bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical profile and patterns of progression (PD) of patients (pts) with advanced nonsquamous non-small cell lung cancer (nsNSCLC) treated with first-line bevacizumab (B): AVVA study.
Authors: De Castro Javier , Domine Manuel , Garcia-Bueno Jose Maria , Saura Salvador , Garcia-Gomez Ramon , Sereno Maria , Juan Oscar , Pujol Eduardo , Rubio Belen , Cobo Manuel
Published: March 2020

e18015

Background: B in combination with platinum doublets prolongs survival and delays PD in chemo-naïve pts with advanced nsNSCLC and its safety profile has been widely described in clinical trials. In this study we aim to evaluate the behavior, clinical profile and patterns of PD of real-life nsNSCLC pts treated with B in 44 Spanish institutions. Methods: AVVA is a multicenter, epidemiological study to define the clinical profile (gender, age, PS, histology, stage, comorbidities, tumor load, Tx, response and tolerability) and describe the patterns of PD. Pts diagnosed with advanced nsNSCLC and evidence of PD after treatment (Tx) with standard chemotherapy (CT) plus B up to 6 cycles followed by maintenance B were included. Results: Data of 158 pts are presented. Clinical profile was: median age 58 years (range 34-79); male 65%; stage IV 91%; adenocarcinoma 77%; ECOG PS 0/1/≥2 (%): 35/56/9; never/current/former smokers (%): 23/40/37. 64% of pts presented relevant concomitant disease at baseline (27% cardiovascular disease, 24% pulmonary disease). Tx received: B plus carboplatin-doublet/cisplatin-doublet/other (%) 70/25/5. Median no. of cycles for CT/B: 6/9. Patterns of PD: 44% presented high tumor load (tumor diameter ≥55mm and ≥5 lesions); 97% of pts presented intra-thoracic disease, 53% presented extra-thoracic disease and 13% only pulmonary disease. High tumor load was associated with extra-thoracic disease (p<0.05). ORR was 53% (95% CI: 45-61) and disease control rate was 85%. Best response was achieved after a median of 4 cycles (range 1-16). ECOG 0/1 at PD (%): 15/50. Median PFS was 7.7 months (95% CI: 7.3-8.1). No differences were found in ORR or PFS according to tumor load and intra/extra-thoracic disease. Grade 3/4 toxicities were: venous thrombosis (3.2%/0), proteinuria (0.6%/0), hemoptysis (0.6%/0), pulmonary embolism (0/0.6%) and mucositis (0.6%/0). Conclusions: B was effective in this real-life patients’ population, irrespective of tumor load and location of the disease. These results confirm the well-established safety profile and the efficacy of B as frontline Tx in nsNSCLC.
EGFR mutation analysis from REASON: A registry for the epidemiologic and scientific evaluation of EGFR mutation status in newly diagnosed NSCLC patients stage IIIB/IV.
Authors: Schuette Wolfgang , Eberhardt Wilfried Ernst Erich , Graf von der Schulenburg J.-Mathias , Dietel Manfred , Schirmacher Peter , Zaun Silke , Thomas Michael
Published: March 2020

e18016^

Background: Somatic mutations in the EGFR gene predict for sensitivity to EGFR TKI in patients with adv. NSCLC, yet limited data exists on EGFR mutation rates of all 4 exons in all NSCLC histologies. Methods: The REASON study (NCT00997230) aims to generate data on EGFR mutation (M) status, association of EGFR-M status with clinico-pathological parameters, treatment decisions and clinical outcomes for EGFR M+ patients from a large sample of stage IIIB/IV NSCLC patients in Germany. 4279 subjects for whom EGFR M testing was planned were enrolled at 151 sites (85% hospital based) in Germany. Standard test method was Sanger sequencing. While analysis of exons 19 and 21 was obligatory, exons 18 and 20 were not routinely done at all labs. Primary objectives are epidemiological data on EGFR M status and correlation with clinico-pathological features. Secondary aims are clinical outcome of all EGFR M+ patients (PFS, OS, DCR), clinical management and pharmaco-economic data associated with diagnosis and treatment of EGFR M+ patients. Results: A 2nd interim analysis provided baseline data on 3973 patients. 63% were male; 82% ever-smokers, 18% never-smokers. Adenocarcinoma is most frequent (69%), followed by squamous epithelial carcinoma (19%). 379 patients had EGFR mutations (9.9%) with 9.5% predicting TKI sensitivity and 0.4% resistance. Most common were exon 19 deletions (50%; with 35% DelE746-A750) followed by exon 21 mutations (36.8%; with 72% L858R). Multivariate analysis revealed association of gender, smoking status and histological subtype with EGFR M status (Table). 50% of M+ patients received 1st line TKI vs. 48% doublet CTX. Conclusions: REASON provides the largest data base yet on EGFR M status in Caucasian patients with newly diagnosed stage IIIB/IV NSCLC. Smoking followed by adeno-carcinoma was the strongest predictive factor for EGFR M. Only 50% of EGFR M+ patients received 1st line TKI. [Table: see text]
Retrospective analysis of the impact of age on overall survival in patients with non-small cell lung cancer.
Authors: Luu Dai Chu Nguyen , Mamet Rizvan , Zornosa Carrie C. , Niland Joyce C. , D'Amico Thomas A. , Kalemkerian Gregory Peter , Koczywas Marianna , Pisters Katherine , Rabin Michael S. , Otterson Gregory Alan
Published: March 2020

