Study Of Gefitinib Research Articles

An exploratory clinical study of gefitinib combined with anlotinib in the first-line treatment of stage ⅢB-Ⅳ EGFR gene mutant non-small cell lung cancer patients with slow progress.

e21089 Background: Anlotinib is a new type of small molecule anti-angiogenic drug that can inhibit the activity of a variety of tyrosine kinase receptors. Based on the initial efficacy of the combination of anti-angiogenic drugs and EGFR-TKIs and a clearer definition of people who are sensitive to EGFR-TKIs treatment, this study explores the slow progress of first-line use of gefitinib in patients with non-small cell lung cancer slowly progress, the efficacy and safety of combined Anlotinib. Methods: Fifteen patients with first-line non-small cell lung cancer who received gefitinib treatment and slowly progressed after enrolled in Xuchang Central Hospital, 15 received anlotinib(12mg/d from day 1 to day 14 in a 21-day cycle) combined with gefitinib（250mg /d） treatment until the disease progressed or died or was intolerable Adverse events. The primary endpoint was the progression-free survival(PFS), and the secondary endpoints were objective response rate (ORR), disease control rate( DCR) and safety. Results: As of January 4, 2021, a total of 15 patients have been enrolled and 14 patients can be evaluated. 0CR, 5PR, 8SD, 1PD. The median progression-free survival was 13.3 months (95% Cl, 3.71-4.89), and the most common adverse reactions were Grade 1, including hypertension (42.86%) and fatigue (21.42%). No higher-grade adverse reactions. Conclusions: Gefitinib combined with Anlotinib Hydrochloride Capsules is safe, effective and well tolerated when the first-line treatment of EGFR gene mutant non-small cell lung cancer patients progresses slowly.

A multicenter, randomized, double-blind study of gefitinib in combination with anlotinib or placebo in previously untreated patients with EGFR mutation-positive advanced non-small cell lung cancer (FL-ALTER).

TPS9131 Background: Preclinical and clinical evidence has demonstrated that the dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutated advanced NSCLC population. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that effectively inhibits VEGFRs, FGFRs, PDGFRs, c-kit and MET. It has been proved to be safe and effective in advanced lung cancer after second-line standard chemotherapy failure. A cohort study of Anlotinib plus Erlotinib has shown a favorable safety profile and promising antitumor activity with an objective response rate (ORR)92.6%. This phase III study aims to evaluate the efficacy and safety of Anlotinib or placebo plus Gefitinib in patients(pts) with untreated EGFR-mutated metastatic NSCLC. Methods: Eligible pts were aged 18̃75 years old, had stage IIIB or IV NSCLC, with an EGFR 19del or 21L858R mutation, an ECOG PS of 0 or 1, measurable lesion according to RECIST v1.1 and adequate organ function. We randomly assigned eligible pts in a 1:1 ratio to receive oral Gefitinib (250 mg QD) plus either Anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) or matching placebo until progressive disease or unacceptable toxicity. Randomization was done by an interactive web response system with a computer-generated sequence and stratified by EGFR mutation status, gender, ECOG PS and pathological type. The primary endpoint is progression-free survival(PFS). Secondary endpoints include overall survival, ORR, disease control rate, time to progression, duration of response, quality of life and the safety profile. The peripheral blood of the pts will be detected three times by polygenic detection to monitor the resistance mechanism (before treatment, during the first evaluation, during tumor progression, each time 10ml peripheral blood). Independent Data Monitoring Committee and Independent Review Committee will be used in this study. According to previous report (Erlotinib plus Bevacizumab vs. Erlotinib alone: 16.0 vs. 9.7 mos, HR 0.54, Lancet Oncol, 15(11):1236-1244), the sample size was determined based on a median PFS of 15 months for the Anlotinib + Gefitinib group and median PFS of 10 months for the Placebo + Gefitinib group. To achieve 80% power at a two-sided α = 0.05 and an anticipated dropout rate of 20%, 310 patients (with 192 events required for the analyses) were needed. In total, 310 patients will be enrolled in this trial at 16 sites in China. From April 2019, 224 patients have been enrolled. Clinical trial information: NCT04028778.

