This material is provided by Roche Products Ltd as a licence requirement for this medicine and forms part of the Risk Management Plan.
- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Assessment of EGFR mutation statusWhen assessing the EGFR mutation status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.
SmokersCurrent smokers should be advised to stop smoking, as plasma concentrations of erlotinib in smokers as compared to non-smokers are reduced. The degree of reduction is likely to be clinically significant (see section 4.5).
Interstitial Lung DiseaseCases of interstitial lung disease (ILD)-like events, including fatalities, have been reported uncommonly in patients receiving Tarceva for treatment of non-small cell lung cancer (NSCLC), pancreatic cancer or other advanced solid tumours. In the pivotal study BR.21 in NSCLC, the incidence of ILD (0.8%) was the same in both the placebo and Tarceva groups. In the pancreatic cancer study in combination with gemcitabine, the incidence of ILD-like events was 2.5% in the Tarceva plus gemcitabine group versus 0.4% in the placebo plus gemcitabine treated group. The overall incidence in Tarceva-treated patients from all studies (including uncontrolled studies and studies with concurrent chemotherapy) is approximately 0.6% compared to 0.2% in patients on placebo. Reported diagnoses in patients suspected of having ILD-like events included pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, Acute Respiratory Distress Syndrome (ARDS), alveolitis, and lung infiltration. Symptoms started from a few days to several months after initiating Tarceva therapy. Confounding or contributing factors such as concomitant or prior chemotherapy, prior radiotherapy, pre-existing parenchymal lung disease, metastatic lung disease, or pulmonary infections were frequent. A higher incidence of ILD (approximately 5% with a mortality rate of 1.5%) is seen among patients with Japanese origin.In patients who develop acute onset of new and/or progressive unexplained pulmonary symptoms such as dyspnoea, cough and fever, Tarceva therapy should be interrupted pending diagnostic evaluation. Patients treated concurrently with erlotinib and gemcitabine should be monitored carefully for the possibility to develop ILD-like toxicity. If ILD is diagnosed, Tarceva should be discontinued and appropriate treatment initiated as necessary (see section 4.8).
Diarrhoea, dehydration, electrolyte imbalance and renal failureDiarrhoea (including very rare cases with a fatal outcome) has occurred in approximately 50% of patients on Tarceva and moderate or severe diarrhoea should be treated with e.g. loperamide. In some cases dose reduction may be necessary. In the clinical studies doses were reduced by 50 mg steps. Dose reductions by 25 mg steps have not been investigated. In the event of severe or persistent diarrhoea, nausea, anorexia, or vomiting associated with dehydration, Tarceva therapy should be interrupted and appropriate measures should be taken to treat the dehydration (see section 4.8). There have been rare reports of hypokalaemia and renal failure (including fatalities). Some cases were secondary to severe dehydration due to diarrhoea, vomiting and/or anorexia, while others were confounded by concomitant chemotherapy. In more severe or persistent cases of diarrhoea, or cases leading to dehydration, particularly in groups of patients with aggravating risk factors (especially concomitant chemotherapy and other medications, symptoms or diseases or other predisposing conditions including advanced age), Tarceva therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patients intravenously. In addition, renal function and serum electrolytes including potassium should be monitored in patients at risk of dehydration.
Hepatitis, hepatic failureRare cases of hepatic failure (including fatalities) have been reported during use of Tarceva. Confounding factors have included pre-existing liver disease or concomitant hepatotoxic medications. Therefore, in such patients, periodic liver function testing should be considered. Tarceva dosing should be interrupted if changes in liver function are severe (see section 4.8). Tarceva is not recommended for use in patients with severe hepatic dysfunction.
Gastrointestinal perforationPatients receiving Tarceva are at increased risk of developing gastrointestinal perforation, which was observed uncommonly (including some cases with a fatal outcome). Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. Tarceva should be permanently discontinued in patients who develop gastrointestinal perforation (see section 4.8).
