Showing papers by "Byoung Chul Cho published in 2014"

Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial.

Abstract: Summary Background Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. Methods In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. Findings Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6–29·6) for patients in the dacomitinib group and 24·4 months (11·5–38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08–7·49] for dacomitinib vs 6·31 months [5·32–7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83–1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91–3·32] vs 1·38 months [0·99–1·74], respectively; HR 0·66 [95% CI 0·55–0·79]; p vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR -mutation-positive tumours (HR 0·98, 95% CI 0·67–1·44) and EGFR wild-type tumours (0·93, 0·71–1·21; p interaction =0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS -mutation-positive tumours (2·10, 1·05–4·22) and patients with KRAS wild-type tumours (0·79, 0·61–1·03; p interaction =0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p vs no controls), acneiform rash (48 [10%] vs one [ vs none), and fatigue (13 [3%] vs four [2%]). Interpretation Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. Funding Canadian Cancer Society Research Institute and Pfizer.

A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer

Abstract: Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto- and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR- or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules.

Screening of ROS1 rearrangements in lung adenocarcinoma by immunohistochemistry and comparison with ALK rearrangements.

Abstract: ROS1 rearrangement is a predictive biomarker for response to the tyrosine kinase inhibitor, crizotinib. We investigated the usefulness of ROS1 immunohistochemistry (IHC) for the detection of patients who harbor ROS1 rearrangements in two separate cohorts. We also compared ROS1 IHC with ALK IHC in terms of diagnostic performance to predict each gene rearrangement. In a retrospective cohort, IHC was performed in 219 cases of lung adenocarcinoma with already known genetic alterations. In a prospective cohort, we performed IHC for 111 consecutive cases of lung adenocarcinoma and confirmed the results by subsequent FISH. In the retrospective cohort, all 8 ROS1-rearranged tumors were immunoreactive, and 14 of 211 ROS1-wild cases were immunoreactive (sensitivity 100% and specificity 93.4%). In the prospective cohort, all IHC-negative cases were FISH-negative, and 5 of 34 ROS1 immunoreactive cases were ROS1-rearranged (sensitivity 100% and specificity 72.6%). In ROS1-wild tumors, ROS1 protein was more expressed in the tumors of ever-smokers than in those of never-smokers (p = 0.003). ALK IHC showed 100% sensitivity and 98.1 to 100% specificity in both patient cohorts. In conclusion, ROS1 IHC is highly sensitive, but less specific compared with ALK IHC for detection of the corresponding rearrangement. ROS1 IHC-reactive tumors, especially when the tumor is stained with moderate to strong intensity or a diffuse pattern, are recommended to undergo FISH to confirm the gene rearrangement.

A multicenter phase II study of everolimus in patients with progressive unresectable adenoid cystic carcinoma

Abstract: Background: The aim of this study was to examine the efficacy and safety of everolimus in patients with progressive unresectable adenoid cystic carcinoma (ACC). Methods: Histologically confirmed ACC patients with documented disease progression within 12 months prior to the study entry were eligible. Everolimus was given at a dose of 10 mg daily until progression or occurrence of unacceptable toxicities. The primary endpoint was a 4-month progression-free survival (PFS). Results: A total of 34 patients were enrolled. The 4-month PFS probability was 65.5% (95% one-sided confidence interval [CI], 47.7 to infinity). Median PFS duration was 11.2 months (95% CI, 3.6 to 15.8). Complete or partial response was not achieved. Twenty-seven (79.4%, 95% CI, 63.2 to 89.6) patients showed stable disease (SD). Tumor shrinkage within SD criteria was observed in 15 patients (44.1%) and SD lasting 6 months was observed in 13 patients (38.2%). Four patients had disease progression. Among the 18 patients with both pre- and post-treatment (at 8 weeks) FDG-PET scans available, 8 patients (44.4%) showed a partial metabolic response, defined as a ≥25% reduction in maximum standardized uptake values (SUVmax). The most common adverse events were stomatitis, anemia, asthenia, and leukopenia. No unexpected everolimus related toxicities were reported.

Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers.