84O - Phase I study of gefitinib (G) + durvalumab (D) for locally advanced/metastatic non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) sensitising mutations

84O - Phase I study of gefitinib (G) + durvalumab (D) for locally advanced/metastatic non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) sensitising mutations

Study of Gefitinib and Pemetrexed as First-Line Treatment in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutation.

To evaluate the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Patients and methods Patients with advanced non-squamous NSCLC harboring asensitive EGFR mutation were included in this study and randomly divided into gefitinib+placebo group and gefitinib+pemetrexed group. Pemetrexed or placebo was administered on day 1 at a dose of 500mg/m(2), and gefitinib was sequentially administered on days 2~16. This treatment regimen was repeated every 3weeks until disease progression. All investigators and participants were masked to treatment allocation. The overall response rate (ORR) and disease control rate (DCR) of gefitinib+pemetrexed group were higher than that of gefitinib+placebo group but only the difference of DCR between two groups was statistically significant (P<0.05). The median progression-free survival (PFS) of gefitinib+placebo group and gefitinib+pemetrexed group were 14.0months vs. 18months respectively and the difference was statistically significant (P<0.05). The 2-year PFS rates of gefitinib+pemetrexed group (20.00%) was higher than that of gefitinib+placebo group (8.89%) and the difference was statistically significant (P<0.05). The median overall survival (OS) of gefitinib+placebo group and gefitinib+pemetrexed group were 32.0months vs. 34months respectively and the difference was not statistically significant (P>0.05). The 3-year OS rates of gefitinib+pemetrexed group (44.44%) was higher than that of gefitinib+placebo group (35.56%) but the difference was not statistically significant (P>0.05). Major grade 3 or 4 hematological toxicities included neutropenia, leukopenia and anemia. The main grade 3 or 4 non-hematological toxicities were infection, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, fatigue, diarrhea and pneumonitis. The difference of toxicities between two groups was not statistically significant (P>0.05). The combination regimen of gefitinib+pemetrexed used in this study showed a higher ORR and DCR, longer median PFS and acceptable toxicity.

Abstract 5447: Association of the hedgehog signal pathway to Gefitinib sensitivity in a 3D cancer cell lines screening

Abstract Drug profiling of cancer cell lines is a useful tool for predictive biomarker discovery, traditional done in two-dimensional cultures, a growing body of evidence suggests that results cannot always be translated into xenografts or in the clinic due to the lack of complexity of the culture conditions. 3D cultures offer the ability to carry out the same type of studies with the added benefit of incorporating the 3-dimentional cellular interactions and physiological gradients normally seen in a tumor microenvironment. In this study we used Numira's 3D cell line screening platform on Gefitinib, a selective inhibitor of epidermal growth factor receptor (EGFR). We determined IC50 of Gefitinib in a panel of 60 cell lines grown as spheroids and used this information to investigate genes associated with sensitivity. Two mutated genes were associated with sensitivity to Gefitinb, as expected, the epidermal growth factor receptor (EGFR) was one of them, since mutations on EGFR are required for clinical efficacy. The second gene was smoothened (SMO), a G protein-coupled receptor of the hedgehog signaling pathway. It has been suggested that blockade of the hedgehog signaling pathway enhances anti-proliferative effects of EGFR inhibitors, we explored this potential synergy in a combination studies of Gefitinib and SMO inhibitors, Cyclopamine and GDC0449, the results are discussed. Citation Format: Gonzalo Castillo, Xiuyun Jiang. Association of the hedgehog signal pathway to Gefitinib sensitivity in a 3D cancer cell lines screening. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5447. doi:10.1158/1538-7445.AM2015-5447

Abstract CT342: Phase I/II study of gefitinib in combination with vorinostat in patients with advanced non-small cell lung cancer (NSCLC) who progressed on prior chemotherapy

