bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic rearrangements in lung adenocarcinoma: Lineage relationships between the in situ and invasive components.
Authors: Murphy Stephen J , Wigle Dennis A. , Harris Faye R , Lima Joema Felipe , Johnson Sarah H , Eckloff Bruce W , Seto Charlie T , Asiedu Michael , Peikert Tobias , Yang Ping , Aubry Marie-Christine , Vasmatzis George
Published: March 2020

7568

Background: The molecular events in the initiation and progression of invasive lung adenocarcinoma remain poorly characterized. These tumors are thought to develop through an adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), invasive adenocarcinoma (AD) sequence. The goal of our study was to assess lineage relationships between in situ and invasive components within adenocarcinomas with prominent lepidic growth patterns. Methods: Frozen tissue from fourteen lung adenocarcinomas with mixtures of AD together with an adjacent in situ component (AIS), varying in ratio between 40 to 80%, were selected from our Lung Specimen Registry. Laser capture microdissection (LCM) of each component was performed separately for each tumor. Genomic DNA was isolated using a direct in situ whole genome amplification (WGA) methodology, and Next Generation Sequencing performed using an Illumina Mate Pair (MP) library protocol. MP sequence reads were mapped to the human genome and primers spanning the fusion junctions were used in validation PCRs. Results: Genomic break points identical and unique to a specific patient were identified between the AIS and AD components in 13 (of 14) cases. The total number of events per case ranged from 4-215, and the number of identical events shared between the AIS and AD components ranged from 30 to 90%. Recurrent genomic breakpoints between cases were also observed, with the 2 most common involving 8q24.3 in 5 cases and FAM19A2 on chromosome 12 in 4 cases. PCR validation of selected genomic alterations confirmed the genomic break points identified from sequencing in both the AIS and AD in all cases. Interestingly, we also observed a limited number of genomic alterations present in a zonal distribution of surrounding normal lung around the tumor mass. Conclusions: Our study demonstrates unique chromosomal alterations present in both the AIS and AD components of individual lung tumors with features of lepidic growth. These data provide evidence for lineage relationship and clonal relatedness between the two components, and provide genomic evidence for a model of stepwise progression from AIS to invasive AD in this subset of lung adenocarcinomas.
Serum miRNA signature to identify a patient’s resistance to high-dose radiation therapy for unresectable non-small cell lung cancer.
Authors: Bi Nan , Schipper Matthew J , Stanton Paul , Wang Weili , Kong Feng-Ming (Spring)
Published: March 2020

7580

Background: There is a growing literature on unique profiles of serum micro RNAs (miRNAs) expression to predict clinical outcome of metastatic and early stage non-small cell lung cancer (NSCLC). However, the predictive role of circulating miRNAs in unresectable NSCLC treated with definitive radiation therapy (RT) is unknown. Methods: 134 patients with inoperable/unresectable NSCLC treated with deﬁnitive RT (18-month minimum follow-up) were eligible. Serum samples were collected prospectively before treatment. 100 patients had enough serum and reliable miRNA profile quality, which were randomly divided into training and validation sets (50 patients each). MiRNA profiling was performed using real-time PCR-based array, containing a panel of 84 miRNAs detectable in human bodily fluids. Spiked-in cel-miR-39 was used for normalization. Stepwise regression Cox model building was used to build a miRNA signature on the training set, which was then assessed on the validation set both alone and with clinical factors. Results: The median age was 67 years; 76% were stages III and 79% received chemoradiation; the median physical dose was 70.0 Gy. A serum hsa-miR-885/hsa-miR-7 signature was identified as significant predictors for overall survival (OS) in the training set, which was validated by the validation set (p=0.02). After adjustment for GTV Volume and KPS, the only two significant clinical factors in univariate analysis, this signature remained significant (p=0.04). In the high-dose RT group (>70 Gy, n=45), individuals with low-risk had a significantly longer OS than patients with high-risk (70.7 vs. 18.8 months, p=0.007); while in the low-dose RT group (≤70 Gy, n=55), no significant association was observed (OS, 22.0 vs. 13.3 months, p=0.43). Conclusions: Circulating hsa-miR-885/hsa-miR-7 signature may be used as a putative non-invasive biomarker for predicting survival and radiation resistance in unresectable NSCLC, which may potentially help to select patients who will not benefit from high-dose radiation. Independent validation studies are needed to conﬁrm our ﬁndings. Clinical trial information: NCT01190527.
A novel microRNA-based treatment approach for malignant pleural mesothelioma.
Authors: Reid Glen , Pel Marcella , Kirschner Michaela , Cheng Yuen Yee , Mugridge Nancy , Weiss Jocelyn , Williams Marissa , Wright Casey , Klebe Sonja , Brahmbhatt Himanshu , MacDiarmid Jennifer , Van Zandwijk Nico
Published: March 2020

