bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase IIb/III double-blind randomized trial of BIBW 2992, an irreversible, dual inhibitor of EGFR and HER2 plus best supportive care (BSC) versus placebo plus BSC in patients with NSCLC failing 1–2 lines of chemotherapy (CT) and erlotinib or gefitinib (LUX- Lung1): A preliminary report
Authors: Yang C. , Hirsh V. , Cadranel J. , Chen Y. , Park K. , Kim S. , Chao T. , Oberdick M. , Shahidi M. , Miller V. 
Published: August 2020

8062 Background: No approved therapy exists for NSCLC patients (pts) who have failed chemotherapy (CT) and the reversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), erlotinib (E) or gefitinib (G). The efficacy of BIBW 2992 (Tovok), a potent, irreversible inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2) with preclinical activity against the secondary resistance mutation T790M, in pts progressing after initial clinical benefit on E/G is being assessed in this randomized trial. Methods: Pts with advanced adenocarcinoma of the lung (Stage IIIB/IV; ECOG 0–2), who have failed one or two lines of CT (including platinum) and progressed following at least 12 weeks of E or G are randomized in a 2:1 ratio to receive BSC plus either oral BIBW 2992 50 mg qd or placebo until disease progression or unacceptable toxicity. Primary endpoint is overall survival, with progression-free survival, objective response and clinical benefit rate and duration, safety and quality of life being secondary endpoints. Enrollment of 400 pts is planned (HR=0.70, 85% power). An unblinded interim analysis of tumor response and safety by the independent Data Monitoring Committee (DMC) after the first 40 evaluable pts treated with BIBW 2992 will determine continuation to full accrual. Results: From May to November 2008, 145 pts have been randomized and 76 are still on treatment. Demographics (n=145): median age 59 (range: 30–82); female 68%, current/ex-smokers 38%; metastatic disease 91%, ECOG 0–1 92%; Asian origin 68%. 50% had one prior line of CT. Main prior EGFR-TKI was G in Asians (70%) and E in non-Asians (85%). 40% of pts had achieved a PR or CR on previous treatment with E/G. Duration of prior E/G treatment was >24 weeks and >48 weeks in 80% and 40% of pts, respectively. As expected, diarrhea, rash, anorexia, stomatitis, paronychia, nausea and vomiting were the most frequently observed adverse events. Conclusions: The trial is continuing recruitment after DMC review of efficacy and safety and updated demographics and blinded safety data will be reported. [Table: see text]
Efficacy and safety of PF-00299804 (PF299) in patients (pt) with advanced NSCLC after failure of at least one prior chemotherapy regimen and prior treatment with erlotinib (E): A two-arm, phase II trial
Authors: Janne P. A. , Reckamp K. , Koczywas M. , Engelman J. A. , Camidge D. R. , Rajan A. , Khuri F. , Liang J. Q. , O'Connell J. , Giaccone G. 
Published: August 2020

8063 Background: Options are limited for pts with NSCLC following chemotherapy and E. PF299 is an oral irreversible small molecule inhibitor of the HER-1,-2, and -4 tyrosine kinases. Based on non-clinical and phase I NSCLC data, this ongoing phase II U.S. trial evaluates PF299 in pts with NSCLC (KRAS wild-type) who have progressive disease after at least 1 prior chemotherapy regimen and after E. Methods: Pts were enrolled by histology: adenocarcinoma (Arm A) and non-adenocarcinoma (Arm B), and received PF299 45 mg QD. Endpoints include objective response rate, duration of response, progression-free survival, survival, safety/tolerability, and pharmacokinetics. Pharmacodynamic endpoints include assessment of serum levels of HER2 and EGFR extracellular domains. Tissue and blood KRAS assays, and EGFR studies on available tissue, are also being performed. Forty-four and 22 response-evaluable pts were planned to be enrolled into Arms A and B respectively. Results: Thirty-four pts with progressive NSCLC (25 female, 14 smoker) have enrolled to date (Arm A: 30; Arm B: 4): median duration of prior E: 11.5 months; median time since E: 2.5 months. Among 20 response-evaluable pts, stable disease (SD) was observed in 9/18 pts in Arm A, and 1/2 pts in Arm B: median duration of SD: 11.5 weeks [range 6+, 32+ weeks]. Observation of disease control included pts who had recently (≤8 weeks) discontinued E; and also pts whose tumor had known EGFR T790M mutations. At time of data cutoff, confirmation per RECIST of 2 partial responses is pending. The most common treatment-related AEs were skin and gastrointestinal disorders, with grade 3 AEs in 19% and 13% of pts, respectively. Two pts experienced grade 4 pulmonary embolus/dyspnea deemed possibly treatment-related, both in the setting of progressive disease. Conclusions: PF299 shows encouraging activity in NSCLC pts after failure of prior chemotherapy and E. The AE profile was predictable and consistent with the prior phase I trial. At submission, enrollment in the adenocarcinoma arm is complete and enrollment in the non-adenocarcinoma arm continues; updated efficacy data and tumor characterization will be presented. [Table: see text]
Phase II trial of erlotinib in chemotherapy-naive women with advanced pulmonary adenocarcinoma
Authors: Jackman D. M. , Cioffredi L. , Lindeman N. I. , Morse L. K. , Lucca J. , Weckstein D. , Huberman M. S. , Lynch T. J. , Johnson B. E. , Janne P. A. 
Published: August 2020

