bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor response to chemotherapy as a surrogate endpoint of survival in advanced non-small cell lung cancer (NSCLC): Results of an individual patients data meta-analysis
Authors: Bruzzi P. , Sormani M. , Tiseo M. , Boni L. , Rosell R. , Ardizzoni A. 
Published: March 2020

7548 Background: In order to assess the validity of objective response to chemotherapy (CT) as a surrogate endpoint of survival in advanced non-small cell lung cancer (NSCLC), we applied the four Prentice criteria to the data collected in the CISCA meta-analysis, comparing the efficacy of carboplatin and cisplatin in the first-line treatment of advanced NSCLC. Methods: Nine trials including 2,968 patients (pts) were analyzed in the CISCA meta-analysis. The prognostic effect of tumor response on survival was analyzed setting a landmark at two months after randomization (time of response recording), in order to eliminate early death from the analysis. After this landmark correction, pts included in the validation analysis were 2,525 with complete data on tumor response and survival. Results: Cisplatin-based CT was associated with a significantly higher tumor response rate compared with carboplatin-based CT (OR = 1.39; 95% CI: 1.18–1.64; p < 0.001). Carboplatin regimens also led to a numerically higher risk of death as compared to cisplatin (HR = 1.06; 95% CI: 0.98–1.16; p = 0.15). Tumor response was a highly significant predictor of survival (HR = 0.50; 95% CI: 0.46–0.55; p < 0.001). When tumor response was introduced in the Cox model (as a four level variable), the hazard ratio in favour of cisplatin treatment changed from 1.06 to 1.004 (95% CI: 0.922–1.093; p = 0.94), indicating that no residual effect of the cisplatin treatment on survival was present once tumor response was adjusted for. This suggests that the overall survival benefit of cisplatin CT was a result of the increase in response rate. The median survival time of patients with complete and partial response was 19.5 months (95% CI: 11.5–27.5 months) and 14.0 months (95% CI: 13.1–14.9 months), respectively; whereas, the median survival time of patients with no response was 7.8 months (95% CI: 7.5–8.1 months). Conclusions: These results support the hypothesis that the achievement of an objective response to CT in advanced NSCLC is associated with a survival benefit. The potential role of objective response as a surrogate endpoint for survival in CT trials of advanced NSCLC warrants further investigation. No significant financial relationships to disclose.
Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC)
Authors: Vansteenkiste J. , Zielinski M. , Linder A. , Dahabre J. , Esteban E. , Malinowski W. , Jassem J. , Passlick B. , Lehmann F. , Brichard V. G. 
Published: March 2020

7554 Background: After complete resection, about 50% of patients with stages IB-II NSCLC disease die within 5 years. Adjuvant chemotherapy improves overall survival at the expense of substantial toxicity. Activity of MAGE-A3 immunotherapeutic (i.e. recombinant MAGE-A3 protein and a potent GlaxoSmithKline adjuvant) was previously demonstrated in metastatic melanoma. As about 35% of NSCLCs express MAGE-A3 antigen, post-operative MAGE-treatment may be a tumor-specific, well tolerated, and effective adjuvant therapy. Methods: Patients with completely resected, MAGE-A3 (+), stage pIB or pII were randomly assigned to postoperative MAGE-A3 or placebo (2:1), with 5 administration at 3-week intervals, followed by 8 administrations every 3 months. Randomization was stratified for stage (IB vs. II), histology (squamous vs. other), and lymph-node (LN) procedure (sampling vs. dissection). Primary endpoint was disease-free interval (DFI); other endpoints were safety, disease-free survival (DFS), and overall survival (OS). This exploratory Phase II study was designed to detect a clinically relevant HR with a 10% one-sided a. Results: 182 patients (122 stage IB, 60 stage II) from 59 centers in 14 countries were randomized over 2 years: Median age 63 (45–81); 87% male; 65% squamous cell carcinoma; 65% lymph-node dissection. After a median follow-up of 28 months, 67 recurrences and 45 deaths were recorded. Group comparisons of DFI, DFS and OS gave respectively a hazard ratio (HR) of 0.74 (95% CI 0.44–1.20, p=0.107), 0.73 (95% CI 0.45–1.16) and 0.66 (95% CI 0.36–1.20) in favor of the MAGE-A3 group. Overall, treatment was well tolerated, with excellent protocol compliance. Subset analysis also suggests that LN dissection may have an effect on survival. Conclusions: The final analysis of this randomized phase II study shows a positive trend for activity of MAGE-A3 treatement in NSCLC with a relative improvement of DFI and DFS of 27%. Further phase III evaluation is planned. This study also suggests that complete lymph-node dissection may have an effect on survival and should be confirmed prospectively. [Table: see text]
Impact of tumor size on survival in stage IB (T2N0M0) non-small cell lung cancer (NSCLC)
Authors: Rajan A. , Newman N. , Vajpayee N. , Husain J. , Graziano S. L. , Gajra A. 
Published: March 2020