7586

Background: Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new approaches are needed. The microRNA miR-16 has been implicated as a tumor suppressor in a range of cancer types, and restoration of miR-16 expression has been shown to inhibit tumor cell proliferation. The miR-16 status in MPM is largely unknown. Methods: MicroRNA expression was analysed by TaqMan-based RT-qPCR in 10 MPM cell lines and 60 tumour specimens consisting of archival blocks from patients undergoing surgery. MicroRNA expression was restored in vitro using mimics corresponding to the sequence of the mature microRNA, and effects on proliferation and target genes were assessed with standard methods. Human xenograft-bearing mice were treated with miR-16 mimics packaged in minicells targeted with EGFR-specific antibodies. Results: Expression of miR-16 was consistently down-regulated in MPM cell lines and MPM tumor specimens as were the co-expressed miR-15a and miR-15b. A decrease of 2- to 5-fold in miR-16 expression was found when MPM cell lines were compared with the normal mesothelial cell line MeT-5A. When tumor specimens were compared with normal pleura, the down-regulation of miR-16 was in the order of 10-fold. Using synthetic miR-16 mimics to restore miR-16 expression in MPM cell lines led to time- and dose-dependent growth inhibition in a panel of MPM cell lines but did not affect growth of MeT-5A. Growth inhibition correlated with cell cycle arrest and concordant down-regulation of miR-16 target genes including Bcl-2 and CCND1. In a series of experiments with nude mice bearing MPM (MSTO-H211) xenografts, intravenous administration of miR-16 mimics packaged in minicells led to consistent and dose-dependent inhibition of tumor growth. Conclusions: Restoring miR-16 expression represents a novel approach to treatment for MPM. Preparations are being made to test miR-16 packaged in minicells as a new treatment approach for patients with recurrent MPM and NSCLC.
Circulating tumor cells as a prognostic factor in patients with small cell lung cancer.
Authors: Igawa Satoshi , Sasaki Jiichiro , Masuda Noriyuki
Published: March 2020

7592

Background: Research on the detection of circulating tumor cells (CTCs) in peripheral blood is currently an important field of research. The aim of this study was to evaluate a new method of detecting CTCs in the peripheral blood of small cell lung cancer (SCLC) patients by using the telomerase-specific replication-selective adenovirus OBP-401. Methods: We prospectively enrolled 30 consecutive newly diagnosed SCLC patients who were being started on chemotherapy or chemoradiotherapy as the subjects of this study. We collected peripheral blood specimens from the SCLC patients and detected viable CTCs in them after incubation with a telomerase-specific, replication-selective, oncolytic adenoviral agent carrying the green fluorescent protein (GFP) gene. We also investigated whether the CTC count per 7.5 ml of peripheral venous blood was associated with the outcome of SCLC. Results: CTCs were detected in 96% of the patients (29 of the 30 patients). The group of 22 patients with a CTC count of < 2 before treatment (baseline) had a significantly longer median survival time than the group of 8 patients with a CTC count of ≥ 2 before treatment (14.8 months and 3.9 months, respectively, P = 0.001). The results of a multivariate analysis showed that the baseline CTC count was an independent prognostic factor for survival (hazard ratio = 5.11, P = 0.038). Conclusions: CTCs in the peripheral blood of SCLC patients can be detected by the OBP-401assay, and based on the results of this study the CTC count before treatment appears to be a strong prognostic factor.
Prospective molecular evaluation of small cell lung cancer (SCLC) utilizing the comprehensive mutation analysis program at Memorial Sloan-Kettering Cancer Center (MSKCC).
Authors: Pietanza Maria Catherine , Varghese Anna M. , Won Helen H. , Wang Lu , Rekhtman Natasha , Krug Lee M. , Paik Paul K. , Riely Gregory J. , Zakowski Maureen Frances , Ladanyi Marc , Berger Michael F. , Kris Mark G.
Published: March 2020

7600

Background: Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC is still unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the small biopsy specimens available in clinical practice has not been performed. Methods: Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and next-generation sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. We tested the feasibility of this approach in a series of patients with SCLC. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH. Results: We identified 11 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies, including 3 core biopsies and 8 fine needle aspirations. 9/11 patients had adequate tissue for MSK-IMPACT, which revealed recurrent mutations in Rb1 (N=7) and p53 (N=7), FGFR1 amplification (N=2), and MET amplification (N=1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SC-MAP program for our patients with SCLC. Conclusions: Comprehensive molecular evaluation of SCLC is feasible on clinically available, small samples. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies.
A phase III study of pemetrexed (Pem) plus carboplatin (Cb) plus bevacizumab (Bev) followed by maintenance pem plus bev versus paclitaxel (Pac) plus cb plus bev followed by maintenance bev in stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC): Overall and age group results.
Authors: Socinski Mark A. , Patel Jyoti D. , Garon Edward B. , Govindan Ramaswamy , Reynolds Craig H. , Spigel David R. , Olsen Mark R. , Liu Jingyi , Guba Susan C. , Bonomi Philip
Published: March 2020

