bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II study of erlotinib (E) or intercalated E with carboplatin/paclitaxel (CP) in chemotherapy-naive advanced NSCLC: Correlation of biomarker status and clinical benefit
Authors: Hirsch F. R. , Dziadziuszko R. , Varella-Garcia L. , Franklin W. , Bunn P. , Kabbinavar F. , Wacker B. , Rusk J. , Richardson K. , Camidge D. R. 
Published: August 2020

8026 Background: E plus chemotherapy showed no additive effects in NSCLC but preclinical studies suggested that intercalation of E and chemotherapy could give synergy. Clinical studies suggested that EGFR mutations could aid in pt selection. KRAS mutation status of tumors was also evaluated. We conducted a randomized phase II study of E and E intercalated with CP in pts with chemonaive NSCLC. Methods: Stage IIIB/IV EGFR+ NSCLC pts were randomized to E 150 mg/d or CP d1 plus E days 2–15 q21 days (ECP). After 4 cycles, E continued until PD. Tumor tissue was evaluated by IHC (EGFR), FISH (EGFR gene copy number), and PCR amplification followed by DNA sequencing (EGFR and KRAS mutations). Results: Among 143 pts randomized 53% EGFR FISH+; 13% activating EGFR mutations and 8% non-activating EGFR mutations (evaluable samples=114); and 22% KRAS mutations (evaluable samples=130). No pt had both EGFR and KRAS mutations. EGFR-activating mutations were higher among females (19% vs 6% males), adenocarcinoma histology (17% vs 0% others), Asians (45% vs 7% non-Asian), and never smokers (29% vs 7% former and 0% current); KRAS mutations were higher in current smokers (41% vs 27% former and 0% never) and adenocarcinoma histology (22% vs 18% squamous). In the E arm, 6-mo PFS probability for the efficacy evaluable population (n=69) was significantly higher in pts with EGFR activating mutations vs no mutations (89% vs 25%, HR=0.17, P=0.001), numerically higher in pts with EGFR FISH+ vs FISH- (40% vs 22%, HR=0.61, P=0.07), and with KRAS wild type vs mutation+ (38% vs 12%, HR=0.56, P=0.10). Response rates, PFS and OS by type of EGFR/KRAS mutation will be presented. In the ECP arm, 6-mo PFS probability for the efficacy evaluable population (n=68) was numerically higher in pts with EGFR activating mutations (42% vs 29%, HR=0.72, P=0.53), numerically higher in pts with wild type KRAS (32% vs 9%, HR=0.57, P=0.08), and numerically lower in pts with EGFR FISH+ vs FISH- (23% vs 30%, HR=0.93, P=0.78). Conclusions: Activating EGFR mutations correlate with increased 6 mo PFS probability in 1st line therapy with E. EGFR FISH + and absence of KRAS mutation trend towards increased 6 mo PFS rate with E. [Table: see text]
Irinotecan plus carboplatin versus etoposide plus carboplatin in extensive disease small cell lung cancer: Results of the German randomized phase III trial
Authors: Schmittel A. H. , Sebastian M. , von Weikersthal L. Fischer , Gauler T. , Hortig P. , Fischer J. R. , Link H. , Binder D. , Eberhardt W. , Keilholz U. 