8065 Background: This single-arm phase II study explored the role of clinical characteristics (female gender, adenocarcinoma histology, no tobacco within 1 year) in selecting pts for 1st-line therapy w/ erlotinib. Available tissue for EGFR mutation analysis was required to assess its impact on outcomes. Methods: Eligible pts were chemotherapy-naïve women, stage IIIB/ IV, PS 0–2, adenocarcinoma, and w/ available tissue for analysis of EGFR mutation status. Pts received erlotinib 150 mg PO daily until disease progression or unacceptable toxicity. Primary endpoint was response rate (RR). Secondary endpoints included toxicity, time to progression (TTP), overall survival (OS), and impact of EGFR genotype on clinical outcomes. Results: From 11/04 - 12/08, 84 pts were treated. Median age 68 (range 34–88); 59 PS 0, 24 PS 1, 1 PS 2; race: 79 white, 3 Asian, 2 black; 16 pts had BAC or predominant BAC features; smoking status: 35 never, 49 former. Tox: Rash (90%; 21% grade 3) and diarrhea (69%; 7% grade 3) were the most common toxicities. 32 pts developed toxicity grade 3+ felt likely related to erlotinib. 2 deaths may be treatment-related (1 DIC, 1 hepatic failure). There were also 3 pts w/ PE's (1 fatal). Efficacy: Response (n=84): 0 CR, 27 PR (RR 32%), 27 SD, 23 PD. 7 pts not evaluable (5 tox, 1 non-progression death, 1 withdrawn consent). Median TTP was 5.6 months (95% CI 4.1–7.4 mos), and median OS was 22.7 months (95% CI 15.8 - 26.0 mos). At the time of analysis, there were 36 deaths, 16 pts on treatment w/o progression, and 5 pts lost to follow-up. Compared to smokers, never-smokers trended toward improved RR (43% vs 22%, p=.06), w/ improved TTP (HR .59; 95%CI .36-.96) but no improvement in OS (HR 1.15, 95%CI .58–2.27). Genotype had a more obvious impact on outcomes: compared w/ 37 known wild-type EGFR, 33 pts w/ known sensitizing mutations had a higher response rate (70% vs 0), and significantly improved hazard ratios for both TTP (.20, 95%CI .11-.36) and OS (.36, 95% CI .18 - .73). Results will be updated and outcomes for rarer mutations will be reported. Conclusions: Clinical characteristics may help select appropriate pts for first-line erlotinib when EGFR mutation status is unavailable. However, when available, EGFR genotype is superior to clinical phenotype in selecting pts for first-line erlotinib. [Table: see text]
Molecular bases for sensitivity to figitumumab (CP-751,871) in NSCLC
Authors: Gualberto A. , Dolled-Filhart M. P. , Hixon M. L. , Christensen J. , Rimm D. L. , Lee A. V. , Wang Y. , Pollak M. , Paz-Ares L. G. , Karp D. D. 
Published: August 2020

8091 Background: Signaling of Insulin like Growth Factors (IGFs) through the IGF type 1 receptor (IGF-IR) induces tumor resistance to cancer therapy. Bioavailability of IGFs is regulated by IGF-binding proteins (IGFBP), of which IGFBP3 is the most abundant. Figitumumab (F) (CP-751,871), a specific IGF-IR inhibitor, has shown phase 2 activity in NSCLC in some histologies (i.e., squamous cell and adenocarcinoma) but not others (i.e, large cell or NOS tumors). Methods: Protein expression of members of the IGF-IR pathway, EGFR and differentiation markers was determined in core biopsies from 230 NSCLC pts, including 52 pts enrolled in F trials. Plasma concentration of IGF-1 and related proteins was determined in 159 NSCLC pts in F trials. Gene expression profiling was conducted in 35 NSCLC cell lines treated with F. Results: Squamous NSCLC had the highest IGF-IR expression (p=0.057). An association with better outcome was seen for E-cadherin expression (HR =0.62, 0.46–0.82 95% CI, p=0.005) and clustering by E-cadherin levels revealed a strong correlation between IGF-IR and EGFR expression in the high E-cadherin group (p<0.001). This subset included 73% of the squamous cell tumors investigated (N=44). Plasma levels of free IGF-1 (fIGF-1) were low and not predictive of response in squamous cell. In contrast, pts with adenocarcinoma had high plasma fIGF-1 levels (p=0.06) that correlated with vimentin expression (Rho=0.732, p=0.06), and both fIGF-1 and vimentin were predictive of F clinical benefit (p=0.03). Large cell/NOS NSCLC expressed the highest levels of vimentin (p<0.001) but had low E-cadherin and IGF-IR expression and low fIGF-1 plasma levels. Analysis of anchorage independent growth in NSCLC cell lines confirmed that F activity is independently associated to IGF-IR overexpression (p=0.02) and IGFBP3 under-expression (p=0.009). Conclusions: IGF-IR overexpression and increased free IGFs/low IGFBP are key independent mechanisms of sensitivity to F in NSCLC of squamous and adenocarcinoma cell histologies. [Table: see text] [Table: see text]
Expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507)
Authors: Gong Y. , Yao E. , Arcila M. , Frankel S. , Teruya-Feldstein J. , Zakowski M. , Thomas R. , Ladanyi M. , Pao W. 
Published: August 2020

