bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of erlotinib followed by chemotherapy on progression in an unselected population of advanced non-small cell lung cancer (NSCLC) patients.
Authors: Horn Leora , Li Chung-I , Pao William , Keedy Vicki Leigh , Johnson David H. , Carbone David P 
Published: March 2020

7568 Background: Erlotinib is now accepted as first line therapy for advanced NSCLC patients with EGFR mutated tumors. However, some patients with EGFR wild-type tumors may benefit as well, and there are no accepted biomarkers to define this subset of patients or to define which patients benefit from chemotherapy. We conducted a single arm phase II trial of erlotinib followed by chemotherapy on progression (carboplatin + paclitaxel +/- bevacizumab) in treatment naïve patients with stage IV NSCLC. Methods: In this multicenter prospective phase II trial, patients with stage IV NSCLC were eligible for enrollment. Blood, frozen tissue and FFPE biopsies for molecular analysis were mandatory at the time of study entry and optional at the time of progression on erlotinib. Additional eligibility included ECOG performance status (PS) 0-2, measurable disease, and adequate marrow, renal and hepatic function. Patients with stable treated brain metastases were allowed. Patients were treated with erlotinib 150 mg daily until disease progression at which time they underwent a biopsy and were switched to carboplatin/paclitaxel +/- bevacizumab. Disease status was assessed after 4 weeks of erlotinib to detect early progression. Results: From 10/07 to 06/11, 127 patients were enrolled: 59% male, 90% Caucasian, 6% African American, 4% Asian, 30% never smokers. 7 patients failed screening. Among evaluable patients on erlotinib, 13% had PR, 48% SD, and 27% PD. Median PFS on erlotinib was 4.7 months (95% CI 3.5 to 8.3 months). In patients who went on to receive chemotherapy on protocol, 24% had PR, 27% SD, and 20% PD. In patients who went on to receive chemotherapy on protocol median progression-free survival (PFS) on chemotherapy was 8.1 months (95% CI 5.5 to 10.9 months). Among the 55 patients who did not receive chemotherapy, 23 had a decline in PS, 14 patients refused, 2 patients enrolled on another protocol, and 6 patients had other therapy. Conclusions: This is the first study to report on PFS in unselected NSCLC patients following first line therapy with erlotinib. Translational studies on this large prospectively collected cohort of tissue samples prior to initiation of erlotinib are ongoing.
Correlation between thymidylate synthetase (TS) expression and progression-free survival (PFS) in patients receiving pemetrexed (pem) for advanced NSCLC: A prospective study.
Authors: Nicolson Marianne , Kerr Keith M , Shah Riyaz N.H. , Potter Vanessa , Upadhyay Sunil , Taylor Paul , Myrand Scott , Nuguyen Tuan Stevon , Das Mayukh , Fennell Dean Anthony 
Published: March 2020

7583 Background: Pem efficacy in non-squamous (NS) NSCLC is hypothesised to be associated with TS expression. Our primary objective was to assess the correlation between TS and PFS, prospectively. Methods: Context: A Phase II, single-arm, exploratory, multicenter, UK study with appropriate approvals and consents. Key eligibility criteria: ECOG PS 0-1, NS-NSCLC histology, stage IIIB/IV. Patients (n=70) received pem/cisplatin induction x 4. Non-progressive patients continued on maintenance pem until tumor progression or discontinuation. All patients were followed until death or study closure. TS by IHC (H-scores) and qPCR (delta CQ values normalized) were assessed on diagnostic FFPE samples. Kaplan-Meier estimates for median PFS (mPFS) and Cox regression to determine the statistical correlation between PFS and TS IHC nuclear score, (continuous variable) were performed. Maximal Chi-square analysis identified the optimal association cutpoints between PFS and low vs. high TS scores. Results: Patient demographics were unremarkable, 32/70 (45.7%) were female. 55 (78.6%) had adenocarcinoma; 15 were not otherwise specified. Maintenance pem was started in 43/70 (61.4%) patients. Evaluable patients had at least one dose of study treatment and a valid TS score (n=60). For the evaluable population, the mPFS from start of induction was 5.5 months (95% CI 3.9-6.9). A statistically significant correlation between PFS and TS IHC nuclear scores was observed [p<0.0001, HR= 1.01 (95% CI 1.01, 1.02)], suggesting higher TS values are associated with shorter PFS. When the population was dichotomized at the identified optimal H-score cutpoint of 70, the mPFS in the low expression group (n=40) was 7.1 months (5.7-8.3) compared to 2.6 months (1.3-4.1) in the high expression group (n=20) [adjusted p=0.0015, HR=0.28 (95% CI 0.16-0.52)]. Similar trends with cytoplasmic TS IHC (p=0.09) and TS qPCR (p=0.05) levels were observed. Statistical correlations were seen among the TS levels. Data is preliminary. Conclusions: Study suggests statistically significant association between low TS IHC nuclear expression and improved PFS in this Phase 2 single-arm trial.
