bluuebunny/crossref_metadata_2025 huggingface dataset:
Are timing of chemoradiation and early therapy response as detected by PET prognostic factors of a multimodality treatment approach for NSCLC stage III? (LUCAS-MD)
Authors: Schmuecking M. , Schneider C. P. , Presselt N. , Baum R. P. , Leonhardi J. , Hoeffken K. , Niesen A. , Mueller K. M. , Wendt T. G. , Bonnet R.
Published: March 2020

7532

Background: A randomized multicenter phase III trial was designed to assess if timing of chemoradiation may alter treatment outcome for patients (pts) with stage III NSCLC in a multimodality treatment approach. Additionally, the role of F-18 FDG PET within clinical trials is evaluated for staging, therapy management, molecular radiation treatment planning (MRTP) and early therapy response and its effect on survival as compared to regression grade (RG). Methods: Inclusion criteria: histologically confirmed NSCLC stage IIIA/IIIB. ECOG PS 0–1. Primary end points: OS, DFS. Secondary end points: TTP, QoL, RR. Neoadjuvant treatment: 2–3 cycles of paclitaxel/carboplatin and a block of chemoradiation (45 Gy, 1.5 Gy b.i.d., concomitant paclitaxel/carboplatin) followed by surgery. Randomization: late (Arm1) vs. early (Arm2) chemoradiation. Staging: PET in addition to CT and/or MRI after randomization, second PET after completion of neoadjuvant therapy. Assessment of standardized uptake values (SUV) in primary tumor (PT) and all metastatic lymph nodes (LN). Documentation of involved LN as detected by PET and LN sampling during surgery according to Naruke/ATS-LCSG classification. Evaluation of RG and correlation with PET for PT and each LN. MRTP using fused PET/CT data. Intent to treat analyses using Kaplan-Meier estimates, log rank tests, Cox multivariate models. Results: 210 eligible pts were enrolled (Arm1: 106, Arm2: 104, well-balanced on all factors). Paraoperative lethality 4.3%. Treatment-related deaths in Arm1: 8.3%, in Arm2: 5.9%. Up-staging in 26/210 pts due to distant metastases, down-staging in 5/210 pts resulting in 15% stage migration. Actuarial tumor specific survival after 60 months: complete vs. incomplete metabolic remission: 56% vs. 24% (p =0.005), RG III/IIb (no/less than 10% of vital tumor cells) vs. RG IIa/I (more than 10% vital tumor cells): 61% vs. 25% (p <0.001). Late vs. early chemoradiation: 30% vs. 45% (p =0.313). Multivariate Cox regression for initial SUV: p >0.05. Conclusions: Long-term survivors with early chemoradiation have a trend to better survival being not statistically significant. Metabolic remission correlates well with RG and may predict therapeutic outcome.

No significant financial relationships to disclose.
Oral talactoferrin extends survival in patients with refractory NSCLC in a randomized, placebo-controlled, phase 2 trial
Authors: Parikh P. K. , Wang Y. , Ranade A. A. , Vaid A. K. , Advani S. H. , Raghunadharao D. , Nag S. , Madhavan J. P. , Varadhachary A.
Published: March 2020

7540

Background: Talactoferrin alfa (TLF), an immunomodulatory protein with a novel anti-cancer mechanism of action, was active preclinically and in non-small cell lung cancer (NSCLC) patients in Phase 1b studies. Randomized Phase 2 studies in NSCLC were conducted with TLF as a single agent and combined with chemotherapy. The 110-patient combination therapy study, which was previously presented (ASCO 2006, #7095), met its primary endpoint with an improved BOR over chemotherapy alone. We now present results from the placebo- controlled single agent study. Methods: 100 Stage IIIB/IV NSCLC patients who had progressed after first or second line therapy were enrolled at 10 leading Indian cancer centers, and randomized to receive best supportive care plus either oral TLF (1.5 g bid) or placebo. TLF/placebo was administered until disease progression, for up to three 14-week cycles (12 weeks on, 2 weeks off), in a centrally monitored trial. The primary endpoint was overall survival (OS) with 80% power to detect an improvement in median OS with an a=0.05. Results: All patients had previously received a 1st line platinum based regimen; 26 also received 2nd line therapy. The TLF and placebo arms enrolled 47 and 53 patients, respectively. Baseline characteristics were similar in both groups, including proportion of patients receiving 1 or 2 prior regimens. All patients were included in the Intent To Treat (ITT) analysis. The trial met its primary endpoint with a 55% increase (2.1 month; p<0.05) in median OS. TLF was well tolerated. Adverse Events (AEs) were generally mild. No drug- related SAEs were reported. Incidence of AEs and Grade 3/4 AEs was similar in both arms. Conclusion: Oral talactoferrin, a promising new anti-cancer agent, significantly improved survival in patients with refractory NSCLC in this randomized, placebo-controlled trial. TLF was well tolerated in this population. Given its favorable toxicity profile, TLF may be particularly attractive in refractory patients with poor performance status.

[Table: see text] [Table: see text]
Prognostic implication of the EGFR gene mutations in a large cohort of Japanese patients with early stage lung adenocarcinoma
Authors: Kosaka T. , Yatabe Y. , Onozato R. , Mitsudomi T.
Published: March 2020