e18018

Background: Clinical trials have failed to demonstrate that age is a significant prognostic indicator among patients treated for non-small cell lung cancer (NSCLC). Clinical trials do not necessarily represent real-world experience, however. We sought to analyze the impact of age on survival in patients in the National Comprehensive Cancer Network (NCCN) NSCLC Outcomes Database. Methods: We performed a retrospective analysis of 6,834 NSCLC patients from the NCCN NSCLC Database representing 8 NCCN institutions. Of this population, 4,943 patients were eligible for our analysis. Exclusion criteria included the following: alive patients with < 180 days of follow-up, patients with incomplete staging, and patients with a prior cancer diagnosis. The study population was separated into five age quintiles with equal number of patients in each group. Variables included institution, smoking status, gender, race, Charlson comorbidity score, ECOG performance status (PS), histology, stage, and receipt of resection, drug and radiation therapy. Multivariable Cox model was performed for the effect of age on survival after adjusting for the above variables. Model assumptions were evaluated via graphs and residual tests. Results: Across the five quintiles (< 54, 54-60, 61-66, 67-72 and ≥ 73) there was a trend towards lower stage and higher Charlson score with increasing quintile. In addition, there was an increased proportion of patients with squamous cancer in the older age group. In the adjusted Cox model, there was a statistically significant longer survival in each of four younger quintiles compared to the reference group of ≥ 73 years of age (p=0.01). The adjusted hazard ratio of death for patients < 54 was .82 (95% CI = .72 to .94), for patients 54-60 was .86 (95% CI = .76 to .97), for patients 61-66 was .84 (95% CI = .74 to .95), and for patients 67-72 was .84 (95% CI = .74 to .95). There were no statistically significant pairwise interactions among age, smoking status and stage. Conclusions: Even after adjusting for institution, comorbidity scores, smoking status, race, gender, ECOG PS, histology, stage and treatment, NSCLC patients who were ≥ 73 years of age had a worse survival when compared to younger age groups.
Efficacy of fexofenadine in preventing tyrosine kinase inhibitor (TKI)-induced interstitial lung disease.
Authors: Ko Ryo , Sasaki Shinichi , Namba Yukiko , Ishimori Ayako , Yoshioka Masakata , Yoshioka Yasuko , Tominaga Shigeru , Takahashi Kazuhisa
Published: March 2020

e18019

Background: Tyrosine kinase inhibitors (TKIs; gefitinib and erlotinib) are widely indicated in NSCLC patients, especially those harboring an active mutation of EGFR, and have shown excellent efficacy. However, severe interstitial lung disease (ILD) can occur as an adverse event with TKIs, and is sometimes fatal. Fexofenadine has been used to prevent TKI-induced skin rash in all patients, who received EGFR-TKIs, since April 2009 in our hospital, and seems to reduce the incidence of ILD. Therefore, we retrospectively analyzed the efficacy of fexofenadine in preventing TKI-induced ILD. Methods: 145 NSCLC patients, in whom TKIs were administered, were analyzed in the study, comprising 54 and 91 patients with and without concomitant administration of fexofenadine, respectively. Univariate and multivariate analyses with logistic regression model were used to investigate whether fexofenadine could prevent EGFR-TKIs-induced ILD or not. Results: ILD occurred in 21 patients (14.5%), and was fatal in 5 (3.4%). The number of ILD patients with/without fexofenadine was 4 out of 54 (8.5%)/17 out of 91 (18.7%), and the mortality was 1 out of 54 patients (1.9%)/4 out of 91 (4.4%), respectively. Fexofenadine appears to reduce the ILD event (p=0.062). Interestingly, severe ILD events (grades 2, 3, 4, or 5) were significantly reduced in patients with fexofenadine compared to patients without fexonadine (p=0.031, Table). Although the administration of fexofenadine was not independent predictive factor for EGFR-TKIs-induced ILD according to multivariate analysis, it seems to reduce the ILD events (p= 0.061). Conclusions: Our data suggest that fexofenadine seem to reduce the incidence of TKI-induced ILD. However, the prospective study needs to be performed to confirm our result. [Table: see text]
Survival post-progression (SPP) in phase III trials of chemotherapy in advanced NSCLC: Its potentially different impact on OS in the first-line and salvage settings.
Authors: Hotta Katsuyuki , Takigawa Nagio , Fujiwara Yoshiro , Hisamoto Akiko , Ichihara Eiki , Tabata Masahiro , Tanimoto Mitsune , Kiura Katsuyuki
Published: March 2020

e18027

Background: We previously demonstrated that in advanced NSCLC, survival after progression to first-line chemotherapy (SPP-1) has significantly improved and has become more closely associated with OS after the initiation of first-line chemotherapy (OS-1), potentially because of the recent development of active agents even in salvage settings (Plos One 2011). We conducted a literature survey to examine time trend in survival after progression to second- or third-line chemotherapy (SPP-2/3) and its potential correlation with OS after the initiation of second- or third-line chemotherapy (OS-2/3). Methods: SPP-2/3 was pragmatically defined in each second- or third-line chemotherapy trial as the interval of MST (OS-2/3) minus median PFS time (PFS-2/3) (OS-2/3 = PFS-2/3 + SPP-2/3). The relationship between PFS-2/3 and OS-2/3 or SPP-2/3 and OS-2/3 was assessed in the regression analysis using the coefficient of determination (r2); higher r2 means a higher correlation. Results: Twenty trials of the second- or third-line chemotherapy initiated between 2001 and 2009, were defined (14,951 patients, 37 chemotherapy arms). Contrary to our previous findings regarding SPP-1, SPP-2/3 has not been significantly prolonged over the years (8.0-day increase per year; p = 0.161) despite a steady increase in OS-2/3 (17.2-dayincrease per year; p = 0.003) and PFS-2/3 (9.8-day increase per year; p = 0.005). Overall, a moderate association was observed between OS-2/3 and SPP-2/3 (r2 = 0.6755), suggesting SPP-2/3 could predict 68% of the variation in OS-2/3. Interestingly, the association between OS-2/3 and SPP-2/3 became less close over the years (r2 = 0.9849, 0.8280, and 0.5667 in 2001–2003, 2004–2006, and 2007–2009, respectively). Conclusions: During the period SPP-2/3 seemed stable, and the association between SPP-2/3 and OS-2/3 has become unclear probably because of recent survival improvement in PFS-2/3 rather than SPP-2/3. This seems in contrast with our previous report that SPP-1 has become more tightly associated with OS-1 over the year, potentially due to the establishment of active post-study treatments just in second- or third-line setting.
Bevacizumab (B), cisplatin (C), and pemetrexed (P) plus maintenance B in chemonaive patients (pts) with advanced nonsquamous non-small cell lung cancer (nsNSCLC): A phase II study.
Authors: Lopez-Vivanco Guillermo , Carrera Sergio , Sancho Aintzane , Marrodan Ines , Azcona Eider , Iruarrizaga Eluska , Rubio Itziar , Muñoz Alberto , Cardona Jose Vicente
Published: March 2020