Abstract Background: Gefitinib has shown marked efficacy in EGFR-mutant NSCLC. However, the development of acquired resistance is inevitable. Additionally, its therapeutic effect in EGFR-wild type NSCLC is controversial. Vorinostat, a histone deacetylase inhibitor, has shown to overcome resistance to gefitinib. We performed a phase I/II study combining gefitinib with vorinostat in previously treated patients with advanced NSCLC. Methods: A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: gefitinib 250/day on days 1 through 28 and vorinostat on days 1-7 and 15-21 at 200, 300 and 400mg/day every 28 days. Phase II eligibility included advanced NSCLC, ≤2 line prior therapy, PS 0-2, adequate organ function. The primary endpoint was to determine the median progression-free survival (PFS) (null hypothesis 3.5 months, alternative hypothesis 6.5 months). Results: Planned dose escalation was completed without reaching the MTD. The RP2D was gefitinib 250mg and vorinostat 400mg. Fifty-two patients were enrolled and treated in this study (43 in phase II). The median age was 59 years (range, 39 to 79 years), 30 were male, 48 had adenocarcinoma, 29 were never smokers, 31 had one prior regimen and 12 had two prior regimens; 21 had sensitive EGFR mutations, 3 had resistant exon 20 mutations and 5 had KRAS mutations. The most common adverse events were mild or moderate diarrhea, anorexia and anemia. In 43 assessable patients in phase II, there were 16 partial responses, 6 stable disease. The median PFS was 3.4 months; overall survival (OS) was 20.3 months. In patient harboring EGFR mutations, response rate (RR) was 88%, median PFS was 9.3 months and median OS was 22.6 months. Conclusions Gefitinib 250mg daily with biweekly vorinostat 400 mg/day was feasible and well tolerated. In unselected patient population, this combination dose not improved PFS compared with historical control of single gefitinib. However, in EGFR-mutant NSCLC, this combination may improve RR and survival compared with historical control of gefitinib in previously treated EGFR-mutant NSCLC. Citation Format: Ji-Youn Han, Soo Hyun Lee, Tak Yun, Young Jooo Lee, Kum Hui Hwang, Sunah Ryu, Heung Tae Kim, Jin Soo Lee. Phase I/II study of gefitinib in combination with vorinostat in patients with advanced non-small cell lung cancer (NSCLC) who progressed on prior chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT342. doi:10.1158/1538-7445.AM2014-CT342

205P - Efficacy Analysis of Gefitinib +/- Ficlatuzumab in Serum Proteomic Based Subgroups of Patients with Previously Untreated Lung Adenocarcinoma

ABSTRACT Aim: Ficlatuzumab (F), a humanized anti-hepatocyte growth factor (HGF) IgG1 mAb, inhibits c-MET receptor activation by neutralizing HGF. HGF/c-MET pathway activation has been implicated in epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer. A randomized Phase 2 study of gefitinib (G) +/- F in Asian patients with previously untreated lung adenocarcinoma (±EGFR mutations) failed to demonstrate improved overall survival (OS) or progression-free survival (PFS) over G alone (NCT01039948) in the intent-to-treat population. VeriStrat® (VS) is a multivariate serum proteomic test that utilizes mass spectrometry to assign a “GOOD” (VSG) or “POOR” (VSP) classification and has demonstrated broad prognostic and predictive utility for EGFR TKI treatments. In part, VS appears to measure a host inflammatory state that may stimulate tumors via alternative pathways, including HGF secretion. Methods: 183 blinded unique patient pretreatment serum samples from the study were sent for VS analysis. Clinical outcomes of F + G vs G alone were analyzed in VS subgroups. Results: 183 serum samples were assigned a VS label (VSG = 145, VSP = 35, and 3 “Indeterminate”). Addition of F to G provided significant clinical benefit to the VSP subgroup: OS hazard ratio (HR) 0.41, P = .032; medians = 23.9 mo for F + G (N = 18) vs 5.8 mo for G alone (N = 17) and PFS HR 0.41, P = .014; medians = 7.4 mo for F + G vs 2.3 mo for G alone. No benefit was observed in the VSG subgroup in either OS (HR 1.18, P = .492; median 24.7 mo for F + G [N = 69] vs not reached for G alone [N = 76]) or PFS (HR 1.06, P = .753; median 5.6 mo for F + G vs 5.6 mo for G alone). Unadjusted interaction test for treatment and VS was statistically significant for OS (HR = 3.31, P = .013) and PFS (HR = 2.51, P = .019). Despite the small sample sizes, similar patterns in OS and PFS based on VS stratification were also observed in patients with known EGFR mutations (n = 71). Conclusions: VS may be predictive for clinical benefit of F + G over G (OS and PFS) in patients classified as VSP. A prospective confirmatory study using VS as predictive biomarker on the combination of F + EGFR-TKI in EGFR mutation–positive patients is planned. Disclosure: J.C. Yang: Advisory boards: Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Roche/Genetech, Astrazeneca, Merck, Bayer, Clovis Oncology Corporate sponsored research: Boehringer Ingelheim; J. Gyuris, M.Han, F. Payumo and Z. Weng have declared: AVEO Oncology employee • Stock • Salary; P. Komarnitsky: (former) AVEO Oncology employee; G. Pestano, J. Roder and D. Spinella have declared: Biodesix employee • Stock • Salary; K. Park: Advisory boards: AVEO, Astellas, AZ, BI, Clovis, Daiichi Sankyo, Eli Lilly, Kyowa Hakko Kirin, Novartis, Roche. All other authors have declared no conflicts of interest.

