bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of life (QOL) impact of adjuvant chemotherapy for early stage non-small cell lung cancer (NSCLC): Final analysis of JBR.10 randomized trial
Authors: Bezjak A. , Lee C. W. , Ding K. , Winton T. , Brundage M. , Graham B. , Whitehead M. , Seymour L. , Shepherd F. A.
Published: March 2020

7585

Background: Adjuvant chemotherapy for early stage NSCLC is now standard of care, but its impact on QOL is not known. We report the final QOL analysis of JBR.10, a North American intergroup randomized trial of adjuvant cisplatin/vinorelbine compared to observation in patients (pts) with completely resected stage IB/II NSCLC (n=482). Methods: QOL, a secondary endpoint of JBR.10, was assessed using the EORTC QLQ-C30 and a trial-specific checklist at baseline, weeks 5 and 9 for those on chemotherapy, and at 3, 6, 9, 12, 18, 24, 30 and 36 months of follow up. A 10-point change in QOL scores from baseline was considered clinically significant. Results: QOL assessment was not mandatory for all pts; 186/242 (76.9%) pts randomized to chemotherapy completed the baseline QOL assessment, compared to 173/240 (72.1%) pts on the observation arm. The overall survival of pts contributing QOL data, and the effect of adjuvant chemotherapy, was not different from the entire study population. Baseline QOL in the two study arms was comparable, with low global QOL scores and a significant symptom burden, especially pain and fatigue, following thoracotomy. A significantly greater proportion of chemotherapy pts experienced worsening symptoms including fatigue (p=0.02), appetite, hair loss, nausea and vomiting. At 6 months, a higher proportion of pts on the observation arm reported improved QOL in the global (p = 0.002), physical (p=0.02) and functional domains, compared to pts on the chemotherapy arm. However, by the 9 month time-point, global QOL of patients on chemotherapy was comparable to QOL of patients on observation, as were the five functional domains. Numbness (change scores: 22 vs 6, p<0.01) and pins & needles in fingers/toes (change scores: 21 vs 5, p<0.01) were the only symptoms that persisted, up to 24 months. Conclusion: Patients on adjuvant chemotherapy experience an initial slower recovery of QOL after thoracotomy, but following completion of treatment reach levels comparable to patients treated with surgery alone, in most aspects of QOL.

[Table: see text]
Final results of ECOG 3503: A pilot study to determine if downstream markers of EGFR linked signaling pathways predict response to erlotinib (OSI-774) in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC)
Authors: Kolesar J. , Brahmer J. , Lee J. , Guaglianone P. , Patel J. , Keppen M. , Hidalgo M. , Carbone D. , Schiller J.
Published: March 2020

7588

Background: Predictors of response and survival in patients (pts) who benefit from Erlotinib (Elb) remain controversial. The primary objective is to prospectively identify downstream markers of EGFR linked signaling pathways that are predictive of response. The secondary objectives are to estimate response rate (RR), disease control rate (dcr), time to progression (ttp), survival, and if a grade (gr) 2 rash is predictive of survival. Methods: Pts with advanced NSCLC (Stage IIIB with pleural effusion and IV, no prior systemic treatment, performance status 0–2, no symptomatic CNS metastasis, and adequate renal, hepatic and hematologic function) were accrued to this single arm study. Elb was taken orally once a day until disease progression or unacceptable toxicity. Starting at 150 mg per day, the dose was escalated by 25 mg once every 2 weeks until a gr 2 rash developed, other toxicities precluded escalation, or 250 mg dose reached. Paraffin- fixed tumor tissue was collected on pts for correlative studies including quantitative immunohistochemistry (IHC) for pMAPK. Results: Of 137 pts recruited, 118 were eligible and 57 pts had adequate tissue to do IHC. Dose escalation occurred in 60/118 pts, with 15 getting up to 250 mg. The RR, by RECIST criteria, was 7% (8/112, 1 CR) with dcr of 46% (51/112). Most pts went off trial because of progression of disease (69%). Median survival was 7.9 months (mo), and median ttp was 3.5 mo. Of the 134 pts evaluated for toxicity, 43 (32%), 66 (49%), and 13 (10%) had a gr 1, 2 and 3 rash respectively. pMAPK was not a predictor for response. Using a median score of 20 as the cutoff for pMAPK as positive or negative, negative pMAPK tended to have a longer survival (7.6 mo vs. 5.3 mo, p=0.051). A gr ≥ 2 rash trended towards an association with prolonged survival (12.6 mo vs. 6.4 mo, p=0.099). Conclusions: Elb used as first-line treatment in an unselected population has a response rate and survival similar to first-line chemotherapy. Negative pMAPK may predict for prolonged survival but does not predict response. EGFR mutation and FISH analysis will be available at the meeting.

No significant financial relationships to disclose.
Correlative analyses of plasma cytokine/angiogenic factor (C/AF) profile, gender and outcome in a randomized, three-arm, phase II trial of first-line vandetanib (VAN) and/or carboplatin plus paclitaxel (CP) for advanced non-small cell lung cancer (NSCLC)
Authors: Hanrahan E. O. , Lin H. Y. , Du D. Z. , Yan S. , Kim E. S. , Lee J. J. , Ryan A. J. , Tran H. T. , Johnson B. E. , Heymach J. V.
Published: March 2020

