bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of the presence of EGFR mutation on definitive chemoradiotherapy in patients with locally advanced non-small cell lung cancer: Pattern of relapses and survival analyses in 145 patients.
Authors: Yagishita Shigehiro , Horinouchi Hidehito , Taniyama Tomoko , Nakamichi Shinji , Kitazono Satoru , Mizugaki Hidenori , Kanda Shintaro , Fujiwara Yutaka , Nokihara Hiroshi , Yamamoto Noboru , Sumi Minako , Shiraishi Kouya , Kohno Takashi , Furuta Koh , Tsuta Koji , Tamura Tomohide
Published: March 2020

7540

Background: EGFR mutational status is an important biomarker in advanced NSCLC patients. However, little is known about the frequency and clinical significance of the presence of EGFR mutation in patients with potentially curable locally advanced NSCLC (LA-NSCLC) eligible for definitive chemoradiotherapy (CRT). Methods: Between Jan 2001 and Dec 2010, we conducted analysis for the presence of EGFR mutations, in consecutive NSCLC patients who were eligible for CRT. The response rate (RR), progression-free survival (PFS), 2-year relapse-free rate, first relapse sites, and overall survival were investigated according to the EGFR mutational status. Results: A total of 528 patients received CRT at the National Cancer Center Hospital during the study period. Of these, 274 were diagnosed as having non-squamous NSCLC, and sufficient specimens for mutational analyses could be obtained from 145 patients. EGFR mutants (EGFR-mt) were found at a frequency of 18% in these patients. In addition to the well-known characteristics of NSCLC patients carrying EGFR mutations (female, adenocarcinoma, and never/ light smoker), the proportion of cases with smaller (T1/2) primary lesions was higher in patients with EGFR-mt than in those carrying wild-type EGFR (EGFR-wt). EGFR-mt showed a slightly better RR (85.7% vs. 72.9%), but similar median PFS (12.2 m vs. 10.6 m) and 2-year relapse free rates (23.8% vs. 29.2%) as compared to EGFR-wt. Local recurrence as first relapse occurred less frequently in EGFR-mt than in EGFR-wt (6% vs. 20%). After disease progression, a majority of EGFR-mt received EGFR-TKIs (62%), and these patients showed longer post-progression survival and a higher 5 year survival rate (60% vs. 40%) than EGFR-wt. Conclusions: Among the LA-NSCLC patients eligible for definitive CRT analyzed, 18% had EGFR- activating mutations. Although definitive CRT was similarly effective in both EGFR-mt and EGFR-wt, slightly better local control rate was noted in EGFR-mt. Treatment with EGFR-TKIs contributed to longer post-progression survival and overall survival in LA-NSCLC patients harboring EGFR mutations.
Scoring system predicting overall survival (OS) in patients (Pts) with non-small cell lung cancer (NSCLC).
Authors: Schild Steven E. , Tan Angelina D. , Wampfler Jason A. , Molina Julian R. , Ross Helen J. , Yang Ping , Sloan Jeff A.
Published: March 2020

7545

Background: Interpretation of lung cancer clinical trials is complicated by the heterogeneity of the patient population due to disease burden and comorbidities making pre-trial assessment of OS probability challenging. Methods: To create and validate a scoring system to estimate OS and improve the quality of future trials, this study evaluated the pretreatment prognostic factors of 2,442 pts with NSCLC. Univariate (UV) and multivariate (MV) Cox models were used to evaluate the prognostic importance of each baseline factor on OS. Those prognostic factors significant on both UV and MV analyses that were used to develop the scoring system included overall quality of life, age, sex, stage, ECOG performance status, the presence of other cancers, and smoking cessation. The score for each factor was determined by dividing the 5-year OS rate (in %) by 10 and summing these scores to form a total score. Multivariate models and the score for each factor were validated using bootstrapping with 1000 iterations from the original samples. Results: The score for each factor ranged from 1 to 7 points and the total scores ranged between 23 and 39 points. Higher scores reflected better OS. Categorization of the score was delineated first by clinician expert opinion (see Table) and then by multiple statistically defined empirical cut points. All categorization schemes demonstrated successful prognostic power. The bootstrap method confirmed the reliability of multivariate Cox model and score (Spearman correlation coefficient= 0.45). Conclusions: Prognostic factors significantly associated with OS on both UV and MV analysis were used to construct a valid scoring system which can be used to predict survival of NSCLC pts. This scoring system can be used by clinicians in counseling pts and for stratification in future trial design. [Table: see text]
Pulmonary pure ground-glass opacity lesions: Use of computed tomography attenuation for predicting tumor progression.
Authors: Eguchi Takashi , Kondo Ryoichi , Kawakami Satoshi , Matsushita Mina , Takeda Tetsu , Sakaizawa Takao , Tominaga Yoshiaki , Saito Gaku , Hashizume Masahiro , Toishi Masayuki , Shiina Takayuki , Yoshida Kazuo , Amano Jun , Koizumi Tomonobu
Published: March 2020