Bullous and exfoliative skin disordersBullous, blistering and exfoliative skin conditions have been reported, including very rare cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal (see section 4.8). Tarceva treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions. Patients with bullous and exfoliative skin disorders should be tested for skin infection and treated according to local management guidelines.
Ocular disordersPatients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist. If a diagnosis of ulcerative keratitis is confirmed, treatment with Tarceva should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Tarceva should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.Very rare cases of corneal perforation or ulceration have been reported during use of Tarceva (see section 4.8).
Interactions with other medicinal productsPotent inducers of CYP3A4 may reduce the efficacy of erlotinib whereas potent inhibitors of CYP3A4 may lead to increased toxicity. Concomitant treatment with these types of agents should be avoided (see section 4.5).
Other forms of interactionsErlotinib is characterised by a decrease in solubility at pH above 5. Medicinal products that alter the pH of the upper Gastro-Intestinal (GI) tract, like proton pump inhibitors, H2 antagonists and antacids, may alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of Tarceva when co-administered with such agents is not likely to compensate for the loss of exposure. Combination of erlotinib with proton pump inhibitors should be avoided. The effects of concomitant administration of erlotinib with H2 antagonists and antacids are unknown; however, reduced bioavailability is likely. Therefore, concomitant administration of these combinations should be avoided (see section 4.5). If the use of antacids is considered necessary during treatment with Tarceva, they should be taken at least 4 hours before or 2 hours after the daily dose of Tarceva.The tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
Erlotinib and other CYP substratesErlotinib is a potent inhibitor of CYP1A1, and a moderate inhibitor of CYP3A4 and CYP2C8, as well as a strong inhibitor of glucuronidation by UGT1A1 in vitro.The physiological relevance of the strong inhibition of CYP1A1 is unknown due to the very limited expression of CYP1A1 in human tissues. When erlotinib was co-administered with ciprofloxacin, a moderate CYP1A2 inhibitor, the erlotinib exposure [AUC] increased significantly by 39%, while no statistically significant change in Cmax was found. Similarly, the exposure to the active metabolite increased by about 60% and 48% for AUC and Cmax, respectively. The clinical relevance of this increase has not been established. Caution should be exercised when ciprofloxacin or potent CYP1A2 inhibitors (e.g. fluvoxamine) are combined with erlotinib. If adverse reactions related to erlotinib are observed, the dose of erlotinib may be reduced.Pre-treatment or co-administration of Tarceva did not alter the clearance of the prototypical CYP3A4 substrates, midazolam and erythromycin, but did appear to decrease the oral bioavailability of midazolam by up to 24%. In another clinical study, erlotinib was shown not to affect pharmacokinetics of the concomitantly administered CYP3A4/2C8 substrate paclitaxel. Significant interactions with the clearance of other CYP3A4 substrates are therefore unlikely.The inhibition of glucuronidation may cause interactions with medicinal products which are substrates of UGT1A1 and exclusively cleared by this pathway. Patients with low expression levels of UGT1A1 or genetic glucuronidation disorders (e.g. Gilbert's disease) may exhibit increased serum concentrations of bilirubin and must be treated with caution.Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and CYP1B1 in tumour tissue also potentially contribute to the metabolic clearance of erlotinib. Potential interactions may occur with active substances which are metabolised by, or are inhibitors or inducers of, these enzymes.Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasma concentrations. In a clinical study, the concomitant use of erlotinib with ketoconazole (200 mg orally twice daily for 5 days), a potent CYP3A4 inhibitor, resulted in an increase of erlotinib exposure (86% of AUC and 69% of Cmax). Therefore, caution should be used when erlotinib is combined with a potent CYP3A4 inhibitor, e.g. azole antifungals (i.e. ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin or clarithromycin. If necessary the dose of erlotinib should be reduced, particularly if toxicity is observed.Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinib plasma concentrations. In a clinical study, the concomitant use of erlotinib and rifampicin (600 mg orally once daily for 7 days), a potent CYP3A4 inducer, resulted in a 69% decrease in the median erlotinib AUC. Co-administration of rifampicin with a single 450 mg dose of Tarceva resulted in a mean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg Tarceva dose in the absence of rifampicin treatment. Co-administration of Tarceva with CYP3A4 inducers should therefore be avoided. For patients who require concomitant treatment with Tarceva and a potent CYP3A4 inducer such as rifampicin an increase in dose to 300 mg should be considered while their safety (including renal and liver functions and serum electrolytes) is closely monitored, and if well tolerated for more than 2 weeks, further increase to 450 mg could be considered with close safety monitoring. Reduced exposure may also occur with other inducers e.g. phenytoin, carbamazepine, barbiturates or St. John's Wort (hypericum perforatum). Caution should be observed when these active substances are combined with erlotinib. Alternate treatments lacking potent CYP3A4 inducing activity should be considered when possible.
