bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II trial of erlotinib (E) plus high-dose celecoxib (HD-C) or placebo (P) in advanced non-small cell lung cancer.
Authors: Reckamp Karen L. , Koczywas Marianna , Cristea Mihaela C. , Dowell Jonathan , Gardner Brian , Milne Ginger L , Figlin Robert A. , Elashoff Robert M. , Dubinett Steven M. 
Published: March 2020

7518 Background: Cyclooxygenase-2 (COX-2)-dependent signalling represents a potential mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy in NSCLC. This is mediated in part through an EGFR-independent activation of MAPK/Erk by the COX-2 metabolite PGE2. In addition, PGE2 promotes downregulation of E-cadherin and epithelial to mesenchymal transition. We hypothesize that EGFR and COX-2 inhibition with E and HD-C will augment EGFR TKI efficacy by increasing tumor E-cadherin expression and blocking PGE2-mediated resistance to EGFR inhibition. Methods: Pts with stage IIIB/IV NSCLC who progressed following at least one line of therapy or refused standard chemotherapy were randomized to E (150mg/day)/HD-C (600mg/2x day) vs E/P in a 28-day cycle. Pts were stratified by smoking status and ECOG PS. The primary endpoint was PFS with 80% power to detect a 50% improvement; assessments were performed every 2 cycles. Secondary endpoints included response rate, OS and evaluation of molecular markers in tissue and serum to assess targeting COX-2-related pathways and evaluate EGFR TKI-resistance. All pts were required to have pre-treatment tissue available. Results: 107 pts were enrolled with comparable baseline characteristics in both arms. Disease control rate (DCR) was similar in both arms, and a trend toward improved PFS was seen in the E/HD-C arm with HR 0.81 (see Table). Analysis of those with EGFR wild type revealed a significantly increased PFS while those with EGFR mutation had similar PFS in both groups. Safety analysis showed similar toxicity in both arms. Additional biomarker correlations will be presented. Conclusions: The combination of E/C in metastatic NSCLC with HD-C is well tolerated and demonstrates significantly improved efficacy in EGFR wt population. This warrants further study into the COX-2-dependent mechanisms of primary resistance to EGFR TKI therapy. Supported by NIH 1P50 CA90388, K12 CA01727 and medical research funds from the Dept of Veterans’ Affairs. [Table: see text]
Rebiopsy of non-small cell lung cancer patients with acquired resistance to EGFR-TKI: Comparison between T790M mutation-positive and -negative populations.
Authors: Hata Akito , Katakami Nobuyuki , Yoshioka Hiroshige , Takeshita Jumpei , Tanaka Kosuke , Nanjo Shigeki , Kaji Reiko , Fujita Shiro , Imai Yukihiro , Monden Kazuya , Matsumoto Takeshi , Nagata Kazuma , Otsuka Kyoko , Tachikawa Ryo , Tomii Keisuke , Kunimasa Kei , Iwasaku Masahiro , Nishiyama Akihiro , Ishida Tadashi 
Published: March 2020

7528 Background: The secondary epidermal growth factor receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitors (TKI). A recent report has demonstrated the presence of T790M predicts a favorable prognosis and indolent progression, compared to the absence of T790M after TKI failure. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M. Methods: We investigated 73 patients harboring EGFR sensitive mutations who had undergone rebiopsy to confirm the emergence of T790M after TKI failure. The peptide nucleic acid-locked nucleic acid PCR clamp method was used in EGFR mutational analyses. Patient characteristics (age, gender, smoking history, performance status, EGFR mutation site, initial TKI, response to initial TKI, line of initial TKI, progression-free survival with initial TKI, and biopsy site) and postprogression survivals (PPS) after initial TKI failure, were retrospectively compared in patients with and without T790M. Results: We identified T790M in 2 (10%) of 21 central nervous system (CNS) (19 cerebrospinal fluid and 2 brain tissue) specimens, and in 20 (38%) of 52 other lesions (25 lung tissue, 24 pleural effusion, and 3 lymph node) (p = 0.0225). Other characteristics had no statistical association with the detection of T790M. Median PPS in patients with T790M was 34.0 months, and in those without T790M, 14.5 months (p = 0.0038). Although none of our patients received TKIs continuously after initial failure, 56 (77%) patients were re-administered TKIs. Regardless of T790M status, PPS in patients with TKI re-administration (23.4 months) was significantly longer than without re-administration (10.4 months) (p = 0.0085). Conclusions: The emergence of T790M in CNS is rare compared with other lesions. Patients with T790M after TKI failure have significantly better prognosis than those without T790M. The effectiveness of TKI re-administration or continuous administration beyond progression is suggested after initial TKI failure.