NEJ009 trial: A randomized phase III study of gefitinib (G) in combination with carboplatin (C) plus pemetrexed (P) versus G alone in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) with EGFR mutation.

TPS8131 Background: Based on the previous phase III studies including our NEJ002 study comparing G with platinum doublet, G alone has been accepted as the standard first-line treatment for patients...

Phase II study of gefitinib and inserted cisplatin plus docetaxel as a first-line treatment for advanced non-small cell lung cancer haboring an epidermal growth factor receptor activating mutation.

8064 Background: Gefitinib yields a longer progression-free survival (PFS) period than platinum–doublet chemotherapy as a first–line treatment for patients with advanced non–small–cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) activating mutation, but most patients develop resistance against gefitinib after the initial response. We hypothesized that the insertion of platinum–doublet chemotherapy during the initial response could prevent the emergence of acquired resistance and prolong survival, compared with gefitinib alone. Methods: We performed a phase ΙΙ study of the following first–line treatment for patients with advanced NSCLC with EGFR mutation. Gefitinib (250 mg) was administrated on days 1–56. After a two–week rest, three cycles of cisplatin (80 mg/m2) and docetaxel (60 mg/m2) were administered on days 71, 92, and 113. Gefitinib was re–started on day 134 and was continued until progression. The primary endpoint was the two–year PFS rate. The sample size was estimated at 33, and this treatment was considered worthy for further development if more than 11 of the 33 patients who started treatment had a 2–year PFS. Results: Thirty–three Japanese patients were enrolled. Twenty–five patients could re–start gefitinib, 12 achieved a PFS period of over 2 years, and 9 continued to receive the protocol treatment without experiencing progression. The 1–, 2–, and 3–year estimated PFS rates were 59.4%, 37.5%, and 33.8%, respectively, and the median PFS time was 19.2 months. The 1–, 2–, and 3–year estimated survival rates were 90.0%, 82.9%, and 62.4%, respectively, and the median survival time had not been reached at the time of analysis. Treatment–related deaths and unexpected severe toxicities were not seen. Conclusions: Our results indicated that first–line treatment consisting of gefitinib and inserted cisplatin plus docetaxel is promising for patients with advanced NSCLC with EGFR mutation. A phase ΙΙΙ study of this treatment compared with gefitinib alone is warranted. Clinical trial information: 000001738.

A randomized trial of combination anastrozole plus gefitinib and of combination fulvestrant plus gefitinib in the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer

EGFR signalling pathways appear involved in endocrine therapy resistance in breast cancer. This trial estimates the antitumor efficacy and toxicity of the EGFR tyrosine kinase inhibitor gefitinib in combination with anastrozole or fulvestrant in postmenopausal hormone receptor positive breast cancer. Subjects with estrogen receptor and/or PgR positive, metastatic breast cancer were randomized into this phase II study of gefitinib (initial dose was 500 mg orally daily, due to high rate of diarrhea, starting dose was reduced to 250 mg orally daily) with either anastrozole 1 mg daily or fulvestrant 250 mg every 4 weeks. The primary endpoint was clinical benefit (complete responses plus partial responses plus stable disease for 6 months or longer). 141 eligible subjects were enrolled, 72 in the anastrozole plus gefitinib arm, and 69 in the fulvestrant plus gefitinib arm. Anastrozole plus gefitinib had a clinical benefit rate of 44% [95% confidence interval (CI) 33-57%] and fulvestrant plus gefitinib 41% (95% CI 29-53%). Median progression-free survival was 5.3 months (95% CI 3.1-10.4) versus 5.2 months (95% CI 2.9-8.2) for anastrozole plus gefitinib versus fulvestrant plus gefitinib, respectively. Median survival was 30.3 months (95% CI 21.2-38.9+) versus 23.9 months (95% CI 15.4-33.5) for anastrozole plus gefitinib versus fulvestrant plus gefitinib, respectively. In general, the toxicity is greater than expected for single agent endocrine therapy alone. Anastrozole plus gefitinib and fulvestrant plus gefitinib have similar clinical benefit rates in the treatment of estrogen and/or PgR positive metastatic breast cancer, and the rates of response are not clearly superior to gefitinib or endocrine therapy alone. Further studies of EGFR inhibition plus endocrine therapy do not appear warranted, but if performed should include attempts to identify biomarkers predictive of antitumor activity.

Phase I/II Study of Gefitinib and Concomitant Preoperative Radiotherapy in Patients with Locally Advanced Rectal Cancer

Objective: To determine the recommended dose (RD) of gefitinib when combined with concomitant radiotherapy (RT) in a preoperative setting in patients with locally advanced rectal cancer. Secondary objectives were to evaluate acute toxicities, pathological response rate, progression-free and overall survival (OS). Materials and Methods: 20 patients with cT3-4 or cN+ cM0 tumors were enrolled. The planned RT consisted in 50 Gy given in 2 daily fractions of 1.25 Gy in 4 weeks. During RT, gefitinib was planned to be given orally once daily with 2 successive dose levels: 250 mg and 500 mg. Rectal surgery was scheduled 5 - 6 weeks after completion of RT. The median follow-up for all patients was 57 months. Results: Among the first cohort of 6 patients, 1 patient presented a dose limiting toxicity (DLT) (Grade 3 diarrhea/dehydration). In the second cohort, 2/6 patients presented with the same DLT so that 250 mg was considered as the RD. Main acute toxicities consisted in diarrhea (grade 2 - 3, 63%), and skin reaction (in RT fields grade 2 - 3 in 42%). The 5-year actuarial OS and loco-regional control rates were of 80% and 84% respectively. Conclusion: The concomitant daily administration of 250 mg of gefitinib with 50 Gy preoperative RT is feasible with manageable toxicity. The major pathologic response rate is encouraging, though it needs further confirmation. Distant metastasis still represents a concern and new strategies to overcome this issue are warranted.

9123 POSTER Final Results of a Phase II Study of Gefitinib as First-line Treatment in Elderly Epidermal Growth Factor Receptor-mutated Patients With Advanced Non-small Cell Lung Cancer – Gefitinib for Elderly Patients With Lung Adenocarcinoma

9123 POSTER Final Results of a Phase II Study of Gefitinib as First-line Treatment in Elderly Epidermal Growth Factor Receptor-mutated Patients With Advanced Non-small Cell Lung Cancer – Gefitinib for Elderly Patients With Lung Adenocarcinoma

9101 POSTER Pre-planned Subgroup Analyses From the Phase III, Randomised, Placebo-controlled, Parallel-group Study of Gefitinib (G) as Maintenance Therapy in Patients (pts) With Locally Advanced or Metastatic Non-small-cell Lung Cancer (NSCLC) (INFORM; C-TONG 0804)

9101 POSTER Pre-planned Subgroup Analyses From the Phase III, Randomised, Placebo-controlled, Parallel-group Study of Gefitinib (G) as Maintenance Therapy in Patients (pts) With Locally Advanced or Metastatic Non-small-cell Lung Cancer (NSCLC) (INFORM; C-TONG 0804)

Efficacy, tolerability, and biomarker analyses from a phase III, randomized, placebo-controlled, parallel group study of gefitinib as maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC; INFORM; C-TONG 0804).