8095 Background: The IGF-1R (IGF receptor type 1) pathway is frequently deregulated in human tumors and has become a target of interest for anti-cancer therapy. We investigated predictive biomarkers of response to an anti-IGF-1R antibody (Ab) in vitro in NSCLC. Methods: We examined the growth inhibitory effects of R1507, a fully-humanized IgG1 anti-IGF-1R monoclonal Ab (Roche), against a panel of 22 NSCLC cell lines using CellTiter Blue assays. Phospho-receptor tyrosine kinase (pRTK) arrays and ELISAs were used to determine the status of IGF-1R and other RTKs. SNP arrays were used to determine IGF-1R copy number. Immunohistochemical (IHC) staining of total IGF-1R was performed with G11 (an anti-total IGF-1R Ab; Ventana) on a tissue microarray (TMA) containing 77 independent NSCLC tumor samples. Staining intensity was scored on a scale of 0 to 3+ by a pathologist (JF). Results: 5 of 22 NSCLC cell lines were moderately sensitive (25–50% growth inhibition) to R1507 alone. ELISA and pRTK array analysis demonstrated that pIGF-1R levels in the presence or absence of serum did not correlate with drug sensitivity. However, 4 of 5 sensitive lines displayed high levels of total IGF-1R vs 1/17 resistant lines (p=0.003 Fisher's Exact). SNP array analysis showed that sensitive lines also harbor relatively higher copy numbers of IGF-1R. There was no correlation with EGFR/KRAS mutational status. 48% of TMA NSCLC tumors had scores of 2+ or greater, while 5% were scored as 3+. Addition of erlotinib or paclitaxel to R1507 led to further growth inhibition in sensitive but not resistant lines. In one EGFR mutant lung adenocarcinoma cell line, R1507 and erlotinib co-treatment induced apoptosis, whereas treatment with either drug alone induced only cell cycle arrest. Apoptosis was mediated, in part, by the survival-related AKT pathway, as pAKT was significantly downregulated by R1507 but not erlotinib. Conclusions: In NSCLC cell lines, high levels of total IGF-1R are associated with moderate sensitivity to R1507. These results suggest a possible enrichment strategy for clinical trials with anti-IGF-1R therapy. [Table: see text]
Tumor regression and pharmacodynamic (PD) biomarker validation in non-small cell lung cancer (NSCLC) patients treated with the ErbB/VEGFR inhibitor BMS-690514
Authors: Bahleda R. , Soria J. , Harbison C. , Park J. , Felip E. , Hanna N. , Laurie S. A. , Armand J. , Shepherd F. A. , Herbst R. 
Published: August 2020