A randomized, double-blind, placebo-controlled phase II study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naive metastatic/unresectable non-small cell lung cancer (NSCLC).
Authors: Von Pawel Joachim , Hadler Dietrich , Fox Tara , Wang Qiang , Greenberg Jonathan , Beckman Robert A. , Krzakowski Maciej Jerzy , Reck Martin 
Published: March 2020

7536 Background: Tigatuzumab (T), a humanized monoclonal antibody that acts as a DR5 agonist induces apoptosis in human cancer cell lines and has shown activity in a phase 1 trial; phase 2 trials are ongoing in several tumor types. In NSCLC cells, single-agent T shows anti-cancer activity. Methods: Patients (pts) with histologically/cytologically confirmed (TNM ed6) NSCLC stage IIIB/IV, measurable disease by RECIST (v1.0), and ECOG-PS 0-1 were enrolled at 15 European sites. Pts received T or placebo (PL) IV + carboplatin/paclitaxel (C/P) every 3 weeks (wks) (1 cycle) for up to 6 cycles. In the case of complete response (CR)/partial response (PR) or stable disease, T or PL was given as maintenance therapy. The dosage regimen was T 10 mg/kg or PL at wk 1/cycle 1 and 8 mg/kg or PL every 3 wks thereafter; P: 175 mg/m2 every 3 wks; C: AUC 6 every 3 wks. Primary endpoint: progression-free survival (PFS); secondary endpoints: overall survival (OS) and objective response rate (ORR) (CR + PR), safety. Efficacy was assessed in both the full population and a prospectively-defined FCGR genotype subset. Results: 97/100 pts (9.3% stage IIIB wet; 90.7% stage IV; 70.1% non-squamous; 29.9% squamous) were eligible for efficacy analyses (49 to T; 48 to PL). Median PFS (95% CI) was 5.4 months (3.3, 6.6) for T vs 4.3 months (4.1, 5.8) for PL; HR = 0.96; 95% CI: 0.6, 1.6. Median OS (95% CI) was 8.4 months (6.9, 16.3) for T vs 9.0 months (7.6, 14.5) for PL (HR = 0.95; 95% CI: 0.6, 1.6). 12 pts (24.5%) in the T arm and 11 pts (22.9%) in the PL arm had PR; no pt had CR. In a subset of pts (n = 25) with FCGR2A-H131R or FCGR3A-V158F genotypes, there was a non-significant trend towards increased PFS with T vs PL (HR = 0.47; 95% CI: 0.16, 1.35) but no difference in OS. T was well tolerated; the only increased grade 3/4 toxicity was grade 3 neutropenia (16% with T vs 4% with PL). The number of treatment cycles was similar in both treatment arms. Conclusions: T does not improve the efficacy of C/P as treatment for systemic therapy-naïve, unselected advanced NSCLC pts. T was well tolerated and is being investigated in other settings.
Intratumoral heterogeneity of EGFR mutation and clinical significance in Chinese patients with advanced non-small cell lung cancer.