Published: August 2020

8029 Background: Superiority of irinotecan over etoposide in combination with cis- or carboplatin was demonstrated in a Japanese and a Scandinavian phase III trial. However, both cisplatin-based North American phase III studies could not detect any difference in efficacy. We report the final results of the German randomized phase III trial comparing etoposide/carboplatin (PE) to irinotecan/carboplatin (IP) in small cell lung cancer (SCLC) extensive disease. Methods: Chemotherapy-naïve extensive disease SCLC patients were randomly assigned to receive carboplatin AUC 5 mg × min/mL either in combination with 50 mg/m2 of irinotecan on days 1, 8 and 15 (IP, Arm A) or with etoposide 140mg/m2 days 1–3 (EP). IP treatment was repeated every 4 weeks, EP every 3 weeks. Response assessment was performed after cycles 2, 4 and 6 and every 3 months thereafter. Toxicity was assessed once weekly. Primary endpoint was detection of progression free survival (PFS), secondary endpoints were overall survival (OS), response rate, and toxicity. Results: A total of 216 patients from 8 centres were randomized. No significant differences in survival or response rate could be detected. Median PFS was 6 months in both arms. Median OS was 10 months (95% confidence interval (CI) 8.3 -11.7) in the IP arm and 9 months (95% CI 7.6 -10.4) in the EP arm. 1 year survival was 37% (95% CI 25.6 - 47.6) and 28% (95% CI 18.2 - 37.4) in the IP and EP arm. 62% of patients in the IP and 63% in the EP arm had a confirmed complete or partial remission according to RECIST criteria. Significant differences in grade 3 and 4 toxicity were observed for thrombopenia (22% IP vs 47% EP) and neutropenia (23% IP vs 61% PE) without differences in the rate of febrile neutropenia. Grade 3 and 4 diarrhea was manageable and as expected significantly more frequent with IP (15%) than with EP (6%). Conclusions: Our phase III trial shows equivalent efficacy of irinotecan when compared to etoposide in combination with carboplatin. [Table: see text]
Pharmacogenomic analysis from a phase III study of pemetrexed plus carboplatin (PC) versus etoposide plus carboplatin (EC) in chemonaive patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC)
Authors: Smit E. F. , Socinski M. A. , Mullaney B. P. , Myrand S. P. , Powell E. , Lorigan P. , Kaiser C. , Guba S. C. , Thatcher N. 
Published: August 2020

8030 Background: We have reported results of a randomized phase III trial in chemonaive patients with ED-SCLC comparing PC to EC. Study enrollment was closed for futility but pharmacogenomic endpoints were not reported. Here we report the results of immunohistochemistry (IHC) analysis from tumor tissues and single nucleotide polymorphism (SNP) analysis of selected genes implicated in pemetrexed, carboplatin, or etoposide activity. Methods: Proteins studied by validated IHC on Benchmark XT were thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyl transferase (GARFT), and folylpolyglutamate synthetase (FPGS). SNP data from whole blood were genotyped by massArray mass spectrometry from 611 samples. One hundred fifty-eight SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylene tetrahydrofolate reductase (MTHFR), folate receptor- α (FR-α), solute carrier 19A1 (SLC19A1) and adjacent regions. Allele frequency and Hardy-Weinberg equilibrium were calculated for each SNP. Results: Of 408 tissue samples (from 908 enrolled pts) available for IHC, 336 samples were assayed for > 1 assay target. The IHC analyses showed improved OS in the EC arm relative to the PC arm for patients with low TSnuclear (12.9 vs 7.5 month, p < 0.001, interaction p value = 0.017). There was no differential treatment effect within the PC arm for low vs. high TS. High vs low ERCC1 levels did not predict outcome following C exposure. GARFT was not associated with outcome by treatment. SNP rs2838952 (adjacent to SLC19A1) was significant for improved OS (HR = 0.590, p = 0.01) in both study arms. SNP rs12379987 (FPGS) was significantly associated with treatment for OS (interaction p value = 0.036). Exploratory analyses found associations between additional SNPs and PFS within and across treatments. Conclusions: Pharmacogenomic analyses of tumor samples show that low TSnuclear expression correlates with OS in the EC arm. Two germline SNPs in regions including FPGS and SLC19A1 were associated with better OS. Further analysis of these pharmacogenomic results is ongoing. [Table: see text]
Blood-based CHRNA3 single nucleotide polymorphisms (SNPs) and outcome in advanced non-small cell lung cancer (NSCLC) patients (p)
Authors: Rosell R. , Ramirez J. L. , Sanchez-Ronco M. , Isla D. , Moran T. , Cobo M. , Massuti B. , Taron M. , Carbone D. , De Aguirre I. 