7574

Background: Prognostic impact of epidermal growth factor receptor (EGFR) gene mutations in lung adenocarcinoma remains controversial. We examined a large cohort of lung adenocarcinoma resected in a single institution for EGFR mutations and evaluated its prognostic implication. Methods: We analyzed 402 patients with lung adenocarcinoma who underwent potentially curative pulmonary resection at our department, from May 2000 through December 2005. Total RNA was extracted and direct sequencing of exons 18–21 of EGFR gene was performed after reverse transcription - polymerase chain reaction. KRAS and TP53 gene mutations were also analyzed in 209 adenocarcinoma patients from this cohort. Results: We found that 196 patients (49%) had EGFR mutations. Of them, exon 19 deletion mutations were 83 (42%) and L858R mutations were 92 (47%). EGFR mutations were significantly frequent in female (P<0.0001), never smokers (P<0.0001), and well to moderately differentiated adenocarcinoma (P<0.0001). In 347 patients who were not treated with gefitinib, prognostic effect of EGFR mutations was evaluated. Patients with EGFR mutations survived for a longer period than those without the mutations after surgery in univariate analysis (P=0.0046, log rank test). We did not detect any difference in overall survival between the patients with exon 19 deletion mutations and those with L858R mutations (P=0.3962). There were tendencies that patients with KRAS mutations or TP53 mutations survived for a shorter period than those without mutations, although there was no statistical significance (P=0.2534 and 0.0859). Multivariate analysis using the Cox proportional hazards model revealed that never smokers (P=0.0253) and disease stage (P<0.0001) were independent prognostic factors. However, all gene mutations were not independent prognostic factors (EGFR; P=0.4763, KRAS; P=0.7998, TP53; P=0.3464). Conclusion: EGFR mutations were not independently associated with prognosis of patients with early stage adenocarcinoma of the lung. Furthermore, there was no difference between exon 19 deletion mutations and L858R mutations in their prognostic impact.

No significant financial relationships to disclose.
Epidermal growth factor receptor (EGFR) immunohistochemistry: Comparison of antibodies (Abs) and cut points to predict benefit from gefitinib in a phase III placebo-controlled study in advanced non-small cell lung cancer (NSCLC)
Authors: Dziadziuszko R. , Hirsch F. R. , Varella-Garcia M. , Thatcher N. , Mann H. , Watkins C. , Speake G. , Holloway B. , Bunn P. A. , Franklin W. A.
Published: March 2020

7576

Background: Tumor tissues obtained from the ISEL phase III trial assessing the efficacy of gefitinib vs placebo in chemotherapy-pretreated NSCLC were used to evaluate two Abs (DAKO and Zymed) and assess whether different cut points of EGFR protein expression improved prediction of response and survival benefit from gefitinib. Methods: EGFR protein expression in tumor samples was assessed by immunohistochemistry using DAKO EGFR pharmDx kit (scoring percent of tumor cells with positive staining, predefined cut point of =10%) and Zymed monoclonal Ab clone 31G7 (scoring proportion of positive cells times staining intensity [scale 0–400], predefined cut point of =200). Results: Clinical characteristics of the patients (pts) assessed with DAKO (n=379) and Zymed (n=357) Abs reflected the overall study population (N=1692) with the exception of fewer never-smokers and Asians. Of the pts evaluated with DAKO/Zymed Abs, females represented 32%/31%; never-smokers, 13%/14%; Asians, 6%/4%; adenocarcinomas, 44%/42%; and 88%/88% of pts were refractory to most recent chemotherapy. With the above criteria, 70% of tumor samples were scored as positive using DAKO Ab and 68% using the Zymed Ab (agreement between assessments 76%). The objective response rates in gefitinib treated EGFR-positive pts defined with various cut points with DAKO Ab (=1% to =90%) varied between 8% and 12%, and with Zymed Ab (score =50 to =350), between 10% and 13%. Lower cut points with the DAKO Ab provided the best discrimination between EGFR positive and EGFR negative patients in terms of survival hazard ratios (HRs) comparing gefitinib to placebo, with a significant treatment/cut point interaction for the 10% cut point (p=0.049). A similar trend was noted for Zymed Ab, although the discrimination between HRs was less apparent and not significant for any cut point analyzed. Conclusion: Assessment with DAKO PharmDx kit, according to percentage of positive staining, may provide more accurate prediction of survival benefit for gefitinib-treated pts than assessment with Zymed Ab and staining index. Use of higher cut points to define positivity does not improve discrimination of the test.

No significant financial relationships to disclose.
P53 protein over-expression but not p53 gene mutation is a poor prognostic marker and a predictive marker for survival benefit from adjuvant chemotherapy in non-small cell lung cancer (NSCLC) in the JBR.10 Trial
Authors: Tsao M. S. , Aviel-Ronen S. , Ding K. , Lau D. , Liu N. , Whitehead M. , Seymour L. , Winton T. , Shepherd F. A.
Published: March 2020

7577

Background: JBR.10, a phase III inter-group trial randomized 482 patients with resected stage IB & II NSCLC to receive 4 cycles of adjuvant cisplatin + vinorelbine or observation alone. Chemotherapy patients had an overall survival (OS) benefit (Hazard Ratio [HR] 0.69, p=0.04). P53 has important regulatory roles in cell cycle progression, apoptosis, gene transcription and DNA repair. We evaluated the prognostic and predictive value of p53 in JBR.10. Methods: P53 protein expression was evaluated by immunohistochemistry (IHC) on tissue micro-arrays (282 available blocks). We used the DO7 antibody, and defined ≥15% nuclear staining as the cutoff for over- expression. Mutations in exons 5–9 were determined by denaturing high performance liquid chromatography (446 available samples), followed by sequencing of aberrant PCR products. Results: Successful assays: p53 mutation, 403/446 patients; p53 IHC, 254/282 patients. P53 gene mutations were found in 126/403 (31%) patients. In the observation arm, mutations were not prognostic of poorer survival (HR = 1.18, 95% CI 0.77–1.81; p= 0.45). Adjuvant chemotherapy effect was not significantly different in p53 mutated and wild type patients (interaction p = 0.66), the estimated HR was 0.68 (95% CI 0.46–1, p=0.047) for patients with wild type p53, and 0.79 (95% CI 0.47–1.33, p=0.37) for mutated patients. P53 protein over-expression was found in 133/254 (52%) patients. Patients with over-expression in the observation arm had a higher risk of death than patients with low expression (HR 1.89, 95% CI 1.07–3.34, p=0.03). However, the adjuvant chemotherapy effect was significantly better in p53 over-expressing patients (interaction p= 0.018), with an estimated HR of 0.53 (95% C.I. 0.31–0.90, p=0.03) for p53 over-expressing patients, and 1.40 (95% C.I. 0.78–2.52, p=0.26) for low expressing patients. Conclusions: P53 protein overexpression but not p53 gene mutation is both a significant prognostic marker of poorer survival in the JBR 10 population and a significant predictive marker for the benefit of adjuvant chemotherapy.