7548

Background: Cases with pure ground-glass opacity (GGO) are increasing with the use of computed tomography (CT). In some cases, pure GGO on follow-up CT may represent tumor enlargement or the presence of solid components. We evaluated the natural progression of pure GGO lesions during a long-term follow-up period of more than 2 years. Methods: We retrospectively investigated 95 patients with pure GGO lesions detected between February 2003 and December 2010, in whom these lesions were monitored using CT for more than 2 years. Results: The median follow-up period was 64.7 months (range, 24–114 months). During the follow-up period, areas showing GGO increased in size or appeared to have solid components in 49 patients (group 1) and showed no change in 46 patients (group 2). We compared patient characteristics and tumor properties between the 2 groups. Mean CT attenuation values of the tumors differed significantly between groups 1 (-639.9 ± 88.9 HU) and 2 (-709.2 ± 60.9 HU). In contrast, no significant differences were noted with regard to age, gender, smoking history, lung cancer history, tumor size, and total numbers of GGO lesions between the 2 groups. The difference in the time to tumor growth according to the initial mean CT attenuation value was estimated using the Kaplan–Meier method. The growth incidence at 114 months for lesions with a mean CT attenuation value of -650 HU or more (n = 35) and less than -650 HU (n = 60) were estimated to be 96% and 48%, respectively. The difference between the 2 Kaplan–Meier curves was statistically significant (p < 0.0001). The usefulness of the mean CT attenuation value in predicting the growth of GGO lesions was evaluated using receiver operating characteristic analysis. The sensitivity and specificity was 63% and 87%, respectively, for a mean CT attenuation cutoff value of -650 HU. The area under the curve was 0.76. Conclusions: Many pure GGO lesions have potential for growth as seen during long-term follow-up. CT attenuation is useful in predicting the growth of GGO lesions.
Dose-escalation study of chemoradiotherapy with use of involved-field conformal radiotherapy and accelerated hyperfractionation for stage III non-small cell lung cancer.
Authors: Yoshimura Naruo , Mitsuoka Shigeki , Kimura Tatsuo , Tanaka Hidenori , Suzumura Tomohiro , Nagata Misato , Umekawa Kanako , Nakai Toshiyuki , Hosono Masako Hosono , Tada Takuhito , Hirata Kazuto , Kudoh Shinzoh
Published: March 2020

7564

Background: To determine a recommended dose (RD) of chemoradiotherapy with use of involved-field conformal radiotherapy and accelerated hyperfractionation (AHF) for stage III non-small cell lung cancer (NSCLC). Methods: Eligible patients had unresectable stage III NSCLC, age of less than 75 years, PS: 0 or 1, V20 of 35% or less. PET was used for staging. Cisplatin (80mg/m2) was administered on day 1 and vinorelbine (20mg/m2) was administered on days 1 and 8 for two cycle. Twice-daily radiation therapy (1.5 Gy per fraction) without elective nodal irradiation started on day 1. Total doses were 60Gy in 40 fractions and 66Gy in 44 fractions at levels 1 and 2 respectively. After concurrent chemoradiotherapy, consolidation chemotherapy regimen was cisplatin (80mg/m2) on day 1 and vinorelbine (20mg/m2) on days 1 and 8 every 4 week for three cycles. The dose-limiting toxicity (DLT) was defined as grade ≥ 3 esophagitis, grade 3 neutropenic fever, grade ≥ 3 other non-hematologic toxicities and interruption of irradiation for more than 2 weeks. DLT was monitored for 90 days. Results: A total of 12 patients were enrolled (6 patients in Level 1, 6 patients in Levels 2). DLTs were noted in 2 patients at Level 1, which were grade 3 esophagitis and grade 3 febrile neutropenia. Radiation dose was escalated up to 66 Gy in 44 fractions (Level 2), and there was no DLT. In principle, Sixty-six Gy in 44 fractions (Level 2) should be the RD. Major toxicities were leucopenia, neutropenia, and anemia. The response rate, the median progression free survival time, and the median overall survival time was 83.3%, 10.4 months, and 36.3 months for all patients, respectively. Conclusions: The RD was 66 Gy in 44 fractions (Level 2). The toxicity of this chemoradiothrapy regimen was manageable and efficacy is promising. The efficacy and safety of this regimen should be confirmed in a phase II study. Clinical trial information: UMIN000003769.
Outcomes of early stage lung cancer treatments in older patients: A SEER database analysis.
Authors: Marr Alissa S. , Shostrom Valerie , Islam K. M , Ganti Apar Kishor
Published: March 2020

7571

Background: Although the majority of lung cancer patients are over the age of 65, there are limited data on outcomes of treatment options for early stage lung cancer in older patients. Methods: Treatment and outcome data of stage I and II non-small cell lung cancer (NSCLC) patients were obtained from the Surveillance, Epidemiology and End Results (SEER) database. Treatment modalities included no treatment, surgery, radiation, and a combination of surgery and radiation. Patients were divided based on age groups into <65, 65-75, and >75 years old. Multivariate logistic regression was used to compare the likelihood of survival in the three age groups while controlling for gender and race. Results: A total of 10,763 patients diagnosed with stage I and II NSCLC between 1988 and 2007 within the SEER database were analyzed. The age distribution was as follows: <65 (n=3558), 65-75 years (n= 4454), >75 years (n=2751). Patients <65 years of age were more likely than those >75 years of age to be treated with surgery (72.5% vs. 53.5%, respectively; p = <0.0001). Patients >75 years of age were more often treated with radiation alone (23%) or no treatment (18.2%) as compared to those patients <65 (9% and 4.9%, respectively; p = <0.0001). Patients <65 years of age with stage I lung cancer had a statistically significant improved lung cancer-specific 5-year survival with surgery alone as compared to those 65-75 years and >75 years. Lung cancer specific mortality at 5 years was 19%, 26% and 30%, respectively; p= <0.0001. Similar results were seen in stage II patients. When stage I patients received radiation therapy, lung cancer-specific deaths at 5 years were not different between the three groups (66% vs. 63% vs. 66%, respectively; p=0.1263). The 5-year lung cancer- related mortality was lower in younger patients who received no treatment (51% in <65, 56% in 65-75, and 57% in >75 years old; p=0.006). Conclusions: Older patients treated surgically for stages I and II NSCLC have a lower lung cancer-specific survival when compared to younger patients. In contrast, there is no difference in lung cancer-specific survival for patients treated with radiation therapy. Hence, careful selection of older patients for surgical therapy of early stage NSCLC is warranted.
Predictive value of BRCA1, ERCC1, ATP7B, PKM2, TOPO-I, TOPO-iia, TOPO-iib, and c-MYC genes in patients with small cell lung cancer (SCLC) who received first-line therapy with cisplatin and etoposide.
Authors: Papadaki Chara , Karachaliou Niki , Lagoudaki Eleni , Trypaki Maria , Sfakianaki Maria , Koutsopoulos Anastasios , Mavroudis Dimitrios , Stathopoulos Efstathios , Georgoulias Vassilis , Souglakos John
Published: March 2020