Single nucleotide polymorphisms (SNPs) of the platinum pharmacogenetic and VEGF pathways: Association with survival of platinum-treated stage IV non-small cell lung cancer (NSCLC) patients.
Authors: Cuffe Sinead , Qiu Xiaoping , Azad Abul Kalam , Qiu Xin , Boyd Kevin , Kuang Qin , Marsh Sharon , Savas Sevtap , Emami Marjan , Perera Nicole , Palepu Prakruthi R. , Chen Zhuo , Patel Devalben , Cheng Dangxiao , Feld Ronald , Leighl Natasha B. , Shepherd Frances A. , Tsao Ming Sound , Xu Wei , Liu Geoffrey 
Published: March 2020

7586 Background: Two potentially important host pathways in lung cancer systemic therapy are: (i) the pharmacogenetic pathway of platinum agents (DNA repair, metabolism, and multidrug resistance genes); and (ii) the vascular endothelial growth factor (VEGF) pathway. We investigated the relationship between SNPs in these two pathways and clinical outcome in platinum-treated NSCLC patients. Methods: 188 platinum-treated Stage IV NSCLC patients underwent SNP genotyping for the platinum-related (48 SNPs in 7 genes) and VEGF (64 SNPs in 3 genes) pathways. SNPs were selected from the literature and through tagging. Association of SNPs and overall (OS) and progression free survival (PFS) were assessed using multivariate Cox proportional hazards models. Results: 72% were Caucasian; 73%, adenocarcinoma; 92%, ECOG PS 0-1; median age, 60 years; 54% received > one line of systemic therapy; 10% received anti-VEGF therapy/placebo; Median OS, 1.3 yrs; median follow up, 2.2 yrs. The top significant SNPs in the platinum-related pathway were in ABCC2 (rs8187710 and rs2756109, r2=0.68). The G variants of the top SNP, ABCC2 rs8187710 (4554G>A), were associated with worse OS (adjusted hazard ratio [aHR], 2.62; 95%CI: 1.5-4.5; p=0.0005) and PFS (aHR, 1.97; 95%CI: 1.2-3.4; p=0.01). Functionally, 4554G>A impairs ATP-ase activity and is associated with higher cellular accumulation of ABCC2 substrates [PMID: 22027652]; furthermore, ABCC2 expression is associated with cisplatin resistance and clinical outcome in other cancers [PMID: 17145840]. Within the VEGF pathway, the top significant SNPs were in the same haplotype block of VEGFR1/FLT1 (rs1324057, rs7324547, r2=1.0): for rs1324057, the aHR for OS was 1.59 (95%CI 1.2-2.1); p=0.001; and the aHR for PFS, 1.48 (95%CI 1.1-1.9); p=0.004. VEGFR1/FLT1 rs7324547 has been associated with esophageal cancer risk [PMID: 21751195], but has not been assessed in lung cancer. Conclusions: SNPS of the VEGFR1 and ABCC2 genes are strongly associated with OS and PFS in this cohort of platinum-treated advanced NSCLC patients. Future studies should assess whether these are predictive or prognostic markers.