7593

Background: VAN (ZD6474) is an oral inhibitor of VEGFR, EGFR and RET. In a phase II trial, 181 patients with advanced NSCLC were randomized to 1st-line treatment with VAN, CP or VAN + CP. Progression free survival (PFS) was prolonged for VAN + CP vs CP (Heymach et al, submitted for ASCO 2007). Exploratory subgroup analyses suggest gender differences in PFS benefit for VAN + CP vs CP (HR 0.47 in females vs 1.05 in males). We performed exploratory analyses of plasma levels of 35 C/AFs to investigate gender differences and potential prognostic or predictive markers. Methods: Plasma was collected at baseline (n = 123; VAN 55, CP 32, VAN + CP 36), day (D) 8 (n = 104), D22 (n = 95), and D43 (n = 83). We used multiplex bead assays to measure 33 plasma C/AFs, including VEGF, basic FGF, EGF, HGF, E-selectin, ICAM-1, MMP-9, multiple chemokines and interleukins (IL). Osteopontin and sVEGFR-2 were measured by ELISA. Cox models were applied on PFS to identify prognostic/predictive markers after rank transformation and adjusted for covariates. Results: Significant gender differences in baseline C/AF levels were seen for IL-15, IL-1RA, IL-2R, MIG, and MIP-1A (all higher in females, all p = 0.022). Controlling for gender and treatment, high baseline E-selectin (p = .01), IL-6 (p = 0.018), and IL-2R (p = 0.008) were adverse prognostic indicators for PFS. Controlling for gender, the tests for treatment by factor interactions (to assess whether treatment effect was different in patients with low and high C/AF levels) were significant for baseline HGF (p = 0.04) and IL-2R (p = 0.008). For both HGF and IL- 2R, low levels were associated with prolonged PFS in the VAN arm, but were not associated with differences in the CP or VAN + CP arms. Significant changes in VEGF (rise) and sVEGFR-2 (decrease) occurred with treatment in the VAN arm; IL12, IL-1RA, MMP-9 and MCP-1 changed in the CP and VAN + CP arms. Conclusions: There are gender differences in PFS benefit from VAN and in plasma C/AF profile. Several C/AFs were of prognostic value, whereas low HGF and IL-2R were predictive of benefit in the VAN but not CP and VAN + CP arms. These gender differences and markers warrant further investigation.

[Table: see text]
Clinicopathologic features and prognostic implications of epidermal growth factor receptor (EGFR) gene mutations detected by denaturing high-performance liquid chromatography (dHPLC) in non-small cell lung cancer (NSCLC)
Authors: Cohen V. , Agulnik J. S. , Ang C. , Kasymjanova G. , Chong G. , Tejada N. A. , Pepe C. , Batist G. , Small D. , Miller W. H.
Published: March 2020

7594

Background: Somatic mutations of the EGFR gene predict sensitivity to erlotinib and gefitinib and confer a favorable prognosis in patients (pts) with NSCLC. We have recently shown that dHPLC is an efficient and more sensitive method for mutation screening compared with DNA sequencing. The goal of this study was to describe the relationship between EGFR status (mutation status and type) and clinicopathologic factors. Methods: Tumor samples were analysed for EGFR exon 19 deletions and exon 21 L858R point mutations. DNA was extracted from paraffin-embedded tumor specimens and genotyped using dHPLC. The results were correlated with gender, smoking status, pathologic subtype, disease stage, and overall survival. Results: 215 NSCLC pts were genotyped. Mutations were present in 25% of cases (54 of 215). Among pts with mutations, 70% (38 of 54) had an exon 19 mutation whereas 30% had EGFR L858R. EGFR mutations were more common in women (31% vs 14%; p=0.008), in nonsmokers than ever-smokers (54% vs 17%; p<0.001), in adenocarcinomas/BAC than with other NSCLC histologies (31% vs 11%; p=0.004) and more frequently detected in advanced-stage than in early-stage disease (36% vs 15%; p=0.001). Median survival times of pts with stage IIIB-IV disease with and without EGFR mutations were 20 and 14 months, respectively. Those with exon 19 deletion mutations had a longer median survival than pts with L858R point mutations. Data describing the impact of tyrosine kinase inhibitor therapy on survival outcomes are pending and will be presented. Conclusion: dHPLC is a reliable tool for EGFR mutation detection. Mutations were preferentially observed in women, nonsmokers, adenocarcinomas/BAC and in patients with advanced disease. Pts with mutations experienced improved survival and those harboring deletions fared better than those with point mutations. These observations warrant confirmation in large prospective trials and exploration of the biological mechanisms of the differences between mutation types.

No significant financial relationships to disclose.
Phase II randomized trial of docetaxel plus cetuximab or bortezomib in patients with advanced NSCLC and performance status (PS) 2—CALGB 30402
Authors: Lilenbaum R. , Wang X. , Gu L. , Kirshner J. , Vokes E.
Published: March 2020

7595

Background: There is no standard treatment for patients (pts) with advanced NSCLC and PS 2. Docetaxel (D) is active and well tolerated on a weekly schedule. Cetuximab (C) and Bortezomib (B) are new agents with activity in NSCLC. We explored these two new combinations in PS 2 pts. Methods: In a multi-center randomized phase II trial, untreated pts with advanced NSCLC and PS 2 were randomized to D 30 mg/m2 d1,8,15 q. 28 days in combination with either C 400 mg/m2 week 1 then 250 mg/m2 weekly, or B 1.6 mg/m2 d1,8,15 q. 28 days for 4 cycles. Pts with CR/PR/SD were allowed to continue C or B until PD. The study was non-comparative and the primary endpoint was progression-free survival (PFS) rate at 6 months. The trial had a type I error of 0.0746 and power of 0.9 to differentiate a 6-mo PFS of <20% vs. >42%. Results: 64 pts were enrolled between 7/05 and 9/06. 5 were ineligible and 3 never received protocol treatment. Results are reported for 55 pts (27 D+C; 28 D+B). Most pts had stage IV adenoCa and 13% had brain metastases. Median age was 70 (range, 35–88) and 65% were male. Response: 10.5% for D+C and 13.6% for D+B. Median PFS was 3.1 mo for D+C and 1.8 mo for D+B. PFS rates at 4 mo (data not yet mature for 6-mo): 33% and 28%, respectively. Median survival: 3.8 mo for D+C and 3.3 mo for D+B. Gr 3/4 hematologic toxicity was 17% in both arms. Gr 3/4 non-heme toxicities were 44% in D+C and 36% in D+B arm. 5 pts died of treatment-related toxicities (3 D+C; 2 D+B). Conclusions: These results confirm the poor prognosis associated with a PS of 2. Based on our preliminary analysis, neither combination produced results that justify further research in this subset of patients. The treatment of PS 2 patients with advanced NSCLC remains a vexing problem and new approaches are urgently needed.