Erlotinib and coumarin-derived anticoagulantsInteraction with coumarin-derived anticoagulants including warfarin leading to increased International Normalized Ratio (INR) and bleeding events, which in some cases were fatal, have been reported in patients receiving Tarceva. Patients taking coumarin-derived anticoagulants should be monitored regularly for any changes in prothrombin time or INR.
Erlotinib and statinsThe combination of Tarceva and a statin may increase the potential for statin-induced myopathy, including rhabdomyolysis, which was observed rarely.
Erlotinib and smokersResults of a pharmacokinetic interaction study indicated a significant 2.8-, 1.5- and 9-fold reduced AUCinf, Cmax and plasma concentration at 24 hours, respectively, after administration of Tarceva in smokers as compared to non-smokers (see section 5.2). Therefore, patients who are still smoking should be encouraged to stop smoking as early as possible before initiation of treatment with Tarceva, as plasma erlotinib concentrations are reduced otherwise. The clinical effect of the decreased exposure has not been formally assessed but it is likely to be clinically significant.
Erlotinib and P-glycoprotein inhibitorsErlotinib is a substrate for the P-glycoprotein active substance transporter. Concomitant administration of inhibitors of Pgp, e.g. cyclosporine and verapamil, may lead to altered distribution and/or altered elimination of erlotinib. The consequences of this interaction for e.g. CNS toxicity have not been established. Caution should be exercised in such situations.
Erlotinib and medicinal products altering pHErlotinib is characterised by a decrease in solubility at pH above 5. Medicinal products that alter the pH of the upper Gastro-Intestinal (GI) tract may alter the solubility of erlotinib and hence its bioavailability. Co-administration of erlotinib with omeprazole, a proton pump inhibitor (PPI), decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61%, respectively. There was no change to Tmax or half-life. Concomitant administration of Tarceva with 300 mg ranitidine, an H2-receptor antagonist, decreased erlotinib exposure [AUC] and maximum concentrations [Cmax] by 33% and 54%, respectively. Increasing the dose of Tarceva when co-administered with such agents is not likely to compensate for this loss of exposure. However, when Tarceva was dosed in a staggered manner 2 hours before or 10 hours after ranitidine 150 mg b.i.d., erlotinib exposure [AUC] and maximum concentrations [Cmax] decreased only by 15% and 17%, respectively. The effect of antacids on the absorption of erlotinib has not been investigated but absorption may be impaired, leading to lower plasma levels. In summary, the combination of erlotinib with proton pump inhibitors should be avoided. If the use of antacids is considered necessary during treatment with Tarceva, they should be taken at least 4 hours before or 2 hours after the daily dose of Tarceva. If the use of ranitidine is considered, it should be used in a staggered manner; i.e. Tarceva must be taken at least 2 hours before or 10 hours after ranitidine dosing.
Erlotinib and GemcitabineIn 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.
Erlotinib and Carboplatin/PaclitaxelErlotinib increases platinum concentrations. In a clinical study, the concomitant use of erlotinib with carboplatin and paclitaxel led to an increase of total platinum AUC0-48 of 10.6%. Although statistically significant, the magnitude of this difference is not considered to be clinically relevant. In clinical practice, there may be other co-factors leading to an increased exposure to carboplatin like renal impairment. There were no significant effects of carboplatin or paclitaxel on the pharmacokinetics of erlotinib.