[Table: see text]
Creation of an epidemic: The tobacco industry (TI) and smoking-related adenocarcinoma (AD) of the lung
Authors: Strauss G. M. , Jemal A. , McKenna M. B. , Strauss J. A. , Cummings K. M.
Published: March 2020

7583

Background: When epidemiologic research first demonstrated an association between cigarette smoking (CS) and lung cancer (LC) in the 1950s, AD comprised about 5% of LCs and was only weakly related to CS. In the 1960s and 1970s, AD increased sharply, and became strongly related to CS. Methods: We conducted an epidemiological and ecological analysis correlating time trends in LC histology with changes in cigarette design and TI actions over the past 30 yrs. We utilized SEER data on 307,797 LCs diagnosed from 1975 to 2003 to analyze time trends of age-standardized incidence rates of each LC subtype: AD, squamous (SQ), small cell, and large cell. Comparisons were drawn based on sex, race, and age. Because SEER contains no data on CS, other sources were utilized to correlate changing histology to time trends in smoking prevalence, the changing cigarette, and TI actions. Results: Among all pts, AD surpassed SQ by 1980–84 to become the most common histology. AD increased 62% from 1975–79 to 1995–99, but fell 8% in 2000–03. SQ peaked in 1980–84 and dropped 35% by 2000–03. AD surpassed SQ in 1985–89 in men, while AD was already most common in women by 1975–79. AD rose 38% in men from 1975–79 to 1995–99, while it doubled in women during this interval. Among whites, AD surpassed SQ by 1980–84, although this did not occur among blacks for another decade. Nonetheless, AD incidence has consistently been higher in black men than in other subgroups. AD was already most common in pts <50 yrs by 1975–79, while AD rapidly increased and surpassed SQ in all other age groups by 1990–94. By 2000–03, AD comprised 47% of all LCs (42% in men; 52% in women; 59% in pts <50 yrs). Currently, AD is the most common histology in both sexes, races, and in all age groups. Trends in AD correlate with the wide-scale adoption by smokers of filtered and low tar cigarettes, and with increasing nitrosamine levels in cigarettes. Conclusions: The rise of AD, particularly in women and younger persons, is consistent with the hypothesis that changes in cigarette design and composition was responsible for this rise. These changes were introduced by the TI in response to mounting evidence that CS caused other forms of LC. While low tar cigarettes do not reduce LC risk, their adoption appears to be responsible for creating an epidemic of smoking-related lung AD.

No significant financial relationships to disclose.
Mutational analysis of EGFR signaling pathway genes in lung adenocarcinomas
Authors: Marks J. L. , McLellan M. D. , Kasai Y. , Fulton L. A. , Mardis E. R. , Wilson R. K. , Zakowski M. F. , Rusch V. W. , Varmus H. E. , Pao W.
Published: March 2020

7584

Background: About fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode signaling proteins in the EGFR signaling pathway, i.e. EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other somatic mutations that could contribute to lung tumorigenesis. Methods: We analyzed genomic DNA from 261 resected, clinically well-annotated non-small cell lung cancer (NSCLC) specimens. 90% of tumors were adenocarcinomas, and 10% were squamous cell carcinomas. The coding sequences of 39 genes, encoding proteins mostly in the EGFR signaling cascade and FGFR1–4, were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Results: First-pass analysis of 9 MB of tumor sequence identified 199 distinct types of genetic variants that differed from published reference sequences. At least one variant was found in each gene analyzed. In addition to 6 variants found in RAS genes, we further examined the 94 variants localized to exons encoding the kinase domain of respective proteins. We have thus far identified known somatic mutations in EGFR, KRAS, BRAF, and PIK3CA, in addition to a number of previously unreported single nucleotide polymorphisms (SNPs). Conclusions: Mutational profiling of genes that encode for components of the EGFR signaling pathway has revealed multiple putative genetic variants in lung adenocarcinomas. Further analysis of potential somatic mutations is in progress.

No significant financial relationships to disclose.
The significant influence of smoking status and gender on the clinical outcome in the patients with non-small cell lung cancer: The large cohort based study
Authors: Kawaguchi T. , Tamura T. , Takada M. , Kusunoki Y. , Matsumura A. , Iuchi K. , Fukai S. , Komatsu H. , Tamura A. , Kawahara M.
Published: March 2020

7587

Background: To determine retrospectively whether smoking status and gender affect the treatment outcome and survival for the Japanese patients with non-small cell lung cancer. Methods: Using the database from the lung cancer registry of the National Hospital Study Group for Lung Cancer between 1987 and 2002, detailed demographic and survival information were obtained. A total of 18,346 (70%) documented smokers including the former and the current and 7,755 (30%) documented never smokers with non-small cell lung cancer were studied. A minimal follow-up period was two years. Among them, the 2,546 patients with stage IV lung adenocarcinoma were studied to examine the relationship between the smoking status or the gender and the chemotherapy effect. Multivariate analysis was performed using the Cox regression method. Results: There was an increased percentage of female subjects (72%) in the never smokers, and an increased percentage of male subjects (90%) in the smokers. The never smokers had lower performance status (PS) and lower clinical stage than the smokers (p<0.001). There was an increased percentage of adenocarcinoma (83%) in the never smokers. Multivariate analysis for all the patients demonstrated that the lower clinical stage, the lower PS, younger age, female and never smoking was an independent good prognostic factor The hazard ratio (HR) and its 95% CI was 3.73 (3.58–3.88), 2.69 (2.59–2.79), 1.21 (1.17–1.25), 1.15 (1.09–1.20), and 1.08 (1.04–1.14), respectively. Multivariate analysis for the stage IV adenocarcinoma also showed that the lower PS, female and never smoking was an independent good prognostic factor. The HR and its 95% CI was 2.37 (2.15–2.61), 1.35 (1.19–1.52) and 1.17 (1.04–1.32) respectively. In the treatment of chemotherapy for the stage IV adenocarcinoma patients, the never smokers had higher disease control rates (CR+PR+SD) than the smokers (p=0.08) and the females had higher response rates (CR+PR) than the males (p=0.02). Conclusions: The never smokers and females with non-small cell lung cancer were found to have a distinct and improved clinical outcome.