No significant financial relationships to disclose.
A phase I/II study of OGX-011 and a gemcitabine (GEM)/platinum regimen as first-line therapy in 85 patients with advanced non-small cell lung cancer
Authors: Laskin J. J. , Hao D. , Canil C. , Lee C. W. , Stephenson J. , Vincent M. , Gitlitz B. , Cheng S. , Murray N. R.
Published: March 2020

7596

Background: OGX-011 is a second-generation antisense oligonucleotide designed to knockdown expression of the cytoprotective chaperone, clusterin, thereby facilitating apoptosis and sensitization of many human cancer cell-lines to chemotherapy. Methods: Eligibility criteria: stage IIIB/IV NSCLC; no prior chemotherapy; =1 measurable lesion; ECOG =1; adequate organ function; no active CNS metastasis. Treatment: infusion of OGX-011 initial loading doses (3 in 1 week), followed by weekly OGX-011 with standard chemotherapy: GEM (1,250 mg/m2) Days 1+8 and either cisplatin (75 mg/m2) or carboplatin (AUC=5) Day 1 q21 days, (maximum 6 cycles). Results: 85 pts (phase I=10 and phase II=75) enrolled between Dec 04 and Nov 06. Based on phase I results, dose of OGX-011 was 640 mg. Data is available on the first 53 pts; all received =1 dose of OGX-011 and were considered evaluable for safety and efficacy. Demographics: female (47%); stage IV (87%); median age 61 (45–79) yrs; ECOG PS =1 (62%); median no. of cycles delivered was 4. Principal grade 3/4 toxicities were hematologic: neutropenia (32%) + thrombocytopenia (17%). Other common toxicities included fatigue, nausea, vomiting, fever, chills, constipation, + anorexia. Two serious adverse events previously reported as associated with GEM/platinum therapy were documented: acute cortical blindness with stroke + thrombotic thrombocytopenic purpura. Responses: 12 confirmed PR (ORR = 23%). Median PFS is 101 days (53–260+). Of the first 24 patients who have all been followed for =1 yr, median survival is 383 days (19–751+); 14/24 (58%) survived >1 yr; 10/14 remain alive as of 12/13/06. Conclusions: 1-yr survival rate =50% may justify a phase III randomized trial. Survival data on 46 pts followed for =1 yr will be presented. OGX-011 is being developed by OncoGenex Technology Inc. + Isis Pharmaceuticals Inc.

No significant financial relationships to disclose.
Exploratory analysis of EGFR FISH criteria in Japanese non-small cell lung cancer patients treated with gefitinib
Authors: Kazuo K. , Morrison L. E. , Kimura H. , Sone T. , Araya T. , Tamori S. , Tanbo Y. , Fujimura M. , Speake G. , Holloway B. R.
Published: March 2020

7599

Background: In the phase III Iressa (gefitinib) Survival Evaluation in Lung cancer (ISEL) trial, high epidermal growth factor receptor (EGFR) gene copy number was a predictor of a gefitinib effect on survival in patients (pts) with refractory advanced non-small-cell lung cancer (NSCLC) (hazard ratio 0.61 vs 1.16 for high vs low copy number; p=0.045) [JCO 2006;24:5034–42]. Although EGFR mutation status may predict response to gefitinib in Japanese pts, there is insufficient data to clarify if high EGFR gene copy number assessed by fluorescence in situ hybridization (FISH) is predictive in these pts. This analysis investigated the applicability of both published Colorado FISH criteria (Colorado Univ) and new FISH criteria to Japanese NSCLC pts. Methods: 58 tumor specimens from gefitinib-treated Japanese pts were analyzed using Vysis LSI EGFR and CEP7 (chromosome 7 control) FISH probes. Specimens were classed as FISH+ or - using Colorado and exploratory (EGFR/cell; CEP7/cell; EGFR/CEP7; % of cells with various numbers of EGFR or CEP7 signals) criteria. Results: Of the 58 pts, 17 (29%) had an objective response (OR). Using Colorado criteria, OR was 50% in the 14 FISH+ pts vs 23% in the 44 FISH- pts (2-sided Fisher's exact test p=0.089). There was a trend for an association between FISH+ status and improved survival (log rank p=0.15). Defining FISH+ as specimens with =5% cells containing >5 EGFR signals, OR was significantly better among FISH+ pts vs FISH- pts (p=0.0030; 52% of the 23 FISH+ pts responding vs 14% of the 35 FISH- pts). A survival advantage was not indicated. Defining FISH+ as =74% of cells with EGFR or CEP7 loss (<2 signals) or gain (>2 signals), OR was significantly better among FISH+ pts vs FISH- pts (p=0.043; 45% of the 22 FISH+ pts responding vs 19% of the 36 FISH- pts). Association with survival had marginal significance (log rank p=0.061). Conclusions: These preliminary data have identified loss or gain of EGFR and CEP7 abnormality as promising biomarkers for response to gefitinib in Japanese NSCLC patients. Analysis of these markers for correlation with time to progression is ongoing. Investigation of these potential markers in other cohorts of patients is worthy of further evaluation.