e18031

Background: B in combination with platinum doublets followed by continuation maintenance with B prolongs survival and delays progression in chemo-naïve pts with advanced (nsNSCLC). P in combination with C is efficacious in advanced nsNSCLC as frontline treatment. This phase II study aims to evaluate the efficacy and safety of B, C and P plus maintenance B in chemo-naïve pts with advanced nsNSCLC. Methods: Chemo-naïve pts with unresectable stage IIIB or IV nsNSCLC were treated of C (75 mg/m2), P (500 mg/m2), and B (7.5 mg/kg) on day 1 every 21 days up to 6 cycles. Pts with response or stable disease (SD) received maintenance B (7.5 mg/kg) every 21 days until disease progression or unacceptable toxicity. The primary endpoint was median progression free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety and analysis of K-ras mutations and plasma VEGF levels. Results: From 4/09 to 12/11, 27 pts were enrolled in the study. Data of 21 pts are presented. Median age was 58 years (range 42-74); male/female (%): 81/19; ECOG 0/1 (%): 5/95; adenocarcinoma/large cell carcinoma (%): 95/5. Median follow-up is 4.7 months. 53% of pts received at least 6 cycles of treatment and 20% received up to 12 cycles. Among the 15 pts assessable for response, the ORR was 47% (95% CI, 21-73) and disease control rate was 87%. Median PFS was 6.0 months (95% CI, 1.9-7.5). Grade 3/4 hematologic toxicity was neutropenia (9%/0). Most frequent grade 3/4 non-hematologic toxicities were fatigue (29%/0), venous thrombosis (14%/0), pulmonary embolism (9%/0) and dyspnea (5%/5%). There were no grade 3/4 hemorrhagic events. Data on survival and the analysis of K-ras mutations and VEGF levels will be presented. Conclusions: Treatment with B, C and P plus maintenance B is feasible and effective as front-line treatment of pts with advanced nsNSCLC. These data provide further evidence that B may be used in combination with multiple standard, platinum-based doublets in this setting.
Definitive thoracic radiotherapy in oligometastatic stage IV non-small cell lung cancer (NSCLC).
Authors: Fernandes Annemarie Therese , Xanthopoulos Eric , Handorf Elizabeth , Grover Surbhi , Sharma Sonam , Eaby-Sandy Beth , Evans Tracey L. , Stevenson James , Langer Corey J. , Mitra Nandita , Apisarnthanarax Smith , Lin Lilie , Rengan Ramesh
Published: March 2020

e18032

Background: Intrathoracic tumor control in patients (pts) with metastatic NSCLC is controversial as most die of distant disease. But a subset of good performance status pts with minimal burden of extrathoracic disease may benefit aggressive treatment. We report outcomes in a subset of pts with oligometastatic NSCLC treated with definitive radiotherapy (RT) to the primary tumor. Methods: We identified29 stage IV pts from 01/04 - 08/10 who had ECOG ≤2 and ≤4 metastases who received ≥50 Gy thoracic RT with chemotherapy. Pts were assessed for local control, overall survival and toxicity. An exploratory analysis was performed matching these pts to pts receiving chemotherapy (CT) alone. Results: In the 29 chemoradiotherapy (CRT) pts, median age was 57 yrs, 72% had ECOG 1 and 91% were staged with PET. Median survival was 22 months. Eight patients had grade 2+ pneumonitis. Nineteen patients had grade 2+ esophagitis. Next, 2 CT pts were matched with each CRT pt on 4 factors: age, ECOG, and presence of multi-organ or contralateral lung disease. We excluded 4 CRT pts who did not match 2 CT controls. Median survival was 22 vs 9 months (p <0.01) for patients given CRT vs CT. Median time to local failure was 18 vs 6 months (p = 0.01). Median survival in locally controlled pts was 39 vs 19 months in pts with local failure (p = 0.02). On multivariable analysis, radiation (p <0.01, OR = 0.33), multiple metastatic organs at diagnosis (p <0.01, OR = 2.14), and gender (p <0.01, OR = 0.41) were associated with overall survival. Conclusions: Treatment ofNSCLC patients with oligometastatic disease with definitive dose radiation therapy may provide a local control and overall survival benefit in a subset of patients with minimal extrathoracic burden of disease.
A study of EGFR mutation in nonsmoker NSCLC: Striking disparity between north and south India patients.
Authors: Aggarwal Shyam , Patil Shekhar , Minhans Sachin , Pungliya Manish , N Soumitra
Published: March 2020

e18041

Background: There is a high incidence of EGFR mutation in non-smokers with adenocarcinoma of lung- 70% the south-east Asia and 15% in Caucasians. There is no study in an Indian population yet. Methods: 55 cases of non smoker advanced adenocarcinoma of lung were enrolled in this study after June, 2008 in a retrospective fashion. 26 patients were enrolled from Sir Ganga Ram Hospital, Delhi in North India and 29 from HCG, Bangalore in South India. Assessment of mutation status was possible in 49 cases. ARMS technique was used to study the EGFR mutation. Results: A total 27 out of 49 cases were positive for EGFR mutation – 7/21 (33%) from North India and 20/28 (65%) from South India. The commonest mutation was del exon 19 (62%), followed by L858R exon 21 (25%), G719X exon 18 (7%) and insertion exon 20 (3%). Patients were treated either with gefitinib or chemotherapy. 8/12 (83%) patients treated with gefitinib upfront responded. Overall survival (OS) was not reached at a follow up of 11 months in EGFR mutation carriers. Only 2/27 patients died. Of the 22 cases with no EGFR mutation, 6 were treated with gefitinib in frontline and the rest with chemotherapy. OS was reached at 10 months in patients with no EGFR mutation. 10/22 of these patients died. Conclusions: The study brings about striking differences in the incidence of EGFR mutation in non-smoker NSCLC cases between North and South India. This could be due to ethnic issues. There is a need to continue to this study in these patient populations.
Outcome of non-small cell lung cancer in females with gefitinib therapy: An experience from eastern India.
Authors: Shahid Tanweer , Mukhopadhyay Soma , Basak Jayasri , Gangopadhyay Sudeshna , Dasgupta Swati , Mukhopadhyay Ashis
Published: March 2020

