bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II randomized study of dose-dense docetaxel (Doc) and cisplatin (Cis) every two weeks with pegfilgrastim (Pfil) and darbepoetin alfa (Darb) with and without the chemoprotector BNP7787 in patients with advanced non-small cell lung cancer (NSCLC): CAL
Authors: Green M. R. , Miller A. A. , Wang X. F. , Gu L. , Vokes E. E. 
Published: March 2020

7617 Background: We sought to explore the toxicity, feasibility, and response rate of dose-dense Doc and Cis with growth factor support without [A] and with [B] a novel chemoprotector in patients with NSCLC. Methods: Patients with measurable disease, stage IIIB (effusion) or IV, performance status (PS) 0–1, no prior chemotherapy, and adequate organ function were eligible. Treatment with Doc 75 mg/m2 ? Cis 75 mg/m2 both IV over 1 hr day 1 with Darb 200 mcg SC day 1 and Pfil 6 mg SC day 2 randomized to without/with BNP before Cis was repeated every other week (1 cycle = 2 weeks) for up to 6 cycles. Response was determined after 3 and 6 cycles. Because of anticipated neurotoxicity (NT), the primary statistical endpoint was to differentiate between grade =2 NT rates of 30% in [A] and 10% in [B]: 90% power, two-tailed p<0.10, 76 patients per arm. Feasibility was prospectively defined as febrile neutropenia in <10% of patients and =1 treatment delay per cycles 1–3 and 4–6 in <20% of patients. Objective response rates of >35% were required to merit further investigation. Results: Between 8/04 and 3/06, 160 patients were enrolled but 5 never started therapy and 4 were ineligible: male/female, 99/52; white/black/other, 126/23/2; median age 62 (range, 30–88); PS 0/1, 69/82; stage IIIB/IV 14/137; [A]/[B], 76/75 well balanced. Sensory/motor/either NT grade =2 occurred in 28/14/32% on [A] and 19/19/29% on [B]. The incidence of febrile neutropenia was 1%. Treatment was delayed in cycles 1–3/cycles 4–6 in 3/3 patients in [A] and 1/5 patients in [B]. Completion rates for 3/6 cycles were 87/51% in [A] and 84/52% in [B]. By intent to treat, complete/partial response rates were 4/46% in [A] and 3/47% in [B]. Median estimated overall/progression-free survival times are10/6 months in [A] and 11/6 months in [B]. Overall, grade 3+4 neutropenia and thrombocytopenia occurred in =10% and anemia in 12% of patients. Non-hematologic toxicity was mild. Six deaths were thought to be treatment related. Conclusions: This dose-dense treatment regimen is feasible, tolerable, and worthy of further investigation in NSCLC. BNP did not result in significant protection from NT. No significant financial relationships to disclose.
Pharmacodynamic separation of erlotinib and docetaxel (DOC) in advanced non-small cell lung cancer (NSCLC): Overcoming hypothesized antagonism
Authors: Davies A. M. , Hesketh P. J. , Beckett L. , Lau D. , Mack P. C. , Lara P. N. , Jernigan J. , LaPointe J. , Gandara D. R. 