Published: August 2020

8033 Background: Nicotonic acetylcholine receptors (nAChRs) are associated with resistance to gemcitabine (gem), cisplatin (cis) and paclitaxel in NSCLC cell lines. Three SNPs of CHRNA3, CHRNA5 and LOC123688 increase lung cancer risk. These SNPs may have influenced outcome in p treated in our phase III trial (Cobo et al. J Clin Oncol 2007;25:2747–54). Methods: Stage IV NSCLC p were treated with customized chemotherapy based on ERCC1 mRNA expression. p in the control arm received docetaxel (doc)/cis; p in the genotypic arm with low ERCC1 levels (low genotypic group [LG]) received doc/cis; p in the genotypic arm with high ERCC1 levels (high genotypic group [HG]) received doc/gem. DNA was extracted from lymphocytes, and CHRNA3 (rs1051730), CHRNA5 (rs16969968) and LOC123688 (rs8034191) SNPs were genotyped with the Taqman allele discrimination assay. Results: A significant interaction was found for CHRNA3 and PS (P = 0.02). In p with PS 0, CT p had a better response than both CC (P = 0.01) and TT (P = 0.02) p, and LG p also had a better response (P = 0.01). When the CHRNA3 genotype was added in the multivariate analysis for progression-free survival (PFS), an improvement was observed in the LG in PS 0 p (P = 0.02). PS 0 p in the LG with the CT genotype attained an 84% response, 12.1-month PFS, and 19-month median survival (MS) ( Table ). Conclusions: CHRNA3 genotyping can improve customized chemotherapy based on tumor ERCC1 mRNA in stage IV NSCLC p with PS 0. [Table: see text] No significant financial relationships to disclose.
Outcomes for the elderly (≥70 years) from a three-arm phase III trial of gemcitabine in combination with carboplatin (GC) or paclitaxel (GP) versus paclitaxel plus carboplatin (PC) for advanced non-small cell lung cancer (NSCLC)
Authors: Ansari R. H. , Edelman M. J. , Belani C. P. , Socinski M. A. , Obasaju C. K. , Monberg M. J. , Chen R. , Treat J. 
Published: August 2020

8052 Background: Approximately 50% of lung cancer patients (pts) are ≥ 70 y, however, this population has been historically underrepresented in clinical trials. Even among pts ≥ 70 y, doublet chemotherapy has been shown to be superior to single-agent therapy (Lilenbaum JCO 2005, Sederholm JCO, 2005), and the efficacy and safety of platinum-based chemotherapy doublets in NSCLC pts ≥ 70 years with good PS have been reported to be similar to those in younger pts (Fossella, ASCO 2003, #2528, Kelly, ASCO 2001, A-1313). The current analysis examined whether any differences were present by age in a three arm trial of GC or GP versus a standard regimen of PC. Methods: 1135 chemonaïve pts with stage IIIB or IV NSCLC were randomized to receive: G 1000 mg/m2 d 1,8 plus C AUC 5.5 d 1; or G 1000 mg/m2 d 1,8 plus P 200 mg/m2 d 1; or P 225 mg/m2 plus C AUC 6.0 d 1. Stratification was based on stage, baseline weight loss, and brain metastases. Cycles were repeated every 21 days up to 6 cycles or disease progression. Clinical results were retrospectively analyzed in by patient age. Results: See Table . Conclusions: In this trial of commonly used regimens for advanced NSCLC, pts 70–74 years of age had significantly longer survival than pts 75–79 years of age. Pts 80+ years of age also had lower survival than the 70–74 year age group, but this difference was not statistically significant. No pts 80+ years of age had brain metastases at study entry. There was no clear pattern with respect to the effectiveness of individual treatment regimens by age group. [Table: see text] [Table: see text]
A multicenter phase II study to evaluate efficacy and safety of gefitinib as the first-line treatment for Korean patients (pts) with advanced pulmonary adenocarcinoma harboring EGFR mutations
Authors: Kim D. , Lee S. , Lee J. , Lee M. , Kang J. , Kim S. , Shin S. , Kim H. , Heo D. S. 