7594

Background: to evaluate the predictive value of genes correlated with cisplatin-etoposide (EP) metabolism or mode of function in patients with SCLC. Methods: Tumor samples from 184 patients, with SCLC were analyzed for ERCCI, BRCA1, ATP7B, TOPOI, TOPOIIA, TOPOIIB PKM2 and C-MYC mRNA expression by quantitative real-time PCR, from microdissected cells derived from patients’ primary tumors. All patients were treated with EP (plus radiotherapy for patients with limited disease-LS) in the department of Medical Oncology of the University Hospital of Heraklion. Results: The median age of the patients was 63 years (min-max: 33-78). One hundred-twenty (65%) patients presented with extended stage (ES), LDH was above the UNL in 75 (41%), while ECOG performance status was 0-1 in 131 (71%) of them. Shorter progression free survival (PFS) was observed in patients with LS-SCLC whose tumors expressed high ERCC1 (p=0.028), PKM2 (p=0.046), TOPO-I (p=0.008), TOPO-IIA (p=0.002) and TOPO-IIB (p<0.001) expression. High expression of ERCC1 (p=0.014), PKM2 (p=0.026), TOPO-IIA (p=0.021) and TOPO-IIB (p=0.019) was correlated with shortened median overall survival (OS) in LS-SCLC patients. In patients with ES-SCLC, only high TOPO-IIB expression was associated with decreased OS (p=0.035). The favorable genotype (low expression of ERCC1, PKM2, TOPO-IIA and TOPO-IIB) was correlated with significantly improved PFS in both LS-SCLC (p<0.001) and ES-SCLC (p=0.007) patients as well as with improved OS in the LS-SCLC (p=0.007) and ES-SCLC (p=0.011) group. Unfavorable genotype was independent predictor of poor PFS (HR: 3.18; p=0.002) and OS (HR: 4.35; p=0.001) in LS-SCLC as well as for both PFS (HR: 3.14; p=0.021) and OS (HR: 3.32; p=0.019) in ES-SCLC. Conclusions: Single gene’s expression analysis as well as the integrated analysis of ERCC1, PKM2, TOPO-IIA and TOPO-IIB may predict treatment outcome in patients with SCLC. The results of our study, if validated prospectively, may help in selecting patients for personalized therapeutic strategies.
Oral (O) versus intravenous (IV) etoposide and platinum in the treatment of extensive-stage small cell lung cancer (SCLC).
Authors: Dorroh Scott Alan , Siegel Eric R , Govindarajan Rangaswamy
Published: March 2020

7597

Background: Platinum and etoposide chemotherapy is the treatment for patients with SCLC. O etoposide is substituted for IV by many clinicians at twice the dose for bioavailability but the outcome of these subjects has not been studied. To compare the efficacy of O vs. IV etoposide in extensive stage SCLC, a retrospective analysis of subjects treated in the VISN 16 network of 10VA hospitals was undertaken. Methods: Subjects with SCLC diagnosed between 10/1/1996 and 9/30/2010 were identified from the VISN-16 tumor registry. Study was limited to extensive disease by excluding those treated with radiation therapy. Chemotherapy details were obtained from the pharmacy data in the VISN 16 database. Overall survival (OS) was computed as the time in months from the first etoposide issue date to the date of death or last contact. Kaplan-Meier methods were used to compute median OS, and etoposide groups were compared via log-rank test. Results: 300 subjects were eligible for analysis, with median age 67 yrs (range 45-84). 295 deaths were observed during 2,419 total months of follow-up. The median OS of all subjects was 6.3 months (interquartile range (IQR) 2.0-11 months). In addition to platinum, 153 subjects received only O etoposide, 147 received some form of IV etoposide. The median duration (IQR) of therapy for all subjects was 29 (1-110) days; 23 days for those who received any IV etoposide and 43 days for those who received only oral etoposide. The median OS was 7.6 months for those who received only O etoposide vs. 5.4 months for any IV etoposide (P<0.0001). In the latter group, those receiving purely IV etoposide had only 1.5 months’ median OS vs. 8.8 months for those receiving both O and IV etoposide (P<0.0001). Conclusions: Survival of subjects with SCLC treated with O etoposide is comparable to those who received a combination of O and IV therapy. Poor OS for those with only IV therapy may be due to selection bias of poor-performance subjects. [Table: see text]
Molecular profiling of small cell lung cancers in Japanese patients.
Authors: Wakuda Kazushige , Kenmotsu Hirotsugu , Serizawa Masakuni , Koh Yasuhiro , Isaka Mitsuhiro , Takahashi Toshiaki , Murakami Haruyasu , Naito Tateaki , Taira Tetsuhiko , Shukuya Takehito , Ono Akira , Akamatsu Hiroaki , Imai Hisao , Mori Keita , Endo Masahiro , Nakajima Takashi , Ohde Yasuhisa , Yamamoto Nobuyuki
Published: March 2020