LBA7511 Background: INFORM (a phase III, randomized, multicenter, parallel group study; NCT00770588 ) investigated the efficacy, safety and tolerability of gefitinib (G) vs. placebo (P) as maintenance therapy in pts with locally advanced/metastatic NSCLC following standard first-line platinum based chemotherapy. Methods: Pts (≥18 years, with stage IIIB/IV NSCLC and WHO performance status 0-2) had completed 4 cycles of first-line platinum based doublet chemotherapy without progression/unacceptable toxicity. Pts were randomized 1:1 to G 250mg/day or P on discontinuation of first-line therapy. Progression-free survival (PFS; primary endpoint) was assessed in the intent to treat population (Cox proportional hazards adjusted for histology [adenocarcinoma vs. non-adenocarcinoma], smoking status [never-smoker vs. smoker], EGFR mutation status [positive vs. negative vs. unknown] and best response to first-line chemotherapy [complete response/partial response vs. stable disease]). PFS was considered superior with gefitinib if the G:P hazard ratio (HR) upper confidence interval (CI) was &lt;1.00. Secondary endpoints included overall survival (OS), objective response rate, disease control rate, symptom improvement and tolerability. Results: 296 pts (n=148 G, n=148 P) were randomized (27 centers in china; 26 September 2008-10 August 2009). PFS data cutoff on 24 January 2011. Median duration of follow-up was 16.8 months: 91% pts progressed; 59% deaths. Demography was balanced between treatments; overall, 54.1% pts were never-smokers, 70.6% had adenocarcinoma, and 40.9% were female. For G vs. P, PFS HR=0.42; 95% CI 0.32-0.54; p&lt;0.0001; median PFS 4.8 vs. 2.6 months. Most common AEs (any grade) with G were rash (49.7%), diarrhea (25.2%), and ALT increase (21.1%) which were generally mild/moderate. Overall incidence of serious AEs: G (6.8%); P (3.4%). Other secondary endpoint data (including OS and biomarkers) will be presented. Conclusions: PFS was significantly longer with G compared with P as maintenance therapy in Chinese patients with locally advanced NSCLC.

Abstract 4119: Association of plasma hepatocyte growth factor (HGF) and insulin-like growth factor binding protein (IGFBP)-3 with gefitinib resistance in patients with advanced non-small cell lung cancer

Abstract Purpose: It has been suggested that hepatocyte growth factor (HGF) and insulin-like growth factor binding protein (IGFBP)-3 are associated with gefitinib resistance in non-small cell lung cancer (NSCLC). We investigated the predictive and prognostic roles of these proteins in NSCLC patients treated with gefitinib. Methods: Of 106 patients enrolled in the randomized phase II study of gefitinib, 97 had plasma samples available for ELISA testing. Of these samples, seven and eight, respectively, had HGF and IGFBP-3 values that could not be measured. Therefore, the correlations between clinical outcomes and plasma levels of HGF and IGFBP-3 were evaluated in 90 and 89 patients, respectively. Results: Plasma HGF levels were significantly higher in older patients, male patients, patients with squamous cell carcinoma, current smokers, and patients with EGFR wild-type tumors. Low HGF levels were significantly associated with higher response rate (RR), and longer progression-free survival (PFS) and overall survival (OS) irrespective of EGFR mutation status. In a multivariate analysis, the presence of EGFR mutations (HR, 0.42; 95% CI, 0.24 to 0.73; P=0.002) and low HGF levels (HR, 0.58; 95% CI, 0.35 to 0.95; P=0.031) were independently predictive of longer PFS, and an ECOG PS of 0 (HR, 2.95; 95% CI, 1.57-5.54; P=0.001) and low HGF levels (HR, 0.40; 95% CI, 0.22-0.72; P=0.002) were independently predictive of longer OS. No statistically significant differences were found for IGFBP-3. Conclusion: High HGF levels are significantly associated with resistance to gefitinib and can be used as a predictive marker for the differential outcome of gefitinib treatment in NSCLC irrespective of EGFR mutation status. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4119. doi:10.1158/1538-7445.AM2011-4119

Evaluation of 18F-FDG PET and MRI Associations in Pediatric Diffuse Intrinsic Brain Stem Glioma: A Report from the Pediatric Brain Tumor Consortium