7557 Background: Patients with stage IB NSCLC have a relatively poor survival of ∼60% despite adequate surgical resection. The role of adjuvant chemotherapy in this disease remains controversial since the results of the IALT, JBR.10, ANITA and CALGB 9633 trials. It is important to risk stratify patients with Stage IB NSCLC and to offer adjuvant therapies to those at greatest risk for recurrence. Methods: We conducted a retrospective review of 216 consecutive, surgically treated patients with stage IB NSCLC. None of the patients received adjuvant chemotherapy. We studied the association of various clinical factors as well as tumor size and visceral pleural invasion upon tumor recurrence, disease free survival (DFS) and overall survival (OS) at 5 years. Results: Of 216 patients, 135 (62%) were male, 97 (45%) had adenocarcinoma, 115 (53%) had poorly differentiated tumors and the majority (88%) were treated with lobectomy. Visceral pleural invasion was noted in 37 (17%) patients. The 5 year OS and DFS rates were 59% and 54% respectively. Tumor size was = 4cm in 120 (56%) patients, 4.1–5 cm and >5cm in 48 (22%) patients each. The 5 year DFS was 40% and 58% for tumors > 5cm and = 5 cm respectively (p < 0.01). The 5 year OS was 49% and 61% respectively for tumors > 5cm and = 5cm. Pleural invasion was a predictor for DFS in the univariate analysis (p < 0.01) but not for OS. In the multivariable analysis, tumor size = 5cm was the only independent predictor of improved DFS (HR 0.46, C.I. 0.25–.84) and OS (HR=0.43, C.I. 0.23–0.80). Age, gender, histology, differentiation and visceral pleural invasion did not impact upon survival. Conclusions: In stage IB NSCLC, tumors > 5cm in diameter have a significantly worse prognosis. These findings if confirmed in other large series, make a case for subdividing Stage IB NSCLC. Tumor size appears to be the most important factor in risk stratification for patients with stage IB NSCLC. Hence patients with large tumors should be offered adjuvant therapy. No significant financial relationships to disclose.
Fluorescence in situ hybridization (FISH) subgroup analysis of TRIBUTE, a phase III trial of erlotinib plus carboplatin and paclitaxel in NSCLC
Authors: Hirsch F. R. , Varella-Garcia M. , Bunn P. A. , Dziadziuszko R. , Xiao Y. , Gajapathy S. , Skokan M. , Lin M. , Waring P. , O'Neill V. 
Published: March 2020

7570 Background: TRIBUTE was a phase III, placebo-controlled study of patients with previously untreated advanced NSCLC. Patients received erlotinib (E) (150 mg/d) or placebo, plus a course of 6 cycles of carboplatin and paclitaxel (CP), followed by maintenance E monotherapy (for those in the CP+E arm who were responding to treatment). 1,059 patients were randomized and treated (526 E; 533 placebo). There were no significant differences in OS, RR, or TTP between the two arms. In subgroup analyses of the pivotal 2nd line trial (BR21) of E in patients with relapsed NSCLC in which E significantly increased median survival (HR=0.71, p <0.0001), patients who scored positively for increased EGFR copy number by fluorescence in situ hybridization (FISH) exhibited prolonged OS (HR=0.44, p=0.008). Here we report on a similar subgroup analysis for TRIBUTE. Methods: FISH analysis was performed on all available tissue samples. FISH+ samples had a high level of polysomy (=four copies of the gene in =40% of cells), or gene amplification (presence of tight gene clusters, gene/chromosome per cell ratio =2, or =15 copies of the genes per cell in =10% of analyzed cells). Results: FISH analysis was successfully performed on 245 patients (121 E, 124 placebo). Outcome in the placebo patients from this subgroup was better than the overall population, suggesting that this subgroup may not be representative. Of the 100 patients (41%) that were FISH+, 33 had amplification and 67 had high polysomy. In FISH+ patients, OS was similar between those treated with CP+E and those treated with CP alone. However, FISH+ patients in the CP+E arm experienced a decrease in RR compared to those in the CP alone arm, and had a marginally significant longer TTP (HR=0.59, 0.35–0.99). The benefit in TTP appeared after approximately 6 months, during the maintenance portion of the trial. Conclusions: In this retrospective analysis, FISH+ did not predict survival benefit in TRIBUTE. A longer TTP, but a lower RR, was observed in the FISH+ patients. The lower RR in the CP+E arm in this group, taken together with the improved TTP during maintenance therapy, suggests that a non-concurrent combination approach (CP followed by E) warrants further investigation. No significant financial relationships to disclose.
Randomized phase II trial of two dose schedules of carboplatin/paclitaxel/cetuximab in stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Saleh M. N. , Socinski M. A. , Trent D. , Dobbs T. , Zehngebot L. M. , Levine M. A. , Stella P. J. 
Published: March 2020