Published: August 2020

8066 Background: This study (D7913L00056) was designed to prospectively evaluate the efficacy and safety of first-line gefitinib treatment in pts with advanced pulmonary adenocarcinoma harboring EGFR mutations and to explore the molecular factors affecting the efficacy of gefitinib. Methods: Chemo-naïve pts with advanced (stage IIIB/IV/recurrent disease) pulmonary adenocarcinoma underwent direct DNA sequencing of tumor EGFR exons 18, 19 and 21. Pts with EGFR mutations received gefitinib 250 mg/d until disease progression or unacceptable toxicity. The primary end-point was objective response rate (ORR). The protocol planned to accrue 45 pts with EGFR mutations in a single stage. Results: Out of 147 screened pts, 45 pts (31%) had EGFR mutations and received gefitinib. The most common EGFR mutations were in-frame exon 19 deletions (del 19, 29 pts, 64%) and L858R point mutations in exon 21 (L858R, 15 pts, 33%). One patient had atypical mutation of L861Q in exon 21. The ORR by RECIST was 53.3% (95% CI, 38.8 to 67.9) and disease control rate (DCR) including stable disease was 86.7%. Progression free survival (PFS) at 12 months (mo) was 74.6% (95% CI, 58.8 to 85.1). Median PFS was not reached after median 10.1 mo follow-up. Treatment was well tolerated. Six pts experienced grade 3 toxicities including rash, pruritis, and anorexia. No grade 4 toxicities were reported. Subgroup analysis according to the EGFR mutation subtypes was carried out. The ORR and DCR were higher in pts with del 19 than those with L858R (62.1% vs 33.3%; P=0.0705 and 96.6% vs 66.7%; P=0.0062, respectively). All 4 pts with progressive disease had an L858R mutation. No secondary resistant mutations such as T790M were found in those pts. In addition, PFS at 12 mo was significantly better in pts with del 19 than those with L858R (63.2% vs 23.8%, P=0.0034). Conclusions: Gefitinib as the first-line treatment for Korean pts with advanced pulmonary adenocarcinoma harboring EGFR mutations was very effective and well tolerated. Subgroup analysis suggests that the benefit from gefitinib treatment was more prominent in pts with the del 19 mutation. [Table: see text]
A phase II trial of erlotinib monotherapy in pretreated patients (pts) with non-small cell lung cancer (NSCLC) who do not possess active EGFR mutations
Authors: Yoshioka H. , Hayashi H. , Kiura K. , Takigawa N. , Hotta K. , Harita S. , Kamei H. , Bessho A. , Tabata M. , Tanimoto M. 
Published: August 2020

8067 Background: Efficacy of gefitinib therapy strongly depends on the presence of active EGFR mutations in Asian NSCLC pts, with objective response rates (ORR) of 71.2% and only 1.1% in active mutant-positive (EGFRmt+) and -negative (EGFRmt-) tumors, respectively [Mok T, ESMO2008]. Recently, the survival advantage of erlotinib, another TKI, is observed even in pts with EGFRmt- tumors (HR=0.74, p=0.09 [Zhu C, JCO2008]), indicating such subpopulation might also benefit from this TKI. The aim of this trial was to evaluate its efficacy and toxicity in Japanese pts with relapsedEGFRmt- tumors. Methods: Primary endpoint was ORR. Patients with EGFRmt--NSCLC previously treated with one to three chemotherapy regimens were enrolled in this trial. The mutation status was assessed by the PCR clamp methods. Erlotinib was administered at a dose of 150mg/day until disease progression or unacceptable toxicities. Results: Thirty pts were enrolled between Jan and Dec 2008. Median duration of erlotinib treatment was 60 days. All pts were assessable for efficacy and safety. Demographics of the pts were as follows: M/F:24/6, Ad/others:20/10, ECOG-PS 0/1/2:7/19/4, and smoker/non-smoker:22/8. Platinum-based regimens were commonly used as the prior chemotherapy. Objective response was obtained in one pt (3.3%; RECIST). Seventeen pts obtained SD (56.7%). Toxicity profiles were almost tolerable with the treatment interruption in 11 pts (median duration; 10 days). Skin rash was common (grades 1, 2 and 3 in 7, 15, and 7 pts, respectively; NCI-CTCAE ver3). One pt developed grade 4 pulmonary embolism, but it seemed due to disease progression. Other 2 pts developed interstitial lung disease (grades 2 and 3 in one pt each). No treatment-related deaths (TRD) occurred. With a median follow-up time of 6.4 months, MST and MPFS time were 8.6 and 2.1 months, respectively. Conclusions: This is a first prospective biomarker study showing that erlotinib therapy for pretreated pts with EGFRmt- tumors seems as almost effective and safe as the standard docetaxel therapy (PR: 5.8%, SD: 42.7%, MST: 7.0 months, MTTP: 2.5 months and TRD: 4.9% [Shepherd JCO2000]). No significant financial relationships to disclose.