7599

Background: Molecular abnormalities discovered in the last decade have led to a paradigm shift in the diagnosis and treatment of lung adenocarcinoma. But there have been few reports about molecular profiling of small cell lung cancers (SCLC). We conducted the Shizuoka Lung Cancer Mutation Study to analyze driver mutations in patients with thoracic SCLC malignancies. Methods: We collected molecular profiling data of SCLC from the biobanking system in conjunction with the clinic, including the pathology lab, where 23 mutations in 9 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN and HER2), EGFR, MET, PIK3CA, FGFR1 and FGFR2 amplifications, and EML4-ALK translocations were assessed using pyrosequensing plus capillary electrophoresis, qRT-PCR, and RT-PCR, respectively. To evaluate mutation status for SCLC patients, we collected patient characteristics data from medical records. Results: Between July 2011 and July 2012, fifty small cell lung cancer patients were assessed in our biobanking system. Patient characteristics were as follows: median age (range) 70 (43 - 82) years; male 82%; smoker 96%; limited disease/extended disease 56/44%; small cell carcinoma/combined small cell carcinoma with adenocarcinoma 94/6%; surgically resected snap-frozen samples 8, formalin-fixed paraffin-embedded samples 40 and pleural effusion 7. We detected driver mutations in 8 cases (16%). Mutations found: EGFR 1 (2%), KRAS 1 (2%), PIK3CA 2 (4%), AKT1 1 (2%), MET amplification 1 (2%), PIK3CA amplification 6 (12%). EGFR and KRAS mutation were found in combined small cell carcinoma with adenocarcinoma. No significant differences in age, sex, disease extent at diagnosis or smoking status were found between patients with mutations and those without mutations. But serum neuron-specific enolase (NSE) levels were significantly higher in patients without mutations (p=0.03). Conclusions: In our analysis, driver mutations were found in 16% of SCLC patients and PIK3CA amplification seemed to be relatively frequent in SCLC. Our results suggest that PIK3CA might become a target of treatment for SCLC patients.
Thymic carcinoma: A cohort study of prognostic factors after surgical resection from the European Society of Thoracic Surgeons database.
Authors: Ruffini Enrico , Detterbeck Frank C. , Van Raemdonck Dirk , Rocco Gaetano , Thomas Pascal Alexandre , Weder Walter , Brunelli Alessandro , Guerrera Francesco , Keshavjee Shaf , Altorki Nasser K. , Schutzner Jan , Toker Alper , Spaggiari Lorenzo , Arame Alex , Lim Eric Kian Saik , Venuta Federico ,   European Society of Thoracic Surgeons Thymic Group
Published: March 2020

7602

Background: Thymic carcinomas are rare tumors which have recently been separated from thymomas due to their different histologic/clinical characteristics. Most of the current literature is composed of small series spanned over extended time periods Methods: The European Society of Thoracic Surgeons (ESTS) developed a retrospective database collecting data on patients with thymic tumors submitted to surgery (1990-2011). Out of 2,265 incident cases, there were 229 thymic carcinomas. Clinical-pathologic characteristics were analyzed including age, gender, stage (Masaoka), histologic subtypes (squamous cell/others), type of resection (complete/incomplete), tumor size, induction and adjuvant therapy (chemotherapy-ChT/radiotherapy-RT), recurrence. Primary outcome was overall survival (OS); secondary outcomes were disease-free survival (DFS) and the cumulative incidence of recurrence. Survival analysis was performed using univariate and multivariate (Cox-shared frailty) competing-risk models. Missing data were analysed using multiple-imputation techniques Results: A multidisciplinary approach (surgery, ChT and RT) was used in most patients. Induction therapy was employed in 78 patients (ChT, 53; ChT/RT 23; RT, 2). Adjuvant therapy was employed in 150 patients (ChT, 19; ChT/RT, 72; RT, 59). Complete resection (R0) was achieved in 71% of the patients. Five and 10-year OS were 60% and 35%. Five and 10-year DFS were 62% and 43%. Cumulative incidence of recurrence was 0.25, 0.32 and 0.40 at 3, 5, and 10 years. Independent OS predictors (multivariate analysis) were young age (p=0.006), stage I/II (vs. III/IV, p=0.02), R0 resection (p<0.001), adjuvant therapy (ChT, RT or both) (p=0.02). Independent predictor of recurrence (univariate analysis) was tumor size (p=0.05). Conclusions: In thymic carcinomas submitted to surgical resection, increased age,Masaoka stages III-IV and incomplete resection had a significant impact in worsening survival. Larger tumors had an increased risk of recurrence. The administration of adjuvant ChT or RT was associated with improved overall survival. A multidisciplinary approach to these rare tumors remains essential.
Thymic epithelial tumors at University Federico II of Naples: A 30-year experience.
Authors: Buonerba Carlo , Federico Piera , Calabrese Filomena , Ottaviano Margaret , Nappi Lucia , Rescigno Pasquale , Matano Elide , Di Lorenzo Giuseppe , Damiano Vincenzo , Palmieri Giovannella
Published: March 2020

7603

Background: According to the 2004 WHO classification, thymic epithelial tumors (TETs) comprise different histologies, including thymomas, thymic carcinoma, typical and atypical carcinoids. Histology classification of TETs has a dramatic impact on the prognosis and therapeutic strategy. We here review all TETs treated at our Institution over the past 30 years. Methods: Eligible patients had a pathologically confirmed TET and had at least one access at our Institution. Relevant demographic and clinical data were retrieved. An exploratory analysis was conducted using a step-wise model in patients with completely resected tumors to seek for factors predictive of recurrence after radical surgery. Results: One hundred and three patients with TETs were included in this retrospective analysis. Forty-three were female, sixty were male. Median age was 43 years (range 32-58). Forty-three patients had myasthenia gravis. Four had a thymic neuroendrocrine tumor, 19 had a thymic carcinoma, while the remaining had a thymoma. Forty-seven patients were alive at the time of analysis. Median overall survival was 5.85 years (range, 2.58-9.9). In the whole sample population, seventy-six patients had a completely resected tumor with clear pathological margins. In this sub-group of 76 patients (median age: 46, 35-55; 30 females, 46 males), 12 had a thymic carcinoma and 30 patients recurred after radical surgery. At multivariate analysis, which included age, sex, adjuvant chemotherapy, adjuvant radiotherapy, maximum tumor diameter, presence of myasthenia gravis and stage, the only factor significantly predictive of recurrence was tumor histology (odds ratio: 3,8182, 95% CI: 1,03 to 14,1; p = 0.04). Conclusions: We showed that patients with thymic carcinomas are at increased risk of recurrence after radical surgery independently on adjuvant chemotherapy/radiotherapy treatment. Additional therapeutic options are required in the adjuvant setting of completely resected thymic carcinomas.
Biomarkers (BM) France: Results of routine EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-small cell lung cancer (NSCLC) patients (pts).
Authors: Barlesi Fabrice , Blons Helene , Beau-Faller Michele , Rouquette Isabelle , Ouafik L'houcine , Mosser Jean , Merlio Jean-Philippe , Bringuier Pierre Paul , Jonveaux Philippe , Le Marechal Cedric , Denis Marc G. , Penault-Llorca Frederique Madeleine , Debieuvre Didier , Soria Jean-Charles , Cadranel Jacques , Mazieres Julien , Missy Pascale , Morin Franck , Nowak Frederique , Zalcman Gerard ,   Intergroupe Francophone de Cancérologie Thoracique (IFCT)
Published: March 2020

