase (ALK)"...
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.
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 TARCEVA 2nd/3rd line regimen. Time to reach steady state plasma concentration would therefore be 7-8 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 TARCEVA for 2nd/3rd line treatment or for maintenance treatment, and in pancreatic cancer patients who received erlotinib plus gemcitabine. The pharmacokinetics of TARCEVA 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, 46-76%) 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 TARCEVA dose was increased from 150 mg to 300 mg. [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS and PATIENT INFORMATION].
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, DRUG INTERACTIONS].
CYP1A2 Inducers or Smoking Tobacco
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 TARCEVA the erlotinib exposure [AUC] was decreased by 46% and the erlotinib maximum concentration [Cmax] was decreased by 61%. When TARCEVA 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 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 was decreased by 15% and the erlotinib Cmax was decreased by 17% [see Dose Modifications, DRUG INTERACTIONS].
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 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 1.0 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 1.0) 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 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 1)
(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 Curves of Investigator-Assessed
PFS in Study 1
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 -Lack Of Efficacy Of TARCEVA In Maintenance Treatment Of Patients Without EGFR Mutations
Lack of efficacy of TARCEVA for the maintenance treatment of patients with NSCLC without EGFR activating mutations was demonstrated in Study 2. Study 2 was a multicenter, placebo-controlled, randomized trial of 643 patients with advanced NSCLC without an EGFR exon 19 deletion or exon 21 L858R mutation who had not experienced disease progression after four cycles of platinum-based chemotherapy. Patients were randomized 1:1 to receive TARCEVA 150 mg or placebo orally once daily (322 TARCEVA, 321 placebo) until disease progression or unacceptable toxicity. Following progression on initial therapy, patients were eligible to enter an open-label phase. Baseline characteristics were as follows: median age 61 years (35% age ≥ 65 years), 75% male, 77% White, 21% Asian, 28% ECOG PS 0, 72% ECOG PS 1, 16% never smokers, 58% current smokers, 57% adenocarcinoma, 35% squamous cell carcinoma, 22% stage IIIB disease not amenable to combined modality treatment, and 78% stage IV disease. Fifty percent of patients randomized to TARCEVA entered the open-label phase and received chemotherapy, while 77% of patients randomized to placebo entered the open-label phase and received TARCEVA.
The main efficacy outcome was overall survival (OS). Median OS was 9.7 months in the TARCEVA arm and 9.5 months in the placebo arm; the hazard ratio for OS was 1.02 (95% CI 0.85, 1.22). Median PFS was 3.0 months in the TARCEVA arm and 2.8 months in the placebo arm; the hazard ratio for PFS was 0.94 (95% CI 0.80, 1.11).
NSCLC - Maintenance Treatment Or Second/Third Line Treatment
Two randomized, double-blind, placebo-controlled trials, Studies 3 and 4, examined the efficacy and safety of TARCEVA administered to patients with metastatic NSCLC as maintenance therapy after initial treatment with chemotherapy (Study 3) or with disease progression following initial treatment with chemotherapy (Study 4). Determination of EGFR mutation status was not required for enrollment.
The efficacy and safety of TARCEVA as maintenance treatment of NSCLC were demonstrated in Study 3, a randomized, double-blind, placebo-controlled trial conducted in 26 countries, in 889 patients with metastatic NSCLC whose disease did not progress during first-line platinum-based chemotherapy. 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.
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)1
(N = 438)
(N = 451)
|Progression-Free Survival (PFS) based on investigator assessment|
|Number of Progression or Deaths (%)||349 (80%)||400 (89%)|
|Median PFS in Months (95% CI)||2.8 (2.8, 3.1)||2.6 (1.9, 2.7)|
|Hazard Ratio (95% CI) 2||0.71 (0.62, 0.82)|
|p-value (stratified log-rank test) 2,3||p < 0.0001|
|Overall Survival (OS)|
|Number of Deaths||298 (68%)||350 (78%)|
|Median OS in Months (95% CI)||12.0 (10.6, 13.9)||11.0 (9.9, 12.1)|
|Hazard Ratio (95% CI) 2||0.81 (0.70, 0.95)|
|p-value (stratified log-rank test) 3||0.0088|
|1 Patients with PD prior to randomization were
excluded from PFS and TTP analysis.
2 Univariate Cox regression model.
3 Unstratified log-rank test.
Figure 2 : depicts the Kaplan-Meier Curves for Overall Survival (ITT Population)
Figure 2: Kaplan-Meier Curves for Overall Survival (ITT Population)
The efficacy and safety of single-agent TARCEVA was assessed in Study 4, 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. Efficacy outcome measures 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 4)
(N = 488)
(N = 243)
|Overall Survival (OS)|
|Number of Deaths||378 (77%)||209 (86%)|
|Median OS in Months (95% CI)||6.7 (5.5, 7.8)||4.7 (4.1, 6.3)|
|Hazard Ratio (95% CI) 1||0.73 (0.61, 0.86)|
|p-value (stratified log-rank test)2||p < 0.001|
|Progression-Free Survival (PFS)|
|Number of Progression or Deaths (%)||402 (82%)||211 (87%)|
|Median PFS in Months (95% CI)||2.3 (1.9, 3.3)||1.8 (1.8, 1.9)|
|Hazard Ratio (95% CI)1||0.59 (0.50, 0.70)|
|Objective Response Rate (95% CI)||8.9% (6.4, 12.0)||0.9% (0.1, 3.4)|
|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.
Figure 3 depicts the Kaplan-Meier curves for overall survival.
Figure 3: Kaplan-Meier
Curves for Overall Survival of Patients by Treatment Group in Study 4
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 Study 5, 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 by intravenous infusion (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:
TARCEVA 100 mg Cohort (Study 5)
|Efficacy Parameter||TARCEVA + Gemcitabine
(N = 261)
|Placebo + Gemcitabine
(N = 260)
|Overall Survival (OS)|
|Number of Deaths||250||254|
|Median OS in Months (95% CI)||6.5 (6.0, 7.4)||6.0 (5.1, 6.7)|
|Hazard Ratio (95% CI) 1||0.81 (0.68, 0.97)|
|p-value (stratified log-rank test) 2||0.028|
|Progression-Free Survival (PFS)|
|Number of Progression or Deaths (%)||225||232|
|Median PFS in Months (95% CI)||3.8 (3.6, 4.9)||3.6 (3.3, 3.8)|
|Hazard Ratio (95% CI)1||0.76 (0.64, 0.92)|
|Objective Response Rate (95% CI)||8.6% (5.4, 12.9)||7.9% (4.8, 12.0)|
|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.
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 Curves for Overall Survival:
100 mg Cohort in Study 5
Last reviewed on RxList: 10/28/2016
This monograph has been modified to include the generic and brand name in many instances.
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