e18043

Background: Non-small cell lung carcinoma is usually an incurable disease with average overall survival of 7-9 months. But studies in recent years have shown that adenocarcinoma in nonsmokers with epidermal growth factor receptor (EGFR) positivity has shown disease control for longer duration. Female patients with adenocarcinoma where EGFR is positive show higher response rate with EGFR blocker. In eastern India, lung cancer contributes 21.3% of all cancers and female lung cancer contributes about 20% of them. The aim of our study was to see the age at diagnosis, histological type, EGFR status, smoking status and the response rate with Gefitinib, an EGFR tyrosine kinase inhibitor, for the female patients with carcinoma of lung. Methods: We randomly selected 50 female lung cancer patients, who had not previously received chemotherapy, during the period from November, 2006 to November, 2011. The mean age group at diagnosis was 55 years (range 26-85 years). 48 patients (96%) never had smoking habit, 2 (4%) were active smokers and the rest were passive smokers. Results: Twenty six (52%) patients had histological type of adenocarcinoma, 18 (36%) had squamas cell carcinoma, 4 were poorly differentiated and 2 (4%) had large cell carcinoma. Trucut biopsy showed EGFR positivity in 22 patients. All patients were started with single agent Gefitinib therapy at least for 6 months; after that according to response rate, same dose was continued. If there were progression of the disease, they were switched over to other chemotherapeutic agents. The median follow up was 1.5 years; the progression free survival (PFS) was seen in 19 (38%) patients. Adenocarcinoma patients with EGFR positivity had significantly higher PFS than those with non-adenocarcinoma and EGFR negative status. There was no difference of response rate between smokers and nonsmokers (never-smokers). Older patients showed higher response rates. Conclusions: Our data suggested that older patients with adenocarcinoma and EGFR positivity had long term progression free survival. So in developing countries like ours, where molecular diagnosis is not feasible many a times, this result might help clinicians to select a beneficial subgroup in female lung cancer patients.
Phase I dose-escalation study of oral vinorelbine (VRLO) plus pemetrexed (PEM) in patients (pts) with advanced or metastatic non-squamous non-small-cell lung cancer (NSCLC).
Authors: Sierra Marta Isabel , Losa Raquel , Tresguerres Maria , Gutierrez Restrepo Eduardo , Perez Quionia , Alvarez Carlos , Berros Jose Pablo , Villanueva Noemi , Gracia Jose Manuel , Esteban Emilio
Published: March 2020

e18044

Background: PEM and VRLO have shown high activity and good safety profile when given as single agent chemotherapy for NSCLC. Platinum combinations are considered the standard of care of first-line advanced NSCLC treatment. However, some patients cannot receive platinum salts, being treated with non-platinum combinations as an alternative treatment option. PEM is indicated for the 1st-line treatment of patients with locally advanced or metastatic NSCLC other than predominantly squamous cell histology. VRLO is indicated for stage III-IV NSCLC and has shown efficacy in all histology subgroups. Their combination could offer a treatment option in non-squamous 1st-line NSCLC. Methods: A phase I study is being conducted to determine the maximal tolerated dose (MTD) of PEM on day 1 plus VRLO given on days 1 and 8, with 3-weeks cycles as 1st-line treatment in locally advanced or metastatic non-squamous NSCLC pts. Results: As of Jan-2012, 18 pts (M/F: 13/5, median age 61, all PS 0-1) had received 104 cycles in 4 dose levels (DL): VRLO (mg/m2)/PEM (mg/m2): 60/500 (5 pts, DL1), 70/500 (7 pts, DL2), 60-80/500 (3 pts, DL3), 80/500 (3 pt-DL4). Safety: dose limiting toxicity as defined per protocol was neutropenia gr 4 with febrile neutropenia at DL2. Other toxicities were: neutropenia gr 3 (3 pts), gr 2 (2 pts); leukopenia gr 2 (3 pts). Other adverse events included: vomiting (gr 3 / 1 pt) (gr 2 / 5 pts); gr 2 asthenia (5 pts); constipation (gr 2 / 1 pt) (gr 1 / 2 pts); diarrhea (gr 1 /3 pts); fever (gr 1/1 pt); alopecia (gr 1/ 1 pt). Efficacy in 15 evaluable pts: CR, 0 pts; PR, 9 pts; NC, 3 pts; PD, 2 pts. Overall response rate, 60% (73% clinical benefit). Conclusions: The administration of PEM plus VRLO is feasible, the MTD being reached at 80/500 mg/m2. Further exploration of the combination will be planned after final analysis.
Final report of an open-label phase II trial of bevacizumab plus docetaxel and gemcitabine in metastatic, previously untreated nonsquamous non-small cell lung cancer (NSCLC).
Authors: Pennell Nathan A. , Kalmadi Sujith R. , Shapiro Marc A. , Daw Hamed , Rodriguez Cristina P. , Haddad Abdo S. , Rich Tara , Samsa Julia , Elson Paul , Ma Patrick C. , Dowlati Afshin
Published: March 2020