Authors: Bai Hua , Wang Jie , Wang Zhijie , Duan Jianchun , Yang Lu , An Tongtong , Zhuo Minglei , Wu Meina , Wang Yuyan 
Published: March 2020

7537 Background: Whether exist intratumoral heterogeneity of epidermal growth factor receptor (EGFR) gene mutation remains controversial. This study aims to evaluate intratumoral heterogeneity of EGFR and its clinical significance in patients with non-small cell lung cancer (NSCLC). Methods: Samples were collected from 85 patients with stage IIIa-IV who had palliative surgery resection. All of the bulk tissues had been routinely detected EGFR mutation, in which contained 30 wild-type and 55 mutant-type EGFR. 28–34 tumor foci for each sample were microdissected. EGFR mutation was detected by ARMS. EGFR copy number was detected by FISH. 23 patients received EGFR-tyrosine kinase inhibitor (TKIs) therapy. Results: 1740 tumor foci from 55 EGFR mutant-type (Group-M) and 959 foci from 30 wild-type cases(Group-W) were fractionated. Mean mutation contents were 73.9%(1285/1740) in Group-M and 0 in Group-W. Accordingly, 28.2%(24/85)consisted of cells with both wild-type and mutated-type EGFR, with the proportion of EGFR mutant cells ranging from 1% to 90%, whereas 71.8%(61/85) samples contained pure mutant-type (n=31) or wild-type EGFR cells(n=30). 31 patients (36.5%) presented EGFR FISH positive. The patients with mutation heterogeneity, regardless of high or low mutation contents, presented lower EGFR copy number than those with pure mutation cases (16.7% vs 71.0%,p<0.05). Among 23 patients who received EGFR-TKIs therapy, the mean mutation content was higher in partial response (71.1%) and stable disease group (43.4%) than in progressive disease group (5.0%) (p=0.005). Conclusions: This study showed that the heterogeneity of EGFR mutation was found in introtumoral region with different degree. The response to EGFR-TKIs was correlated with EGFR mutant content.
A phase II multicenter study of aflibercept (AFL) in combination with cisplatin (C) and pemetrexed (P) in patients with previously untreated advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC).
Authors: Chen Hongbin , Modiano Manuel R. , Neal Joel W. , Brahmer Julie R. , Rigas James R. , Jotte Robert M. , Leighl Natasha B. , Liu Liming , Lisano Julie M. , Adjei Alex A. , Wakelee Heather A. 
Published: March 2020

7541 Background: AFL is a recombinant human fusion protein that acts as a decoy receptor and prevents the interaction of vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor with their receptors. This study evaluated the efficacy and safety of AFL in combination with first-line chemotherapy of C and P in NSCLC. Methods: This phase II, single arm, open label, multicenter trial in patients with previously untreated, locally advanced, or metastatic NSCLC excluded patients with squamous histology, cavitating lesions, ECOG > 1, uncontrolled hypertension, or brain/CNS metastases. All patients received IV AFL 6 mg/kg, P 500 mg/m2, and C 75mg/m2, every 3 weeks for up to 6 cycles. For those who completed the combined chemotherapy, Q3W administration of AFL was to continue until disease progression, intolerable toxicity, or any other cause for withdrawal. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). Planned sample size was 72 patients. Results: The study was closed prematurely due to 3 confirmed cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 54.8% were male, 85.7% white and 50% ECOG 0. A median of 4 cycles of AFL was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. The 3 patients with RPLS were Caucasian women. Two had a history of hypertension and both experienced elevated BP and reduced CrCl. Of the 38 patients evaluable for response, ORR was 26.3% (95% CI, 12.3-40.3%) and median PFS was 5 months (95% CI, 4.3-7.1). Conclusions: The rate of RPLS observed in this study with AFL + C + P was higher than anticipated. A meta-analysis of safety from three large placebo-controlled studies reported no RPLS among 1333 patient treated with AFL + chemotherapy, and none was reported in prior combination studies of AFL + P or AFL + C + docetaxel. Though the study was stopped early, ORR and PFS were in accordance with most historical first-line NSCLC studies.