8004

Background: This study compared Pem+Cb+Bev followed by Pem+Bev maintenance (Pem arm) to Pac+Cb+Bev followed by Bev maintenance (Pac arm). The primary endpoint of improved overall survival (OS) for the Pem arm was not met. Methods: Advanced NS-NSCLC pts, ECOG PS 0/1, were randomized to 4 cycles of induction Pem+Cb+Bev with folic acid+vitamin B12 or Pac+Cb+Bev (Pem 500 mg/m2or Pac 200 mg/m2; Cb AUC 6; Bev 15 mg/kg) every 3 weeks. Eligible pts received maintenance Pem+Bev or Bev. OS, progression-free survival (PFS), overall response (ORR), and toxicity were evaluated. A hazard ratio (HR) of 0.80 required 676 OS events/900 pts with 2-sided type-I error .05 and at least 80% power for superiority of Pem over Pac arm. Exploratory Cox models estimated treatment HRs with 95% confidence intervals (CIs) for each age subgroup analyzed: ≤ or >65, 70 (prespecified) and ≤ or >75 yrs (not prespecified). Results: 939 pts (median age, 64.7) were randomized. Median (m) OS for ITT pem and pac arms was 12.6 vs 13.4 mos (HR 1.00, p=0.949); mPFS was 6.0 vs 5.6 mos (HR 0.83, p=0.012) Subgroup efficacy is shown in the Table; ≤ or >65 data were similar to ITT. Pem pts had significantly more drug-related grade 3/4 thrombocytopenia, anemia (except >75 yrs) and fatigue (except >70 and >75 yrs). Pac pts had significantly more grade 3/4 neutropenia (except >70 and >75 yrs), sensory neuropathy (except >75 yrs) and grade 1/2 alopecia. Results parallel overall safety data. Conclusions: OS was not significantly different in any of the age subgroups. PFS was significantly longer in Pem arm overall and for pts ≤70, but was similar for pts >70, >75 yrs. Toxicity profiles differed; subgroup safety data paralleled overall data. Clinical trial information: NCT00762034. [Table: see text]
Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed for KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial.
Authors: Kelly Karen , Mazieres Julien , Leighl Natasha B. , Barlesi Fabrice , Zalcman Gerard , Gordon Michael S. , Reckamp Karen L. , Gandara David R. , Gomez-Roca Carlos Alberto , Bennouna Jaafar , Cho Byoung Chul , Park Keunchil , Infante Jeffrey R. , Richards Donald A. , Wu Yuehui , Schramek Daniel J. , Cox Donna S. , Gardner Olivia S. , Peddareddigari Vijay Gopal Reddy , Blumenschein George R.
Published: March 2020

8027

Background: Lung cancer patients with mutated KRAS tumors present a treatment challenge. Trametinib + pemetrexed (pem) enhanced growth inhibition and apoptosis compared with either agent alone in lung cancer cell lines with WT or mutated RAS/RAF. Methods: This 2-part, multiarm, phase I/Ib, open-label study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase II dose (RP2D) for trametinib + pem in patients (pts) with advanced solid tumors. In part 2, NSCLC pts were stratified as KRAS WT or mutation unknown (WT) or KRAS-mutant (KRAS) and were treated with trametinib + pem at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Exploratory mutational profiling was done using circulating-free DNA from plasma and available archival tumor tissue. Results: As of January 2013, 42 NSCLC pts (22 WT [82% had ≥ 2 prior therapies], 20 KRAS [55% had ≥ 2 prior therapies]) have been treated at the trametinib + pem RP2D (1.5 mg + 500 mg/m2). Nausea, fatigue, and peripheral edema were the 3 most frequent toxicities. 26% of pts reported grade 3-4 hematologic toxicity. Dose reduction occurred in 15 pts (33%), most often for diarrhea, decreased ejection fraction, and fatigue (all 7%). Preliminary PK suggests no drug-drug interaction. In KRAS pts, the best investigator-assessed response (confirmed + unconfirmed) was 3 partial response (PR; RR = 15%) and 10 stable disease (SD; 50%); additionally, 3 pts had > 20% tumor shrinkage. The disease control rate (DCR) was 65%. Final response and progression-free survival (PFS) data will be reported upon maturity. In WT pts, 3 PR (RR = 14%) and 13 SD (59%) were observed (73% DCR); preliminary median PFS was 5.8 months (95% CI, 2.8-6.7 months). Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are ongoing. Conclusions: MEK inhibition with trametinib + pem demonstrates tolerability and clinical activity in both KRAS-mutant and WT NSCLC, exceeding expectations for each drug alone and warranting further study. Clinical trial information: NCT01192165.
Lume-lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy.
Authors: Hanna Nasser H. , Kaiser Rolf , Sullivan Richard N. , Aren Osvaldo Rudy , Ahn Myung-Ju , Tiangco Beatrice , Zvirbule Zanete , Barrios Carlos H. , Demirkazik Ahmet , Gaschler-Markefski Birgit , Voccia Isabelle , Barrueco Jose , Kim Joo-Hang
Published: March 2020