EML4-ALK-gene rearrangement comparative analysis in circulating tumor cells and in tumor tissue of patients with lung adenocarcinoma.
Authors: Ilie Marius , Long Elodie , Butori Catherine , Hofman Veronique , Coelle Celine , Mauro Virginie , Zahaf Katia , Marquette Charles Hugo , Mouroux Jerome , Paterlini-Brechot Patrizia , Hofman Paul 
Published: March 2020

7591 Background: The implementation of new theranostic biomarkers in Oncology is leading to impressive therapeutic improvements. In patients with lung cancer, the possibility to use Circulating Tumor Cells (CTCs) as a non-invasive theranostic approach is a clinically appealing challenge. Adenocarcinomas with EML4-ALK rearrangement are a new molecular subgroup of lung tumors with very good response to Crizotinib, an ALK inhibitor. We have thus aimed at developing an informative assay characterizing the ALK-gene status in CTCs isolated from patients with lung cancer. Methods: CTCs were isolated preoperatively using Isolation by Size of Epithelial Tumor cells method (ISET) from 65 patients with lung adenocarcinoma and blindly screened for ALK-gene status. ALK break-apart fluorescence in situ hybridization (FISH) (LSI ALK dual colour probes set) and immunochemistry using an anti-ALK antibody (5A4 clone) were blindly performed on CTCs and corresponding tumor tissues and results were compared. Results: Two patients consistently showed ALK-gene rearrangement and strong ALK protein expression in CTCs and corresponding tumor samples. Negative results (both ALK FISH and ALK immunochemistry) were found in CTCs and corresponding tumor samples from the other 63 patients. Conclusion: We have developed an approach allowing to characterize ALK-gene status in CTCs from patients with lung cancer and shown consistent results in CTC and tumor tissues. These preliminary results encourage larger studies and open new avenues for non-invasive, real-time, theranostic monitoring of cancer patients.
MIMEB: A phase II trial to evaluate FDG-PET/FLT-PET and DCE-MRI for early prediction of efficacy in patients with advanced non-small cell lung cancer treated with erlotinib and bevacizumab.
Authors: Scheffler Matthias , Bos Marc Christiaan Allardt , Sos Martin , Nogova Lucia , Mattonet Christian , Papachristou Irini , Kahraman Deniz , Kobe Carsten , Boellaard Ronald , Lammertsma Adriaan A. , Heukamp Lukas Carl , Büttner Reinhard , Elter Thomas , Toepelt Karin , Engel-Riedel Walburga , Stoelben Erich , Neumaier Bernd , Dietlein Markus , Zander Thomas , Wolf Juergen 
Published: March 2020

7603 Background: Since the introduction of targeted therapy into the treatment of NSCLC, molecular imaging tools gain in importance for assessment of pharmacodynamics, pharmacokinetics and prediction of therapeutic outcome. Tumor metabolism (by FDG-PET), proliferation (by FLT-PET), and vascularization (by DCE-MRI) can be noninvasively assessed to quantify the effects of targeted therapy on tumor biology. We set up a trial to evaluate the effects of combined erlotinib (E) and bevacizumab (B) treatment in patients with advanced non-squamous cell NSCLC and to identify prospectively patients who benefit from this combination. Methods: Patients with non-squamous NSCLC stage IV without prior systemic therapy received at least six weeks of combined E and B. FLT and FDG-PET scans as well as DCE-MRI-scans were performed at baseline, after 1 week of therapy and after 6 weeks of therapy. Standard uptake values of the PET scans and vascularization parameters of the DCE-MRI scans were analyzed and coregistrated. Tumor specimens were analysed within a network screening panel. The primary objective of this trial was to evaluate the accuracy of the imaging tools for early prediction of nonprogression and PFS and its association with molecular markers. Results: Of the 40 patients, all received FDG-PET analyses, whereas FLT-PET was performed in 38 patients and DCE-MRI in 36 patients. Median OS was 13.4 months, median PFS was 5.9 months. Until January 2012, tissue specimens from 25 patients have been genetically analysed. First results show that even patients with KRAS, PI3K and BRAF mutations profiting from the combination either by response or prolonged PFS could be identified by early imaging assessment. Conclusions: The efficacy of E +B in unselected patients with NSCLC was comparable with platinum-based chemotherapy. In order to identify imaging-based predictive biomarkers to identify the subpopulation of patients with pronounced benefit of this combination FDG-, FLT- PET and DCE–MRI were successfully implemented in the treatment plan. Results of the imaging analysis and the correlation with tissue-based biomarkers will be presented.