The purpose of this study was to assess (18)F-FDG uptake in children with a newly diagnosed diffuse intrinsic brain stem glioma (BSG) and to investigate associations with progression-free survival (PFS), overall survival (OS), and MRI indices. Two Pediatric Brain Tumor Consortium (PBTC) therapeutic trials in children with newly diagnosed BSG were designed to test radiation therapy combined with molecularly targeted agents (PBTC-007: phase I/II study of gefitinib; PBTC-014: phase I/II study of tipifarnib). Baseline brain (18)F-FDG PET scans were obtained in 40 children in these trials. Images were evaluated by consensus between 2 PET experts for intensity and uniformity of tracer uptake. Associations of (18)F-FDG uptake intensity and uniformity with both PFS and OS, as well as associations with tumor MRI indices at baseline (tumor volume on fluid-attenuated inversion recovery, baseline intratumoral enhancement, diffusion and perfusion values), were evaluated. In most of the children, BSG (18)F-FDG uptake was less than gray-matter uptake. Survival was poor, irrespective of intensity of (18)F-FDG uptake, with no association between intensity of (18)F-FDG uptake and PFS or OS. However, hyperintense (18)F-FDG uptake in the tumor, compared with gray matter, suggested poorer survival rates. Patients with (18)F-FDG uptake in 50% or more of the tumor had shorter PFS and OS than did patients with (18)F-FDG uptake in less than 50% of the tumor. There was some evidence that tumors with higher (18)F-FDG uptake were more likely to show enhancement, and when the diffusion ratio was lower, the uniformity of (18)F-FDG uptake appeared higher. Children with BSG for which (18)F-FDG uptake involves at least half the tumor appear to have poorer survival than children with uptake in less than 50% of the tumor. A larger independent study is needed to verify this hypothesis. Intense tracer uptake in the tumors, compared with gray matter, suggests decreased survival. Higher (18)F-FDG uptake within the tumor was associated with enhancement on MR images. Increased tumor cellularity as reflected by restricted MRI diffusion may be associated with increased (18)F-FDG uniformity throughout the tumor.

Optimal Management of Patients with Non-Small Cell Lung Cancer and Epidermal Growth Factor Receptor Mutations

In recent years, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, which have promising activity and a favourable toxicity profile, have been used in the management of advanced non-small cell lung cancer (NSCLC). The knowledge that EGFR-activating mutations confer sensitivity to EGFR TKIs has led to the design and analysis of phase II and III studies of gefitinib or erlotinib treatment in various clinical scenarios. We review the important NSCLC clinical trials of the efficacy of EGFR TKIs in the context of EGFR-activating mutations. In all phase II single-arm studies or phase III randomized comparative studies, EGFR TKIs as monotherapy were superior to combination chemotherapy in terms of response rate and progression-free survival in patients with activating EGFR mutations. EGFR TKIs have contributed to the superior overall survival time in NSCLC patients with EGFR mutations compared with those patients without EGFR mutations. The results of these studies have led to a paradigm shift in the treatment of patients with advanced NSCLC. NSCLC with EGFR mutations constitutes a new entity requiring different personalized treatment strategies.

A phase II study of gefitinib versus vinorelbine or gemcitabine in chemotherapy-naïve elderly patients with advanced non-small cell lung cancer based on epidermal growth factor receptor mutation status.

7559 Background: Elderly patients are more vulnerable to toxicity from chemotherapy, possibly from progressive organ failure and comorbidities. Activating epidermal growth factor receptor (EGFR) mu...

Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy.

7551 Background: Gefitinib and erlotinib are potent inhibitors of the epidermal growth factor receptor tyrosine kinase (EGFR TK), with single agent antitumor activity. In this randomized, single-ce...

A phase II study of gefitinib (G) versus carboplatin and gemcitabine (CG) in chemotherapy-naïve patients with advanced non-small cell lung cancer (NSCLC) and ECOG performance status (PS) 2.

e18090 Background: Patients (pts) with PS 2 and advanced NSCLC have poor response and tolerance to chemotherapy. G-an epidermal growth factor receptor tyrosine kinase inhibitor-is a more convenient...