Published: March 2020

7618 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) given concurrently with chemotherapy do not improve patient (pt) outcomes compared with chemotherapy alone in advanced NSCLC. Based on our preclinical data, we hypothesized that G1 cell cycle arrest from EGFR-TKI antagonizes the cytotoxicity of concurrent chemotherapy, and that pharmacodynamic separation (PDS) by intermittent delivery of EGFR-TKIs with chemotherapy would increase efficacy (Gumerlock, ASCO 2003, Davies, ASCO 2005). To test this concept, we conducted a phase I-II study of intermittent erlotinib combined with DOC. Methods: 37 previously treated IIIB (pleural effusion) or IV NSCLC pts received DOC 70–75 mg/m2 IV on day 1 every 21 days and erlotinib orally days 2–16 (150–200 mg). Patients without progression after 6 cycles continued erlotinib alone. Primary endpoint was response rate. Results: Pt characteristics: Age: median/range 57/35–80; Sex: 14 M; KPS ≥90=13; smoker/non-smoker/unknown 20/13/4, Median cycles: 5. Adenoca: 18. Prior chemotherapy regimens: 1 - 26; >1 - 11. In 34 evaluable pts: 1 CR, 11 PR (35% response rate), 16 stable disease. Median time to progression (TTP) was 5.6 months (95% CI: 3.7 - 7.9). MST: not reached. Treatment was generally well tolerated. Most common grade (Gr) 3/4 toxicities included: neutropenia (60%), diarrhea (16%), infection (11%), febrile neutropenia (8%). Gr 1/2 acneform rash: 88%. PK analysis showed that PDS was achieved in nadir levels of erlotinib in 4 pts tested. Correlative studies examining biomarkers for response with EGFR TKIs are ongoing. Conclusions: 1) DOC every 3 weeks plus intermittent dosing of erlotinib (2 weeks on, 1 week off) achieved PDS in limited PK sampling. 2) This combination resulted in a favorable response rate and TTP in previously treated NSCLC, with MST not yet reached. 3) Febrile neutropenia necessitated the prophylactic use of G-CSF. 4). Further clinical study of this concept is warranted, and trials are currently ongoing. [Table: see text]
A randomized phase II trial of early change of a chemotherapeutic doublet compared to four cycles of chemotherapy in advanced non-small cell lung cancer (NSCLC): The 03–01 Groupe Francais de Pneumo-Cancerologie (GFPC) study
Authors: Vergnenegre A. , Corre R. , Barlési F. , Bérard H. , Vernejoux J. , Le Caer H. , Fournel P. , Delhoume J. , Arpin D. , Thomas P. , Tillon J. 
Published: March 2020

7631 Background: The optimal strategy in advanced NSCLC with stable disease is not well known. There is no published study assessing an early change of chemotherapeutic drugs in these patients. This study was designed to evaluate the efficacy and safety of early modification of chemotherapy doublets in patients with advanced non small cell lung cancer with stable disease (SD). Methods: Patients with stage IV NSCLC and measurable disease were included in a randomized phase II trial comparing for patients with stable disease after 2 cycles of a platin (P)-gemcitabine doublet (P d1: 75 mg/m2, gemcitabine 1 250 mg/m2 d1, d8 every three weeks) two subsequent cycles of this doublet (arm A) to a switch to another doublet (arm B): paclitaxel 100 mg/m2 d1, d8, d15, gemcitabine 1 250 mg/m2 d1, d8, every four weeks. Results: Between October 2003 and august 2006, 228 patients (pts) were enrolled (187 males, 41 females), median age 57 y (30–70). Evaluation (EVA) 1 showed 11.8% not assessable patients (NA), 19.3% with objective responses (OR), 25.9% with progressive diseases. 98 patients (43%) had stable diseases. 87 patients were randomized in the study. 48.3% with PS0, 51.7% with PS1 and a majority of adenocarcinoma (62.1%). 41.4% had only one metastatic site. There were no differences between the two groups. Efficacy at eva 2 is depicted above. Overall survival (OS) was similar between the two arms: 9.8 months (m) [7.0 - 14.2] for arm A, 9.2 m [7.4 - 10.5] for arm B. TTP was 5.4 m in arm A and 5.7 in arm B. There were 1 grade III/IV haematological toxicities in arm A (1.2%) and 2 in arm B (2.4%). There were 4 grade III/IV non haematological toxicities in arm A (4.8%) and 6 in arm B (7.3%). Conclusions: The switch between the two regimen is feasible without any major toxicities. Despite higher response rate in favour of the switch strategy, OS and TTP are similar between the two arms. No significant financial relationships to disclose. [Table: see text]
MDM2 309 and TP53 Arg72Pro single nucleotide polymorphisms (SNPs) and clinical outcome in advanced lung cancer patients
Authors: Novello S. , Mandrile G. , Giachino D. F. , Ghio P. , Selvaggi G. , Gregori D. , De Marchi M. , Scagliotti G. V. 