A phase III randomized intergroup trial (S0016) comparing CHOP plus rituximab with CHOP plus iodine-131-tositumomab for front-line treatment of follicular lymphoma: Results of subset analyses and a comparison of prognostic models.
Authors: Press Oliver W. , Unger Joseph M , LeBlanc Michael Leo , Rimsza Lisa M. , Friedberg Jonathan W. , Czuczman Myron Stefan , Kaminski Mark Stefan , Braziel Rita M , Spier Catherine M , Maloney David G. , Cheson Bruce D. , Miller Thomas P. , Fisher Richard I. ,   Southwest Oncology Group
Published: March 2020

8001 Background: Advanced follicular lymphomas (FL) are considered incurable with chemotherapy and there is no consensus on the best treatment. Outcomes are variable, but can be partially predicted by defined prognostic factors. SWOG and CALGB compared the safety and efficacy of 2 immunochemotherapy regimens in a Phase III trial enrolling 554 patients between 3/1/2001 and 9/15/2008. Methods: Patients were eligible if they had bulky stage II, III or IV FL and had not received prior therapy. Patients randomized to CHOP-R received 6 cycles of CHOP every 21 days + 6 doses of rituximab. Patients randomized to CHOP-RIT received 6 cycles of CHOP, followed by consolidative radioimmunotherapy with tositumomab/iodine I-131 tositumomab. A Cox proportional hazards multi-variable regression analysis assessed the prognostic impact of age, stage, LDH, LN size and number, performance status, hemoglobin, β2 microglobulin, BM involvement, and B symptoms. The prognostic value of 3 multi-variable models were compared. Results: Outcomes were outstanding with either CHOP-R or CHOP-RIT (2 yr PFS: 76% vs 80% [ p =0.11]; 2 yr OS: 97% vs 93% [p =0.08], respectively). Subset analyses so far have not identified any subgroups clearly benefitting to a greater degree from CHOP-R or CHOP-RIT in terms of both PFS and OS. Cox multivariable regression analysis identified serum-β2M, LDH level, and FLIPI index as the strongest prognostic factors associated with worse PFS and OS. Conclusions: Both regimens produced outstanding PFS and OS, and no statistically significant differences between them were observed. FLIPI, FLIPI2, and LDH + β2M models were all strong predictors of patient outcomes. A combination of LDH + β2M was as good as the FLIPI index, and was simpler to apply. (Supported in part by NCI grants CA32102 and CA38926 from the NCI and GlaxoSmithKline.) [Table: see text]
Daratumumab, a CD38 mab, for the treatment of relapsed/refractory multiple myeloma patients: Preliminary efficacy data from a multicenter phase I/II study.