8034

Background: Nintedanib (N) is an oral inhibitor of VEGFR, FGFR, and PDGFR. This global phase 3 study investigated the safety and efficacy of N + pemetrexed (PEM) vs placebo (P) + PEM in patients (pts) with advanced, non-squamous NSCLC previously treated with chemotherapy. Methods: Pts were randomized 1:1 to N 200 mg po bid + PEM 500 mg/m2 iv q21d (n=353, Arm A) or P + PEM (n=360, Arm B). Continuation until PD or unacceptable toxicity with N, P, PEM, or a combination was permitted. 1° endpoint was centrally reviewed PFS. The null hypothesis was tested on the ITT population after 394 events had occurred (two sided α=5%). 2° endpoints included OS, investigator-assessed PFS, response rate (RR), safety, and QoL. Results: Baseline pt characteristics were balanced between Arm A vs B (median age 59 y, female 45–42%, ECOG PS 1 62-61%, adenocarcinoma 95–93%, prior bevacizumab 8%). Based on a planned DMC futility analysis of investigator-assessed PFS, enrolment was halted after randomizing 713/1300 planned pts (no safety issues identified). Ongoing pts were unblinded and follow-up continued per protocol. Subsequent ITT analysis of the 1° endpoint (centrally reviewed PFS) favored Arm A vs B (median 4.4 vs 3.6 mo, HR 0.83 [95% CI: 0.7–0.99], p=0.04). Disease control was also significantly improved in N-treated pts (61 vs 53%, odds ratio 1.37, p=0.039). No difference in OS (HR 1.03) or RR (9%) was found. Exploratory analyses identified time since start of 1st-line therapy as a predictive marker of improved outcome with N + PEM (ASCO 2013). There was no increase in SAEs or G5 AEs with N + PEM. Addition of N to PEM resulted in a higher incidence of ≥G3 elevated ALT (23 vs 7%), elevated AST (12 vs 2%), and diarrhea (3 vs 1%), but no difference in ≥G3 hypertension, bleeding, thrombosis, mucositis, or neuropathy. Conclusions: The 1° endpoint was met even though the study was stopped prematurely. Treatment with N + PEM significantly improved centrally reviewed PFS vs P + PEM in pts with advanced non-squamous NSCLC previously treated with chemotherapy, and had a manageable safety profile. Clinical trial information: NCT00806819.
Combination chemotherapy with irinotecan and cisplatin (IP) for advanced large-cell neuroendocrine carcinoma (LCNEC) of the lung: A multicenter phase II study.
Authors: Niho Seiji , Kenmotsu Hirotsugu , Sekine Ikuo , Ishii Genichiro , Ishikawa Yuichi , Noguchi Masayuki , Oshita Fumihiro , Watanabe Shun-ichi , Nakajima Ryu , Tada Hirohito , Nagai Kanji
Published: March 2020

8037

Background: LCNEC and small cell lung cancer (SCLC) are recognized as high-grade neuroendocrine carcinoma of the lung. A differential diagnosis between LCNEC and SCLC using a tiny biopsy specimen is frequently difficult. Consequently, prospective clinical trials examining chemotherapy for advanced LCNEC have seldom been reported. We conducted a phase II study of combination chemotherapy with IP in patients (pts) with advanced LCNEC. Methods: The eligibility criteria included a chemotherapy-naïve status, a histological diagnosis of advanced LCNEC, an age of 20-75 years, and an ECOG PS of 0-1. Pts received I (60 mg/m2, days 1, 8, and 15) and P (60 mg/m2, day 1) every 4 weeks for up to 4 cycles. The primary endpoint was the response rate (RR). The sample size was determined to be 44, with a one-sided alpha of 0.1, a beta of 0.2, and expected and threshold values for the primary endpoint of 50% and 30%. Results: 44 pts from 11 institutes were enrolled between Jan 2005 and Nov 2011. The median age was 62.5 years; 21 pts had a PS of 0, and 35 pts were male. 5 pts had stage IIIB, 28 had stage IV, and 11 had recurrences after surgical resection. The RR was 54.5% (95% CI, 38.8-69.6). Grade 3 or 4 neutropenia was observed in 24 pts, but only 3 pts experienced febrile neutropenia. Other toxicities were mild and manageable. The median progression-free survival (PFS) was 5.9 months (95%CI, 5.5-6.3), and the median survival time (MST) was 15.1 months (95%CI, 11.2-19.0). Pathological specimens for a pre-planned central review were available for 41 pts. 30 pts were diagnosed as having LCNEC, whereas 10 pts were diagnosed as having SCLC, and 1 patient was diagnosed as having non-SCLC with a neuroendocrine morphology. Subgroup analyses were shown in the Table. Conclusions: Combination chemotherapy with IP was active in pts with advanced LCNEC, but the RR and the overall survival period in pts with LCNEC seemed to be inferior to those in pts with SCLC. Clinical trial information: UMIN000004796. [Table: see text]
A phase II trial comparing pemetrexed with gefitinib as the second-line treatment of nonsquamous NSCLC patients with wild-type EGFR (CTONG0806).
Authors: Yang Jinji , Cheng Ying , Zhao Mingfang , Zhou Qing , Yan Hong hong , Zhang Li , Song Yong , Chen Jianhua , Feng Weineng , Xu Chong-Rui , Wu Yi Long ,   Chinese Thoracic Oncology Group (CTONG)
Published: March 2020