8000

Background: Personalized medicine is now a reality for advanced NSCLC pts on the basis of routine screening for EGFR mutation and ALK gene fusion assessment. The French NCI (INCa) also decided to additionally fund the routine assessment of 4 additional BM (HER2, KRAS, BRAF, PI3KCA). Methods: Starting on April 2012, these BM analyses were prospectively collected into a database head by the IFCT (www.ifct.fr) with 15-20,000 analyses awaited after one year. The physicians prescribing each of these BM analyses were then connected to this database and were asked to regularly complete epidemiological, clinical and therapeutic data for each corresponding patient. Results: 10,000 BM analyses were collected and entered into the BM France database at the time of this first analysis (January 2013). On the basis of available data, the patients were mainly male (63.8%), (ex)smokers (83.3%) and stage IV pts (64%). The tumors were mainly adenocarcinomas (76.1%). The samples for BM analysis were collected under bronchoscopy, surgery or transthoracic biopsy in 27.4, 28.1 and 24.2%, respectively. The 10,000 molecular profiles were characterized by 9.4% EGFR (including 0.8% EGFR resistant), 0.9% HER2, 26.9% KRAS, 1.6% BRAF, and 2.6% PI3KCA mutated and 4.0% EML4-ALK fusion genes. Double mutations were seen in 0.9% of the tumors. On January 2013, data on treatment were available for 18.6% of patients among whom 56.9% of patients received a treatment according to their molecular profile (labeled drugs or bio-guided trials). Updated data will be presented during the meeting. Conclusions: Biomarkers France is the largest ever conducted biomolecular study on advanced NSCLC patients and provides solid data on the value of a nationwide BM screening policy for NSCLC patients.
Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC.
Authors: Shaw Alice Tsang , Mehra Ranee , Kim Dong-Wan , Felip Enriqueta , Chow Laura Quan Man , Camidge D. Ross , Tan Daniel Shao-Weng , Vansteenkiste Johan F. , Sharma Sunil , De Pas Tommaso , Wolf Juergen , Katayama Ryohei , Lau Yi-Yang Yvonne , Goldwasser Meredith , Boral Anthony , Engelman Jeffrey A.
Published: March 2020

8010

Background: Lung cancers harboring anaplastic lymphoma kinase (ALK) gene rearrangements are sensitive to the tyrosine kinase inhibitor (TKI) crizotinib (CRZ), but invariably develop resistance. LDK378 is a novel, more potent ALK TKI than CRZ, with significant antitumor activity in preclinical models. Methods: In this multicenter phase I study, 131 patients (pts) with advanced malignancies harboring a genetic alteration in ALK, including 123 with ALK-rearranged (ALK+) NSCLC (as determined by FISH), were enrolled. LDK378 was administered orally at doses of 50–750 mg once daily. All pts were assessed for PK, response to therapy, and adverse events (AEs). In >20 pts with CRZ-resistant disease, tumor biopsy was performed before LDK378 treatment to identify CRZ resistance mutations. Results: As of November 8, 2012, 131 pts had been enrolled (38% male, median age 53 years), including 59 pts in the dose escalation phase, during which the MTD of 750 mg once daily was established, and 72 pts in an expanded cohort at the MTD. Among 88 evaluable NSCLC pts who received LDK378 at 400–750 mg daily, the overall response rate (ORR) was 70%, with 40 confirmed and 22 unconfirmed responses. In the subset of 64 CRZ-resistant pts, the ORR was 73%, with 31 confirmed and 16 unconfirmed responses. As of November 8, 2012 50% of pts with unconfirmed responses were ongoing. Responses were observed in pts with different CRZ resistance mutations as well as in pts without detectable mutation. Responses were also seen in pts with untreated CNS metastases. Among NSCLC pts with confirmed response, median duration of response (DOR) was 7.4 months (95% CI, 6.7 – NR), and 78% had a DOR of ≥6 months. In all 123 NSCLC pts, median PFS was 8.6 months (95% CI, 4.3 – 19.3). The most common AEs were nausea (72%), diarrhea (69%), vomiting (50%), and fatigue (31%). The most common Grade 3/4 AEs were ALT elevation (12%), diarrhea (7%), and AST elevation (6%). Conclusions: LDK378 induces durable responses in the majority of pts with advanced, ALK+ NSCLC, including CRZ-resistant pts with and without CRZ resistance mutations. These results suggest that more potent ALK inhibition by LDK378 represents a highly efficacious treatment strategy for ALK+ pts, particularly those who relapse on CRZ. Clinical trial information: NCT01283516.
Clinical next generation sequencing (NGS) to reveal high frequency of alterations to guide targeted therapy in lung cancer patients.
Authors: Ali Siraj M. , Palma Norma Alonzo , Wang Kai , Ross Jeffrey S. , Stephens Philip J. , Yelensky Roman , Palmer Gary A. , Lipson Doron , Miller Vincent A.
Published: March 2020