Delay of chemotherapy through use of post-progression erlotinib in patients with EGFR-mutant lung cancer.
Authors: Oxnard Geoffrey R. , Lo Peter , Jackman David Michael , Butaney Mohit , Heon Stephanie , Johnson Bruce E , Sequist Lecia V. , Janne Pasi A. 
Published: March 2020

7547 Background: 1st-line tyrosine kinase inhibitor (TKI) therapy for patients (pts) with EGFR-mutant lung cancer prolongs progression free survival (PFS) and improves quality of life. When pts develop acquired resistance to TKI, chemotherapy is the only approved systemic treatment. Anecdotal evidence suggests that change of therapy can be delayed in some pts through continued TKI beyond progression (PD), but the effectiveness of this approach has not been quantified. Methods: Through an IRB-approved mechanism, pts with advanced lung cancer and EGFR sensitizing mutations treated on 3 prospective trials of 1st-line erlotinib were identified. Only pts with RECIST PD while on erlotinib were studied. Time from PD until use of an alternate systemic therapy (or death) and characteristics at PD (development of new extra-thoracic metastases or cancer-related symptoms) were assessed. Results: 42 eligible pts were identified with the following characteristics: median age 70, 86% female, 93% non-Asian, 50% never-smokers, 83% adenocarcinoma, 100% EGFR-mutant (55% exon 19, 36% exon 21, 9% exon 18). Median PFS on erlotinib was 13 months. After PD, alternate systemic therapy was delayed >3 months in 19 pts (45%; 95%CI: 31%-60%), through a combination of post-PD erlotinib (16 pts), radiation (6 pts), and/or surgery (3 pts), or on observation alone (2 pts). These 19 pts commonly had exon 19 deletions and were more likely to have no cancer-related symptoms at PD (Table), and had a median post-PD survival of 29 months. Alternate systemic therapy was delayed >12 months in 8 pts (19%). Conclusions: In a subset of pts with EGFR-mutant lung cancer and acquired resistance to TKI, chemotherapy can be delayed with the aid of post-PD TKI and local treatment modalities. This indolent PD is likely due to ongoing tumor EGFR dependence. In pts who are tolerating TKI and have asymptomatic progression, we recommend this palliative treatment strategy as an option for delaying chemotherapy and maximizing quality of life. [Table: see text]
Molecular marker analysis of SWOG S0636, a phase II trial of erlotinib and bevacizumab in never-smokers with advanced NSCLC.
Authors: Mack Philip C. , Moon James , West Howard Jack , Franklin Wilbur A. , Varella-Garcia Marileila , Wynes Murry W. , Wozniak Antoinette J. , Redman Mary Weber , Hirsch Fred R. , Gandara David R. 
Published: March 2020

7552 Background: S0636 investigated the combination of erlotinib and bevacizumab in never-smoking NSCLC patients with confirmed adenocarcinoma histology (H. West ASCO 2011). Patient eligibility was not restricted by molecular selection. Median PFS and OS were encouraging at 8 and 26 months. An analysis of molecular markers was undertaken, focusing initially on the EGFR pathway. Methods: EGFR analysis included gene copy number, mutation and protein expression. Copy number was conducted by FISH using the Colorado scoring system. An immunohistochemistry H score was developed for EGFR protein expression analysis, ranging from 0 to 400. Specimens were evaluable from 42 of the 85 eligible patients. Results: FISH positivity was identified in 17/35 pts (49%), 11 with high polysomy and 6 with true gene amplification. EGFR activating mutations were seen in 10/33 pts (30%). IHC H-score >200 was observed in 17/40 pts (43%). All EGFR markers were significantly correlated with one another. In the EGFR WT subgroup, FISH-positive patients outperformed FISH-negative pts (mPFS 20 vs, 6 months, p=0.06). Conclusions: Careful analysis of EGFR markers (mutation, FISH and IHC) identified S0636 patients with favorable PFS and encouraging trends for OS. EGFR FISH and IHC provided additional predictive information beyond that of EGFR mutation status. Supported in part by DHHS: CA32102 and CA38926, and in part by Genentech. [Table: see text]
Radiographic assessment and therapeutic decisions at RECIST progression in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors.