No significant financial relationships to disclose.
A randomized phase II study of 500 mg/m2 and 1,000 mg/m2 of pemetrexed in patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had prior chemotherapy
Authors: Ichinose Y. , Nakagawa K. , Tamura T. , Kubota K. , Yamamoto N. , Adachi S. , Nambu Y. , Nishiwaki Y. , Saijo N. , Fukuoka M.
Published: March 2020

7590

Background: Pemetrexed (Pem) 500 mg/m2 (Pem 500) is currently the standard treatment for pts with locally advanced or metastatic NSCLC who had prior chemotherapy. In a recent Japanese phase I study with full vitamin supplementation, 1,000 mg/m2 was determined as the recommended dose. This study was to determine if Pem 1,000 mg/m2 (Pem 1,000) could lead to a better treatment outcome with an acceptable toxicity profile compared with Pem 500 in pts with NSCLC in a 2nd or 3rd line setting. Methods: Pts with PS 0–2, measurable, Stage III/IV NSCLC, who had previously received 1 or 2 chemotherapy regimens, were randomized to receive either Pem 500 or Pem 1,000 on day 1 of a 21-day cycle. The primary endpoint was overall response rate (ORR) based on the RECIST. Secondary endpoints included progression-free survival (PFS), duration of response (DR) and toxicity profile. The planned total sample size for the study was 214 pts. Results: From October 2004 to March 2006, 244 pts were enrolled at 28 centers, 226 pts were randomized and treated, and 216 pts were evaluable for efficacy. Baseline patient characteristics (Pem 500/Pem 1,000: 108/108) were: Males 63%/64%; median age 62/62 years (total range: 26–74); PS 0–1 94%/94%; Stage IV 81%/80%. The median number of treatment cycles completed on both arms was 3 (range 1–20+ for Pem 500 and 1–15+ for Pem 1,000). 11% of the Pem 500 pts and 6% of the Pem 1,000 pts completed at least 10 cycles. ORRs were 18.5% (90% CI: 12.6%-25.8%) for Pem 500 and 14.8% (90% CI: 9.5%- 21.6%) for Pem 1,000, and the respective disease control (PR+SD) rates were 55.6% and 46.3%. Median PFS with Pem 500 and Pem 1,000 was 3.0 and 2.4 months and median DR was 4.7 and 3.8 months, respectively. Grade 4 toxicities observed in more than 1% of pts were neutropenia (3.5% with Pem 500, 3.6% with Pem 1,000) and decreased lymphocyte count (2.6%, 1.8%). One drug related death for interstitial lung disease was reported with Pem 500. Conclusions: Pem 1,000 as well as Pem 500 showed remarkable efficacy outcomes with tolerable toxicity. Since Pem 1,000 showed treatment outcomes similar to Pem 500, this study supports the use of Pem 500 for Japanese pts with NSCLC in a 2nd or 3rd line setting.

[Table: see text]
14–3-3 σ and checkpoint with forkhead and ring finger (CHFR) methylation in serum in erlotinib-treated non-small-cell lung cancer (NSCLC) patients (p) with EGFR mutations
Authors: Reguart N. , Porta R. , Provencio M. , Cardenal F. , Cuello M. , Ramirez J. L. , Mayo C. , Lianes P. , Taron M. , Rosell R.
Published: March 2020

7600

Background: 14–3-3 proteins have 130 potential binding partners, including Cbl. 14–3-3 expression can prevent mutant EGFR binding to Cbl, impairing ubiquitination and endocytosis. 14–3-3s is frequently methylated in NSCLC; we hypothesized that in the presence of EGFR mutations, methylated 14–3-3s could permit the formation of the EGFR-Cbl complex. CHFR is a checkpoint that delays entry into metaphase in response to mitotic stress. Methods: 73 stage IV NSCLC p with EGFR exon 19 deletion or exon 21 L858R mutation received first- or second-line erlotinib single therapy. 14–3-3s and CHFR methylation was examined in the baseline serum of these p. Results: Median age, 63 (range, 26–83); females, 48 p (65.8%); Caucasian, 72 p, Asian, 1 p; never-smokers, 45 p, ex-smokers, 21 p, smokers, 7 p; adenocarcinoma, 64 p, large cell carcinoma, 9. PS: 0, 19 p, 1, 42 p, 2–3, 12 p. 14–3-3s was methylated in 39.7% and CHFR in 42.5% of p. No differences in p characteristics were observed according to methylation status. Complete response was observed in 11.1% of p, and partial response in 75.4%. Overall response was 86.5%. There was a trend toward a higher response rate in p with unmethylated CHFR (94.4% vs 76.6%; P=ns). Overall median time to progression (TTP) and survival (MS) have not been reached either in first- or second-line. However, when split according to methylation status, there was a trend toward better TTP and MS in both first- and second-line in p with methylated 14–3-3s. TTP in second-line in p with methylated 14–3-3s has not been reached, while it was 10.8 months (m) for p with unmethylated 14–3-3s (P=ns). TTP in second-line in p with methylated CHFR was 5.2 m but was not reached for p with unmethylated CHFR (P=0.05). Conclusions: Methylated 14–3-3s can permit Cbl binding to mutant EGFR and predict longer-lasting response to erlotinib in p with EGFR mutations. The precise role of CHFR warrants further research. Complete data will be presented.