Erlotinib and CapecitabineCapecitabine may increase erlotinib concentrations. When erlotinib was given in combination with capecitabine, there was a statistically significant increase in erlotinib AUC and a borderline increase in Cmax when compared with values observed in another study in which erlotinib was given as single agent. There were no significant effects of erlotinib on the pharmacokinetics of capecitabine. Erlotinib and proteasome inhibitorsDue to the working mechanism, proteasome inhibitors including bortezomib may be expected to influence the effect of EGFR inhibitors including erlotinib. Such influence is supported by limited clinical data and preclinical studies showing EGFR degradation through the proteasome.
PregnancyThere are no adequate data for the use of erlotinib in pregnant women. Studies in animals have shown no evidence of teratogenicity or abnormal parturition. However, an adverse effect on the pregnancy can not be excluded as rat and rabbit studies have shown increased embryo/foetal lethality, (see section 5.3). The potential risk for humans is unknown.
Women of childbearing potentialWomen of childbearing potential must be advised to avoid pregnancy while on Tarceva. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the foetus.
Breast-feedingIt is not known whether erlotinib is excreted in human milk. Because of the potential harm to the infant, mothers should be advised against breast-feeding while receiving Tarceva.
FertilityStudies in animals have shown no evidence of impaired fertility. However, an adverse effect on the fertility can not be excluded as animal studies have shown effects on reproductive parameters (see section 5.3).The potential risk for humans is unknown.
|Erlotinib N = 485||Placebo N = 242|
|NCI-CTC Grade||Any Grade||3||4||Any Grade||3||4|
|MedDRA Preferred Term||%||%||%||%||%||%|
|Total patients with any AE||99||40||22||96||36||22|
|Infections and infestations Infection*||24||4||0||15||2||0|
|Metabolism and nutrition disorders Anorexia||52||8||1||38||5||<1|
|Eye disorders Keratoconjunctivitis sicca Conjunctivitis||12 12||0 <1||0 0||3 2||0 <1||0 0|
|Respiratory, thoracic and mediastinal disorders Dyspnoea Cough||41 33||17 4||11 0||35 29||15 2||11 0|
|Gastrointestinal disorders Diarrhoea** Nausea Vomiting Stomatitis Abdominal pain||54 33 23 17 11||6 3 2 <1 2||<1 0 <1 0 <1||18 24 19 3 7||<1 2 2 0 1||0 0 0 0 <1|
|Skin and subcutaneous tissue disorders Rash*** Pruritus Dry skin||75 13 12||8 <1 0||<1 0 0||17 5 4||0 0 0||0 0 0|
|General disorders and administration site conditions Fatigue||52||14||4||45||16||4|
|Erlotinib N = 259||Placebo N = 256|
|NCI-CTC Grade||Any Grade||3||4||Any Grade||3||4|
|MedDRA Preferred Term||%||%||%||%||%||%|
|Total patients with any AE||99||48||22||97||48||16|
|Infections and infestations Infection*|
|Metabolism and nutrition disorders Weight decreased|
|Psychiatric disorders Depression|
|Nervous system disorders Neuropathy Headache|
|Respiratory ,thoracic and mediastinal disorders Cough||16||0||0||11||0||0|
|Gastrointestinal disorders Diarrhoea** Stomatitis Dyspepsia Flatulence|
48 22 17 13
5 <1 <1 0
<1 0 0 0
36 12 13 9
2 0 <1 <1
0 0 0 0
|Skin and subcutaneous tissue disorders Rash*** Alopecia||69 14||5 0||0 0||30 11||1 0||0 0|
|General disorders and administration site conditions Fatigue Pyrexia Rigors||73 36 12||14 3 0||2 0 0||70 30 9||13 4 0||2 0 0|
|Body System||Very common (≥1/10)||Common (≥1/100 to <1/10)||Uncommon (≥1/1,000 to <1/100)||Rare (≥1/10,000 to <1/1,000)||Very rare (<1/10,000)|
|Eye disorders||-Keratitis -Conjunctivitis1||-Eyelash changes 2||-Corneal perforations -Corneal ulcerations -Uveitis|