Abstract: Background: Lung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers has not been conducted. Methods: We analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohort sets. Candidate loci were validated by target capture and Sanger sequencing. Gene set analysis was performed using Ingenuity Pathway Analysis. Results: We identified 27 genes potentially implicated in the pathogenesis of lung adenocarcinoma. These included targetable genes involved in PI3K/mTOR signaling (TSC1, PIK3CA, AKT2) and receptor tyrosine kinase signaling (ERBB4) and genes not previously highlighted in lung adenocarcinomas, such as SETD2 and PBRM1 (chromatin remodeling), CHEK2 and CDC27 (cell cycle), CUL3 and SOD2 (oxidative stress), and CSMD3 and TFG (immune response). In the expansion cohort (N = 70), TP53 was the most frequently altered gene (11%), followed by SETD2 (6%), CSMD3 (6%), ERBB2 (6%), and CDH10 (4%). In pathway analysis, the majority of altered genes were involved in cell cycle/DNA repair (P <0.001) and cAMP-dependent protein kinase signaling (P <0.001). Conclusions: The genomic makeup of EGFR/KRAS/ALK-negative lung adenocarcinomas in never-smokers is remarkably diverse. Genes involved in cell cycle regulation/DNA repair are implicated in tumorigenesis and represent potential therapeutic targets.

A randomized phase 2 trial of MM-121, a fully human monoclonal antibody targeting ErbB3, in combination with erlotinib in EGFR wild-type NSCLC patients.

Abstract: 8051 Background: Heregulin induced activation of ErbB3 has been implicated as a mechanism of resistance to many targeted therapies such as EGFR-TKIs in preclinical models. MM-121 is a monoclonal an...

A prospective phase II trial of S-1 and cisplatin-based chemoradiotherapy for locoregionally advanced esophageal cancer

Abstract: Purpose S-1 is a novel oral fluoropyrimidine anticancer agent designed to enhance clinical efficacy, reduce gastrointestinal toxicity, and enhance radiotherapy effectiveness A phase II trial was conducted to evaluate the efficacy and safety of preoperative chemoradiation with S-1 and cisplatin in locoregionally advanced esophageal cancer

NCIC CTG BR.26: A phase III randomized, double blind, placebo controlled trial of dacomitinib versus placebo in patients with advanced/metastatic non-small cell lung cancer (NSCLC) who received prior chemotherapy and an EGFR TKI.

Abstract: 8036^ Background: Dacomitinib (D) is an irreversible pan-HER inhibitor with evidence of activity in previously treated NSCLC patients (pts). Methods: BR26, a phase III randomized double blind place...

Phase II Study of Afatinib as Third-Line Treatment for Patients in Korea With Stage IIIB/IV Non-Small Cell Lung Cancer Harboring Wild-Type EGFR

Abstract: The Oncologist 2014;19:702-703; first published on May 27, 2014; doi:10.1634/theoncologist.2013-0419 The affiliation for authors Keunchil Park, Myung-Ju Ahn, and Jin Seok Ahn has been corrected to include the full name of their institution: Samsung Medical Center, Sungkyunkwan University School of Medicine.

Tumor MET expression profile predicts the outcome of non‐small cell lung cancer patients receiving epidermal growth factor receptor tyrosine kinase inhibitors

Abstract: Background This study assesses whether MET expression in tumor tissue is associated with an increased sensitivity to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients. Methods This retrospective study included 69 NSCLC participants with available tumor tissue and data on treatment response and survival. MET and hepatocyte growth factor expression in tumor tissue were evaluated by immunohistochemistry. Results Positive tMET expression correlated with a shorter progression-free survival (PFS; P = 0.003) and overall survival (OS; P = 0.05). Positive pY1234/1235 expression was significantly associated with a longer PFS (P = 0.031) and OS (P = 0.012). In multivariable analyses, tMET and pY1234/1235 expression were independent factors for PFS and OS, respectively. (tMET, PFS; P = 0.02, OS; P = 0.0007 and pY1234/1234, PFS; P = 0.01, OS; P = 0.004). Conclusions This study suggests that total and phosphorylated MET expression in tumor tissue is potentially useful for the selection of NSCLC patients who are likely to benefit from EGFR-TKIs, irrespective of their EGFR status.

Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers

Abstract: Background: Lung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers has not been conducted. Methods: We analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohort sets. Candidate loci were validated by target capture and Sanger sequencing. Gene set analysis was performed using Ingenuity Pathway Analysis. Results: We identified 27 genes potentially implicated in the pathogenesis of lung adenocarcinoma. These included targetable genes involved in PI3K/mTOR signaling (TSC1, PIK3CA, AKT2) and receptor tyrosine kinase signaling (ERBB4) and genes not previously highlighted in lung adenocarcinomas, such as SETD2 and PBRM1 (chromatin remodeling), CHEK2 and CDC27 (cell cycle), CUL3 and SOD2 (oxidative stress), and CSMD3 and TFG (immune response). In the expansion cohort (N = 70), TP53 was the most frequently altered gene (11%), followed by SETD2 (6%), CSMD3 (6%), ERBB2 (6%), and CDH10 (4%). In pathway analysis, the majority of altered genes were involved in cell cycle/DNA repair (P <0.001) and cAMP-dependent protein kinase signaling (P <0.001). Conclusions: The genomic makeup of EGFR/KRAS/ALK-negative lung adenocarcinomas in never-smokers is remarkably diverse. Genes involved in cell cycle regulation/DNA repair are implicated in tumorigenesis and represent potential therapeutic targets.

Abstract CT311: A randomized, open-label phase 2 study of efatutazone and erlotinib as second- or third-line therapy for non-small cell lung cancer (NSCLC)

Abstract: Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Introduction: Efatutazone is a potent, highly selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist active in preclinical cancer models, including NSCLC. In phase 1 studies, efatutazone showed anticancer activity and a manageable safety profile. An in vitro study combining a PPARγ agonist and an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), similar to erlotinib, showed an increase in the antiproliferative effects of the EGFR-TKI in NSCLC cells (Lee et al. Lung Cancer. 2006). This study evaluated the safety and efficacy of efatutazone added to erlotinib as second- or third-line NSCLC therapy. Methods: Patients from Germany, India, Korea, and the United States with NSCLC that progressed after first-line platinum therapy and no more than 1 additional therapy were stratified by Eastern Cooperative Oncology Group (ECOG) status (0/1 vs 2) and randomized 1:1 to efatutazone + erlotinib (E+E) or erlotinib alone (E). Efatutazone (0.5 mg) was administered orally, twice daily; erlotinib (150 mg) was administered orally, once daily. Treatment was given continuously in the absence of disease progression, withdrawal of consent, or unacceptable toxicity. The primary end point was progression-free survival (PFS) assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Results: Characteristics of the 90 randomized patients for E+E and E treatment groups, respectively, were: median age, 60 vs 61 years; male sex, 75.6% vs 55.6%; never smoker, 31.1% vs 46.7%; ECOG status 0/1, 91.1% vs 91.1%; and partial response (PR) as best response to prior therapy, 15.6% vs 26.7%. PFS was not different between treatments (hazard ratio [HR], 0.93; P = 0.79) with median PFS of 4.1 vs 2.8 months in the E+E vs E arms, respectively. The objective response rate was also similar at 20.5% vs 20.0% for E+E and E, respectively. Overall survival was not statistically different between the E+E vs E arms (median, 7.6 vs 11.4 months; HR, 1.20; P = 0.46). The most frequent adverse events (≥ 25%) or those of special interest for E+E and E, respectively, were anemia (36.4% vs 6.7%), diarrhea (40.9% vs 40.0%), peripheral edema (38.6% vs 2.2%), decreased appetite (40.9% vs 22.2%), dermatitis acneiform (34.1% vs 20.0%), rash (25.0% vs 31.1%), and pleural effusion (22.7% vs 0%).Conclusions: Efatutazone did not improve the efficacy of erlotinib as second- or third-line therapy for NSCLC. Adverse events associated with efatutazone in combination with erlotinib were related to anemia and fluid retention as expected with this drug class. Citation Format: Ana B. Oton, Byoung Chul Cho, Myung-Ju Ahn, Sang-We Kim, Kirushnakumar Subramanian, Chirag Desai, Dale Shuster, Terri Goldberg, Hamim Zahir, Dipen Dutta, Shuquan Chen, Richard Von Roemeling, Joachim von Pawel. A randomized, open-label phase 2 study of efatutazone and erlotinib as second- or third-line therapy for non-small cell lung cancer (NSCLC). [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 CT311. doi:10.1158/1538-7445.AM2014-CT311