No significant financial relationships to disclose.
A phase II study of erlotinib treatment in advanced non-small cell lung cancer after failure of gefitinib: Is a clinical benefit still achievable?
Authors: Cho B. , Im C. , Choi H. , Shin S. , Sohn J. , Kim J. , Kim S. , Moon J. , Kim Y.
Published: March 2020

7609

Background: To evaluate the efficacy and toxicity of erlotinib in patients (pts) with advanced NSCLC who had progression after treatment with gefitinib. Methods: The study included stage IIIB/IV recurrent or metastatic NSCLC pts who have received 2 or 3 prior chemotherapy regimens and showed documented disease progression during or within 4 months after treatment with gefitinib. Pts received erlotinib 150 mg daily until disease progression or unacceptable toxicity. We analyzed EGFR mutations and other genetic abnormality from available tumor samples. Results: Pts and disease characteristics (n = 21) included median age 56 years; number of prior chemotherapy regimens (two, n=10; three, n=11); male (n=10); adenocarcinoma (n=15); and smoking status (never, n=11; former, n=3; current, n=7). Among the 17 pts with tumor samples available, EGFR mutation were detected in 5 (29.4 %). The DCR and RR for all pts were 28.6% (95% CI, 16.7 to 59.6%) and 9.5% (95% CI, 5.6 to 19.8%). All responders were EGFR nonmutants, with long duration of disease control on prior gefitinib therapy (>180 days). The median duration of disease control was 125 days (95% CI, 73–261 days). The median progression-free survival and overall survival were 60 days (95% CI, 43–77 days) and 158 days (95% CI, 141–175 days), respectively. Pts who had SD on gefitinib showed significantly higher DCR (75% vs. 17.6% in non-SD pts, P= 0.050) and RR (50.0% vs. 0% in non-SD pts, P= 0.029). These pts also showed longer median PFS (140 vs. 37 days in non-SD pts, P= 0.005) and OS (not reached vs. 120 days in non-SD pts, P= 0.043). Among 17 pts with biomarker results available, EGFR nonmutants who had SD on gefitinib showed significantly higher DCR (100% vs. 21.4% in non-SD and/or EGFR mutants, P= 0.029) and RR (RR, 66.7 % vs. 0 % in non-SD and/or EGFR mutants, P= 0.022). Conclusions: Erlotinib seems to be a potential therapeutic option for the treatment of selected pts with gefitinib-nonresponsive, EGFR nonmutant, advanced NSCLC.

No significant financial relationships to disclose.

[Table: see text]
A phase II study of erlotinib (E) and bevacizumab (B) in patients (pts) with previously untreated stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Groen H. J. , Smit E. F. , Dingemans A.
Published: March 2020

7625

Background: In advanced NSCLC, E and B either as a single agent (E) or in combination with chemotherapy (B) show improved survival. Combinations of targeted agents may prove to be effective and better tolerated than chemotherapy. Methods: This is a multi-center 2-stage phase II study (Simon's optimal design; p0=40%, p1=60%, a=0.05, β=0.20). Primary endpoint is non-progression (NPR) at 6 weeks defined by CT and FDG-PET. If 7 or less of the first 16 pts had NPR, the study would close. If 24/46 pts had NPR at 6 wks treatment would be declared to have sufficient activity for further testing. Pts (PS 0–2) with advanced non- squamous NSCLC who had received no prior chemotherapy were treated with E (150 mg/day) plus B (15 mg/kg every 21 days) until PD or unacceptable toxicity. Results: Between 30/01/06 and 08/12/06, 38 pts were included; 33 pts are evaluable for safety, 32 for efficacy. M/F 17/16; median age 59 (range 34–80); stage IIIB/IV 8/25; PS 0/1/2: 16/13/4; smoking status: current/former/never 12/17/4. Treatment-related adverse events (all grades) were: rash (32%); diarrhea (18%); hemorrhage (2.6%); hypertension (2.7%); and thrombosis (2.7%). Grade 3/4 events were rash (9.9%); thrombosis (1.8%); diarrhea (0.9%); and hypertension (0.9%). Six pts withdrew early from the study: 2 due to toxicity (trombosis and mucositis); 2 due to death (1 death for unknown reason, 1 due to pneumonia); 2 for treatment unrelated reasons. Six pts had E dose reductions due to toxicity. Five pts had delays of less than 2 wks before receiving B. Percentage of NPR at 6 weeks is 75% (24/32). The median follow-up: 6.3 months (95% CI 3.5–9.2). Median TTP: 5.5 months (95% CI 1.9 - 9.2), At time of analysis 22/33 patients are alive, 17 patients are without PD. Conclusions: E + B regimen is well tolerated, with a low rate of grade 3/4 adverse events and no unexpected toxicities. The primary endpoint has already been met. Updated results including correlative imaging studies will be presented.

No significant financial relationships to disclose.
Observing patients with advanced non-small cell lung cancer (NSCLC): An overview of real world treatments and outcomes in Europe
Authors: Bischoff H. G. , Anderson H. , van den Borne B. , Langer F. , Leschinger M. I. , Moneley C. , Pimentel F. , Riska H. , Thatcher N. , Thomas M.
Published: March 2020