8042

Background: Pemetrexed or gefitinib is one of the standard second-line treatments for advanced non-squamousNSCLC in East Asia. The CTONG 0806 a multi-center, randomized, controlled, open-label phase II trial was designed to explore the efficacy of pemetrexed versus gefitinib as the second-line treatment in advanced NSCLC patients without EGFR mutation. Methods: The patients with locally advanced or metastatic, non-squamous NSCLC previously treated with platinum-based chemotherapy and no EGFR mutation in exons 18-21 were enrolled. Patients were 1:1 randomized to receive either gefitinib 250 mg per oral every day (G arm) or pemetrexed 500 mg/m2 iv day 1 with vitamin B12 and folic acid supplement every 21 days (P arm) until disease progression, unacceptable toxicity, or discontinuation of treatment due to other reason. The primary endpoint was progression-free survival (PFS). The secondary endpoints were 4-month and 6-month progression-free survival rate, overall survival (OS), objective response rate (ORR), quality of life using the FACT-L questionnaire and safety, EGFR and K-ras mutation status were evaluated and correlated with outcomes. Results: From Feb. 2009 to Aug. 2012, 157 evaluable patients were randomized (81 cases in G arm and 76 in P arm). Baseline age, gender, and ECOG performance status were balanced between arms. The primary endpoint of PFS was met with 1.6 months for G arm versus 4.8 months for P arm, the HR is 0.51 (95% CI 0.36~0.73, P<0.001). Overall response rates were 14.7 % and 13.3 % (P=0.814) and DCR were 32.0% and 61.3% (P<0.001) for G arm and P arm, respectively. OS data were not yet mature. More skin rash and diarrhoea were seen in G arm, but more fatigue and ALT increased in P arm. CTCAE grade 3 or 4 of AEs was 12.3% in G arm and 32.9% in P arm (p=0.002). The further analyses of efficacy evaluated by IRR and biomarkers analysis will be presented on the ground. Conclusions: CTONG0806 is the first trial to show significant improvements in PFS and DCR with pemetrexed compared with gefitinib in second-line setting for advanced NSCLC with EGFR wild type. Patients with EGFR wild type did not benefit from EGFR TKI gefitinb in second-line setting. Clinical trial information: NCT00891579.
Prospective randomised phase II trial of oral vinorelbine (NVBo) and cisplatin (P) or pemetrexed (Pem) and P in first-line metastatic or locally advanced non-small cell lung cancer (M or LA NSCLC) with nonsquamous (Non SCC) histological type. NAVoTRIAL01: Final results.
Authors: Bennouna Jaafar , Havel Libor , Krzakowski Maciej , Kollmeier Jens , Gervais Radj , Dansin Eric , Serke Monika , Favaretto Adolfo G. , Cobo Manuel , Szczesna Aleksandra , Ciuffreda Libero , Jassem Jacek , Nicolini Mario , Ramlau Rodryg , Amoroso Domenico , Melotti Barbara , Almodovar Teresa , Vaissiere Nathalie , Riggi Marcello , Tan Eng Huat
Published: March 2020

8043

Background: NVBo+P is considered as a standard treatment in M or LA NSCLC. The recent approval of Pem+P as front line chemotherapy (CT) for non SCC demonstrates that today, histology could become a “new guidance” to treat patients (pts). The importance of histological types was highlighted in a phase III trial (Scagliotti. JCO 2008). Moreover, the higher chemosensitivity of non SCC is recognised and reported with other chemotherapies (Ardizzoni. JNCI 2007). In GLOB 3 study, NVBo+P also showed better survival in adenocarcinoma (11.7m) than in SCC (8.9m) (Tan. Ann Oncol. 2009). This trial was set up to assess the efficacy of NVBo+P (Arm A) and Pem+P (Arm B) for pts with Non SCC histological type, evaluated in terms of Disease Control Rate (DCR) (SD+PR+CR). Methods: Pts were randomised to receive q3w NVBo 80 mg/m² D1D8 (60 at Cycle 1) + P 80 mg/m² D1 (Arm A) or Pem 500 mg/m² + P 75 mg/m² D1 (Arm B). After 4 cycles of combination, pts with DCR received single agent NVBo (Arm A) or PEM (Arm B) as maintenance until progression or toxicity. Pts were randomised on a 2/1 basis and stratified according to stage (IIIB - IV - relapse), non SCC confirmed by histology or cytology, gender, smoking status and centre. Results: From 11/09 to 02/11, 153 pts were randomised to Arm A (102 pts) or Arm B (51 pts). DCR after combination and maintenance was 75.0% (95% CI, 65.3 to 83.1) in Arm A and 76.5% (95% CI, 62.5 to 87.2) in Arm B. Median PFS was 4.2 (95% CI, 3.6 to 4.7) and 4.3 months (95% CI, 3.8 to 5.6) in Arm A and Arm B, respectively. Median OS was 10.2 months (95% CI, 7.8 to 11.9) and 10.8 months (95% CI, 7.0 to16.4) in Arm A and Arm B, respectively. During the combination period grade 3/4 neutropenia was 44.0% in Arm A and 18.3% in Arm B but febrile neutropenia was 2% in both arms; grade 3/4 thrombopenia was 0% and 6% in Arm A and Arm B, respectively. Conclusions: Even if the current results should be confirmed in a phase III study, the choice of a platinum-based doublet with oral vinorelbine as front-line chemotherapy could be a useful alternative in non SCC. Clinical trial information: 2009-012001-19.
Association between baseline tumor dimensions and survival in advanced non-small cell lung cancer (NSCLC).
Authors: Ahn Daniel H. , Dahlberg Suzanne Eleanor , Sandler Alan , Perry Michael C. , Schiller Joan H. , Brahmer Julie R. , Johnson David H. , Gerber David E. ,   Eastern Cooperative Oncology Group
Published: March 2020