Authors: Nishino Mizuki , Heon Stephanie , Dahlberg Suzanne Eleanor , Jackman David Michael , Ramaiya Nikhil H. , Hatabu Hiroto , Rabin Michael S. , Janne Pasi Antero , Johnson Bruce E 
Published: March 2020

7553 Background: EGFR mutated advanced NSCLC treated with EGFR TKIs typically progresses after initial response due to acquired resistance. TKI therapy is often continued beyond RECIST progression (PD). We investigated the frequency of this practice and patterns of RECIST PD via imaging findings, as well as the association between patient characteristics and discontinuation of TKI among patients (pts) who progressed while on TKI. Methods: Among a cohort of 101 advanced NSCLC pts with sensitizing EGFR mutations treated with first-line erlotinib or gefitinib at DFCI, 70 pts treated between 2002 and 2010 had at least two CT scans for retrospective radiographic assessments using RECIST1.1; 56 pts had experienced PD by the data closure date of June 2011. Results: Among 56 pts experiencing PD, 46 (82%) were female, median age was 63 (range 35-79), 28 (50%) were never-smokers, 32 (57%) had distant mets, 32(57%) had exon 19 deletion, and 50 (89%) received erlotinib. 49 pts (88%) continued TKI therapy for at least 2 mos beyond retrospectively assessed PD. 31/32 (97%) pts who progressed by increase of target lesions continued TKI. 13/16 (81%) pts who progressed by new lesion remained on TKI. Two pts with PD in non-target lesions discontinued therapy at PD. 5/6 (83%) pts with both increase of target lesions and new lesion at PD continued TKI. In 49 continuing pts, the median time from RECIST PD to termination of TKI was 10.1 mos (range: 2.2-64.2 mos). 15/49 (31%) pts who continued TKI received additional chemo compared to 0/7 pts who discontinued (Fisher’s p=0.17). Pts who discontinued therapy (n=7) were significantly younger (median 48 yrs) than those who continued TKI at PD (median 64 yrs, Wilcoxon p=0.003). Median OS beyond RECIST PD among those who continued TKI was 31.8 mos (95% CI 15.9- not reached) and though underpowered, this did not appear to be impacted by TTP when adjusted in a Cox model (p=0.84). Conclusions: 88% of EFGR-mutant NSCLC pts who progressed on first-line TKI continued therapy beyond RECIST PD, which is not the single determining factor for terminating TKI in EGFR-mutant NSCLC pts. Additional progression criteria specific to this population are needed to better guide therapeutic decision making.
Elderly and younger patients with non-small cell lung cancer (NSCLC) derive similar benefit from second-line chemotherapy: A retrospective subset analysis of second-line chemotherapy trials conducted from the Hellenic Cooperative Research Group (HORG).