7626

Background: ACTION (Assessment of Costs and ouTcomes of chemotherapy In an Observational setting in patients with advanced NSCLC) is a prospective, pan-European observational study. The objective of ACTION is to describe advanced NSCLC treatment in routine clinical practice. Methods: Chemonaive patients (pts) aged = 18 yrs with stage IIIb/IV NSCLC were observed for 18 months from presentation for initiation of chemotherapy (CT). All pt care, including CT given, was at the discretion of the pt/physician. Pts were excluded if participating in a clinical trial. Results: 975 pts [Germany (571), UK (193), Finland (99), Netherlands (76), Portugal (36)] were enrolled from April 2003 to September 2004 and observations completed June 2006. Median age was 65 yrs (32–90) with 28.3% of pts aged =70 yrs; 71.3% were male; 65.2% had stage IV disease. WHO performance status (PS) was 0/1 (86.2%), 2 (10.0%), 3/4 (3.8%). Of 487 pts who experienced weight loss, 172 (33.4%) lost >10% body weight in 4 weeks prior to start of CT. First-line CT given: gemcitabine (gem) 10.3%, vinorelbine (vin) 4.3%, gem+platinum 45.0%, vin+platinum 14.6%, taxane+platinum 11.7%, other 14.2%. Complete response (CR) to first-line CT was observed in 1.8% of pts, partial response (PR) 37.9%, stable disease (SD) 28.5%, progressive disease (PD) 17.8%, unknown 13.8%. Second-line CT was planned for 29.2% (285) pts. Median time from initiation of 1st-line to initiation of 2nd-line CT was 5.8 months. Median age was 62 yrs (32–84); 69.8% were male; WHO PS at initiation of 2nd line CT: 0/1 (79%), 2 (17%), 3/4 (4%). Best response to 2nd-line CT: CR 0.4%, PR 9.1%, SD 19.3%, PD 48.8%, unknown 14.3%. Unadjusted median survival time for all pts: 9.3 months (95% CI 8.6–10.3). Overall estimated 1-yr survival was 39.5%. Conclusions: ACTION was the first large-scale observational study in pts with advanced NSCLC in Europe. Overall response rates and survival were consistent with clinical trial results, even though approximately one- third of pts enrolled may have been excluded from clinical trials on the basis of their baseline demographics.

No significant financial relationships to disclose.
Impact of second hand smoke (SHS) exposure on the likelihood of mutations in epidermal growth factor receptor (EGFR) gene in patients with non-small cell lung cancer (NSCLC) who had never smoked
Authors: Lee Y. , Cho B. , Choi H. , Sohn J. , Kang S. , Kim S. , Bae S. , Ryoo H. , Kim J.
Published: March 2020

7633

Background: The presence of EGFR mutations in NSCLC has strongly associated with never-smoking history. SHS exposure is associated with higher risk of lung cancer. We have conducted this study to evaluate the association between SHS exposure and likelihood of mutations in EGFR gene in NSCLC patients who had never smoked. Methods: SHS exposure information from a total of 93 never smokers (<100 lifetime cigarettes) with newly diagnosed primary NSCLC was obtained using a standardized questionnaire. Patients were asked whether they were regularly exposed to SHS at home or work places, respectively. Nucleotide sequencing of the kinase domain of EGFR (exons 18 to 21) was performed using nested PCR amplification of individual exons. Results: Patient characteristics (n=93) included median age 57 years; female (n= 81); adenocarcinoma ± bronchoalveolar carcinoma (n= 82); EGFR mutation (1 mutation in exon 18 G719, 31 in-frame deletions in exon 19, 10 mutations in codon 858 in exon 21). Fifty-two (55.9%) of the patients reported having been exposed to SHS, including 46 (49.5%) exposed at home and 13 (14.0%) exposed at work. The incidence of EGFR mutations was not associated with female gender and adenocarcinoma histology. Patients with SHS exposure showed a trend towards lower incidence of EGFR mutations (36.5% vs. 56.1%, P= 0.060) and a significantly lower incidence of deletion mutations in exon 19 (57.9% vs. 87.0%, P= 0.033). When the incidence of EGFR mutations was compared, no difference between SHS exposure at home and work places was found. No significant differences were found for other clinicopathological factors according to SHS exposure. Conclusions: Our results indicate weak evidence of relationship between likelihood of mutation in EGFR gene and SHS exposure. The deletion mutations in exon 19 were significantly less common in patients with SHS exposure.

No significant financial relationships to disclose.
Why did the gender difference influence survival in patients with completely resected stage I adenocarcinoma of the lung?
Authors: Tsuboi M. , Kato H. , Ichinose Y. , Ohta M. , Hata E. , Tsubota N. , Tada H. , Wada H. , Hamajima N.
Published: March 2020

7647

Background: This study evaluates the influence of gender on survival and tumor recurrence in patients with completely resected stage IA and IB adenocarcinoma of the lung based on the analysis of the Japan Lung Cancer Research Group trial, which was a randomized prospective study of adjuvant chemotherapy with uracil-tegaful for stage I pulmonary adenocarcinoma. Methods: Patients were randomized to receive either oral uracil-tegaful (250 mg of tegaful/m2/day) for 2 years postoperatively or no adjuvant treatment. Survival was calculated from randomization until death. Survival estimated using the Kaplan-Meier method, and difference in survival between two groups was compares with the log-rank test. Results: The 5-year survival rate was 88.9% for the 502 women and 84.3% for the 477 men (median follow-up 72 months, p=0.0066). The relative risk of death for men vs women was 0.658 (95% C.I., 0.476–0.910, p=0.011), although the mean age of men was significantly less than that of women (p=0.041). There was no interaction between the gender differences and the efficacy of uracil-tegaful (p=0.657). However men presented with significantly more preoperative complications, more T2 diseases (p=0.0006), less non-papillary growth for histology (p=0.0078), less well differentiated subtype (p<0.001), higher serum carcinoembryonic antigen (CEA) level (p=0.004), and more smoking history than women (p<0.0001). Disease recurrence patterns were similar between the genders. The postoperative mortality showed a tendency to go up in men. Conclusions: Although longer life expectancy for women in Japan may in part explain, gender influences survival after complete resection for stage IA-B lung adenocarcinoma. The reasons for prolonged survival of women with this disease may be related to the several differences in the distribution of preoperative complications, smoking history and tumor biological behaviors such as T descriptor, histologic subtype, and serum CEA level. However cause- specific mortality was difficult to be explained. Further molecular epidemiologic and molecular profiling studies regarding gender as a prognostic and predictive factor for survival should be done.