Incidence and outcomes associated with brain metastases (BM) in a three-arm phase III trial of gemcitabine in combination with carboplatin (GC) or paclitaxel (GP) versus paclitaxel plus carboplatin (PC) for advanced non-small cell lung cancer (NSCLC)
Authors: Edelman M. J. , Belani C. P. , Socinski M. A. , Ansari R. , Obasaju C. K. , Monberg M. J. , Chen R. , Treat J. 
Published: August 2020

8076 Background: A limited number of randomized phase III studies of advanced or metastatic NSCLC have included a mixed population of patients (pts) with and without BM at presentation. Analyses of pts with lung cancer from the 1970s and 1980s indicated that the incidence of BM at the time of diagnosis was approximately 10%. Methods: 1135 chemonaïve pts with stage IIIB or IV NSCLC were randomized to receive: G 1000 mg/m2 d 1, 8 plus C AUC 5.5 d 1; or G 1000 mg/m2 days 1 and 8 plus P 200 mg/m2 d 1; or P 225 mg/m2 plus C AUC 6.0 d 1. Stratification was based on stage, baseline weight loss, and presence or absence of BM. Cycles were repeated every 21 d up to 6 cycles or disease progression. Pts who developed BM as the only evidence of progression were able to be treated with whole brain radiation and steroids and remained on study. Results were retrospectively analyzed in by presence or absence of BM at study entry. Results: BM rates by subgroup were as follows (%): overall (17.1), nonsquamous (19.3), squamous (6.9), <70 y (21.3), ≥ 70 y (7.1), female (19.2), male (15.7), Caucasian (16.7), African American (18.8%), Hispanic (22.2), PS 0 (12.9), PS 1 (19.7), weight loss <5% (18.3), weight loss ≥ 5% (15.1), and stage IV (19.0). Among pts with (N=194) and without (N=941) BM, response rates=28.9% and 29.1%, median survival = 7.7 mos (95% CI: 6.7, 9.3) and 8.6 mos (95% CI: 7.9, 9.5), and median time to progression = 4.3 mos (95% CI: 3.4, 5.6) and 4.6 mos (95% CI: 4.2, 5.1), respectively. Rates of grade 3 or 4 adverse events were not different among pts with and without BM. Median survival among pts with BM was 7.6 mos for GC (N=66, 95% CI: 6.3, 10.1), 8.2 mos for GP (N=64, 95% CI: 4.6, 10.5), and 7.7 mos for PC (N=64, 95% CI: 6.1, 10.2). Conclusions: 1) The higher incidence of BM (17.1%) observed in this trial may be related to the increasing incidence of adenocarcinoma, or to the increasing sensitivity of imaging modalities. 2) There was no difference in response, time to progression or survival for pts with or w/o BM. [Table: see text]
Cost-effectiveness of zoledronic acid versus placebo in the management of skeletal metastases in lung cancer patients (LC pts): Comparison across three European countries
Authors: Stephens J. , Kaura S. , Botteman M. F. 