|Respiratory, thoracic and mediastinal disorders||-Epistaxis-Serious interstitial lung disease (ILD)3|
|Gastro-intestinal disorders||-Diarrhoea7||-Gastro-intestinal bleeding4, 7||-Gastrointestinal perforations7|
|Hepato biliary disorders||-Liver function test abnormalities 5||-Hepatic failure 6|
|Skin and subcutaneous tissue disorders||-Alopecia -Dry skin1-Paronychia -Folliculitis -Acne/ Dermatitis acneiform -Skin fissures||-Hirsutism -Eyebrow changes -Brittle and Loose nails -Mild skin reactions such as hyperpigmentation||-Palmar plantar erythrodys-aesthesia syndrome||-Stevens-Johnson syndrome/Toxic epidermal necrolysis7|
|Renal and urinary disorders||-Renal insufficiency1||-Nephritis1-Proteinuria1|
SymptomsSingle oral doses of Tarceva up to 1000 mg erlotinib in healthy subjects, and up to 1600 mg in cancer patients have been tolerated. Repeated twice daily doses of 200 mg in healthy subjects were poorly tolerated after only a few days of dosing. Based on the data from these studies, severe adverse reactions such as diarrhoea, rash and possibly increased activity of liver aminotransferases may occur above the recommended dose.
ManagementIn case of suspected overdose, Tarceva should be withheld and symptomatic treatment initiated.
Mechanism of actionErlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor type 1 (EGFR also known as HER1) tyrosine kinase inhibitor. Erlotinib potently inhibits the intracellular phosphorylation of EGFR. EGFR 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.EGFR mutations may lead to constitutive activation of anti-apoptotic and proliferation signaling pathways. The potent effectiveness of erlotinib in blocking EGFR-mediated signalling in these EGFR mutation positive tumours is attributed to the tight binding of erlotinib to the ATP-binding site in the mutated kinase domain of the EGFR. Due to the blocking of downstream-signaling, the proliferation of cells is stopped, and cell death is induced through the intrinsic apoptotic pathway. Tumour regression is observed in mouse models of enforced expression of these EGFR activating mutations.
Clinical efficacy- First-line Non-Small Cell Lung Cancer (NSCLC) therapy for patients with EGFR activating mutations (Tarceva administered as monotherapy):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 daily or up to 4 cycles of platinum based doublet chemotherapy. The primary endpoint was investigator assessed PFS. The efficacy results are summarized in Table 4.Figure 1: Kaplan-Meier curve for investigator assessed PFS in trial ML20650 (EURTAC) (April 2012 cut-off) Table 4: Efficacy results of Tarceva versus chemotherapy in trial ML20650 (EURTAC)
|Tarceva||Chemo-therapy||Hazard Ratio (95% CI)||p-value|
|Pre-planned Interim Analysis (35% OS maturity) (n=153) Cut-off date: Aug 2010||n=77||n=76|
Investigator Assessed **
Independent Review **
|Best Overall Response Rate (CR/PR)||54.5%||10.5%||p<0.0001|
|Overall Survival (OS) (months)||22.9||18.8||0.80 [0.47-1.37]||p=0.4170|
|Exploratory Analysis (40% OS maturity) (n=173) Cut-off date: Jan 2011||n=86||n=87|
|PFS (median in months), Investigator assessed||9.7||5.2||0.37 [0.27-0.54]||p<0.0001|
|Best Overall Response Rate (CR/PR)||58.1%||14.9%||p<0.0001|
|OS (months)||19.3||19.5||1.04 [0.65-1.68]||p=0.8702|
|Updated Analysis (62% OS maturity) (n=173) Cut-off date: April 2012||n=86||n=87|
|PFS (median in months)||10.4||5.1||0.34 [0.23-0.49]||p<0.0001|
|OS*** (months)||22.9||20.8||0.93 [0.64-1.36]||p=0.7149|