No significant financial relationships to disclose.
IND.175: Phase I study of daily oral AZD2171, a vascular endothelial growth factor receptor inhibitor (VEGFRI), in combination with gemcitabine and cisplatin (G/C) in patients with advanced non-small cell lung cancer (ANSCLC): A study of the NCIC Clinical Trials Group
Authors: Goss G. D. , Laurie S. , Shepherd F. , Leighl N. , Chen E. , Gauthier I. , Reaume N. , Feld R. , Powers J. , Seymour L.
Published: March 2020

7649

Background: AZD2171 is an oral an inhibitor of the tyrosine kinase activity of all VEGFR subtypes. Objectives: To determine recommended phase II dose (RPTD), dose limiting toxicity (DLT), toxicity, pharmacokinetics and efficacy of AZD2171 with G/C, in pts with untreated ANSCLC. Methods: Eligibility: stage IIIB/IV NSCLC; PS 0–2; no prior chemotherapy (CT) for advanced disease; adequate hematological, biochemical and end-organ function; no significant hemoptysis or bleeding. Treated stable brain metastases were permitted. G 1,250 mg/m2 day 1 & 8 and C 80 mg/m2 day 1 was given q3 weekly with AZD2171 starting day 2 cycle 1. Planned dose levels (DL) of AZD2171 were 30 and 45 mg once daily PK assayed in cycle 1&2, response (RECIST) every 2nd cycle. Results: 14 pts enrolled. 30 mg (5 pts) and 45 mg (9 pts). Pt characteristics (n=13) median age 56; 11 PS 0–1; 9 males. No DLTs seen in initial 3 pts at 30 mg dose; nor in 9 pts at 45 mg dose. Actual median dose intensity for AZD2171 in cycle 1 (C1) was similar to planned in C1 for both DL (200 mg and 300 mg)), but was higher for 30 mg vs 45 mg for subsequent cycles (150 mg vs 134 mg). At the 45 mg DL 13 dose reductions occurred in 9 pts. Grade 3 adverse events occurred in 2 of 3 30 mg pts (1 hypertension (HT), 1 fatigue); at 45 mg 6 pts of 9 pts had grade 3 events (HT, fatigue, diarrhea, voice changes); 2 pts had grade 4 toxicity (1 reversible CNS ischemia, 1 fatigue). PK: no effect of AZD2171 on gemcitabine PK Objective response: 9 pts are evaluable (4 too early At 30 mg-PR 2, SD 1; at 45 mg-PR 3, SD 3. 2 additional patients were accrued at the 30 mg DL. Conclusions: Toxicities of this combination are manageable and predictable. HT was easily controlled with a standardized treatment algorithm. MTD was not reached at the 30 or 45mg dose level, but 30mg of AZD2171 appears better tolerated in combination with G/C and is suggested as the RPTD. Encouraging anti-tumor activity has been observed which does not appear dose dependent at the doses tested.

No significant financial relationships to disclose.
Multivariate analysis of prognostic variables associated with survival from a phase III study of cisplatin (P) plus etoposide (E) plus chest radiation (XRT) with or without consolidation docetaxel (D) in patients with unresectable stage III non-small cell lung cancer (NSCLC)
Authors: Ademuyiwa F. O. , Breen T. E. , Johnson C. , White A. , Yiannoutsos C. , Hanna N.
Published: March 2020

7668

Background: Concurrent chemoradiation is standard treatment against stage III NSCLC. HOG LUN 01–24 examines whether consolidation therapy with D improves overall survival. We present an analysis investigating the association of patient characteristics with overall survival from patients on this study. Methods: Eligible patients had untreated stage III NSCLC, FEV1 ≥ 1 liter, PS of 0–1, and weight loss < 5%. Patients received P 50 mg/m2 days 1, 8, 29, 36 with E 50 mg/m2 days 1–5, 29–33, and concurrent 5,940 cGy XRT. Patients with non-progressive disease were randomized to D 75 mg/m2 q3wk X 3 cycles vs observation. A multivariable parametric accelerated failure time model was performed to identify factors that affected survival and to estimate the treatment effect adjusting for these factors. Results: A multivariate analysis was performed on 203 patients who were the subject of a DSMB interim analysis. Median follow up was 25.6 months. Variables analyzed included age (<70 vs ≥ 70), sex, race, body mass index, PS (0 vs 1), FEV-1 (> 2 vs ≤ 2), smoking status, hemoglobin (≥12 vs <12), and stage. A multivariable parametric accelerated failure time model demonstrated the association of age <70 vs =70 years (p=0.0447), FEV1 >2 vs =2 (p=0.0153), and pre-treatment hemoglobin values (p=0.0083) as independent prognostic factors for overall survival. The median survival for hemoglobin <12 was 16.8 vs 21.5 months for hemoglobin ≥12 (p=0.0432). Similarly, the median survival with FEV >2L was 21.6 vs 18.9 months for FEV =2 L. Survival was not significantly influenced by smoking status, sex, race, PS, stage, or BMI. Conclusions: This analysis suggests that age <70, FEV-1 >2L and higher pre-treatment hemoglobin values are associated with improved overall survival in patients with stage III NSCLC.