8046

Background: It is not known to what extent radiographic tumor burden is associated with survival in patients with advanced NSCLC. The purpose of this study is to assess whether baseline tumor dimensions are associated with patient survival in advanced NSCLC. Methods: Data were derived from the Eastern Cooperative Oncology Group (ECOG) 4599 trial of carboplatin-paclitaxel (CP) ± bevacizumab (B) for advanced nonsquamous NSCLC. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD) and progression-free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models. Results: 759 of 850 patients (89%) enrolled in E4599 had measurable disease and were included in the analysis. 76% of patients were age < 70 years, 46% were female, and 86% were white. Median number of target lesions was 2; median BSLD was 7.5 cm. In univariate Cox models, BSLD predicted OS (HR 1.41; P<0.001) and had a trend toward association with PFS (HR 1.14; P=0.08). OS was 12.6 months (mos) for BSLD < 7.5 cm, compared to 9.5 mos for BSLD ≥ 7.5 cm. This association persisted across both treatment groups (CP: median OS 11.5 vs 8.5 mos; CP+B: median OS 14.1 vs 10.7 mos), when BSLD was categorized according to quartile (median OS: 13.3, 11.5, 11.6, and 8.3 mos; P<0.001), and in a multivariable model controlling for prognostic factors and the presence and site of extrathoracic disease (OS HR 1.24; P=0.01). Conclusions: Radiographic disease burden, as determined by RECIST BSLD, is associated with survival in the E4599 trial. If validated in other populations, this parameter merits consideration in the stratification of patients for clinical trials and may provide important prognostic information for patients and clinicians.
Occurrence of HER2 amplification in EGFR-mutant lung adenocarcinoma with acquired resistence to EGFR-TKIs.
Authors: Altavilla Giuseppe , Arrigo Carmela , Tomasello Chiara , Santarpia Mariacarmela , Mondello Patrizia , Benecchi Sara , Pitini Vincenzo
Published: March 2020

8047

Background: Patients with EGFR-mutant lung adenocarcinoma develop progression of disease on TKIs therapy after a median of 12 months;this acquired resistance is mainly due to a secondary mutation in EGFR (T790 M) in about 50% of patients, amplification of MET in 15%, PIK3CA mutations in 5%, an unknown mechanism in almost 30% and a SCLC transformation in some pts. Recently, Takezawa and colleagues pointed out that HER2 amplification is a mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers without EGFR T790M mutation. To aid in identification and treatment of these patients we examined a cohort of patients whose cancers were assessed with tumor biopsies at multiple times before and after their treatment with TKIs. Methods: 41 lung adenocarcinomas pts. (20 male, 21 female, median age 55 years) with EGFR mutations at 19 or 21 exons received TKIs as first line of treatment. 31 pts. (75%) showed a clinical response and relapsed after a mTTP of 12 months. At the time of relapse a new biopsy was performed, histologic samples were reviewed to re-confirm the diagnosis, EGFR, MET and HER-2 amplification were identified by FISH, while EGFR mutations have been tested by DNA sequencing. Results: At the time that drug resistence was acquired all 31 pts. retained their original activating EGFR mutations, 16 pts. developed EGFR T790M resistance mutation with pronunced EGFR amplification in 5, 4 pts. developed MET amplification, 3 pts. were found to have a diagnosis of small cell lung cancer. HER2 amplification was observed in four pts. (13%), with dramatic progression and a median OS of 5 months after treatment with CDDP + pemetrexed. Notably all 4 cases were EGFR T790M negative. Conclusions: Among pts. with acquired resistence to EGFR TKIs the presence of HER2 amplification defines a clinical subset with a more adverse prognosis and rapid progression. Interestingly, recent data suggest that afatinib combined with cetuximab could have promising activity in pts. with acquired resistance due to HER2 amplification.
Randomized phase III trial of gemcitabine and cisplatin versus gemcitabine alone in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) 2: CAPPA-2 study.
Authors: Morabito Alessandro , Gebbia Vittorio , Cinieri Saverio , Viganò Maria Grazia , Bianco Roberto , Barbera Santi , Cavanna Luigi , De Marinis Filippo , Montesarchio Vincenzo , Costanzo Raffaele , Sandomenico Claudia , Montanino Agnese , Mancuso Gianfranco , Nacci Angelo , Giordano Pasqualina , Daniele Gennaro , Gridelli Cesare , Rocco Gaetano , Gallo Ciro , Di Maio Massimo
Published: March 2020

8066

Background: Platinum-based chemotherapy (CT) is the standard treatment for patients (pts) with advanced NSCLC, but the evidence of its efficacy among ECOG PS2 pts is weak, because these pts are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard CT in these pts. No prospective randomized trial has tested the addition of cisplatin to single-agent CT in pts with advanced NSCLC and PS2. Methods: CAPPA-2 was a multicentre, randomized phase III study for first-line treatment of PS2 pts with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI ed.) and adequate organ function. Patients in standard arm received gemcitabine 1,200 mg/m2 dd1 and 8.Patients in experimental arm received cispaltin 60 mg/m2 d1 plus gemcitabine 1,000 mg/m2 dd1 and 8. All treatments were repeated q3w, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. Results: The study was stopped in June 2012 after the enrolment of 57 pts, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin + gemcitabine (HR 0.52, 95% CI 0.28-0.98, p=0.039). Combination CT produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27-0.89, p=0.017) and higher response rate (4% vs. 18%, p=0.19), without substantial increase in toxicity. Conclusions: Addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC. Clinical trial information: NCT00526643.
Screening for RET and ROS1 fusions in an enriched cohort of pan-negative never-smokers with advanced lung adenocarcinomas to identify patients for treatment in targeted therapy trials.
Authors: Drilon Alexander Edward Dela Cruz , Wang Lu , Hasanovic Adnan , Joubert Philippe , Kris Mark G. , Riely Gregory J. , Ladanyi Marc , Rizvi Naiyer A.
Published: March 2020