8020

Background: Cancer genomic profiling via NGS in a clinical setting can reveal additional actionable genomic alterations (GA) in patients with lung cancer (LC) previously tested only by hotspot analysis and leading to unanticipated avenues of targeted treatment. Methods: We performed an NGS-based diagnostic test (FoundationOne) to characterize all classes of GA across 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on 386 LC FFPE specimens in a CLIA-certified lab (Foundation Medicine). Specimens included fine needle aspirates, core needle biopsies, and malignant effusions. 95% of cases were NSCLC (367/386). Actionable GAs are defined as those linked to targeted anti-cancer therapies approved or being evaluated in clinical trials. NGS confirmed known hotspot results for EGFR, KRAS and EML4:ALK in 100% of cases. Results: Genomic profiles were generated from 364/386 (94%) of lung cancer cases, identifying 1205 GA, averaging 3.31 alterations per tumor (range 0 to 10). 85% of tumors (310) harbored at least one actionable GA, with a mean of 1.79 GA per tumor (range 0 to 6). In 68% of tumors (248), at least one GA was detected that would be missed by current ‘hotspot assays’. ERBB2 harbored base substitutions or indels in 1.3% of cases. BRAF and C-Kit were altered at frequencies of 2% and 1% respectively. The mTOR/PI3K pathway is likely to be activated via alterations in tumor suppressors STK11 (11%), NF1 (6%) and PTEN (4%), as well as by alterations of PIK3CA (10%) and in AKT1/2/3 (4%), suggesting possible benefit from mTOR/PI3K inhibitors. The Hedgehog pathway (PTCH1/SMO/SUFU) was altered in 2% of cases. ALK and RET were rearranged in 4% and 2% of cases, respectively, with several cases initially diagnosed negative by FISH testing. Conclusions: Profiling the tumor genomes of 364 LC patients led to the identification of a series of GA not detectable by hotspot testing that could significantly inform targeted treatment decisions. Moreover, actionable GA appeared in unexpected tumor type, i.e. an EGFR mutation in a SCLC, reinforcing the likely utility of clinical cancer genomic profiling for the personalized treatment of LC patients.
Comparison of the characteristics and clinical course of 677 patients with metastatic lung cancers with mutations in KRAS codons 12 and 13.
Authors: Yu Helena Alexandra , Sima Camelia S. , Shen Ronglai , Kass Samantha Lindsay , Kris Mark G. , Ladanyi Marc , Riely Gregory J.
Published: March 2020

8025

Background: Patients (pts) with KRAS mutant lung cancers have a shorter survival compared to pts with KRAS/EGFR wild type tumors (Johnson et al, Cancer 2012). Whether outcomes for patients with KRAS mutant metastatic lung cancers differ by smoking status or specific amino acid substitution is unknown. In order to understand the impact of KRAS mutation subtype in the metastatic setting, we analyzed a large cohort of patients with KRAS mutant metastatic lung cancer. Methods: We identified all pts with KRAS mutant metastatic or recurrent lung cancers from Feb 2005 to Aug 2011. KRAS mutation type, clinical characteristics, and outcomes from diagnosis were obtained from the medical record. A multivariate cox proportion hazard model was used to identify factors associated with overall survival. Results: KRAS mutations were identified in 677 pts (53 at codon 13, 624 at codon 12). Median age: 66 (range 31-89), women: 62%, never smokers: 7%. Pts with transition mutations (n=157) were more likely to be never-smokers (p<0.0001). There was no difference in outcome for pts with KRAS transition versus transversion mutations (p=1) or when comparing current/former smokers to never smokers (p=0.33). There was no difference in overall survival (OS) when comparing specific amino acid substitutions (G12C=366, G12V=141, G12D=114, G12A=68, G13C=27, G13D=23, G12S=19, G12F=11)(p=0.20). Pts with KRAS codon 13 mutant tumors had inferior OS compared to pts with codon 12 mutant tumors, median 13 months (mo) (95% CI 13-17 mo) and 16 mo (95% CI 9-16 mo), respectively (p=0.009). There was no difference in frequency of receiving platinum-based chemotherapy or chemotherapy of any kind between pts with codon 12 and 13 mutant tumors. In a multivariate Cox model which included age, gender and smoking status, KRAS codon 13 mutation was associated with worse overall survival than KRAS codon 12 mutation (HR 1.52 95% CI 1.11-2.08 p=0.008). Conclusions: Among pts with KRAS mutant metastatic lung cancers, smoking history, and specific amino acid substitution do not affect outcome. Patients with KRAS codon 13 mutant metastatic lung cancer have shorter survival compared to pts with KRAS codon 12 mutant lung cancer.
MEK114653: A randomized, multicenter, phase II study to assess efficacy and safety of trametinib (T) compared with docetaxel (D) in KRAS-mutant advanced non–small cell lung cancer (NSCLC).
Authors: Blumenschein George R. , Smit Egbert F. , Planchard David , Kim Dong-Wan , Cadranel Jacques , De Pas Tommaso , Dunphy Frank , Udud Katalin , Ahn Myung-Ju , Hanna Nasser H. , Kim Joo-Hang , Mazieres Julien , Kim Sang-We , Baas Paul , Rappold Erica , Redhu Suman , Bellew Kevin M. , Streit Michael R. W. , Wu Frank S. , Janne Pasi A.
Published: March 2020