7586 Background: Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) on both normal and tumor cells, has been investigated in advanced NSCLC as a single agent and in combination with chemotherapy. This ongoing randomized phase II open-label trial evaluates cetuximab in combination with carboplatin (Cb) and paclitaxel (Pac) when given in two dose schedules to patients (pts) with previously untreated stage IIIB/IV NSCLC. Methods: Eligible pts were randomized to 1 of 2 treatment arms. Cetuximab treatment was identical in both arms: 400 mg/m2 IV on day 1 and 250 mg/m2 weekly thereafter. Beginning on day 8, a schedule of Cb AUC=6 IV and Pac 225 mg/m2 IV given on a 3-week cycle was compared with a schedule of Cb AUC=6 IV q4 weeks and Pac 100 mg/m2 IV given weekly for 3 weeks of each 4-week cycle. Pts who achieve CR, PR, or SD after 4 cycles may continue weekly cetuximab monotherapy until disease progression or unacceptable toxicity. The primary objectives were to estimate median progression-free survival (PFS) and the PFS rate at 6 months. Secondary objectives included response rate. Results: The study has completed accrual, with 168 pts randomized and 165 treated. Data are available for 164 pts and confirmed responses for 155 pts. Conclusions: Cetuximab combined with Cb and Pac in both dose schedules demonstrated activity and an acceptable toxicity profile in pts with NSCLC. Final PFS and overall survival data are pending. No significant financial relationships to disclose. [Table: see text]
A phase II study of RAD001 (R) (everolimus) monotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) failing prior platinum-based chemotherapy (C) or prior C and EGFR inhibitors (EGFR-I)
Authors: Papadimitrakopoulou V. , Soria J. C. , Douillard J. Y. , Giaccone G. , Wolf J. , Crino L. , Cappuzzo F. , Sharma S. , Gross S. H. , Shepherd F. A. 
Published: March 2020

7589 Background: R is an oral inhibitor of mammalian target of rapamycin (mTOR) with anti-tumor activity. Single-agent R and in combination with other anticancer agents showed efficacy in in vitro and in vivo NSCLC models. In a phase I study, 4 disease stabilizations (SD) and 1 partial response (PR) were reported from 14 NSCLC pts treated with R monotherapy. Methods: Advanced NSCLC pts with adequate organ function, performance status ≤ 2, failing either ≤ 2 C (arm 1) or ≤ 2 C and an EGFR-I (arm 2) were treated with R at 10 mg qd if tolerable until progression (PD). Study applied a Simon-2-stage design with primary endpoint of objective tumor response rate (RR) according to RECIST. CT scans were performed every 28 days until month 4 and then every 2 months thereafter. Adverse events (AE) were assessed using NCI CTC v. 2.0. Results: This analysis is based on data acquired up to 20 Sep 2006. 85 pts were enrolled between 08/2005 and 05/2006. Demographics and patient disposition were (arm 1/arm 2): 42/43 (7 pts ongoing), female 38.1%/51.2%, never smoker 14.3%/44.2%, adenoca. 57.1%/62.8%, squamous cell ca. 21.4%/14.0%, BAC 2.4%/16.3%, others 19.1%/6.9%. Median age was 60 years (range 21–74). R was given on arm 1 as 2nd line therapy in 64.3% of pts., as 3rd line in 35.7% and on arm 2 as 3rd line in 58.1%, as 4th line in 41.9%. 90.6% pts had stage IV disease. The trial did not proceed to stage 2 based on RR for 74 pts in the efficacy population. Best overall tumor response (arm 1/2 in %): confirmed PR (5.3/2.8), SD (44.7/44.4); SD ≥ 12 weeks (34.2/41.7), duration of SD in days arm 1 (58 –267) and arm 2 (68 –231). Median PFS on arm 1 is 11.3 weeks (95% CI: 8.1; 12.4) and on arm 2 is 9.7 weeks (7.3; 13.0). Most frequent AEs (pts, all grades/grade 3 and 4): stomatitis/mucositis (43/5), cough (27/1), dyspnea (33/8), rash (26/0), fatigue (25/10), anorexia (25/1), nausea (20/0), anemia (18/3), epistaxis (18/0), diarrhea (17/2). Analyses of molecular markers in tumor tissue samples are ongoing. Conclusions: 10 mg qd R monotherapy is well tolerated and shows limited activity in pretreated advanced NSCLC pts. Combination trials with both standard chemotherapy and targeted agents are in progress. No significant financial relationships to disclose.
Phase II study of erlotinib in chemo-naive women with advanced pulmonary adenocarcinoma
Authors: Jackman D. , Lindeman N. I. , Lucca J. , Morse L. K. , Rabin M. S. , Marcoux J. P. , Huberman M. , Johnson B. E. , Janne P. A. 
Published: March 2020