8067

Background: RET and ROS1 fusions have been identified pre-clinically as drivers of tumor growth in lung adenocarcinomas. In addition, based on response to crizotinib in ROS1-positive tumors and emerging data on RET inhibition in some tumors, these fusions represent druggable targets. While each occurs in 1-2% of unselected patients, a screening paradigm based on testing never-smokers whose tumors have no known oncogenic mutations or fusions may enrich identification for ongoing clinical trials. Methods: Patients with a never-smoking history (<100 lifetime cigarettes) and advanced pan-negative lung adenocarcinomas (absence of mutations in EGFR, KRAS, NRAS, BRAF, HER2, PIK3CA, MEK1, and AKT, and ALK fusions) were selected for testing. Screening for RET and ROS1 fusions was performed in real-time via dual-probe FISH breakapart assays, RT-PCR, and next-generation sequencing in selected cases. We enrolled patients onto a phase II trial of cabozantinib for RET fusion-positive lung cancers (NCT01639508) and, as part of the Lung Cancer Mutation Consortium (LCMC), a phase I trial of crizotinib for ROS1-positive lung cancers (NCT00585195). Results: Thirty five (n=35) never-smokers with advanced pan-negative lung adenocarcinomas were identified. A RET or ROS1 fusion was found in 31% [n=10/32, 95% CI, 15-47%] of patients. RET and ROS1 fusions were found in 15% [n=5/34, 95% CI, 3% - 27%] and 15% [n=5/33, 95% CI, 2%-27%] of patients, respectively. 1 patient had a novel TRIM33-RET fusion. 3 of 5 patients with RET fusion-positive tumors were eligible for treatment with cabozantinib, 2 of which had partial responses to therapy. 1 of 5 patients with ROS1 fusion-positive tumors was treated on-protocol with crizotinib and achieved a partial response. Conclusions: 31% of never-smokers with pan-negative advanced lung adenocarcinomas harbor a gene fusion involving either RET or ROS1. Until multiplexed mutation and fusion testing is routinely available, targeting this population for screening represents an interim enrichment strategy for patient identification and enrollment on clinical trials where responses are already being documented.
A retrospective analysis of the prevalence of EGFR or KRAS mutations in patients (pts) with crizotinib-naïve and crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC).
Authors: Gainor Justin F. , Varghese Anna M. , Ou Sai-Hong Ignatius , Kabraji Sheheryar , Awad Mark M , Katayama Ryohei , Pawlak Amanda , Mino-Kenudson Mari , Yeap Beow Y. , Riely Gregory J. , Iafrate Anthony John , Arcila Maria E. , Ladanyi Marc , Engelman Jeffrey A. , Dias-Santagata Dora , Shaw Alice Tsang
Published: March 2020

8083

Background: Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of NSCLC. Recently, several studies have reported that ALK+ pts occasionally harbor concomitant mutations in other oncogenic drivers. Methods: We retrospectively analyzed tumor genotyping data from 1,683 pts with NSCLC seen at 3 U.S. centers from 2009 – 2012 to determine rates of overlapping alterations in EGFR, KRAS and ALK. Mutations in EGFR and KRAS were mainly identified using the SNaPshot multiplexed assay (>95% of cases). ALK FISH was performed in all cases. To determine if this prevalence is impacted by crizotinib, we also updated our earlier analysis (Katayama et al., Sci Transl Med, 2012) of a series of repeat biopsy specimens from 34 crizotinib-resistant, ALK+ pts. Resistant specimens were examined using ALK FISH, SNaPshot, and direct sequencing of the ALK tyrosine kinase domain (TKD). Results: Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. 4 pts with KRAS mutations also had abnormal ALK FISH patterns, involving isolated 5’ green probes (3/4 cases) and an isolated 3’ red probe that was unusually small (1/4 cases). Sufficient tissue was available for confirmatory ALK immunohistochemistry (clone 5A4, Novacastra, UK) in 3 of these cases, all of which were negative for ALK expression. Among pts with ALK+ NSCLC and acquired crizotinib resistance, repeat biopsy specimens remained ALK fusion positive in 28/28 (100%) cases. Secondary mutations in the ALK TKD (1151Tins, L1196M, G1202R, S1206Y, and G1269A) were identified in 7/34 (20.6%) cases. L1196M was the most common secondary mutation (3/34, 8.8% cases). ALK gene amplification was present in 3/28 (10.71%) pts. No EGFR or KRAS mutations were identified in 23 crizotinib-resistant, ALK+ pts with sufficient tissue for testing. Conclusions: Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK+ pts with acquired resistance to crizotinib.
Multitargeted antiangiogenic tyrosine kinase inhibitors in advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials.
Authors: Liang Wenhua , Zhang Li
Published: March 2020