Published: March 2020

7636 Background: The TP53 Arg72Pro (rs1042522:C>G) and MDM2 SNP309 (rs2279744:T>G) SNPs of the DNA damage response pathway have been shown to affect lung cancer risk. We aimed to investigate their relationship with the clinical outcome of chemotherapy (CT). Methods: We prospectively recruited 426 consecutive patients with advanced disease (352 NSCLC and 74 SCLC, 57% metastatic) referred for chemotherapy at our institution from July 2002 to January 2006: 82% male, median age at diagnosis 63 years, 56% current and 11% never smokers, 81% receiving combined platinum CT. Median follow up time was 10.5 months. Controls were 254 medical students. We designed specific TP53 and MDM2 primers for typing both SNPs using the Pyrosequencing assay. Results: Patients genotype frequencies were: TP53 Arg/Arg 51%, Arg/Pro 40%, Pro/Pro 8%, (61%, 35%, 4% among controls, p=0.02), MDM2 T/T 37%, T/G 46%, G/G 17%, (31%, 55%, 14% among controls, p=0.07). Both groups were in Hardy-Weinberg equilibrium. At multivariable analysis adjusted for gender, smoking status, type of chemotherapy, disease stage, and side effects, survival was significantly associated with performance status (PS) [HR 1.54 (1.2–2.0)], histology [SCLC vs. NSCLC - HR 1.51(1.1–2.1)] and objective response [yes vs. no HR 0.56 (0.4–0.7)] but with neither SNP; in contrast, grade 3–4 toxicity and objective response were concomitantly associated with the SNPs of TP53 [Pro carriers vs. Arg/Arg HR 1.40 (1.1–1.8) and 1.44 (1.0–2.0)] and MDM2 [GG vs. TT 0.57 (0.4–0.9) and 0.61 (0.4–0.97)]. These findings are in agreement with the notion that MDM2 GG homozygous cells express higher levels of mdm2, thus attenuating the p53 pathway, but don’t easily fit with the alleged greater apoptotic potential of p53 Arg72. We also observed significant associations of toxicity with platinum therapy, of objective response with histology and of both outcomes with PS (not shown). Conclusion: The study provides preliminary evidence that germ-line TP53 and MDM2 SNPs affect toxicity and objective response to CT in lung cancer patients, probably depending on a variable DNA damage response but not survival time that may mainly result from the tumor aggressiveness and somatic mutational status. [Table: see text]
Promising preliminary results of erlotinib in previously chemotherapy treated Taiwanese NSCLC patients in a large expanded access program study
Authors: Perng R. 
Published: March 2020

7641 Background: Erlotinib is the first EGFR tyrosine kinase inhibitor which demonstrated the survival benefit to NSCLC patients in randomized trial. An expanded access program (EAP) was conducted to evaluate the efficacy and safety profiles of erlotinib in Taiwanese patients with NSCLC. Methods: Patients with proven stage IIIB/IV NSCLC and received at least first line standard chemotherapy or radiation therapy were enrolled in this study. No more than 2 prior chemotherapy regimens are permitted. All patients were given oral erlotinib, 150 mg/day till disease progression. Patients were monitored monthly and tumor assessments were evaluated every 2 months according to RECIST criteria. Results: From Apr. 2005 to Mar. 2006, 300 patients were entered from 15 medical centers in Taiwan. This interim study evaluated the first 297 patients (data cut-off date of November 8, 2006). Of them, 53% pts were male, 80% pts were with ECOG PS 0 or 1, 68% pts had adenocarcinoma, 62% pts receiving erlotinib as 2nd-line treatment, and 55% patients were non- smoker. The best response rate was 27.8% PR and 47.1% SD in 263 evaluable patients according to RECIST (disease control rate= 74.9%). Non-smoker (p=0.048 and 0.002), adenocarcinoma (p=0.001 and <0.001), female (p=0.0005 and <0.0001), and skin rash (Gr 3–4, p=0.0095 and 0.0019) were significantly correlate with best response and disease control to the treatment. Skin rash was a common adverse event (any grade: 83%, Gr 3–4: 15%). Erlotinib-related SAEs were seen in 4% patients and 3% patients discontinued treatment due to treatment-related SAEs. 24% of patients needed dose reductions, mainly due to skin rash. The median time to progression and median overall survival will be matured at the time of ASCO annual meeting. Conclusions: This is the largest multicenter prospective clinical study of NSCLC in Taiwan. This interim results demonstrating the superb response rates, time-to-progression and overall survival of erlotinib in a large population of Taiwanese or Chinese in previous chemotherapy or radiotherapy treated NSCLC patients. No significant financial relationships to disclose.
ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer
Authors: Lee K. , Han S. , Min H. , Oh D. , Lee S. , Kim D. , Kim Y. , Kim T. , Heo D. , Bang Y. 
Published: March 2020

7646 Background: To investigate whether excision repair cross-complementation group 1 (ERCC1) expression, as determined immunohistochemically, and mutations of epidermal growth factor receptor (EGFR) are related to the prognosis of curatively resected non-small cell lung cancer (NSCLC), and whether these two markers are related. Methods: One-hundred and thirty-three consecutive patients with NSCLC who did not receive adjuvant chemotherapy after curative surgery were included in this study. Representative areas from formalin-fixed paraffin-embedded tumor samples were chosen for tissue microarray analysis. Immunohistochemistry was performed for ERCC1 and the median semiquantitative H-score was used as a cut-off. EGFR mutations (exons 18, 19, and 21) were analyzed by the direct sequencing of tumor samples. Results: ERCC1 expression was evaluable in 130 patients and ERCC1 was found to be positive in 80 patients (61.5%). Moreover, ERCC1 was expressed more frequently in smokers and in squamous cell carcinomas. Patients with positive ERCC1 expression survived longer (median overall survival 2,742 days for ERCC1-positive vs. 1,423 days for ERCC1-negative, P=.0463). EGFR mutations were found in 27 patients (20.3%) but they were not found to affect overall survival. Interestingly, EGFR mutations were more frequent in ERCC1-negative tumors (12.5% in ERCC1-positive vs. 30% in ERCC1-negative tumors, P=0.014). Conclusions: ERCC1 expression was identified as a prognostic marker of longer survival in resected NSCLCs. In addition, EGFR mutations were more frequently found in ERCC1-negative tumors, but were not found to affect survival in our patient group. No significant financial relationships to disclose.
Correlation of tumor response and survival in advanced NSCLC patients treated with paclitaxel plus carboplatin (PC) versus paclitaxel plus carboplatin plus gemcitabine (PCG)
Authors: Paccagnella A. , Oniga F. , Bearz A. , Favaretto A. , Barbieri F. , Chella A. , Ceresoli G. , Biason R. , D'Amanzo P. , Ghi M. G. 