- ITT population results:The primary PFS analysis in all patients (n=889) showed a PFS hazard ratio (HR) of 0.71 (95% CI, 0.62 to 0.82; p<0.0001) for the Tarceva group relative to the placebo group. The mean PFS was 22.4 weeks in the Tarceva group compared with 16.0 weeks in the placebo group. PFS results were confirmed by an independent review of the scans. Quality of life data did not suggest a detrimental effect from erlotinib compared with placebo. A PFS HR of 0.69 (95% CI, 0.58 to 0.82; p < 0.0001) was observed in the coprimary patient population with EGFR IHC positive tumours (n=621). The mean PFS was 22.8 weeks in the Tarceva group (range 0.1 to 78.9 weeks) compared with 16.2 weeks in the placebo group (range 0.1 to 88.1 weeks). The progression free survival rate at 6 months was 27% and 16%, respectively for Tarceva and placebo. Concerning the secondary endpoint of overall survival, the HR was 0.81 (95% CI, 0.70 to 0.95; p=0.0088). The median overall survival was 12.0 months in the Tarceva group versus 11.0 months in the placebo group. Patients with EGFR activating mutations had the largest benefit (n= 49, PFS HR=0.10, 95% CI, 0.04 to 0.25; p<0.0001). In patients with EGFR wild type tumours (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).
- Patients with Stable Disease after chemotherapy:Patients with stable disease (SD) (n= 487) had a PFS HR of 0.68 (95% CI, 0.56 to 0.83; p<0.0001; median 12.1 weeks in the Tarceva group and 11.3 weeks in the placebo group) and an overall survival HR of 0.72 (95% CI, 0.59 to 0.89; p= 0.0019; median 11.9 months in the Tarceva group and 9.6 months in the placebo group).The effect on overall survival was explored across different subsets of patients with SD receiving Tarceva. This did not show major qualitative differences between patients with squamous cell carcinoma (HR 0.67, 95% CI, 0.48-0.92) and non-squamous cell carcinoma (HR 0.76, 95% CI 0.59-1.00) and between patients with EGFR activating mutations (HR 0.48, 95% 0.14-1.62) and without EGFR activating mutations (HR 0.65, 95% CI 0.48-0.87).- NSCLC treatment after failure of at least one prior chemotherapy regimen (Tarceva administered as monotherapy):The efficacy and safety of Tarceva as second/third-line therapy was demonstrated in a randomised, double-blind, placebo-controlled trial (BR.21), in 731 patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen. Patients were randomised 2:1 to receive Tarceva 150 mg or placebo orally once daily. Study endpoints included overall survival, progression-free survival (PFS), response rate, duration of response, time to deterioration of lung cancer-related symptoms (cough, dyspnoea and pain), and safety. The primary endpoint was survival.Demographic characteristics were well balanced between the two treatment groups. 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 PS 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. The adjusted hazard ratio (HR) 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 percent of patients alive at 12 months was 31.2% and 21.5%, for the Tarceva and placebo groups, respectively. The median overall survival was 6.7 months in the Tarceva group (95% CI, 5.5 to 7.8 months) compared with 4.7 months in the placebo group (95% CI, 4.1 to 6.3 months).The effect on overall survival was explored across different patient subsets. The effect of Tarceva on overall survival was similar in patients with a baseline performance status (ECOG) of 2-3 (HR = 0.77, 95% CI 0.6-1.0) or 0-1 (HR = 0.73, 95% CI 0.6-0.9), male (HR = 0.76, 95% CI 0.6-0.9) or female patients (HR = 0.80, 95% CI 0.6-1.1), patients < 65 years of age (HR = 0.75, 95% CI 0.6-0.9) or older patients (HR = 0.79, 95% CI 0.6-1.0), patients with one prior regimen (HR = 0.76, 95% CI 0.6-1.0) or more than one prior regimen (HR = 0.75, 95% CI 0.6-1.0), Caucasian (HR = 0.79, 95% CI 0.6-1.0) or Asian patients (HR = 0.61, 