8089

Background: Novel multitargeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have showed promising advantages in combination with chemotherapy or as monotherapy in treatments of advanced non-small cell lung cancer (NSCLC). Since the efficacy and safety of these small molecules have been evaluated by several phase II/III randomized controlled trials (RCTs), we seek to summarize the current evidences by performing a meta-analysis. Methods: PubMed, EMBASE, the Cochrane Library as well as the ASCO and ESMO databases were searched for eligible literatures. We defined the experimental arm as MATKI-containing group while the control arm as MATKI-free group. The endpoints being evaluated included overall survival (OS), progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR), as well as adverse events (AEs). Pooled hazard ratios (HRs) for survival outcomes and odds ratio (ORs) for dichotomous data, with 95% confidence intervals (CI) were calculated using REVMAN 5.0. Subgroup analysis was conducted according to each agent respectively. Results: Five agents (vandetanib, sunitinib, cediranib, sorafenib, motesanib) with comparable data could be analyzed. Fifteen phase II/III RCTs that involved a total of 8854 participants were included. Compared to MATKI-free group, MATKI-containing group was associated with significant longer PFS (HR 0.824, 95% CI 0.759 to 0.895, P<0.001), superior ORR (OR 1.27, 95% CI 1.13 to 1.42, P<0.0001) and DCR (OR 1.14, 95% CI 1.04 to 1.25, P=0.006). However, although some improvement in OS was observed, the benefit did not reach statistical significance (HR 0.962, 95% CI 0.912 to 1.015, P=0.157). In terms of subgroup results, sorafinib was revealed to yield no improvement in all endpoints. The specific AEs in patients who received these agents were rash, diarrhea and hypertension. Conclusions: Regimens consisting of multitargeted antiangiogenic TKIs were superior to those without these agents in terms of tumor response and PFS in patients with advanced NSCLC. However, no significant benefits in OS were observed. In addition, sorafinib seemed to has no substantial efficacy for NSCLC patients.
Potential chemo-sensitization effect of tergenpumatucel-L immunotherapy in treated patients with advanced non-small cell lung cancer (NSCLC).
Authors: Morris John Charles , Rossi Gabriela R. , Harold Nancy , Tennant Lucinda , Ramsey William Jay , Vahanian Nicholas N. , Link Charles J.
Published: March 2020

8094

Background: Lung cancer is the leading cause of cancer-related mortality. Tumor progression after initial chemotherapy has a poor prognosis. A major obstacle is chemo-resistance, thus targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents with limited toxicities are needed. We report that tergenpumatucel-L (HyperAcute-Lung immunotherapy, HAL) shows signs of chemo-sensitization to follow-up treatment after progression in immunized patients. This drug exploits a potent innate immune mechanism that normally functions to destroy cells expressing a common xenoantigen (αGal). HAL immunotherapy consists of injecting patients with genetically modified allogeneic NSCLC cells bearing αGal moieties on their cell surface. Methods: This phase II study included 28 patients with metastatic or recurrent NSCLC, age ≥18, ECOG PS ≤2, ≤2 prior systemic therapies. Trial objectives were response rate, safety and immunogenicity. Patients received 300 x 106HAL cells q2wks x 8 doses. Adverse events were assessed using CTCAE v3. Immunogenicity was assessed by changes in serum anti-αGal titers and IFN-γ response. Patients progressing on study trial (n=16) received follow up chemotherapy. Response was evaluated using RECIST criteria. Results: Twenty-eight (28) patients were evaluable for response and 16 progressing patients received salvage chemotherapy. Median overall survival (OS) was 11.3 months (95% CI 3.8-21.9). Eight of 28 patients demonstrated stable disease (SD) ≥16 wks including one patient that progressed and later regressed to survive >50 months. Fifty six percent (9/16) of the progressing patients receiving follow up chemotherapy showed a response. Five (31%) achieved a PR and 25% (4/16) had SD after initial progression during the trial suggesting a chemo-sensitization effect of tergenpumatucel-L. Conclusions: HAL immunotherapy is safe and feasible. The median OS compared favorably to that reported in patients receiving 2nd line chemotherapy for relapsed or advanced NSCLC. The potential chemo-sensitization effect of tergenpumatucel-L is highly encouraging and currently being studied in a phase IIB/III trial. Clinical trial information: NCT00073398.
Randomized, blinded, placebo-controlled phase II trial of docetaxel and bavituximab as second-line therapy in locally advanced or metastatic non-squamous non-small cell lung cancer.
Authors: Shtivelband Mikhail , Spigel David R. , Gerber David E. , Jain Minish Mahendra , Ponomarova Olga V. , Giorgadze Davit , Shan Joseph , Menander Kerstin B. , Belani Chandra Prakash
Published: March 2020

8095

Background: Bavituximab (B) is a monoclonal antibody against phosphatidylserine (PS) with a selective tumor vascular-directed immune response. The purpose of this trial is to evaluate the efficacy and safety of B or placebo (P) combined with docetaxel (D) in patients with locally advanced or metastatic non-squamous NSCLC. Methods: Patients were randomized 1:1:1 to receive 75 mg/m2 of D every 21 days for up to 6 cycles combined with weekly blinded infusions of P, 1mg/kg B or 3 mg/kg B until disease progression or unacceptable toxicity. Primary efficacy endpoint was overall response rate (ORR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). Safety was evaluated by adverse events (AEs), vital signs, CBC, biochemistry, urinalysis, coagulation, ECG. Post study unblinding, a PK substudy revealed vial coding discrepancies in the P and 1 mg/kg vials. As a result, data from these two groups were pooled to form the control (C) arm in the analysis. Results: Forty-one patients were entered into the 3mg/kg B+D arm and 80 into the control arm. No significant differences were seen in age, gender, ethnicity or disease stage. ECOG 2 was 13% in C and 24% in 3 mg/kg B+D arms. At this analysis, 54% death events have been reported in 3 mg/kg B+D and 71% in C arm. ORR is 17.1%/13.8% and median PFS is 4.5/3.3 months for 3 mg/kg B+D/C. Median OS is 11.7 months for 3 mg/kg B+D and 7.3 months for C. The safety profile for 3 mg/kg B+D was similar to that of C in severity and frequency. No other safety signal was identified. Conclusions: This randomized, placebo-controlled phase 2 trial demonstrated a positive trend favoring 3 mg/kg B+D in ORR, PFS and OS. 3 mg/kg B in combination with D was well tolerated and is the planned dose forPhase 3. Clinical trial information: NCT01138163.