e18046

Background: Platinum and non-platinum doublet chemotherapy has similar efficacy in advanced NSCLC patients (pts). Bevacizumab (B) improves outcomes when added to platinum doublets, but its safety and efficacy in combination with non-platinum doublets is unknown. This study was designed to test the combination of B, docetaxel (D), and gemcitabine (G) in first-line treatment of advanced NSCLC. Methods: Pts with metastatic, non-squamous NSCLC, PS 0-1, and measurable disease by RECIST were enrolled in this open-label, single arm phase II trial. Pts received D (75 mg/m2) on d1, G (900 mg/m2) on d1 & 8, and B (15 mg/kg) on d1 every 21d for up to 6 cycles, followed by B maintenance until progression or 12 mos total. Pts received growth factor d9. CT scans were performed every 6 wks. The primary endpoint was 1-yr progression-free survival (PFS), with secondary endpoints of safety, objective response rate (ORR), overall PFS, and overall survival (OS). Pts with tumor cavitation, untreated brain metastases, and hemoptysis were excluded. Planned enrollment was 46. Results: 13 pts were enrolled from 12/2009 to 4/2011. Pt characteristics: Median age 63 (35-69), 85% male, PS 0 (38%), PS 1 (62%). The median # of cycles of chemotherapy was 6 (1-6), median # cycles of B was 4 (1-15), with 2 pts coming off study prior to the first evaluation (1 grade 5 encephalopathy, 1 grade 4 febrile neutropenia). 5 pts (38%) had chemo dose reduction and 4 (31%) discontinued treatment for toxicity. 3 pts (23%) discontinued B prior to progression, 2 for tumor cavitation and 1 for grade 1 hemoptysis. The grade 3-5 non-hematologic toxicity rate was 69%, with 6 pts (46%) hospitalized with pneumonitis/pneumonia felt possibly related to study drugs. At this point enrollment was halted for safety concerns. The 1-yr PFS was 8%, and the median PFS was 6.9 mos (95% CI 2.0-NYR). 11 pts were evaluable for response, and 6 pts had partial responses for an ORR of 55%. The median OS was NYR with median follow up of 10.9 mos. Conclusions: The combination of B, D, and G was not tolerable at the doses and schedule used in this study. A formal phase I trial is needed if this combination is to be investigated further.
Effect of metformin on the effects of TKI on human lung carcinoma cells harboring KRAS or EGFR-T790M mutation.
Authors: Wang Yongsheng , Ma Yu , Li Dan , Guo Fuchun
Published: March 2020

e18051

Background: K-ras and egfr-T790M mutation show primary and acquired resistance to EGFR-TKI in non-small cell lung cancer, respectively. The antidiabetic drug metformin has been associated with a decreased incidence and a better prognosis of lung cancer. The affects of metformin on the EGFR-TKI resistance in non-small cell lung cancer remain unknown. Methods: The effects of metformin on EGFR-TKI were investigated in k-ras mutant A549 cells, and egfr-T790M mutant H1975 cells both in virto and in vivo. The proliferation and apoptosis were tested. The underlying mechanisms were also analyzed. Results: Our data showed metformin significantly enhanced the inhibition activity of gefitinib both in A549 and H1975 cells in vitro. At the molecular level, metformin inhibited multiple signaling including LKB1-AMPK-S6K, PI3K-AKT and Raf-MEK-MAPK in a dose-dependent manner. Furthermore, the increased tumor inhibitions were observed in nude mice models of A549 (P<0.05)and H1975 (P<0.01). Conclusions: Metformin can increase the effects of EGFR-TKI in lung adenocarcinoma harboring K-ras and egfr-T790M mutation. Our study may provide a new strategy to overcome the EGFR-TKI resistance in NSCLC.
Weekly paclitaxel and bevacizumab as fourth-line treatment or beyond for metastatic nonsquamous non-small cell lung cancer.
Authors: Habib Stefanie , Delourme Julie , Dhalluin Xavier , Scherpereel Arnaud , Lafitte Jean-Jacques , Cortot Alexis B.
Published: March 2020

e18066

Background: Paclitaxel (P) and bevacizumab (B) showed synergistic antitumor efficacy in preclinical models. In combination with carboplatin, PB prolonged progression-free survival (PFS) and overall survival (OS) in selected metastatic non-squamous Non Small Cell Lung Cancer (NSCLC) patients compared to carboplatin and paclitaxel. Currently, there are no standard treatments beyond third-line therapy in NSCLC. We sought to determine the efficacy of weekly paclitaxel and bevacizumab (wPB) in non-squamous NSCLC as fourth-line therapy or beyond. Methods: we retrospectively reviewed patients with metastatic non-squamous NSCLC who have been treated with wPB in our institution. Patients were identified from a prospective database. Treatment consisted in P 80mg/m² on days 1, 8, 15 and B 15mg/kg on day 1, every 3 weeks until progression or unacceptable toxicity. Patients were evaluated every 3 cycles. PFS and OS were calculated from the date of initiation of wPB and analyzed using the Kaplan-Meier method. Results: Twenty patients received at least one cycle of wPB between 2008 and 2011. All patients received wPB as fourth-line treatment or beyond. Eight patients (40%) had a partial response, 7 patients (35%) had stable disease and 5 patients (25%) had progressive disease. Grade 3-4 adverse events included neutropenia (20%), onycholysis (10%), infection (10%), pulmonary haemorrhage (5%), neuropathy (5%) and hypertension (5%). One patient died from a bowel perforation following second cycle of wPB. The median PFS was 6.4 months (CI95% 4.1-9) and the median OS was 9.6 months (CI95% 7-19.7). One patient who previously received bevacizumab as part of first-line chemotherapy and another patient harbouring an ALK rearrangement benefited from wPB during more than 8 months and 18 months, respectively. Conclusions: In our experience, wPB exhibited acceptable toxicity and had encouraging anti-tumor efficacy as fourth-line treatment or beyond in non-squamous NSCLC patients, supporting further evaluation in larger prospective studies.
Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab for Japanese nonsquamous non-small cell lung cancer.
Authors: Yokoi Takashi , Torii Yoshitaro , Katashiba Yuichi , Sugimoto Hiroyuki , Hayashi Mina , Shimizu Toshiki , Nomura Shosaku
Published: March 2020