95% CI 0.4-1.0), patients with adenocarcinoma (HR = 0.71, 95% CI 0.6-0.9) or squamous cell carcinoma (HR = 0.67, 95% CI 0.5-0.9), but not in patients with other histologies (HR 1.04, 95% CI 0.7-1.5), patients with stage IV disease at diagnosis (HR = 0.92, 95% CI 0.7-1.2) or < stage IV disease at diagnosis (HR = 0.65, 95% CI 0.5-0.8). Patients who never smoked had a much greater benefit from erlotinib (survival HR = 0.42, 95% CI 0.28-0.64) compared with current or ex-smokers (HR = 0.87, 95% CI 0.71-1.05). In the 45% of patients with known EGFR-expression status, the hazard ratio was 0.68 (95% CI 0.49-0.94) for patients with EGFR-positive tumours and 0.93 (95% CI 0.63-1.36) for patients with EGFR-negative tumours (defined by IHC using EGFR pharmDx kit and defining EGFR-negative as less than 10% tumour cells staining). In the remaining 55% of patients with unknown EGFR-expression status, the hazard ratio was 0.77 (95% CI 0.61-0.98). The median PFS was 9.7 weeks in the Tarceva group (95% CI, 8.4 to 12.4 weeks) compared with 8.0 weeks in the placebo group (95% CI, 7.9 to 8.1 weeks).The objective response rate by RECIST in the Tarceva group was 8.9% (95% CI, 6.4 to 12.0). The first 330 patients were centrally assessed (response rate 6.2%); 401 patients were investigator-assessed (response rate 11.2%). The median duration of response was 34.3 weeks, ranging from 9.7 to 57.6+ weeks. 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).A survival benefit of Tarceva was also observed in patients who did not achieve an objective tumour response (by RECIST). This was evidenced by a hazard ratio for death of 0.82 (95% CI, 0.68 to 0.99) among patients whose best response was stable disease or progressive disease.Tarceva resulted in symptom benefits by significantly prolonging time to deterioration in cough, dyspnoea and pain, versus placebo.
-Pancreatic cancer (Tarceva administered concurrently with gemcitabine in study PA.3):The efficacy and safety of Tarceva in combination with gemcitabine as a first-line treatment was assessed in a randomised, double-blind, placebo-controlled trial in patients with locally advanced, unresectable or metastatic pancreatic cancer. Patients were randomised to receive Tarceva 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. The primary endpoint was overall survival. 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 erlotinib/gemcitabine arm compared with the placebo/gemcitabine arm:
|Baseline ECOG performance status (PS) = 0||31%||32%|
|Baseline ECOG performance status (PS) = 1||51%||51%|
|Baseline ECOG performance status (PS) = 2||17%||17%|
|Metastatic disease at baseline||77%||76%|
|Outcome||Tarceva (months)||Placebo (months)||Δ (months)||CI of Δ||HR||CI of HR||P- value|
|Median overall survival||6.4||6.0||0.41||-0.54-1.64||0.82||0.69-0.98||0.028|
|Mean overall survival||8.8||7.6||1.16||-0.05-2.34|
|Median overall survival||5.9||5.1||0.87||-0.26-1.56||0.80||0.66-0.98||0.029|
|Mean overall survival||8.1||6.7||1.43||0.17-2.66|
|Locally Advanced Population|
|Median overall survival||8.5||8.2||0.36||-2.43-2.96||0.93||0.65-1.35||0.713|
|Mean overall survival||10.7||10.5||0.19||-2.43-2.69|
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Tarceva in all subsets of the paediatric population in Non Small Cell Lung Cancer and Pancreatic cancer indications (see section 4.2 for information on paediatric use).
Tablet core:Lactose monohydrateCellulose, microcrystalline (E460)Sodium starch glycolate Type ASodium laurilsulfateMagnesium stearate (E470 b)
Tablet coat:Hydroxypropyl cellulose (E463)Titanium dioxide (E171)MacrogolHypromellose (E464)
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