8029

Background: KRAS mutations are detected in 25% of NSCLC, and there are no approved targeted therapies for this subset of NSCLC. D, an approved second-line treatment for NSCLC, has a response rate of < 10%. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. This phase II trial (NCT01362296) evaluated the efficacy of T vs D in pts with advanced KRAS-mutant NSCLC who had received prior platinum-based chemotherapy. Methods: Pts were randomized 2:1 to T (2 mg QD) or D (75 mg/m2 IV every 3 weeks) and stratified by type of mutational status and gender. Crossover to the other arm after progressive disease was allowed. Primary endpoint was PFS in pts with KRAS-mutant NSCLC (modified ITT; mITT). Secondary endpoints were OS, ORR, duration of response, and safety. PFS and OS were compared using a stratified log-rank test. The trial was stopped early for futility at a planned interim analysis; 92 PFS events were reported at the time of study termination. Results: Between September 2011 and July 2012, 134 pts were randomized to T (89) or D (45); 129 pts had KRAS-mutant NSCLC. Mean age was 61.4 y and 53% were male. In the mITT, 61/86 pts (71%) on T and 31/43 (72%) on D had a PFS event. HR for PFS was 1.14 (95% CI, 0.75-1.75; P = .5197) with a median PFS of 11.7 vs 11.4 wk for T vs D. ORR was 12% for T (10/86) and for D (5/43). With 27 (31%) deaths on T and 15 (35%) on D, HR for OS was 0.97 (95% CI, 0.52-1.83; P= .934). Five fatal SAEs were reported during treatment with T but none with D; 1 unspecified death was considered related to T. Frequent AEs reported with T were rash (59%), diarrhea (47%), nausea (34%), hypertension (34%), and dyspnea (33%). Grade 3/4 AEs with T were hypertension (16%/0), dyspnea (7%/3%), rash (6%/3%), diarrhea (6%/0), and asthenia (6%/0). Rate of treatment related SAEs was 15% with T and 12% with D. Conclusions: T did not improve PFS in pts with KRAS-mutation–positive NSCLC compared with D. However, an ORR of 12% for T in KRAS-mutant NSCLC suggests that an effort to better identify responsive mutations is warranted. The safety profile did not favor T, but is, in general, consistent with the overall T safety profile. Clinical trial information: NCT01362296.
Survival and long-term follow-up of the phase I trial of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC).
Authors: Brahmer Julie R. , Horn Leora , Antonia Scott J. , Spigel David R. , Gandhi Leena , Sequist Lecia V. , Sankar Vindira , Ahlers Christoph Matthias , Wigginton Jon M. , Kollia Georgia , Gupta Ashok Kumar , Gettinger Scott N.
Published: March 2020

8030

Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. Nivolumab, a PD-1 receptor blocking antibody, was evaluated in a phase 1 study in pts with various tumors including NSCLC (Topalian et al, NEJM 2012;366:2443). Methods: Pts with ≥1 prior chemotherapy regimen received nivolumab (1-10 mg/kg IV Q2W) for ≤12 cycles (4 doses/8W cycle) or until discontinuation criteria were met. We report initial overall survival (OS) and updated safety and response data for NSCLC pts. Results: 127 pts evaluable for safety received nivolumab at 1, 3, or 10 mg/kg as of July 2012. Common drug-related AEs were decreased appetite (9%), anemia (8%), diarrhea, nausea, and pruritus (7% each). The most common G3/4 AEs were fatigue, pneumonitis, and elevated AST (2% each). Two drug-related deaths from pneumonitis occurred early in the trial and led to increased monitoring without further deaths from pneumonitis. Median OS (mOS) across all dose cohorts was 9.2 mo and 9.6 mo for squamous (sq) and non-sq NSCLC, respectively. mOS was not reached at the 3 mg/kg dose (phase 3 dose) for either histology. Sustained OS was observed, with 44%/ 41% and 44%/ 17% of pts (sq/non-sq) alive at 1 and 2 years, respectively (Table). Prolonged ORs occurred in both histologies (Table). Conclusions: In this long-term follow-up of a phase I trial, nivolumab had an acceptable safety profile and showed an encouraging sustained OS benefit across histologies in previously treated advanced NSCLC. Follow-up through a Feb 2013 data cut (≥1 yr follow-up for all pts) will be provided at presentation. Clinical trial information: NCT00730639. [Table: see text]
A phase I/II study with a highly selective ALK inhibitor CH5424802 in ALK-positive non-small cell lung cancer (NSCLC) patients: Updated safety and efficacy results from AF-001JP.
Authors: Nakagawa Kazuhiko , Kiura Katsuyuki , Nishio Makoto , Seto Takashi , Maemondo Makoto , Inoue Akira , Hida Toyoaki , Yamamoto Nobuyuki , Yoshioka Hiroshige , Harada Masao , Ohe Yuichiro , Nogami Naoyuki , Takeuchi Kengo , Shimada Tadashi , Tanaka Tomohiro , Tamura Tomohide
Published: March 2020