No significant financial relationships to disclose.
Risk of intracranial hemorrhage and cerebrovascular accidents in non-small cell lung cancer brain metastasis patients
Authors: Srivastava G. , Rana V. , Taylor S. , Debnam M. , Huang Y. , Feng L. , Suki D. , Karp D. , Stewart D. , Oh Y.
Published: March 2020

7671

Background: Brain metastases confer significant morbidity and a poorer survival in non-small cell lung cancer (NSCLC). Vascular endothelial growth factor-targeted antiangiogenic therapies (AAT) have demonstrated benefit for patients with metastatic NSCLC and are expected to directly inhibit the pathophysiology and morbidity of brain metastases, yet patients with brain metastases have been excluded from most clinical trials of AAT for fear of intracranial hemorrhage (ICH). This is a low suspected risk, but needs to be quantitated to plan clinical trials of AAT for NSCLC brain metastases. Methods: Data from MD Anderson Cancer Center Tumor Registry and electronic medical records from January 1998 to March 2006 was interrogated. 2143 patients with metastatic NSCLC registering from Jan 1998 to Sept 2005 were followed till March 2006. 776 patients with and 1367 patients without brain metastases were followed till death, date of ICH, or last date of study, whichever occurred first. Results: The incidence of ICH seemed to be higher in those with brain metastasis compared to those without. However, the rates of symptomatic ICH were not significantly different. All ICH patients with brain metastasis had received radiation therapy for them and were not anticoagulated. Most of the brain metastasis-associated ICH's were asymptomatic, detected during radiologic surveillance. The rates of symptomatic ICH, or cerebrovascular accidents were similar and not significantly different between the two groups. The following table depicts the rates of CVA and/or ICH in metastatic NSCLC patients. Conclusions: In metastatic NSCLC patients, the incidence of spontaneous ICH appeared to be higher in those with brain metastases compared to those without, but was very low in both groups nonetheless without a statistically significant difference. These data suggest minimal risk of clinically significant ICH for NSCLC brain metastasis patients and justifies for them clinical trials of AAT.

No significant financial relationships to disclose.

[Table: see text]
Cost-effectiveness analysis (CEA) of third-line erlotinib therapy compared to best supportive care for advanced non-small cell lung cancer (NSCLC) in British Columbia (BC)
Authors: van der Hoek K. , Taylor S. C. , Peacock S. , Johnston K. , Melosky B. L.
Published: March 2020

7678

Background: Erlotinib was approved for funding as a systemic therapy treatment for 3rd line management of advanced NSCLC by the BC Cancer Agency (BCCA) in April 2004. BCCA patient outcome and cost data are routinely collected to verify the therapeutic effectiveness and cost-effectiveness of systemic treatment policies. Methods: This was a pragmatic retrospective analysis of all patients who received 3rd line erlotinib compared to a historical group treated with 2nd-line docetaxel then no further active treatment, both according to BCCA protocol. The primary end-point was cost-effectiveness, measured in terms of cost per-life-year-gained. Secondary end-points included: median overall survival (MOS); overall survival (OS) at 1 year; and comparison to phase III efficacy results. Data was retrieved from the Cancer Agency Information System (CAIS) and Systemic Therapy Data Warehouse. Life-years- gained were calculated from the area under the survival function curve. CEA took the BCCA perspective and costs included all direct drug costs for treatment of advanced disease. Sensitivity analyses included varying life expectancy across its 95% CI, cost to the extremes of ranges, and start date for length of survival: method 1. progression after 2nd line therapy or 3 weeks post last dose of chemotherapy for control group and start date of erlotinib for treatment group; method 2. last date of 2nd line therapy for both groups Results: 75 control and 70 erlotinib patients were included in the analysis. Results are presented in the table . The Incremental Cost-Effectiveness Ratio (ICER) was $28,516 per life-year-gained under method 1, and $17,632 under method 2. The erlotinib group had similar 1-year OS compared to literature (36 vs. 31%). Conclusions: Erlotinib appears to be cost-effective in terms of life-expectancy under a range of assumptions.

No significant financial relationships to disclose.

[Table: see text]
Randomized phase II study of erlotinib alone and in combination with bortezomib in previously treated advanced non-small cell lung cancer (NSCLC)
Authors: Lynch T. J. , Fenton D. W. , Hirsh V. , Bodkin D. J. , Middleman E. , Chiappori A. , Halmos B. , Liu H. , Eton O. , Shepherd W. F.
Published: March 2020

7680

Background: Treatment options for previously treated NSCLC are limited, warranting consideration of novel combinations. This study evaluated the activity and toxicity of erlotinib with bortezomib, a proteasome inhibitor. Dosing was based on the approved indication for erlotinib and on phase I data for the combination. Methods: Patients (pts) with Stage IIIB/IV NSCLC who progressed following one prior line of chemotherapy, with no prior exposure to an EGF-receptor inhibitor and ECOG performance status 0 or 1 were randomly assigned to erlotinib 150 mg po daily alone (arm A) or in combination with bortezomib 1.6 mg/m2 iv on days 1 and 8 (arm B) of a 21-day cycle. Response was evaluated by RECIST and toxicity was graded using NCI CTCAE 3.0. A Simon optimal two-stage design was used to evaluate anti-tumor activity in response-evaluable pts. Results: Fifty pts were treated at 17 sites (January-June 2006); baseline characteristics and treatment intensity were comparable in both arms. Among 24 response-evaluable pts in each arm, there were 3 partial responses (PR) and 1 complete response in arm A and 2 PR in arm B. Median progression-free survival (PFS) was 2.7 and 1.4 months in arms A and B, respectively. The study was halted as required at the planned interim analysis due to insufficient clinical activity in arm B. Activity and toxicity in arm A were consistent with published reports for erlotinib alone. Adverse-event profiles were as expected in both arms, with no significant additivity. In arm B, one pt died of pneumonia. The most common grade 3 treatment-related toxicity was skin rash (12% arm A and 8% arm B), and rash severity correlated with PFS: grades 2/3, 2.8 months PFS (20 pts); grades 0/1, 1.4 months PFS (28 pts), p=0.032. In arm B, one pt each had grade 3 anorexia, hypokalemia, and worsened peripheral sensory neuropathy compared with baseline. There were no grade 4 treatment related toxicities in either arm. Conclusions: The combination of erlotinib and bortezomib in the doses and schedules used in this trial was well tolerated but did not show sufficient activity at this dose and schedule to warrant further development.

No significant financial relationships to disclose.