e18081

Background: Until recently non–small-cell lung cancer was treated as a single disease with “platinum-based doublet chemotherapy” comprising first-line treatment for advanced disease. However, survival outcome of advanced non-squamous non–small-cell lung cancer are improving since the appearance of pemetrexed and bevacizumab. These drugs show a high effect especially to Adenocarcinoma, but there are few reports of the regimen which combined these both agents. Then, we designed this study to evaluate the efficacy and safety of pemetrexed, carboplatin, and bevacizumab followed by maintenance pemetrexed and bevacizumab in patients with chemotherapy-naïve Japanese stage IIIB or stage IV non-squamous non–small-cell lung cancer. Methods: Patients received pemetrexed 500 mg/m2, carboplatin area under the concentration-time curve of 6, and bevacizumab 15 mg/kg every 3 weeks for up to six cycles. For patients who is not progressed after pemetrexed, carboplatin and bevacizumab therapy, pemetrexed and bevacizumab were continued until disease progression or unacceptable toxicity. Primarity endpoint is response rate. Results: 23 patients were enrolled between March 2010 and April 2011 and treated. Median age was 64 (40-74), 15 patients were male, 6 patients were PS 0, 20 patients were Stage IV. Response rate was 69.5% and disease control rate was 100%. Median PFS was 8.5 months and median OS was not reached. Median time to response was 1.2 months. There were no grade 3 or worse hemorrhagic events. The feasibility was modest. Conclusions: Pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab was efficacy and tolerable regimen in Japanese patients with non-squamous non-small-cell lung cancer. This regimen also has a trend of shorter period for response. It may contribute to the better QoL.
Clinical characteristics of NSCLC harboring ALK 2p23 translocation at Cleveland Clinic.
Authors: Feng Yan , Pennell Nathan A. , Samsa Julia , Lanigan Christopher , Arrossi A. Valeria , Farver Carol , Tubbs Raymond R. , Ma Patrick C.
Published: March 2020

e18085

Background: The ALK 2p23 translocation, ALK(+), is an important druggable target in 5-7% of non-small cell lung cancer (NSCLC). However, the break-part FISH assay is labor-intensive. Better understanding of the target population’s clinical features and alternative screening tests are desirable to enable cost-effective patient selection for molecular therapy. Methods: NSCLC patients (N=120) seen at the Cleveland Clinic (CC) who had clinical screening ALK 2p23 FISH (Abbott Molecular) were included in this retrospective analysis. Biopsy specimens were also tested using immunohistochemistry (IHC) for ALK overexpression via clone D5F3 (Cell Signaling Tech.) with OptiView ultrasensitive detection (Ventana Medical Sys.). Clinical data were extracted from electronic medical records. Comparison was performed using Fisher’s exact test, Wilcoxon rank sum test or log-rank test. Results: Of the 120 tumors tested, 34 (28.3%) were ALK(+) by FISH, predominantly adenocarcinomas (33/34). 97% of the samples were also tested by ALK-IHC, with a concordance rate of 99%. Comparing to ALK (-) group, ALK(+) patients were younger (median 53 vs 65, p<0.01) and mostly never/light smokers (91% vs 43%, p<0.01). ALK(+) tumors tended to have higher number of metastatic sites at diagnosis, especially for liver metastasis (26.5% vs 10.5%, p=0.04). Interestingly, venous thrombosis (DVT/PE) was also significantly more common in ALK(+) patients (35.3% vs 16.3%, p=0.03). 17 (50%) patients were treated with crizotinib in the ALK(+) group. Two cases with positive screening ALK-IHC helped to identify FISH(+) tumor areas. Of those tumors with EGFR status available (n=103), 6 were EGFR mutation-positive, all being ALK(-). No significant OS difference was seen in ALK(+)/EGFR(-) patients (n=28) compared to ALK(-)/EGFR(-) patients (n=69). Conclusions: ALK 2p23 (+) NSCLC at CC was more commonly seen in younger patients and never/light smokers. They tended to have greater number of metastases, especially in the liver, and significantly higher risk of venous thrombosis. ALK-ultrasensitive IHC using the D5F4 clone helped to identify FISH(+) tumor areas and may be considered a cost-effective screening test demonstrating high concordance with ALK FISH.
Effect of loss of a chromosome 7 containing multiple copies of EGFR gene on acquired resistance to EGFR-TKIs in EGFR mutated NSCLC.
Authors: Furugaki Koh , Iwai Toshiki , Moriya Yoichiro , Fujimoto-Ouchi Kaori
Published: March 2020

e18091

Background: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show notable effects for non-small cell lung cancers (NSCLC) harboring EGFR activating mutations. However, almost all patients eventually acquire resistance to EGFR-TKIs within several years. The major mechanisms of acquired resistance are acquisition of a secondary EGFR mutation T790M and amplification of MET. However, the mechanisms of other resistance remain unclear. In this study, we established novel erlotinib-resistant NSCLC cells and examined their resistant mechanism. Methods: Resistant cells were established by continuously exposing EGFR mutated NSCLC cells HCC827 to 0.1, 1 or 10 μM of erlotinib in 96 well plates for three months. The resistant mechanisms were determined by direct sequence analysis and EGFR FISH analysis. Results: Resistant cells were emerged from 14/96 and 3/96 wells by 0.1 μM and 1 μM of erlotinib exposure, respectively. No resistant cells appeared in the wells of 10 μM of erlotinib. The IC50 values of these resistant cells were more than 100-fold higher than that of parental cells. No secondary mutation of T790M was detected in any of the resistant cells. Instead, we found that 13/17 resistant cells were dominated by EGFR not amplified cells and one of resistant cells B10 consisted of more than 99.9% of them, while the parental cells consisted of 2.5% of EGFR not amplified cells. Then, we isolated EGFR not amplified clone 4D8 from parental cells and found that this clone also had a resistance to erlotinib comparable to the resistant cells B10. Metaphase FISH analysis showed that EGFR amplified cells in parental cells had a chromosome 7 containing multiple copies of EGFR, while EGFR not amplified cells in B10 did not have it. Furthermore, we found that EGFR not amplified cells were constantly emerged from EGFR amplified clone isolated from parental cells under normal cell culture condition. Conclusions: Loss of a chromosome 7 containing multiple copies of EGFR causes acquired resistance in HCC827 cells when exposed to relatively low concentration of erlotinib, while high concentration of erlotinib deprives HCC827 cells of the chance of emergence of resistant cells.
EGFR mutation analysis and treatment outcomes with tyrosine kinase inhibitors in EGFR mutants: The Manchester Lung Cancer Group Experience.
Authors: Peck Rahul , Connolly Elizabeth , Taylor Paul , Faivre-Finn Corinne , Blackhall Fiona Hellen , Wallace Andrew , Lee Lip , Bayman Neil , Burt Paul , Summers Yvonne J.
Published: March 2020