Authors: Plesner Torben , Lokhorst Henk M , Gimsing Peter , Nahi Hareth , Lisby Steen , Richardson Paul Gerard Guy 
Published: March 2020

8019 Background: Daratumumab (HuMax-CD38) is a human CD38 monoclonal antibody with broad-spectrum killing activity; it effectively kills CD38-expressing tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and apoptosis. From an ongoing first-in-human (FIH) dose-escalation study (ClinicalTrials.gov CT00574288), it has been shown that daratumumab has an acceptable safety profile (Gimsing: ASH 2011 abstract 1873). The objectives of this FIH study are to establish the safety profile and MTD. In addition efficacy is evaluated. Methods: Pts ≥18 years and previously diagnosed with MM requiring systemic therapy and considered relapsed or refractory (RR) to at least two different prior lines of therapy and not eligible for salvage ASCT were enrolled. The design of this study encompasses an accelerated dose-escalation based on a classical 3+3 design. Daratumumab is administrated over a 9 wk period encompassing 2 pre-doses and 7 full-doses. The doses range from 0.005 mg/kg to 24 mg/kg. The decision to dose escalate is based on recommendation by an external Independent Data Monitoring Committee. Evaluation of efficacy data was according to Rajkumar (Blood 2011;117:4691-5). The results presented in this abstract are based on preliminary data analyzed before database lock. Results: Data from 23 pts including the 4 mg/kg group are collected. Preliminary efficacy evaluation is based on best paraprotein response as reflected by change in serum and/or urine M-component. For groups ≤ 1 mg/kg, 3/17 pts achieved a reduction in serum M-component (12%, 14%, 19%), in the 2 mg/kg group, 1/3 pts had a reduction in urine M-component (55%), and in the 4 mg/kg group, 3/3 pts had a reduction in the serum M-component of 49%, 55, and 64%, respectively. In the 4 mg/kg group a marked reduction in the percentage of plasma cells in the bone marrow was seen in all pts (80%, 89%, and 97%). The toxicity was manageable. Conclusions: Daratumumab treatment resulted in reductions in M-component and bone marrow plasma cells in pts with RR MM. Toxicity has been manageable. Additional data will be presented at the meeting.
Role of radiotherapy for elderly DLBCL patients in the rituximab (R) era: Final results of the RICOVER-60-no-rx study of the DSHNHL.
Authors: Held Gerhard , Murawski Niels , Ziepert Marita , Poeschel Viola , Zwick Carsten , Reiser Marcel , Wilhelm Sibylla , Gaska Tobias , Heike Michael , Schubert Joerg , Schmitz Norbert , Loeffler Markus , Ruebe Christian , Pfreundschuh Michael ,   German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Published: March 2020

8022 Background: 117/306 (38%) of the total of 1,222 elderly (61-80 y) DLBCL pts. treated in RICOVER-60 with 6xR-CHOP-14+2R were assigned to receive additional radiotherapy (Rx) to bulky disease (Pfreundschuh et al., Lancet Oncol. 2008). To study the relevance of Rx to bulky disease (Bx), 166 pts. were prospectively treated without Rx in the R-CHOP-14-noRx amendment of RICOVER-60. Methods: The outcome of 166 R-CHOP-14-noRx patients was compared with the 306 patients who had received 6xR-CHOP-14+2R plus radiotherapy to Bx (≥7.5 cm) in RICOVER-60. Methods: The outcome of 166 R-CHOP-14-noRx patients was compared with the 306 patients who had received 6xR-CHOP-14+2R plus radiotherapy to Bx (≥7.5 cm) in RICOVER-60. Results: 164/166 R-CHOP-noRx patients are evaluable (median observation: 39 mos). Patients in R-CHOP-noRx were older (71 vs. 69 y.; median; p=0.018), more frequently in advanced stages (60% vs. 50%; p=0.037), and with extranodal involvement (63% vs. 53%; p=0.024), while Bx was more frequent in R-CHOP-14-Rx (38% vs. 29%; p=0.038). Overall response to therapy, EFS and OS were similar in the two studies adjusting for the prognostic imbalances between the cohorts. Patients with Bx who received received additional radiotherapy to Bx in R-CHOP-14-Rx had a better 3-year EFS (80% vs. 54%; p=0.001), a better PFS (88% vs. 62%; p<0.001), and a better OS (90% vs. 65%; p=0.001) compared to R-CHOP-14-noRx. This was due the worse outcome of pts. with Bx in R-CHOP-14-noRx not achieving CR or CRu after 6xR-CHOP, since there was no difference in 3-year EFS in patients with Bx in CR or CRu after 6xR-CHOP-14 with and without additional radiotherapy (3-year EFS and PFS: 84% vs. 75%; p=0.430); OS 87% vs. 79%; p=0.839). Conclusions: In the R era, radiotherapy to bulky disease does not improve the outcome of elderly pts. in CR/CRu after completion of R-CHOP-14 immunochemotherapy, but appears to be beneficial for pts. with Bx not achieving CR/Cru. By restricting Bx radiotherapy to patients not achieving a CR/CRu, 43% of the patients with Bx could be spared radiotherapy. Supported by Deutsche Krebshilfe.