Abstract 2856: Fibroblast growth factor receptor 1 gene amplification as an independent prognostic factor for recurrence in patients with resected squamous cell esophageal cancer

Abstract: Purpose To evaluate investigate the prognostic role of fibroblast growth factor receptor 1 (FGFR1) amplification in patients with surgically resected esophageal squamous cell carcinoma (ESCC). Patients and methods Gene copy number of FGFR1 was investigated in microarrayed tumors from 549 patients with ESCC who underwent curative esophagectomy. Gene copy number was evaluated by fluorescent in situ hybridization, and an FGFR1 amplified tumor (FGFR1 amp + ) was prespecified if one of the following criteria is fulfilled: (I) FGFR1/centromer 8 (CEN8) ration is ≥ 2.0, (II) average gene copy nucleus is ≥ 6.0, and (III) percentage of tumor cells containing ≥ 15 gene copies or large cluster is ≥ 10%. Results FGFR1 amplification was detected in 8% (44 of 549) of ESCC. The average copy number per nucleus was 2.7 (range, 0-15.5) and the mean FGFR1/CEN8 ratio was 2.2 (range, 0-6). The 5-year disease free survival of the FGFR1 amp + group was significantly shorter compared with that of the FGFR1amp - group (38.8% vs 63.7% P=0.012). In Cox proportional hazard model, patients with FGFR1 amp + had a significantly greater risk of recurrence compare to amp - group after adjusting for sex, smoking status, pathologic stage, histology, and adjuvant chemotherapy (HR 1.74; 95% CI, 1.10-2.76, P=0.018). Of note, there was a trend toward worse overall survival for FGFR1 amp + group compare to amp - group (5-year OS 32.0% vs 50.8%, P=0.11). FGFR1 amp + group was significantly more likely to be smokers than FGFR1amp - group (97.7 % vs 2.3%, P=0.001). With increment of total cigarette smoking dosage, the incidence of FGFR1 amp + significantly increased (P trend =0.005). Conclusions FGFR1 amplification is an independent prognostic factor for recurrence in surgically resected ESCC. FGFR1 amplification may have potential clinical application to the development of novel therapeutic strategies for ESCC Citation Format: Hyo Song Kim, Seung Eun Lee, Yoon Sung Bae, Joo Hang Kim, Hye Ryun Kim, Dae Joon Kim, Hyunki Kim, Yoon-La Choi, Byoung Chul Cho. Fibroblast growth factor receptor 1 gene amplification as an independent prognostic factor for recurrence in patients with resected squamous cell esophageal cancer. [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 2856. doi:10.1158/1538-7445.AM2014-2856

A Favorable Treatment Response of Erlotinib in Lung Adenocarcinoma with Concomitant Activating EGFR Mutation and ROS1 Rearrangement

Abstract: The rearrangement of c-ros oncogene 1 (ROS1) has been recently identified as an important molecular target in non small cell lung cancer (NSCLC). ROS1 rearrangement and epidermal growth factor receptor (EGFR) mutation were mutually exclusive each other in previous studies, and the clinical implication of co-existence of the two genetic alterations has not been determined. We report a case of 46-year-old female never-smoker NSCLC patient whose tumor harbored ROS1 rearrangement and EGFR mutation concomitantly. She had undergone curative surgery for stage IIIA NSCLC, and the recurrence in left pleura and brain occurred at 2 years after the surgery. She received several lines of chemotherapy including docetaxel plus carboplatin, erlotinib, pemetrexed, and gemcitabine. Erlotinib therapy showed a favorable treatment response with progression-free survival of 9.5 months and partial response of tumor on radiologic evaluations. This case represents a successful erlotinib treatment in a NSCLC patient with concurrent ROS1 rearrangement and EGFR mutation. (Ewha Med J 2014;37(1):46-51) Received September 27, 2013, Accepted January 14, 2014