Unknown Epidermal Growth Factor Receptor Status Research Articles

Erlotinib in Patients with Advanced Non-small Cell Lung Cancer in Middle Eastern Population

Abstract Background: Although erlotinib is widely used in the management of non-small cell lung cancer (NSCLC), no prior studies were conducted in Middle Eastern population. Our study aims at evaluating erlotinib prospectively in this population. Patients and Methods: This open-label, prospective, single-arm, multicenter Phase IV clinical trial of erlotinib as single agent evaluated safety and efficacy of Erlotinib in Middle Eastern patients with advanced NSCLC. Results: A total of 56 patients were enrolled in five sites in Saudi Arabia. Majority of patients were males (60%) with median age of 57 years (34–80), Stage IV (98%), and adenocarcinoma (84%). Eastern Cooperative Oncology Group performance Status III (41.1%). Epidermal growth factor receptor (EGFR) mutations were present in 24 patients out of 36 patients tested (67%). The most common reported adverse events (AEs) were rash 36 (64%), diarrhea 29 (52%), fatigue 10 (18%), and anorexia 5 (9%). Grade 4 or 5 AEs were not observed. Complete response was achieved in 2 (3.6%) and overall disease control was 60.8%. Median overall survival (OS) was significantly longer in patients with EGFR mutation than wild type (20 vs. 3 months, P = 0.002). Progression-free survival was 10 months and significantly longer in patients with EGFR mutation than wild type (16 vs. 6 months, P = 0.037). Patients with unknown EGFR status had PSF and OS better than wild-type patients and worse than patients with EGFR mutation. Cox regression analysis showed that older age (P = 0.029, HR 1.064), EGFR wild type (P = 0.014, hazard ratio [HR]: 8.497), and receiving radiation (P = 0.033, HR 6.433) significantly increase risk of death for patients receiving erlotinib. Conclusion: Erlotinib has efficacy and safety profile in Middle Eastern population similar to the reported literature. The empiric use of erlotinib in patients with unknown EGFR status in our patient population is warranted due to high prevalence of the mutation. However, it should not be used in confirmed wild-type disease.

Intercalating and maintenance gefitinib plus chemotherapy versus chemotherapy alone in selected advanced non-small cell lung cancer with unknown EGFR status

Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) are standard treatment for advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation. However, EGFR mutation testing is not attainable in approximately 20% of patients. The current study examined intercalating and maintaining gefitinib treatment in stage IIIB/IV non-squamous NSCLC, never or former light smoking patients with unknown EGFR mutation status. Briefly, 219 patients who achieved stable disease (SD) with gemcitabine (1250 mg/m2) plus carboplatin (5 AUC) were randomized at 1:1 ratio to continue chemotherapy (n = 110) or intercalating gefitinib (250 mg/day on days 15–25 of each cycle until disease progress (n = 109). Progression-free survival (PFS) was 9.7 vs. 4.2 month in the gefitinib vs. control arm (HR: 0.41, 95% CI: 0.31–0.56; P < 0.001). Overall survival (OS) was also longer in the gefitinib arm (20.1 vs. 15.4 months; HR: 0.68; 95% CI 0.48–0.97; P = 0.0323). Adverse events, including diarrhea, dermal reaction and thrombocytopenia, were more common in the gefitinib arm. In conclusion, intercalating and maintenance gefitinib treatment is a viable option for advanced NSCLC patients with unknown EGFR mutation status in subpopulations with high EFGR mutation rate.

Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study)

ObjectiveThe phase III IUNO trial assessed the benefit of maintenance erlotinib versus erlotinib at progression in advanced/metastatic non-small-cell lung cancer (NSCLC) that had not progressed following four cycles of platinum-based chemotherapy. Materials and MethodsPatients had stage IIIB/IV NSCLC, no known epidermal growth factor receptor (EGFR)-activating mutation, and objective response or disease stabilization after platinum-based induction chemotherapy. Central EGFR-mutation testing was undertaken on tumors from patients with unknown or wild-type EGFR status following local testing. Patients were randomized to receive blinded maintenance erlotinib 150mg/day (‘early erlotinib’) or placebo. Those who progressed on placebo received open-label erlotinib (‘late erlotinib’); patients who progressed on erlotinib received approved second-line chemotherapy or best supportive care. Primary endpoint: overall survival (OS). Results643 patients were randomized to receive maintenance erlotinib (n=322) or placebo (n=321). As of March 23, 2015, 242 (75.2%) OS events had occurred with ‘early erlotinib’ versus 235 (73.2%) with ‘late erlotinib’. Median OS was 9.7 and 9.5 months with ‘early erlotinib’ and ‘late erlotinib’, respectively (HR, 1.02, 95% CI: 0.85–1.22; log-rank p=0.82). No progression-free survival, objective response rate, or disease control rate benefit was observed with maintenance erlotinib. 410 patients entered the second-line phase of the study: 160 patients (50%) from the maintenance erlotinib arm and 250 patients (78%) from the maintenance placebo arm. The pattern of adverse events (AEs) was consistent with previous trials; 11 patients who received blinded erlotinib and 3 who received placebo died during the blinded maintenance phase due to nontreatment-related AEs. ConclusionsOS with maintenance erlotinib was not superior to second-line treatment in patients whose tumor did not harbor an EGFR-activating mutation. Safety results were consistent with the established safety profile of erlotinib. Thus, maintenance treatment with erlotinib in patients with advanced/metastatic NSCLC without EGFR-activating mutations is considered unfavorable.