7591 Background: Erlotinib is associated with a survival benefit over placebo for pts with advanced NSCLC who had received 1–2 prior regimens. Its role as initial therapy in clinically defined subgroups or in pts prospectively tested for EGFR mutations is less clear. Methods: Chemotherapy-naive women with adenocarcinoma, stage IIIB/IV, PS 0–1, who had formerly or never smoked, were enrolled and treated with erlotinib 150 mg PO daily, until the time of disease progression or unacceptable toxicity. Response rate was the primary endpoint. Secondary endpoints included overall survival, progression-free survival and toxicity. Tumor tissue adequate for genomic analysis was mandated and prospectively collected for determination of EGFR and KRAS mutations by direct sequencing. Results: From 11/04 to 10/06, 40 women were treated. Demographics: median age 65 yrs (range 36–87); 38 white, 1 black, 1 Asian; 30% PS 0, 70% PS 1; 20% BAC or adenoCA w/ predominant BAC features, 80% adenoCA w/o BAC features; smoking status: 63% former, 37% never. Toxicity: Rash (95%; 30% grade 3) and diarrhea (73%; 10% grade 3) were the most common toxicities. 50% of pts developed toxicity of grade 3 or greater. 5 pts were discontinued due to toxicity, with 2 deaths that were possibly treatment-related: 1 DIC, 1 hepatic failure. There were also two pts with PE (one fatal). Response: CR 0, PR 12 (30%), SD 11 (28%), and PD 10 (25%), 7 not evaluable. To date, 27 patients have progressed, with 14 deaths. Median PFS was 5.6 months; median overall survival has not yet been reached and exceeds 23 months. Of 32 patients sequenced for EGFR to date, there were 9 exon 19 deletions, 3 L858R mutations, and 1 exon 20 insertion. For the 12 pts prospectively determined to have classic EGFR mutations, RR was 75% (9 PR, 2 SD, 1 not evaluable). Of 15 pts w/ wild-type EGFR, only 1 response (7%) was achieved. The pt w/ the exon 20 insertion developed PD. Of 28 pts evaluated to date for KRAS, 6 KRAS mutations were found, w/ no responses in this group (2 PD, 4 SD). Conclusions: Preliminary results suggest that first-line erlotinib monotherapy may be a useful treatment strategy for women with adenocarcinoma and a limited smoking history. Response rate is particularly impressive for those subjects prospectively found to have an EGFR mutation, and poor for those with KRAS mutations. No significant financial relationships to disclose.
Trends in stage distribution for patients with non-small cell lung cancer: A National Cancer Database Survey
Authors: Morgensztern D. , Goodgame B. , Chitneni P. , Baggstrom M. Q. , Gao F. , Govindan R. 
Published: March 2020