[Table: see text]
Pemetrexed and carboplatin plus bevacizumab for advanced non-squamous non-small cell lung cancer (NSCLC): Preliminary results
Authors: Patel J. D. , Hensing T. A. , Villafor V. , Hart E. , Bonomi P.
Published: March 2020

7601

Background: Pemetrexed in combination with carboplatin has been shown to have promising activity and favorable toxicity profile in NSCLC. Bevacizumab has been shown to improve response rates and survival in pts with advanced non-squamous NSCLC when combined with carboplatin and paclitaxel. This study of pemetrexed and carboplatin plus bevacizumab was designed to evaluate the toxicity profile and to estimate the activity of the regimen in this pt population. Methods: Eligibility required that pts were chemotherapy-naive, had stage IIIB (effusion)/IV non-squamous NSCLC, PS 0–1, with no evidence of CNS metastases. Pts received pemetrexed 500 mg/m2 over 10 minutes, carboplatin AUC 6 over 30 minutes, and bevacizumab 15 mg/kg over 30–90 minutes on a 21-day cycle for 6 cycles. Pts with SD or PR received pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg every 21 days until disease progression or toxicity. All pts received folic acid, vitamin B12 and steroid prophylaxis. Results: From 8/05 to 9/06, 39 pts (of planned 50) were enrolled: 20 M/19 F; median age 64 (range 41 - 80). One pt enrolled and subsequently refused treatment. Median number of cycles was 6 (range 1–22), and 25/38 (66%) completed at least 6 cycles of therapy. There was no grade 4 hematological toxicity. Grade 3 hematological toxicities were anemia (5%, N=2) and thrombocytopenia (3%, N=1). The most common grade 3/4 non-hematological toxicities included proteinuria (3%, N=1, gr 3), venous thrombosis (3%, N=1, gr 3), infection (3%, N=1, gr 4), and diverticulitis (11%: 8%, N=3, gr 3/3%, N=1, gr 4). 1 pt with diverticulitis experienced bowel perforation that required surgical intervention. The trial was temporally suspended and the group of pts with diverticulitis was analyzed separately. The only risk factor identified was previous history of diverticulitis. One CR, 20 PRs were observed for an overall response rate of 55% (95%, CI 43–75%). Conclusions: Treatment with pemetrexed and carboplatin plus bevacizumab in pts with advanced non-squamous NSCLC is feasible with an acceptable toxicity profile. The encouraging activity justifies further development of this regimen. However, pts with a prior history of diverticulitis should be excluded until this observation can be investigated further.

No significant financial relationships to disclose.
Extent of lymphadenectomy (LA) and outcome for patients with stage I non-small cell lung cancer (NSCLC)
Authors: DeCamp M. M. , Recht A. , Nikolov M. , Flickinger J. C. , Varlotto J. M.
Published: March 2020

7604

Background: It is uncertain if LA affects overall survival (OS) or disease-free survival (DFS) rates for patients with stage I NSCLC and, if performed, what is the minimum number of nodes that should be recovered. Methods: 24,273 patients with stage I NSCLC diagnosed from 1992–2002 underwent a definitive surgical procedure and were included in the SEER data-base. For patients diagnosed from 1998–2002, outcome was examined separately for patients having only N1 (2,683 patients) or N2 nodal (1,019 patients) dissections. Results: For the entire population, LA was associated with an increase in the 5-year OS rate from 41.7% to 58.4% (p <0.0001) and in DFS from 58.4% to 72.9%, compared to not having LA. For patients undergoing only N1 dissection, LA was also associated with significant improvements in OS and DFS, compared to no LA (p=0.056 and 0.043). The maximum difference between those with no LA and those with only N1 dissection was when 11–16 nodes were removed (4-year OS, 40.0% vs. 68.2%; DFS, 40.0% vs. 60.4%). For patients undergoing only N2 dissection, LA was associated with a significant improvement in OS (p=0.045) and a trend for a DFS benefit (p=0.086), with the maximum difference between those with no LA and those with 7–10 nodes removed (4-year OS, 75.0% vs. 77.7%; DFS, 75.0% vs. 85.0%). Those patients undergoing removal of ≥ 11 N2 nodes were found to have a significantly increased risk of death to cardiopulmonary/infectious causes (5.56% vs 1.79%) as compared to those patients having < 11 nodes removed (p = 0.023). Conclusions: LA was associated with increased rates of OS and DFS, compared to no LA. Our results also suggest the minimum number of recovered nodes needed to see the maximum staging accuracy of LA.

No significant financial relationships to disclose.
3p and 10q deletions detected by fluorescence in situ hybridization (FISH): A potential new tool for early detection of non-small cell lung cancer (NSCLC)
Authors: Yendamuri S. , Vaporciyan A. A. , Zaidi T. , Fernandez R. , Rice D. C. , Spitz M. , Swisher S. , Walsh G. L. , Roth J. A. , Katz R. L.
Published: March 2020