Published: March 2020

7650 Background: We showed that PCG significantly increases both response rate (RR) (43.6% vs 20%) and median survival (10.8 mo vs 8.3 mo) over PC and that at Cox analysis, the only independent prognostic factors were PS and treatment (Paccagnella et al, J Clin Oncol 2006;24: 681–687). According to the Prentice criteria (Stat Med 1989;8: 431–440), to directly relate response and survival it is necessarily that responding patients (and non responding) of both arms have a similar survival and that the survival difference between the two arms disappear when the response factor is included in the multivariate analysis. Methods: Out of 324 pts included in the original analysis, 26 pts were not evaluable for response (early death, toxicity, refusal) before the planned response evaluation at two months and were excluded (15 pts from PC arm and 11 pts from PCG arm). The analysis however was also performed considering the non evaluable patients as non responders. Results: Overall, Responder patients had a median Survival that nearly doubled that of no responders: 14.73 mo vs 7.67 mo (HR: 0.49; CI: 0.31–0.54; P=0.000). No responder pts from PC and PCG arms had a similar survival (median 7.53 mo and 8.07 mo respectively; P= 0.96) as well as responder (CR + PR) patients (median 14.13 mo and 15.40 mo respectively; P=0.38). The principal difference between the two arms was that more than the double of patients in PCG arm responded (43.6% vs 20%) and consequently had a survival advantage of clinical relevance in comparison to patients in PC arm. When tumor response was introduced in the Cox model (as a four level variable), the difference in Overall Survival between PCG and PC changed from a significant level (HR=1.28; CI 1.00–1.63; P=0.049) to a not significant level (HR=0.99; CI: 0.76 - 1.28; P=0.97). Conclusions: To our knowledge this is the first report showing a significant direct correlation between response and survival in advanced NSCLC according to Prentice criteria. No significant financial relationships to disclose.
Association between different potential predictive markers from TRUST, a trial of erlotinib in non-small cell lung cancer (NSCLC)
Authors: Laack E. , Schneider C. , Gutjahr T. , Heinmöller E. , Lutz V. , Moecks J. , Rohr K. , Schmidtgen C. , Spleiss O. , Reck M. 
Published: March 2020

7651 Background: Recent studies have examined potential predictive markers in NSCLC patients (pts) treated with EGFR tyrosine kinase inhibitors. However, few data are available on inter-relationships between different markers. Clinical and molecular markers were analyzed for patients from TRUST, an open label, non-randomized trial initiated to provide erlotinib access to pts with advanced NSCLC. Methods: 393 German pts (99% Caucasian) with stage IIIb/IV NSCLC were included. Markers/characteristics assessed were: EGFR (282 pts) and phosphorylated MAPK (pMAPK; 109 pts) using immunohistochemistry (IHC; positive status was defined as: ≥10% of tumor cells with any membrane staining for EGFR; and H-score ≥200 for pMAPK), EGFR gene copy number (135 pts) using fluorescence in-situ hybridization (FISH), EGFR mutations (86 pts), KRAS mutations (108 pts), tumor type (281 pts), smoking status (392 pts) and gender (393 pts). Results: EGFR FISH+ pts were likely to also be EGFR IHC+: 92.9% (26/28) of EGFR FISH+ pts were EGFR IHC+, and 92.6% of EGFR IHC- pts were also EGFR FISH- (p<0.1). pMAPK expression status was not related to other markers. 15.7% (17/108) pts had KRAS and 7.0% (6/86) had EGFR mutations; no pts had mutations in both genes, indicating that these mutations might be mutually exclusive. Both KRAS mutations and histology were associated with smoking status. 94.1% (16/17) pts with KRAS mutations and 91.6% (87/95) pts with squamous-cell carcinoma were smokers. In female pts, the occurrence of adenocarcinoma was significantly higher (73.6% vs 55.4% in males; p<0.001), possibly influenced by a lower incidence of smokers in this group (51.3% vs 92.2% in males; p<0.001). Conclusions: The availability of a large number of tumor samples from the TRUST study, and assessment of a broad range of markers allows investigation of relationships between various tumor/patient characteristics. Understanding these complex inter-relationships may shed light on the role of each marker. Specific combinations of markers may prove useful in predicting clinical benefit from erlotinib. As the study is ongoing, additional data will be available and presented. No significant financial relationships to disclose.
IFCT0401-bio trial: Predictive biological markers for disease control (DC) of patients with non-resectable, adenocarcinoma with bronchioloalveolar carcinoma features (ADC-BAC) treated with gefitinib
Authors: Wislez M. , Antoine M. , Poulot V. , Morere J. F. , Perol M. , Souquet P. J. , Lebitasy M. P. , Zalcman G. , Coulet F. , Cadranel J. 