Oral weekly MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): A phase I/II study.
Authors: Richardson Paul Gerard Guy , Berdeja Jesus G. , Niesvizky Ruben , Lonial Sagar , Roy Vivek , Hari Parameswaran , Berg Deborah , Liu Guohui , Gupta Neeraj , Di Bacco Alessandra , Hui Ai-Min , Kumar Shaji 
Published: March 2020

8033 Background: MLN9708 is an oral, reversible 20S proteasome inhibitor. The feasibility of combining a proteasome inhibitor with an immunomodulatory drug and a steroid in previously untreated MM has been demonstrated with the RVD regimen. This is the first study of MLN9708 in combination with lenalidomide and dexamethasone (NCT01217957). Here we report the phase (Ph) 1 MTD and preliminary Ph 2 results. Methods: Pts with previously untreated MM, aged ≥18 yrs with measurable disease received oral MLN9708 (phase 1: 1.68–3.95 mg/m2) days 1, 8, and 15, lenalidomide 25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15, and 22, for up to twelve 28-day cycles. Primary objectives were determination of safety, MTD, and recommended phase 2 dose (RP2D) (Ph 1), and CR+VGPR rate (Ph 2). Results: At data cut-off (Dec 1, 2011), 29 pts had been enrolled (15 Ph 1, 14 Ph 2). Median age was 64 yrs (range 40–82); 69% ISS stage II/III. In Ph 1, the MLN9708 MTD was determined as 2.97 mg/m2 and the RP2D as 2.23 mg/m2; for Ph 2, the RP2D was converted to a 4.0 mg fixed dose based on population PK results. Ph 1 pts have received a median of 6 treatment cycles (range 1–11), 8 received ≥6 cycles; 6 stopped to receive ASCT, 7 are ongoing. Ph 2 pts received a median of 1 (range 1–2), all are ongoing. Grade ≥3 hematologic toxicity was reversible and included anemia (n=2) and thrombocytopenia (n=1). Grade ≥3 nonhematologic toxicity included erythematous rash, syncope, and vomiting (2 pts each). All-grade drug-related peripheral neuropathy was seen in 6 pts (21%), including grade 2 with pain in 2 (both Ph 1 at doses above the MTD). Two pts discontinued due to AE; there were 5 pts who had serious drug-related AE (all Ph 1). Of 19 response-evaluable pts (Ph 1 + Ph 2), all achieved ≥PR, including 5 CR (1 sCR), 4 VGPR, and 10 PR; all remain in response with duration of confirmed response of up to 9.5 months. Of 4 response-evaluable Ph 2 pts, 1 has achieved VGPR and 3 PR to date. Conclusions: Oral MLN9708 plus lenalidomide and dexamethasone appears well tolerated with manageable toxicity. These data show antitumor activity at the RP2D in pts with previously untreated MM, with ≥PR in all pts to date.