e18095

Background: The presence of Epidermal Growth Factor Receptor (EGFR) activating mutations in patients with NSCLC was first described in 2005. Tumours exhibiting these mutations show sensitivity to treatment with an oral Tyrosine Kinase Inhibitor. Testing for EGFR mutations in patients with non-squamous NSCLC began in the Greater Manchester and Cheshire network in the last quarter of 2009. Methods: We audited the notes of consecutive patients who were identified with an activating EGFR mutation by the Central Manchester Genetics Laboratory between November 2009 and October 2011. Results: A total of 110 mutations were identified in tumour tissue from 98 patients. 13.6% were in exon 18, 38.2% in exon 19, 15.4% in exon 20 and 32.8% in exon 21. 65% of patients were female. The median age was 69 years (36-89). Notes were available for 85 patients, 59 of whom received treatment with an EGFR TKi. 7 had previously received radical treatment and 19 never received treatment. 7% were current smokers, 40% were ex-smokers, 30.6% had never smoked and smoking history was not documented in 22.4%. An initial response to treatment was seen in 55%, with stable disease in 15%.The mean duration of treatment was 7.6 months (2 weeks – 23 months), with 24 patients still receiving a TKi at the time of data analysis. The most commonly seen toxicities were diarrhoea and rash. Only 1 patient had no documented toxicity from their TKi. 17 patients (29%) had treatment discontinued or interrupted because of toxicity. In 8 of these, treatment was re-introduced at a reduced dose, and 3 patients went back to full dose. Conclusions: Our results confirm that treatment with a TKi is effective for those patients whose tumours harbour EGFR mutations, with a side effect profile consistent with published data.
Is EGFR gene sequencing useful in squamous cell lung cancer?
Authors: Antunes Ana , Barroso Ana , Conde Sara , Neves Sofia , Parente Barbara
Published: March 2020

e18111

Background: NCCN guidelines for NSCLC, currently do not recommend EGFR gene mutation study in squamous cell carcinoma (SLC), based on its low frequency of mutation (only 3% of SLC) and on the assumed low predictive value of these mutations in this population. Aim: To evaluate EGFR mutation rate in SLC, as well as response to treatment with erlotinib (disease control and survival) of patients with SLC, according to the mutational status of the EGFR gene. Methods: Revision of clinical and pathological features of patients with SLC for which we had performed EGFR sequencing. In the group of SLC patients with stage IIIB//IV at diagnosis treated with erlotinib 150 mg/day after at least one line of chemotherapy, comparison of response to erlotinib – disease control, overall survival (OS) and survival after the introduction of erlotinib (SE) – among the mutated and wild-type EGFR was performed. Results: Between January 2006 and December 2011, 98 patients with SLC were subject to EGFR sequencing – 89 males, 9 females; mean age 66.2 ±11.1 years; 82 smokers or former smokers. EGFR mutation was found in 11 patients (11.2%), 10 of which were male. Of these 98 patients, 22 were treated with erlotinib. 18 patients were in stage IIIB/IV at diagnosis and 5 had mutated EGFR. Of these 18 patients, median OS was 21.52 months and median SE was 5.5 months. Disease control was achieved in 6 (33%) patients. Median OS was 27.45 months in EGFR mutated SLC, against 19.5 in wild-type (p<0.05). Median SE was 13.5 months in mutated EGFR against 4.3 months in the wild-type (p<0.05). EGFR mutation was related with disease control – OR 22 (95% CI 1.53-314.3). Conclusions: In spite of the small sample size, this study shows that EGFR mutation rate of SLC in a Caucasian population is not insignificant and its presence is associated to a greater disease control and longer survival, as it has been described to lung adenocarcinoma.
Outcomes in Latin American NSCLC patients harboring wild-type or activating mutations of EGFR (CLICaP Registry).
Authors: Cardona Zorrilla Andres Felipe , Arrieta Oscar , Bramuglia Guillermo Federico , Campos-Parra Alma Delia , Becerra Ramirez Henry Alberto , Claudio Martin MARCELO , Richardet Eduardo , Serrano Silvia J , Archila Pilar , Rosell Rafael
Published: March 2020

e18114

Background: Previous exploratory analysis of EGFR status in tumor samples from five LATAM countries suggested that frequency of mutations lies between that of Asian and Caucasian populations and therefore support the genetic heterogeneity of NSCLC around the world. Methods: We analyzed the EGFR sequence of tumor samples from advanced stage NSCLC patients previously participated in the CLICaP registry. We compared the outcomes (overall and progression free survival) of 175 patients (from Argentina, Colombia and México) with an activating EGFR mutation with 414 subjects without this condition. Results: Mutations were more frequent in women (57,1%), in patients who had never smoked (67,4%), and in those with adenocarcinomas (89,4%) (P<0,002 for all comparisons). The mutations were deletions in exon 19 (58,3%) and L858R (36%). Median progression-free survival and overall survival for 175 patients who received tyrosine-kinase inhibitors (TKIs) were 13-mo (95%CI 11,2-14,8) months and 36-mo (95%CI 25,4-46,5), respectively. TKIs produced higher response rates (used as first or second line therapy) in the EGFR mutation-positive patients (70,8% vs. 29,2%; P<0,001), as well as improved PFS (13,0 vs. 3,0; P<0,001). OS is significantly different between treatment groups (36 vs. 14; P<0,001). Conclusions: The analysis of a large comparative registry of Latin-American EGFR mutated and wild type patients confirms the results of individual clinical trials previously published.
Correlation of single nucleotide polymorphisms in NER pathway genes with toxicity in advanced non-small cell lung cancer patients treated with chemotherapy.
Authors: Zhang Ling
Published: March 2020