8033

Background: Anaplastic lymphoma kinase (ALK) is a constitutively activated tyrosine kinase in a subset of NSCLC with ALK fusion gene derived from chromosomal rearrangement. Previously, CH5424802, a highly selective, second-generation ALK inhibitor, has demonstrated clinically meaningful antitumor activity and a favorable toxicity profile (ESMO 2012). Here we report the updated results of this study. Methods: Patients (Pts) with ALK-positive NSCLC and no prior ALK inhibitor therapy were treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity to investigate the efficacy and safety. Results: As of the cut-off date of Dec. 14, 2012, 58 pts have been treated with CH5424802: median age 49.5 years, M/F 25/33, ECOG PS 0/1 26/32, never-smoker 60.3%, ≥2 prior chemotherapy regimens 62%. Among the 46 pts in phase II part of this study, the overall response rate was 93.5% (95% CI: 82.1%, 98.6%) with 2 CRs and 41 PRs. Tumor shrinkage by 30% (PR) was achieved quickly with 65% occurring within 3 weeks of treatment and 87% within 6 weeks. With a median follow-up period of 12.6 months, 47/58 pts (40/46 pts in phase II part) were still on study treatment, and the median treatment duration has passed 10.3 months. The major treatment-related AEs were dysgeusia (21/58, 36%), rash, AST increased, blood bilirubin increased (19/58, 33% each), constipation and blood creatinine increased (17/58, 29% each), mostly grade 1-2. The major treatment-related grade 3 AEs were neutrophil count decreased (4/58, 7%). No grade 4 or fatal AEs were observed. Treatment-related visual disorders, vomiting and nausea were rare and mild. Conclusions: In patients with ALK-positive NSCLC but naïve to any ALK inhibitor therapy, treatment with CH5424802 demonstrated generally mild toxicity and lead to high response rate of 93.5% and durable treatment beyond 10 months, expecting that treatment duration can be longer than that of crizotinib. CH5424802 is therefore a promising new ALK inhibitor for NSCLC. Clinical trial information: JapicCTI-101264.
Randomized phase II trial of NGR-hTNF in combination with standard chemotherapy in previously untreated non-small cell lung cancer (NSCLC).
Authors: Gregorc Vanesa , Zilembo Nicoletta , Grossi Francesco , De Pas Tommaso M , Rossoni Gilda , Pietrantonio Filippo , Rijavec Erika , Citterio Giovanni , Lambiase Antonio , Bordignon Claudio
Published: March 2020

8035

Background: NGR-hTNF, a selective antivascular agent, induces at low dose an initial vascular normalization that greatly enhances the intratumoral chemotherapy uptake, with synergistic effects that were noted especially in combination with cisplatin and gemcitabine. Methods: Chemo-naive patients (pts) with advanced NSCLC were stratified by histology (nonsquamous or squamous) and PS (0 or 1) and randomly assigned to receive cisplatin 80 mg/m2/d1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1+8 (squamous) every 3 weeks (q3w) for 6 cycles, with (arm A) or without (arm B) NGR-hTNF given at 0.8 μg/m2/d1/q3w until progression. Progression-free survival (PFS) was primary aim (1-β=80%, 1-sided α=10%, n=102). Secondary aims comprised adverse events (AEs), response rate (RR), and overall survival (OS). Results: Baseline characteristics in arm A (n=62) vs B (n=59) were: median age: 62 vs 63 years; men: 37 vs 39; PS 1: 23 vs 23; squamous: 18 v 17; smokers: 41 vs 43. For the nonsquamous stratum, 299 cycles were given in arm A (mean 7.0; range 1-20) and 192 in arm B (4.8; 1-6), while for the squamous stratum, 113 in arm A (6.7; 1-31) and 52 in arm B (3.5; 1-6). Rates of grade 3/4 AEs were similar (arm A vs B): neutropenia 13% vs 18%, anaemia 7% vs 4% and fatigue 7% vs 11%. No grade 3/4 AEs related to NGR-hTNF or bleeding/pulmonary hemorrhage events were reported in the squamous subset. With median follow-up time of 24.2 months, median PFS (5.8 vs 5.6 months; HR=0.92), RR (25% vs 21%) and 1-year OS (53% vs 53%) were similar between the two treatment arms. However, by predefined analysis in the squamous stratum, median PFS was 5.6 months for arm A and 4.3 months for arm B (hazard ratio, HR=0.75) and median OS was 14.2 months for arm A and 9.7 months for arm B (HR=0.49; p=0.07). In pts with squamous histology, RR was 38% for arm A and 27% for arm B (odds ratio=1.6), while the median changes in tumor size on treatment from baseline to 2nd, 4th and 6th cycle for arm A vs B were -32% vs -20%, -41% vs -19%, and -42% vs -14%, respectively. Conclusions: Clinical tolerability and benefit were noted in squamous NSCLC with NGR-hTNF plus cisplatin and gemcitabine, which deserve further investigation. Clinical trial information: NCT00994097.
Clinical trial risk reduction in non-small cell lung cancer though the use of biomarkers and receptor-targeted therapies.
Authors: Falconi Adam , Lopes Gilberto , Parker Jayson L.
Published: March 2020

8040

Background: We analyzed the risk of clinical trial failure duringnon-small cell lung cancer (NSCLC) drug development between 1998 and 2012. Methods: NSCLC drug development was investigated using trial disclosures from publically available resources. Compounds were excluded from the analysis if they began phase I clinical testing before 1998 and if they did not use treatment relevant endpoints. Analysis was conducted in regards to treatment indication, compound classification and mechanism of action. Costs of clinical drug development for advanced NSCLC were calculated using industry data and assumptions, a 9% yearly discount rate and assuming a clinical trial length of 2.5 years for phase I trials, 4 years for phase II trials, 5 years for phase III trials and an average of 5 phase I trials, 7 phase II trials, and 4 phase III trials per approved drug. All funding costs are in US dollars (USD). Results: 2,407 clinical trials met search criteria. 676 trials and 199 unique compounds met our inclusion criteria. The likelihood, or cumulative clinical trial success rate, that a new drug would pass all phases of clinical testing and be approved was found to be 11%, which is less than the expected industry aggregate rates (16.5%). The success of phase III trials was found to be the biggest obstacle for drug approval with a success rate of only 28%. Biomarker-guided targeted therapies (with a success rate of 62%) and receptor targeted therapies (with a success rate of 31%) were found to have the highest likelihood of success in clinical trials. The risk-adjusted cost for NSCLC clinical drug development was calculated to be 1.89 billion US dollars. Use of biomarkers decreased drug development cost by 26% to 1.4 billion US dollars. Potential savings may be even higher if fewer clinical trials are required for successful development. Conclusions: Physicians that enroll patients in NSCLC trials should prioritize their participation in clinical trial programs that involve either a biomarker or receptor targeted therapy, which appear to carry the best chances for a successful treatment response. Given the high adjusted cost of clinical testing alone in NSCLC, efforts to mitigate the risk of trial failure need to explore these factors more fully.