Clinical Experience of Gefitinib in the Treatment of 32 Lung Adenocarcinoma Patients with Brain Metastases

背景与目的脑转移是晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）常见的转移部位，预后欠佳。吉非替尼是一种表皮生长因子受体（epithelial growth factor receptor, EGFR）酪氨酸激酶抑制剂，用于治疗晚期NSCLC。本研究旨在探讨吉非替尼治疗肺腺癌脑转移的疗效及毒副反应。方法回顾性分析32例肺腺癌脑转移患者的临床资料，所有患者均口服吉非替尼250 mg Qd，直到疾病进展或发生不可耐受的毒副反应。结果全组32例患者的中位生存时间（median overall survival, mOS）和中位无进展生存时间（median progression-free survival, mPFS）分别为24.7个月和11.2个月，有效率（response rate, RR）和疾病控制率（disease control rate, DCR）分别为62.5%和93.8%。吉非替尼用于初治患者的mOS和mPFS分别为35.6个月和11.3个月，RR和DCR分别为75.0%和100.0%。吉非替尼用于复治患者的mOS和mPFS分别为18.6个月和6.7个月，RR和DCR分别为50.0%和83.3%。EGFR敏感性突变患者的mOS和mPFS分别为24.8个月和10.8个月，RR和DCR分别为75.0%和100.0%。EGFR突变状态不明患者的mOS和mPFS分别为35.6个月和12.3个月，RR和DCR分别为53.3%和86.7%。全组患者耐受性好，未观察到严重毒副反应。常见的毒副反应包括：皮疹15例（46.9%）、腹泻7例（21.9%）、口腔溃疡1例（3.1%）。结论吉非替尼对肺腺癌脑转移患者有效率较高且耐受性好，可以作为肺腺癌脑转移患者的一种治疗选择。

Erlotinib therapy after initial platinum doublet therapy in patients with EGFR wild type non-small cell lung cancer: results of a combined patient-level analysis of the NCIC CTG BR.21 and SATURN trials.

The clinical benefit of erlotinib in treating epidermal growth factor receptor (EGFR) wildtype non-small cell lung cancer (NSCLC) has been questioned. We examined the impact of erlotinib in confirmed EGFR wildtype patients in two placebo-controlled phase III trials: the National Cancer Institute of Canada Clinical Trials Group BR.21 (BR.21) and Sequential Tarceva in Unresectable Non-Small Cell Lung Cancer (SATURN) trials. Combined re-analysis of progression-free survival (PFS) and overall survival (OS) in patients with known wildtype EGFR, estimated by Kaplan-Meier curves and compared by two-sided log-rank test. Cox proportional hazards model was used to estimate hazard ratios (HR) adjusted for potential confounders. Additional analyses assessed comparability of patients with known and unknown EGFR mutation status to determine generalizability of the two study populations. Mutation status was known in 25% (n=184 of 731) of the BR.21, and 49% (n=437 of 889) of the SATURN populations, of which 82% (n=150) and 89% (n=388) respectively had wildtype EGFR. HR for PFS was 0.71 (95% CI, 0.59-0.85; P<0.01) and for OS was 0.72 (95% CI, 0.59-0.88; P<0.01). Baseline characteristics and outcome (PFS and OS) distributions were similar for patients with known and unknown EGFR status, suggesting generalizability of the EGFR wildtype data. Erlotinib benefit was sustained in all clinical subsets. Erlotinib provided a consistent and significant improvement in survival for patients with EGFR wildtype NSCLC in both studies, individually and in combination. The benefit of erlotinib does not appear to be limited to patients with activating mutations of EGFR.

CPC-073 Influence of First-Line Egfr Therapy on Survival and Mortality Rates in Non-Small Cell Lung Cancer

BackgroundThe efficacy of chemotherapy has reached a plateau for advanced non-small cell lung cancer (NSCLC). Increasing evidence has demonstrated that patients with sensitising mutations in the epidermal growth factor receptor...

Activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in chemotherapy-pretreated non-small cell lung cancer (NSCLC) patients (pts) prospectively selected according to specific molecular predictive factors

18006 Background: EGFR TKIs are effective in a small proportion of chemotherapy-pretreated NSCLC pts. A number of molecular alterations along the EGFR pathway have been proposed as predictors of response to EGFR TKIs, but to date none of them has been prospectively validated. Methods: Advanced, chemotherapy-pretreated, NSCLC pts were screened for the following EGFR pathway alterations: EGFR gene mutations (by SSCP and sequencing) and/or increased copy number (by FISH), EGFR protein expression (by IHC), and HER-2, phosphorylated AKT (pAKT), and total AKT protein expression (by IHC). Upon progression, pts were then assigned to treatment with an EGFR TKI (Iressa™ or Tarceva™) according to one of the following groups: A) mutated (regardless of any other parameter); B) non-mutated, amplified (either true gene amplification or high-grade polysomy in &gt; 40% of the tumor cells); C) non-mutated, non-amplified, EGFR positive (IHC score = 1+); D) Adk or BAC histology and no smoking history (non-mutated, non-amplified, EGFR-negative pts or unknown EGFR status). Results: From January 2005, 129 pts were screened for EGFR pathway alterations, while undergoing chemotherapy. Thirteen pts were identified in group A (6 with exon 19 deletions, 6 with exon 21 point mutations, 1 with both); 39 pts in group B (including 7 pts with true gene amplification); 32 pts in group C (including 19 pts with a pAKT IHC score = 1+); 7 pts in group D (including 2 pts with BAC histology). Treatment results in the different subgroups are reported in Table 1 . Conclusions: Based on the data available so far, there seems to be a continuum of response/ disease control rate that progressively declines from group A to group C. Accrual to the study will be continued in all 4 subgroups until computer simulations using a continual reassessment method will allow to confidently exclude a true response rate = 10% in any of the groups. [Table: see text] No significant financial relationships to disclose.