7606

Objectives: To study the feasibility of detecting chromosomal deletions at the 3p and 10q regions in bronchoscopic brush biopsies and touch preparations by FISH and to study their distribution in different areas of the airway in patients with NSCLC. Methods: Bronchoscopic brush biopsies from the mainstem bronchus on the normal side contralateral to the tumor (NBB) and normal mainstem bronchus on the tumor side (TBB) were obtained from 120 patients who underwent surgical resection. Touch preparations from the tumor (TTP) and normal lung parenchyma from the involved lung (NTP) and from bronchi adjacent to the tumor (TAB) were also obtained. Two FISH assays using probes complementary to 3p22.1 and 10q22.3 were used for evaluation of chromosomal deletions at each site. The ratios of the percentage of deletions detected at different anatomical sites were compared using the Wilcoxon signed rank test. Correlations between deletions at TTP and other sites were estimated with a Spearman coefficient. Results: Contralateral normal bronchial tissue (NBB) showed a relatively low deletion rate of 3p and 10q compared to TTP (p<0.0001). FISH on brush biopsies at TBB showed a significantly higher rate of deletions compared to NBB (p<0.05) for both 3p and 10q. A significantly higher deletion rate was seen at TTP compared to NTP at both the 3p (p<0.0001) and 10 q regions (p<0.0001). Significant correlations were seen between the rate of deletions between TTP and TBB at 3p (ρ=0.61, p<0.0001) and between TTP and TAB at 10q (ρ=0.64, p<0.0001). Conclusions: Chromosomal deletions of the 3p and 10q regions can be reliably detected by FISH in bronchoscopic biopsies and touch preparations. As one progresses from the contralateral normal bronchus to the bronchus on the side of tumor and the tumor itself, the percentage of chromosomal deletions increases in a statistically significant fashion,supporting an etiological role of these changes. Deletions at the bronchoscopically normal main and adjacent bronchus on the side of the tumor correlate with an increased deletion rate in the tumor itself. This suggests that FISH analysis of bronchoscopic brushes may be useful for identifying patients at high risk for developing NSCLC.

No significant financial relationships to disclose.
Impact of epidermal growth factor receptor (EGFR) pathway alterations on the outcome of non-small cell lung cancer (NSCLC) patients (pts) treated with first-line chemotherapy (CHT)
Authors: Gelibter A. , Buttitta F. , Nuzzo C. , Visca P. , Cianciulli A. M. , Rinaldi M. , Terzoli E. , Sperduti I. , Ceribelli A. , Cognetti F.
Published: March 2020

7607

Background: Molecular alterations along the EGFR pathway have been proposed to be the major determinant of clinical outcome in response to EGFR tyrosine kinase inhibition in NSCLC pts. However, their potential impact on sensitivity to CHT has not been studied in detail. Methods: Advanced NSCLC pts undergoing CHT were screened for EGFR gene mutations (by SSCP and sequencing) and/or increased copy number (by FISH), EGFR protein expression (by IHC), and HER-2, phosphorylated AKT (pAKT), and total AKT protein expression (by IHC). Correlation between specific molecular alterations and clinical outcome (ORR, PFS, and OS) was then retrospectively explored using both the Cox regression model as well as classification and regression trees (CART) analysis. Results: One hundred and twenty seven pts were screened and 93 received 1st-line CHT. The frequency of EGFR pathway alterations is shown in Table 1 . At a median follow up of 13 mos, survival analysis revealed that true EGFR gene amplification is the only significant predictor of worst OS (p=0.004). No significant correlation was found with PFS. ORR was significantly worse in HER-2-positive pts (p=0.03). CART analysis confirmed that true EGFR gene amplification negatively affect OS, followed by EGFR gene mutation and chromosome 7 polysomy in non-amplified and non-amplified/non-mutated pts, respectively. Conclusions: EGFR pathway alterations significantly impact on outcome following 1st-line CHT for advanced NSCLC. HER-2 overexpression negatively impacts on ORR, but not on PFS and OS. This information maybe useful in selecting appropriate treatment algorithm for advanced NSCLC pts.

No significant financial relationships to disclose.

[Table: see text]
Correlation of the EGFR gene mutation, gene amplification and protein expression in non-small cell lung cancer with clinical outcomes of erlotinib monotherapy: An exploratory analysis of biomarkers by the Korean Cancer Study Group
Authors: Ahn M. , Ahn J. , Kim S. , Kim H. , Lee J. , Cho J. , Song H. , Park S. , Shin S. , Park K.
Published: March 2020

7608

Background: Mutations in epidermal growth factor receptor (EGFR) are considered to be strong predictive marker for response to the EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients. The aim of this study conducted by the Korean Cancer Study Group (KCSG) was to determine the clinical implications of EGFR gene mutation, increased gene copy number or protein over- expression in Korean patients with advanced NSCLC who had been treated with erlotinib. Patients and Methods: A total of 120 patients received erlotinib at a dose of 150 mg daily as part of an open label phase II monotherapy trial between January 2005 and May 2006 in Korea. Ninety-two tissue samples obtained from these patients were analyzed for EGFR mutations (exon 18–21), 88 samples for EGFR gene amplification by real time PCR, and 77 samples for EGFR protein expression by immunohistochemical (IHC) staining. Results: Twenty-four out of 92 patients (26.1%) had EGFR mutations in exon 18, 19, or 21, most commonly in exon 19 (75%, 18/24). A higher frequencies were noted in female patients (40.0% vs 17.5%, p=0.017). Higher rate of response to erlotinib was noted in patients with EGFR mutations compared to wild type (N=14/24 (58.3%) vs 11/68 (16.2%), p<0.001). With the median follow-up duration of 14.5 months, time to progression (TTP) and overall survival (OS) were also significantly longer in patients with mutations than those without mutations (p=0.003, p=0.042). Increased EGFR gene copy number was found in 44.9% (36/88). Patients with increased gene copy number achieved higher rate of response to erlotinib (N=14/36 (38.9%) vs 9/52 (17.3%), p=0.023). Also patients with high gene copy number showed longer TTP and OS (p<0.001, p=0.022). Forty six out of 75 patients showed (+) IHC staining for EGFR protein although there was no relationship between the EGFR expression and the response to erlotinib, TTP or OS (p=0.82, p=0.35, p=0.83). Conclusion: EGFR mutation and gene amplification were shown to be important predictive markers not only for response but also for survival of the Korean patients with advanced NSCLC who had been treated with erlotinib.