Published: August 2020

8081 Background: Zoledronic acid (ZOL) reduces the risk of skeletal-related events (SREs) in LC pts with bone metastases. The present retrospective analysis compared the economic impact of ZOL in LC pts in France, Germany, and the United Kingdom (UK). Methods: Estimated direct costs and quality-adjusted life-years (QALYs) experienced by LC pts with bone metastases receiving placebo (PBO) or ZOL were modeled and compared. Overall survival (OS), SRE incidence, and number of infusions administered were obtained from a 21-mo randomized clinical trial comparing the proportion of pts who experienced an on-study SRE with 4 mg ZOL or PBO every 3 wk (Rosen et al. JCO. 2003). Costs of treatments and SREs were estimated using national reimbursement listings (eg, diagnosis-related groups), private databases, and published literature. Mean number of SREs was calculated by multiplying mean SRE rate by OS for LC pts in the study. For QALYs, OS was multiplied by a utility factor of 0.53. Consistent with similar economic analyses, it was assumed that quality of life (QOL) decreased 20% to 80% (depending on the SRE type) for 1 mo after each SRE experienced. Sensitivity analyses were performed to test the effects of alternate scenarios, with < €30,000/QALY considered cost-effective. Results: During the median OS of 179 days, PBO pts (n = 120) experienced a mean of 2.07 SREs vs 1.32 SREs among ZOL pts (n = 124). QALYs were estimated at 0.352/pt (ZOL pts) and 0.335/pt (PBO pts). Use of ZOL resulted in a net increase of 0.017 QALY/pt vs PBO. ZOL drug-related costs were €1,610, €1,510 and €1,597 per pt in France, Germany, and the UK, respectively. Use of ZOL resulted in reductions in SRE costs of €2,221, €2,031, and €2,014 per pt, respectively. Overall, ZOL saved €598 per pt in France, €521 in Germany, and €417 in the UK. In sensitivity analyses, ZOL was cost-effective under a variety of scenarios (total range, -€98,356 to +€34,052 per QALY). Conclusions: ZOL leads to fewer SREs, better estimated QOL, and lower estimated costs relative to PBO in German, French, and UK LC pts with bone metastases. Use of ZOL in these populations is therefore cost-saving and highly cost-effective. [Table: see text]
Genetic and proteomic features associated with survival after treatment with erlotinib in first-line therapy of non-small cell lung cancer
Authors: Amann J. M. , Lee J. , Roder H. , Brahmer J. , Schiller J. , Carbone D. P. 
Published: August 2020

8089 Background: An improved understanding of molecular features of cancers and cancer patients associated with benefit from targeted therapies could allow the rational personalization of therapies to increase the probability of efficacy and decrease toxicity and cost. Multiple biomarkers have been proposed for predicting benefit after therapy with EGF receptor targeted therapies in first line colon and second line lung cancer therapy. Methods: In this study, we analyzed available tumor and serum samples from ECOG 3503, a single arm phase II study of erlotinib in first line lung cancer, for mutations in Kras and EGFR, as well as the previously described serum MALDI proteomic classifier (Veristrat). Out of 137 enrolled patients, there were 93 serum samples and 43 tumor samples available. Results: Molecular analysis of a subset of tumors from patients enrolled in ECOG 3503 shows that 10/43 (23%) contained Kras mutations and 3/43 (7%) harbored EGFR mutations. Classification of the 93 available sera for the pattern of proteins previously published as associated with survival after treatment with gefitinib identified 68/93 (73%) as predicted to be “good” and 25/93 (27%) predicted to have poor survival. Of the 6 responders with available serum, 5 were classified as MALDI good. Correlation with survival demonstrated a highly statistically significant correlation with MALDI status (p < 0.001), and a marginally significant association of EGFR mutation with survival (p = 0.05), but no correlation with ras mutation status. Median survival was 10.8 months in MALDI good patients and 3.9 in MALDI poor patients. MALDI status was independent of both ras and EGFR mutation status. Conclusions: Thus, in distinct contrast to colon cancer, ras gene mutations do not appear to be associated with survival after first line EGFR-targeted therapy in lung cancer. The previously defined MALDI predictor is potent and highly clinically significantly associated with survival after first line treatment with erlotinib, and is independent of mutations in ras and EGFR in this dataset. [Table: see text]