e18115

Background: New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying NSCLC could influence chemosensitivity. We assessed whether polymorphisms in genes of NER pathway, such as ERCC5, ERCC6, MMS19L, CCNH, XPC, RRM1, can affect the tolerability of platinum-based chemotherapy in advanced NSCLC pts. Methods: Eligible pts had histological or cytological confirmed stage IV or IIIB (with malignant pleural effusion) chemo-naïve NSCLC, ECOG PS of 0 to 2 and adequate organ function. Pts received vinorelbine 25 mg/m2 or gemcitabine 1000 mg/m2 on day 1 and 8, or docetaxel 75 mg/m2 or taxel 175 mg/m2 on day 1 plus cisplatin 75 mg/m2 or carboplatin AUC=5 on day 1, every 21 days per cycle, for a maximum of six cycles, unless disease progression or unacceptable toxicity occurred. Hematology and biochemistry analyses were repeated every cycle or before chemotherapy for d8 treatment. Toxicity was classified according to CTC AE 3.0. Venous blood was collected and genomic DNA was isolated. Polymorphisms were assessed. SNPs in ERCC6 (A/G 1413, A/G 1213 and A/G 1097), XPC (T/C 500 and A/C 940), ERCC5 (G/C 1104), RRM1 (−37C/A), CCNH (T/C 270) and MMS19L (G811A) were assessed. Results: Totally 388 pts were included prospectively from Oct 2005 to Mar 2009. Median age was 61 years; 68.8% were male, 36.2% were ECOG PS 1, 33.2% had stage IIIB. The median follow-up time was 18 months (range 8–66 months). Hematological toxicity was the most common AE. SNPs of MMS19L and ERCC6 can predict the AE of chemotherapy in NSCLC,leucopenia (P=0.020), jaundice (P=0.039) by MMS19L. In terms of grade 3-4 AE, SNPs of MMS19L and RRM1 -37C/A have much more predictive effect. SNPs of MMS19L were good at total AE (P=0.042), thrombopenia (P=0.035), SNPs of RRM1 -37C/A were for vomiting (P=0.046) and jaundice (P=0.014). Conclusions: Polymorphisms in ERCC6, MMS19L, RRM1, can predict the tolerability of platinum-based chemotherapy in advanced NSCLC patients. Polymorphisms in other genes of NER pathway, such as ERCC5, CCNH, XPC, have no predictive effect.
Phase II trial of carboplatin, pemetrexed, and bevacizumab in metastatic nonsquamous (NSC) lung cancer.
Authors: Guarino Michael J. , Masters Gregory A. , Biggs David , Schneider Charles , Misleh Jamal Ghazi , Simpson Pamela S. , Suppiah Kathiresan , Wozniak Timothy F. , Grubbs Stephen S.
Published: March 2020

e18122

Background: The trial was designed to examine PFS, OS and toxicities of a novel 3 drug combination in advanced NSC lung cancer. The first patient was entered 3/08 and the last in 5/11. Methods: Treatment consisted of Carboplatin AUC 5,Pemetrexed %00mg/m2, Bevacizumab 15mg/kg q21d x 6 cycles; then Bev maintenaince q3wk for up to one year. Eligibile pts. had metastatic non-squamous NSC lung ca, EGOG 0-1, first line Rx. Fifty patients were entered, all available for response and toxicity analysis: 26 M, median age 64, 45 white. Results: 52% RR by RECIST (2% CR, 50% PR); 26% SD. Median PFS 24 wks; median overall survival will be in excess of 49 weeks. 62% of patients received all planned 6 cycles and went on to maintenance. Treatment was out-patient and well tolerated with modest toxicities, including 2 DVT's, one PE, one TIA and one episode of F+N Conclusions: The 3 drug combination of Carboplatin, Pemetrxed and Bevacizumab for met NSC lung cancer is effective and well tolerated; and is a resonable choice of Rx for patients with non-squamous tumors hoping to avoid more neurotoxic or myelotoxic options.
Human papillomavirus in non-small cell lung cancer in never smokers in east Asia: A systematic review of the literature.
Authors: Hasegawa Yoshikazu , Ando Masahiko , Kubo Akihito , Isa Shunichi , Yamamoto Satomi , Tsujino Kazuyuki , Kurata Takayasu , Ou Sai-Hong Ignatius , Takada Minoru , Koshiol Jill , Kawaguchi Tomoya
Published: March 2020

e18128

Background: Non-small cell lung cancer (NSCLC) in never-smokers has emerged as a global health concern, but its cause is undetermined. Epidemiological studies have shown that the disease is frequently observed in East Asia. Human papillomavirus (HPV) infection has been widely investigated in NSCLC, particularly in Asia. However, few studies have focused on regional differences in the prevalence of HPV in NSCLC tissue from never smokers. Methods: We performed a systematic search of PubMed for articles of HPV infection in human subjects with NSCLC between Jan. 1993 and Dec. 2011. We included studies that used polymerase chain reaction (PCR) as the primary HPV detection method. Because smoking status was not fully reported in all studies, we contacted the authors by e-mail to supplement this information. Differences in the distribution of patients with and without HPV infection were tested with the Chi squared test. Results: We identified 42 eligible articles, including 21 from Asian countries (N=2095 NSCLC cases), 17 from European countries (N=1430) and 4 from North and South America (N=160). The HPV prevalence was 28.0% (95% confidence interval (CI): 26.1-30.0%), 8.7% (95% CI: 7.3-10.3%) and 21.2% (95% CI: 15.2-28.4%), respectively. Seven studies from East Asia (N=939) and 4 from Europe (N=569) provided information on smoking status. The number of never smoker was 314 patients (33.4%) in East Asia and 54 patients (9.5%) in Europe. The HPV prevalence in East Asian countries was similar between never and ever smokers (38.2% vs 39.5%, P=0.94) and was significantly higher compared with European countries, where the prevalence was14.8% in never smokers (P<0.001) and 2.9% in ever smokers (P<0.001). In East Asia, the HPV prevalence was particularly high in Taiwan, the central part of China and Okinawa, south of mainland Japan. Conclusions: The prevalence of HPV is high in NSCLC tumor tissues from East Asia. Although the numbers of never smokers from European studies are very small, the different patterns of HPV prevalence from Asian and European countries is intriguing and deserves further study.