No significant financial relationships to disclose.
An open-label, phase II trial of nanoparticle albumin bound paclitaxel (nab-paclitaxel), carboplatin, and bevacizumab in first-line patients with advanced non-squamous non-small cell lung cancer (NSCLC)
Authors: Reynolds C. , Barrera D. , Vu D. Q. , Jotte R. , Spira A. I. , Weissman C. H. , Boehm K. A. , Ilegbodu D. , Pritchard S. , Asmar L.
Published: March 2020

7610

Background: The development of nab-paclitaxel has circumvented many of the infusion difficulties that are associated with standard solvent based paclitaxel (in cremophor). In this open label, phase II trial, patients with advanced (stage IIIB or IV) nonsquamous NSCLC received the combination of nab-paclitaxel, carboplatin and bevacizumab. Methods: 50 patients were enrolled between October 2005 and April 2006. Patients received intravenous (IV) nab-paclitaxel 300 mg/m2, carboplatin IV AUC=6, and bevacizumab 15 mg/kg on day 1 of each 21-day cycle. Responding patients received at least 4 cycles of treatment; however, therapy was discontinued for patients with progression or intolerable toxicity. The primary endpoint was response rate based on RECIST. Results: The median patient age was 67 years; 80% were white and 56% were female. Patients received a median of 4 cycles (range, <1–6). The preliminary efficacy results are PR 30% and SD 48%; no complete responses were noted. Median progression-free survival was 7.1 months (range, <1–10.6); median survival has not yet been reached. Grade 3–4 treatment related toxicities were neutropenia (52%); fatigue (19%); neuropathy (15%); thrombocytopenia (10%) dyspnea (6%), anorexia, constipation, febrile neutropenia, hemoptysis, and nausea and/or vomiting (4% each). 64% of patients are currently alive. 32 patients have come off study, prior to 4 cycles due to disease progression (12%), adverse event (10%), investigator request (8%), sudden death (6%), and withdrawal of consent (2%); 16 patients had normal study completion (completed 4 cycles of therapy). Conclusions: This combination of nab-paclitaxel, carboplatin and bevacizumab was well tolerated, with moderate neutropenia. Adverse events were manageable. The preliminary analysis from this study indicates that this combination has promising activity in first-line patients with non-squamous NSCLC. This research was supported, in part, by a research grant from Abraxis BioScience, Inc., Santa Monica, CA.

No significant financial relationships to disclose.
Docetaxel compared with vinorelbine in elderly patients with advanced non-small cell lung cancer (NSCLC): A randomized phase II Hellenic Oncology Research Group trial
Authors: Karampeazis A. , Vamvakas L. , Agelidou A. , Chandrinos V. , Tsiafaki X. , Christophylakis C. , Chainis K. , Kakolyris S. , Kalykaki A. , Mavroudis D.
Published: March 2020

7615

Background: To compare docetaxel versus vinorelbine as front-line treatment of elderly patients with advanced non-small-cell lung cancer (NSCLC). Methods: Chemotherapy-naive patients >65 years, with stage histologically or cytologically documented IIIB/IV NSCLC and performance status (PS) 0–3 were randomly assigned to receive docetaxel 38 mg/m2 (days 1 and 8) or vinorelbine 25 mg/m2 (days 1 and 8) every 21 days. Treatment was continued for a maximum of six cycles and was interrupted in case of disease progression or unacceptable toxicity. Results: A total of 112 patients with median age of 76 years (range, 66–87) were enrolled onto the study. PS 2–3 had 39 (35%) patients. The two treatment groups were well balanced. There was no statistical difference between the 2 arms in median overall survival (6.27 months vs 3.97 months; p=0.129), in median time to progression (2.2 months vs 2 months; p=0.863.) and in overall response rate (5.3% vs 11.3%; p=0.247). Docetaxel conferred a statistically significant survival benefit compared to vinorelbine only in patients with PS 0–1 (11.4 months vs 4.3 months; p=0.009). Among patients treated with docetaxel there was a significant difference in median overall survival for patients with PS 0–1 compared with patients with PS 2–3 (11.4 months vs 2.5 months; p=0.004) while there was no statistical difference in the vinorelbine arm (4.3 months vs 2.8 months; p=0.970).The most common grade 3 and 4 toxicity was neutropenia (3.4% for docetaxel; 27.8% for vinorelbine; p=0.0001). Other toxicities were mild, well tolerated and similar for both groups with the exception of asthenia grade 2 (8.6% for docetaxel; 24.1% for vinorelbine; p=0.026). Conclusions: Docetaxel improves survival compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer and good performance status without increasing toxicity.

No significant financial relationships to disclose.
The effects of changing the world health organization definition of bronchioloalveolar carcinoma
Authors: Varlotto J. M. , Recht A. , Nikolov M. , Flickinger J. C. , DeCamp M. M.
Published: March 2020

7632

Background: In 1999 the World Health Organization (WHO) changed its definition of bronchioloalveolar carcinoma (BAC). We examined the effects of this change. Methods: Patients included in the Surveillance, Epidemiology, and End Results program from 1992–2002 with Stages I-IIIB non-small cell lung carcinoma (NSCLC) who underwent a definitive surgical procedure were divided into a Cohort A (1,348 patients with BAC diagnosed from 2000–2002), Cohort B (2,955 patients diagnosed with BAC from 1992–1998), and Cohort C (36,861 patients with other NSCLC from the entire period). Overall survival (OS) and disease-free survival (DFS) rates were compared according to potential prognostic factors, including use of a matched-pair analysis. We also compared the demographic, histopathologic, and treatment factors associated with the three groups. Results: The proportion of BAC increased both as a percentage of NSCLC and as a percentage of adenocarcinoma for cohort A(12.5%, 22%) as compared to Cohort B(10.9%, 20%). The proportions of patients with smaller tumor size, female sex, non-black or non-white race, resections less than a pneumonectomy, no radiotherapy, Stage I disease, and well- differentiated tumor grade were similar between Cohorts A and B and statistically different between them and Cohort C. Cohorts A and B also had very similar OS/DFS to each other. Matched patients with Stage I cancer in Cohort A had better OS than in Cohort C; OS was similar for other stages. DFS was improved for all stages in Cohort A as compared to Cohort C (except for Stage II). Conclusions: Patients with BAC diagnosed before or after 1999 have similar outcomes to each other and better outcomes than patients with other NSCLCs. Furthermore, both BAC groups had analogous patient demographic, histopathologic and treatment factors, but differed from those of non-BAC NSCLC during this time period. Surgically-resected BAC defined using the 1999 WHO criteria remains distinctly different than non-BAC NSCLC. Therefore recommendations for adjuvant therapy may need to be different for this patient population.