Published: March 2020

7653 Background: A French prospective multicentric phase II trial (IFCT0401) evaluated gefitinib as first-line treatment in non- resectable ADC-BAC. Tissue samples were collected for central pathological review and molecular analysis in attempt to identify biological markers associated with DC by gefitinib. Methods: Tumor samples were classified as BAC variants or ADC-other types according to the 2004 WHO histological classification and as non-mucinous or mucinous/mixed according to cytology. Immunohistochemistry was performed using antibodies against TTF1, Ki67, phosphorylated AKT, erbB2, and EGFR. Polysomy/amplification was examined for EGFR and erbB2. EGFR 18–21 and K-ras 2 exons were amplified and sequenced. Results: Tissue specimen were collected from 65 of the 88 eligible participants. This subgroup did not differ from the overall trial population in terms of sex ratio, proportion of non-smokers and DC rate. DC was achieved in 22/64 patients (DCR=34.4%, CI=[22–41]). 81% were BAC variants (n=50) and 19% ADC other types. Of the 50 BAC variants, half were non-mucinous and half mucinous. EGFR high polysomy/amplification was present in 6/40 samples (15%). EGFR exon 19, 20 and 21 mutations were detected in 6/57 (10.5%), 1/49 (2%) and 0/58 samples, respectively and K- ras mutation in 11/53 (20.7%). Expression of TTF1 (p<0.0001) and EGFR (p=0.04) as well as polysomy/amplification of EGFR (p=0.04) were significantly higher in the non-mucinous than in the mucinous type. There was also a trend for more frequent detection of EGFR mutations among non-mucinous than mucinous type (p=0.08). DC with gefitinib was significantly associated with female gender (p=0.02), non- smoker status (p=0.03), non-mucinous subtype (p=0.006), high TTF1 expression (p=0.02) and EGFR mutation (p=0.0003). K-ras mutation was associated with progression (p=0.04). Conclusions: Among patients with histologically proven ADC-BAC who received gefitinib, female gender, non-smoker status, non-mucinous subtype, high TTF1 expression, and EGFR mutation are associated with DC, while K-ras mutation is associated with disease progression. Multivariate analysis will be released at ASCO meeting. No significant financial relationships to disclose.
Erythropoietin and erythropoietin receptor coexpression is associated with poor survival in stage I non-small cell lung cancer
Authors: Saintigny P. , Besse B. , Callard P. , Vergnaud A. , Czernichow S. , Colombat M. , Girard P. , Validire P. , Breau J. , Bernaudin J. , Soria J. 
Published: March 2020

7655 Background: The role of erythropoietin (EPO) and its receptor (EPO-R) in tumor biology is under active investigation. This study was designed to evaluate the prognostic impact of EPO and EPO-R expression in stage I non-small cell lung cancer (NSCLC) patients. Methods: EPO and EPO-R expression in 158 tumor samples from resected stage I NSCLC was evaluated using immunohistochemistry and tissue-array technology. Disease specific survival time was calculated from the date of surgery to death from cancer-related causes. Results: EPOR and EPO were highly expressed in 20.9% and 35.4% of the tumors respectively. High EPO-R compared to negative or low level of expression was associated with a poor 5-year disease specific survival (60.6% versus 80.8%, logrank test: p=0.01). High EPO compared to negative and low level of expression was associated with a trend toward a poor 5-year disease specific survival (69.6% versus 80.4%, logrank test: p=0.13). High level of EPO-R and EPO coexpression compared to other groups of patients was associated with a poor 5- year disease specific survival (50.0% versus 80.0% of survival at the end of follow-up, logrank test: p=0.005). In multivariate analysis for disease specific survival, high level of EPO-R and EPO coexpression was an independent prognostic factor for disease specific survival (HR 2.214, 95% CI: 1.012–4.848, p=0.046). Conclusions: These results establish for the first time the pejorative prognostic value of EPO and EPO-R expression in early stage resected NSCLC and suggest a potential paracrine and/or autocrine role of endogenous EPO in NSCLC aggressiveness. No significant financial relationships to disclose.