7598 Background: We have previously reported a significant change in stage distribution for non-small cell lung cancer (NSCLC) among patients diagnosed at our institution (ASCO 2006 # 7205). To confirm this observation, a larger sample population was evaluated. Methods: Patients with NSCLC registered at the National Cancer Database (NCDB) and diagnosed between the years 1998 and 2003 were evaluated for demographic characteristics including age, race, gender, and stage at presentation. Results: 551,248 patients were identified. Patients with stage 0 or unknown stage were excluded from the study, leaving 510,942 eligible for the final analysis. The annual proportions of stage IV disease at the time of diagnosis are described in the table below. Stage distribution remained stable from 1998 to 2000, but a sharp increase in the percentage of stage IV was noticed between 2000 and 2001 (35.7% to 38.9%). This increase in the percentage of stage IV patients was sustained in the subsequent years and present across the other demographic variables. Conclusions: We have documented a significant change in the NSCLC stage distribution over the last six years. The NCDB is the largest database available and currently captures approximately 62% of all NSCLC patients diagnosed in the United States. The increase in stage IV disease coincides with the widespread adoption of FDG-PET, suggesting an earlier diagnosis of metastatic disease and confirming our previous findings. No significant financial relationships to disclose. [Table: see text]
Pilot phase II study of preoperative gefitinib in early stage non-small cell lung cancer with assessment of intratumor gefitinib levels and tumor target modulation
Authors: Haura E. B. , Sommers E. , Becker A. , McKillop D. , Bepler G. 
Published: March 2020

7603 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) can provide clinical benefit in advanced non-small cell lung cancer patients. Here we examined the effect of single agent gefitinib in patients with early stage NSCLC with additional assessment of plasma and tumor concentrations of gefitinib. Previous studies have suggested considerably higher tumor concentrations of gefitinib compared to levels identified in blood, yet the results in human lung cancers is unknown. Methods: We conducted a pilot phase II study of a 28 day preoperative course of gefitinib 250 mg PO daily followed by surgical resection for patients with stage IA to selected IIIA non-small cell lung cancer. Response was assessed by RECIST using CT and changes in FDG metabolism were assessed using PET. Tumor penetration of gefitinib was assessed in surgically resected tumor samples along with plasma assessment on day 28. Results: Sixteen patients (7 men, 9 women) completed therapy on protocol and all who started on gefitinib were able to undergo a complete surgical resection. There were 0/16 objective responses (CR/PR), 14/16 SD, and 2/16 PD. Three of the 6 patients had more than 20% reductions in FDG SUVmax assessed by PET scanning. Day 28 plasma concentrations of gefitinib averaged 531 ± 344 nM (range 65 to 1,211 nM) while tumor concentrations of gefitinib averaged 33,108 ± 44,312 nM (range 474 to 134,669 nM). Conclusions: Our results demonstrate that NSCLC tumor penetration of gefitinib is much higher than concentrations found in plasma. Assessment of pharmacodynamic markers including tumor EGFR and downstream signaling pathways is ongoing. PET scanning may be an early marker of clinical benefit of EGFR TKI. No significant financial relationships to disclose.
Comparison of the epidermal growth factor receptor gene mutation in matched primary tumor and lymph node metastasis of non-small cell lung cancer
Authors: Park S. , Park B. , Hwang I. , Lee S. , Cho E. , Kang W. , Ahn J. , Ahn M. , Park K. 
Published: March 2020

7614 Background: Mutations in epidermal growth factor receptor (EGFR) are considered as a strong predictive marker to EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Recent studies suggested EGFR status may change between primary NSCLC and corresponding metastatic site. However, it has not fully been evaluated whether EGFR mutation differs in metastases compared to primary NSCLC. Methods: In total, 128 tumor samples from 64 NSCLC patients were investigated comparing matched 64 primary tumors, and 64 lymph node metastases. The epidermal growth factor receptor mutation status was analyzed by a direct sequencing method (exons 18–21 in EGFR) on tumor samples of primary NSCLC and corresponding lymph node metastasis. Results: In 17.2% of patents (11/64), EGFR mutation was identified in either primary NSCLC or metastasis by DNA sequencing. Six (54.5%) out of eleven cases showed discordance of EGFR mutation in the primary tumor/metastasis site. Two cases showed EGFR mutation in the metastasis but not in the primary tumor, while, in four cases, EGFR mutation was detected in the primary tumor but not in the metastasis site. The majority of discordance of EGFR mutations was identified in exon 19 (83.3%, 5/6). The median overall survival (OS) was 17.7 months (95% confidence interval, 9.4–20.0). Median OS was not varied by the discordance of EGFR mutation status between primary NSCLC and corresponding metastatic site. Conclusions: The status of EGFR mutation in primary NSCLC and that in corresponding metastasis site varied in considerable cases by DNA sequencing. Whether the status of EGFR mutation changes during the process of metastasis remains to be evaluated. Future study to evaluate the correlation of tumour response to TKIs and the discordance of the EGFR mutation status is warranted. No significant financial relationships to disclose.