No significant financial relationships to disclose.
The use of statins may prolong survival of non-small cell lung cancer patients: Final update from 1,205 cases
Authors: Hanbali A. S. , Wang D. , Jankowski M. , Urbaez E. , Syed A. , Farhan S.
Published: March 2020

7638

Background: Hypercholesterolemia is one of the most common morbidities in United States. Statins have been proven as effective cholesterol-lowering agents and have been widely used in this country. They have been reported reducing the incidence and risk of various cancer types. However, the impact of using statins on the survival of 407 patients with diagnosed non-small cell lung cancer (NSCLC) was initially reported (Wang, et al. Abstract #7149, ASCO Meeting 2006). Methods: 1,233 patients with diagnosed non-small cell lung cancer were identified from the Tumor Registry at Henry Ford Health System between January 1999 and December 2004. The data from 1,206 patients were extracted from their available electronic medical records. Statistical analyses were performed and stratified for statin users versus non statin users. Results: Data from 1,205 eligible patients were included in this updated report. There were 391 patients with hypercholesterolemia, 250 of them were statin users at the time of their non-small cell lung cancer diagnosis. Average age was 68 (range 46–90) years for statin users and 65.9 (range 29–94) years for non statin users. Overall median survival of 1,205 subjects was 9.85 months. After stratifying for statin use, the median survival of statin users was 13.9 (95% C.I. 9.9 - 17.4) months while the median survival of non statin users was 9.6 (95% C.I. 8.1 - 10.4) months, with a P value of 0.0001. After having several prognostic variables (age, stage, co-morbids, other cancers, performance status, anti-cancer therapies, and serum albumin, etc.) adjusted, statin use still demonstrated protection from death with a hazard ratio of 0.74 (95% C.I. 0.59 - 0.95, P=0.017). Conclusion: The trend of survival benefit from NSCLC among statin users was shown in our previous report and it has maintained with further enhanced statistical significance in this update. Though statin use will unlikely become an independent anti-cancer regimen by itself, the choice of continuation of statin among NSCLC patients may still provide survival benefit to this population. The favorable impact of statin use on NSCLC patients is intriguing; a prospective study of co-morbidity management with statins in patients with non-small cell lung cancer is warranted.

No significant financial relationships to disclose.
XPD 312 single nucleotide polymorphism (SNP) in stage IIIA-B non-small cell lung cancer (NSCLC) patients (p) <59 years (y) treated with chemotherapy followed by surgery
Authors: Santarpia M. , Garrido P. , Gonzalez-Larriba J. , Azagra P. , Cardenal F. , Ramirez J. , de Aguirre I. , Sanchez-Ronco M. , Taron M. , Rosell R.
Published: March 2020

7652

Background: SNPs in DNA repair genes may affect response to cytotoxic therapy. We investigated SNPs in XPD codons 751 and 312 and in RRM1 −37 in 109 stage IIIA (N2) and IIIB NSCLC p treated with neoadjuvant chemotherapy and correlated results with event- free (EFS) and median (MS) survival. Methods: p eligible for surgery received cisplatin day (d) 1, gemcitabine d 1,8, docetaxel d 1,8,15, every 3 weeks for 3 cycles, followed by thoracotomy. DNA was extracted from baseline peripheral lymphocytes and genotyping was performed by Taqman. Results: Median age, 60 y (range 31–77); 92 males (84%); 45 squamous cell (41%). 4 p (3.9%) attained complete response; 55 (53.9%) partial response. 75 p underwent surgery (62 complete, 13 incomplete resection); remaining 34 p were unresectable. Median follow-up was 15.7 months (m) (range, 0.5–74). MS for p still alive is 49.8 m (range, 6.7–74). MS: 48 m with complete resection, 13 m with incomplete resection, 17 m for unresected p. In the univariate analysis of survival, age <59 y (P=0.03), resection (P<0.001) and XPD312 AspAsp (P=0.05) emerged as predictive markers of longer survival. For all 109 p, those with XPD312 AspAsp had longer EFS and MS than p with Asn variants ( Table ). In addition, for 51 p <59 y, EFS was longer for 24 p with XPD312 AspAsp (36.4 m) than for 27 p with Asn variants (9.8 m) (P=0.009); MS in this group of younger p was 45.4 m for AspAsp vs 15.8 m for Asn (P=0.04). No other significant correlation between SNPs and survival was observed ( Table ). Conclusions: Interaction between SNPs, age and risk of lung cancer has previously been described. XPD312 AspAsp in p <59 y predicts longer survival in stage IIIA (N2) and IIIB NSCLC treated with neoadjuvant chemotherapy.

No significant financial relationships to disclose.

