|Pharmacotherapeutic group: antineoplastic agent protein kinase inhibitor, ATC code: L01XE03|
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 of investigator assessed PFS was determined at a pre-planned interim analysis (n=153, HR= 0.42, 95 % CI, 0.27 to 0.64; p<0.0001 for the Tarceva group (n=77) relative to the chemotherapy group (n=76)). A 58% reduction in the risk of disease progression or death was observed. In the Tarceva versus chemotherapy arms respectively, median PFS was 9.4 and 5.2 months and Best Overall Response Rate (CR/PR) was 54.5 % and 10.5%, p<0.0001. PFS results were confirmed by an independent review of the scans, median PFS was 10.4 months in the Tarceva group compared with 5.4 months in the chemotherapy group (HR= 0.47, 95% CI, 0.27 to 0.78; p=0.003). The number of patients included in the investigator assessment of PFS was 129, the number of patients assessed by IRC was 107. The overall concordance rate between investigator and IRC assessment of PFS was 70 %.The overall survival data were immature at the time of interim analysis (HR= 0.80, 95 % CI, 0.47 to 1.37, p=0.4170).In a further exploratory analysis (n=173) significant benefit was observed in PFS (HR=0.37, 95% CI, 0.27 to 0.54; p<0.0001; median PFS was 9.7 and 5.2 months) and Best Overall Response Rate (58.1 % versus 14.9%, p<0.0001) with erlotinib compared to chemotherapy. Overall survival data were still immature at the time of the exploratory updated analysis (HR= 1.04, 95 % CI, 0.65 to 1.68, p=0.8702).- Maintenance NSCLC therapy after first-line chemotherapy (Tarceva administered as monotherapy):The efficacy and safety of Tarceva as maintenance after first-line chemotherapy for NSCLC was demonstrated in a randomized, double-blind, placebo-controlled trial (BO18192, SATURN). This study was conducted in 889 patients with locally advanced or metastatic NSCLC who did not progress after 4 cycles of platinum-based doublet chemotherapy. Patients were randomized 1:1 to receive Tarceva 150 mg or placebo orally once daily until disease progression. The primary endpoint of the study was progression free survival (PFS) in all patients and in patients with an EGFR IHC positive tumour. Baseline demographic and disease characteristics were well balanced between the two treatment arms. Patients with ECOG PS>1, significant hepatic or renal co-morbidities were not included in the study.
- 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:
Survival was evaluated in the intent-to-treat population based on follow-up survival data. Results are shown in the table below (results for the group of metastatic and locally advanced patients are derived from exploratory subgroup analysis).
|Baseline ECOG performance status (PS) = 0
|Baseline ECOG performance status (PS) = 1
|Baseline ECOG performance status (PS) = 2
|Metastatic disease at baseline
In a post-hoc analysis, patients with favourable clinical status at baseline (low pain intensity, good QoL and good PS) may derive more benefit from Tarceva. The benefit is mostly driven by the presence of a low pain intensity score. In a post-hoc analysis, patients on Tarceva who developed a rash had a longer overall survival compared to patients who did not develop rash (median OS 7.2 months vs 5 months, HR:0.61). 90% of patients on Tarceva developed rash within the first 44 days. The median time to onset of rash was 10 days.
||CI of Δ||HR||CI of HR||P- value
|Median overall survival
|Mean overall survival
|Median overall survival
|Mean overall survival
|Locally Advanced Population
|Median overall survival
|Mean overall survival
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).