Authors: Agelaki Sofia , Hatzidaki Dora , Vamvakas Lampros , Pallis Athanasios G. , Karampeazis Athanasios , Agelidou Athina , Agelidou Maria , Chandrinos Vassilis , Polyzos Aristidis , Georgoulias Vassilis 
Published: March 2020

7564 Background: Elderly patients (pts) achieve a similar survival benefit, with acceptable toxicity, from first-line chemotherapy for the treatment of advanced NSCLC compared with their younger counterparts. There have been no second-line trials specifically designed for elderly pts and few data exist on the efficacy and tolerability of second-line therapy in this population. Moreover, little if any information exists on the frequency of administration of second-line chemotherapy in these pts. Methods: The files of 2004 pts with advanced NSCLC enrolled into first-line chemotherapy trials performed by HORG from 1995 to 2007 were reviewed. A total of 600 pts who received second-line chemotherapy within the context of clinical trials were identified. Patients’ data were analysed for efficacy and toxicity according to age. Results: Second-line chemotherapy was administered in 24% and 34% of pts ≥65 and <65 years old after failure of prior therapy (p=0.0001). A total of 219 (24.8%) of 600 pts who received second-line treatment were ≥65 years old (median age 70 yrs, range 65-82). Response rates to second-line therapy were 11.9% for older pts compared to 12.3% for younger pts (p=ns). TTP was 2.8 and 3.1 months for older and younger pts, respectively (p=ns). Elderly pts receiving second-line chemotherapy had a median survival of 7.7 months compared with 8.2 months for younger pts (p=ns). Similar rates of haematological and non-haematological toxicities were encountered between the two groups. Conclusions: The participation of elderly pts to second-line chemotherapy trials was lower compared to younger patients. There was no significant difference in outcome or toxicity between elderly and younger pts. For elderly pts with advanced NSCLC and good performance status, second-line chemotherapy is appropriate. However, specific second-line trials in older pts are required since those included in the current analysis were probably highly selected to fit the inclusion criteria.
Rare and complex mutations of epidermal growth factor receptor (EGFR) and efficacy of tyrosine kinase inhibitor (TKI) in patients with non-small cell lung cancer (NSCLC).
Authors: Keam Bhumsuk , Kim Dong-Wan , Park Jin Hyun , Lee Jeong-Ok , Kim Tae Min , Lee Se-Hoon , Jeon Yoon-Kyung , Chung Doo Hyun , Heo Dae Seog 
Published: March 2020

7566 Background: Other than in-frame deletional mutation (MT) in exon 19 and Leu858Arg point MT in EGFR gene, there are many rare and complex MT. The purpose of this study was to investigate was to clarify the clinical significance of rare and complex MT, and the efficacy of EGFR TKI in these patients. Methods: Rare MTs were defined any MT other than deletional MT in exon 19, Leu858Arg in exon 21, and Thr790Met in exon 20. Complex MT was defined two different EGFR MTs co-occurring within the single tumor sample. We have analyzed consecutive database of NSCLC patients who were treated with either gefitinib or erlotinib at Seoul National University Hospital between Jan. 2002 and Dec. 2011. For analysis of EGFR MT, coding sequences from exon 18 to 21 were amplified by nested PCR and subjected to direct sequencing methods. Results: Among the 1,159 TKI treated patients, 301 patients had EGFR MT (177 patients (58.8%) with del-19, 104 patients (34.6%) with Leu858Arg, and 20 patients (6.6%) with rare MT). Twenty-three (7.6%) patients have complex MT, and 55 (18.3%) patients have Gln787Gln polymorphism particularly associated with Leu858Arg MT. Identified rare MT were follows; exon 18: Leu692Phe, Glu707Lys, Glu709Gly, Lys714Asn, Gly7Ala, Thr725Thr, exon 19: Ala755Asp Lys737Thr, exon 20: Val786Met, exon21: Ala871Gly, Gly873Gln, Leu833Val, Val834Leu, Arg836Cys, Pro848Leu, Ala859Thr, Leu861Gln. When categorizing 3 groups (group A: classic MT alone, group B: complex MT with classic + rare MT, group C: rare MT alone or complex MT with rare MTs), response rate (RR) to TKI was different between each groups (RR= 78.7% in group A vs. 69.2% in group B vs. 38.5% in group C, respectively, P < 0.001). Progression-free survival (PFS) was also poorer in rare MT (median PFS: 12.1 mo vs. 7.6 mo vs. 2.1 mo, respectively, P= 0.020,). Gln787Gln polymorphism of exon 21 was not associated with RR or PFS (P= 0.101, P= 146, respectively) Conclusions: In this large case series, NSCLC patients who harboring rare MT other than del-19 and Leu858Arg, does not seems response to EGFR TKI. However, complex MT with the classical MT showed similar treatment efficacy toward EGFR TKI with that of classical MT alone.