[Table: see text]
A phase II study of nedaplatin (CDGP) and docetaxel (TXT) in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Fujino S. , Asada Y. , Nakano Y. , Suzumura Y. , Inoue S. , Nagao T. , Hajiro T. , Tezuka N. , Sawai S.
Published: March 2020

7660

Background: Nedaplatin (CDGP) is a cisplatin derivative developed in Japan. In non-small cell lung cancer (NSCLC), its response as monotherapy has been reported to be 20.5%, while when used in combination with vindesine, its efficacy is similar to cisplatin (CDDP). With respect to adverse effects, it causes less nausea/vomiting and nephrotoxicity compared to CDDP. By these data, we conducted a phase II study of combination treatment with CDGP and docetaxel (TXT) in advanced NSCLC. Methods: Forty six patients (Male/Female 39/7, median age 65 years (40–79), IIIB/IV 20/26) were enrolled from March 2004 to March 2006. Eligibility criteria included signed informed consent, age over 20 and under 80, measurable disease, ECOG PS 0–1, adequate bone marrow reserve, no previous chemotherapy or radiotherapy, and life-expectancy of at least 12 weeks. Treatment consisted of 80 mg/m2 CDGP and 60 mg/m2 TXT on day one with about 1,000 ml of hydration every 3–4 weeks. Results: One hundred and forty four cycles were given to 46 pts (mean cycles 3.1) and the mean dosages actually administered were 75.5±6.1 mg/m2 for CGDP and 57.7±4.6 mg/m2 for TXT. An over all response rate was 52.2% (squamous cell carcinoma 66.7%, adenocarcinoma 44.0%), median survival time was 12 months and 1-year survival rate was 50%. NCI-CTC grades 3–4 leukopenia, neutropenia, nausea/vomiting and appetite loss occurred in 44 (29.2%), 50 (34.7%), 5 (3.5%), 6 (4.2%) cycles, respectively. There was no grade 3–4 anemia, thrombocytopenia and neuropathy. Conclusions: This combination of chemotherapy was well tolerated, and its activity and survival for advanced NSCLC were acceptable. The update data will be presented at the meeting.

No significant financial relationships to disclose.
Investigating gender specific metabolic differences in non-small cell lung cancer by F-18 FDG PET
Authors: Howard G. , Zakalik D. , Vashist P. , Wong C. O.
Published: March 2020

7663

Background: Lung cancer is the leading cause of cancer death in women, killing more women than breast, ovarian, and uterine cancers combined. Recent evidence suggests differences in lung cancer between the sexes. Women have better rates of survival, different histology, genetic, and molecular factors as compared to men. Metabolic characteristics of lung cancer have prognostic value. The use of F-18 FDG Positron Emission Tomography (PET) has been demonstrated in multiple studies to better determine outcome, improve diagnostic and staging techniques. Methods: 251 (M:F=101:150) patients with newly diagnosed biopsy proven NSCLC and evaluated by F-18 FDG PET(CT), without other malignancies, prior radiation or chemotherapy, were analyzed retrospectively from our institution. PET scans were obtained 1 hour after injection of 370 MBq F-18 FDG using a dedicated whole body PET-CT or PET scanner. The PET images were reconstructed with attenuation correction by either radioisotope or CT transmission scan. The SUV, defined as tumor activity divided by dose injected per lean body mass, from the PET cameras had been cross validated to produce the same value in a given phantom and patient. The maximum SUV was measured by searching the maximum value within a volume of known primary cancer. Results: The two groups were matched for age. Females had significantly less squamous cell carcinomas (18% vs. 29%, p=0.025) and more adenocarcinomas (41% vs. 30%, p=0.041) than males. Although there were no significant differences stage by stage between males and females, there was gradual transition or increment of SUV by stage in all female NSCLC with the SUV of stage I NSCLC being lower than that of cancers in stages II, III or IV (p=0.00022, 0.0088, and 0.0026 respectively). However, there were no such distinctions among male patients. There were no differences in SUV among various histological types of NSCLC between the sexes. Conclusions: The study suggests there are gender differences in the metabolic properties of NSCLC with distinctively more metabolically aggressive NSCLCs upon advancing stage in women but not in men. This gender specific metabolic difference is another discriminator besides other known gender factors and is potentially useful in the management of early stage NSCLC in women.

No significant financial relationships to disclose.
Cost-effectiveness of erlotinib vs. docetaxel or pemetrexed in the treatment of refractory non-small cell lung cancer (NSCLC)
Authors: Carlson J. , Oestreicher N. , Lubeck D. P. , Ramsey S. D. , Veenstra D. L.
Published: March 2020

7664

Background: Multiple treatment strategies are now available for stage IIIB/IV non-small cell lung cancer (NSCLC) after failure of 1st line treatment, but their relative economic and clinical value is not clear. Methods: We developed a health state transition model with 3 health states (progression free, disease progression, and death) to estimate the direct medical costs and quality-adjusted life-years (QALYs) of treating refractory NSCLC from the US healthcare system perspective. The treatments considered were erlotinib, docetaxel, and pemetrexed, and the time horizon was 2 years. Mean survival and progression free survival were assumed equal for all three treatments based on published pivotal clinical trials; side effect data were derived from the same studies. Utilities were obtained from a recent community-based study performed in the UK. Costs were obtained from published sources, and costs and effects were discounted at 3%. Sensitivity analyses were performed to evaluate uncertainty in the results. Results: Total costs in the base case were $31,000 for erlotinib, $33,700 for docetaxel, and $38,200 for pemetrexed. Drug acquisition and administration costs were $11,800, $12,200, and $18,700, respectively. Adverse event costs were $200, $2,500, and $500 on average per patient, and disease costs were equivalent at $19,000. QALYs were slightly greater for erlotinib versus docetaxel and pemetrexed (an increase of 0.02 and 0.01, respectively), due to differences in side effect profiles. The cost differences were robust to sensitivity analyses; when the utility for IV vs. oral therapy were assumed equal, erlotinib had 0.1 greater QALY than docetaxel and equivalent QALYs to pemetrexed. Conclusions: The results of our study suggest erlotinib in the treatment of refractory NSCLC in the United States is cost-saving compared with alternative treatments, with a slight improvement in patient quality of life. The results of ongoing comparative clinical trials will be useful for further evaluation of potential survival benefits.

[Table: see text]