8098 Background: BMS-690514 is an oral selective inhibitor of EGFR, HER2, and VEGFR1–3. Previous results from the phase I portion of this phase I/II study established 200 mg/day as safe and tolerable (ASCO 2008; abstr 2564). Methods: Erlotinib-naïve and erlotinib-resistant adult patients with advanced/metastatic, measurable NSCLC received BMS-690514 200 mg/d. Eligible patients had an ECOG PS ≤1 and adequate organ function. Objectives were to assess disease control rate (DCR; CR, PR, SD ≥4 months), safety, PK and potential predictive and PD biomarkers of BMS-690514. Response was assessed every 8 weeks (modified WHO criteria). Predictive biomarkers included EGFR copy number, and EGFR and KRAS mutations. PD biomarkers included immunohistochemistry of EGFR signaling proteins in skin biopsies, circulating sVEGFR2, blood pressure, skin rash and diarrhea. Results: For 60 patients treated, DCR were 11/28 (39%) and 7/32 (22%) for erlotinib-naive and -resistant patients, respectively. DCR was significantly higher among patients harboring an EGFR mutation (6/8) than those with WT EGFR (5/18). One erlotinib-naive patient had PR (57 wks) and subsequent surgical removal of remaining tumor. Regression (48%) was seen in one erlotinib-naive patient harboring a KRAS G13D mutation. One erlotinib-resistant patient had PR (66%, 31 wks). Two erlotinib-resistant patients with EGFR T790M mutations had SD with 6% and 31% decrease in tumor burden. Most frequent treatment-related AES were diarrhea (90%), skin rash (31%), asthenia (29%), anorexia (27%), hypertension (26%), and reversible acute renal insufficiency (11%). sVEGFR2 (14% decrease from baseline, n=14) and decreased pMAPK levels from skin biopsies (14 of 18 pts) were consistent with EGFR and VEGFR2 inhibition. Conclusions: BMS-690514 200 mg/d showed evidence of anti-tumor activity and disease control in patients with NSCLC, including erlotinib-resistant and those with WT EGFR, EGFR T790M or KRAS mutations. Predictive and PD clinical biomarkers confirmed inhibition of both EGFR and VEGFR signaling pathways by BMS-690514. A randomized phase II trial versus erlotinib in NSCLC is underway. [Table: see text]
Longitudinal evaluation of EGFR mutation in plasma for non-small cell lung cancer patients with front-line chemotherapy
Authors: Hua B. , Zhao J. , Wang S. H. , Yang L. , Duan J. C. , Wu M. N. , Wang J. 
Published: August 2020

8099 Background: To investigate longitudinally epidermal growth factor receptor (EGFR) mutation status in the plasma of pre- and post-chemotherapy for patients with advanced non-small cell lung cancer. Methods: Total of 153 advanced lung cancer patients were included in this study. Plasma samples in pre- and post-chemotherapy ( 2 cycles after) were collected. The DNA concentration was determined by real-time PCR. The EGFR exon 19 and 21 were amplified by mutant-enriched PCR and detected by denaturing high performance liquid chromatograph (DHPLC). The associations between EGFR mutation, DNA level and chemotherapeutic response were analyzed. Results: Among the 153 pts, EGFR mutation were detected 41.2% (63/153) and 27.4% (42/153) in plasma of pre-and post-chemotherapy, respectively. The objective response rate was 31.4% (48/153) and the circulating DNA level trend to decrease after chemotherapy in PR group but increase in PD group (p=0.012). 25 and 73 cases showed consistent EGFR mutation and wild-type status in pre-treatment and post-treatment plasma, respectively. Among 38 patients with change from pre-treatment EGFR mutant-type to post-treatment wild-type status, 11 gained PR, 12 SD and 15 PD. While for 17 patients with change from pre-treatment EGFR wild-type to post-treatment mutant-type, PR, SD and PD were 8, 7 and 2, respectively. The change to mutant-type in post-treatment plasma were found to be significantly higher in PR and disease control than PD(P=0.047, P=0.042). Conclusions: The data indicated that chemotherapy could not only affect the DNA concentration but also change the EGFR mutation detection in plasma for pts with advanced NSCLC. Reason for EGFR mutation change related with response of chemotherapy deserves further study. No significant financial relationships to disclose.
Topoisomerase II, carbonyl reductase I, and chemosensitivity for amrubicin in the treatment of patients with small-cell lung cancer
Authors: Seto T. , Yamanaka T. , Masuda N. , Eguchi K. , Takiguchi Y. , Okamoto H. , Ogura T. , Yokoyama A. , Ichinose Y. , Watanabe K. 
Published: August 2020

8104 Background: Amrubicin (AMR) has been suggested to provide a new effective therapeutic option for small-cell lung cancer (SCLC). It is a totally synthetic 9-aminoanthracyclin and converted by carbonyl reductase I (CBR-I) to its active form, amrubicinol, that has higher potent activity than the parent drug and inhibits purified human topoisomerase II (topo-II). We previously reported the promising result of a prospective phase II trial for AMR monotherapy in patients with second-line SCLC (Thoracic Oncology Research Group Study 0301). Using blood samples at enrollment in this trial, the clinical significance of topo-II and CBR-I expression levels on antitumor effect as well as toxicity has been examined. Methods: Total RNA was extracted from the blood with an RNeasy Mini Kit (Qiagen Inc.) and DNase treatment was performed using the RNase-Free DNase Set (Qiagen Inc.). RT-PCR analysis was performed using TaqMan technology. Quantification of target cDNA (Top-II alpha, CBR-I and beta-actin gene) was conducted using an ABI PRISM 7700 Sequence Detection System (Applied Biosystems Inc.). Quantification was performed using the relative standard curve method. Results: The trial registered a total of 60 patients, of which 40 blood samples were available. Nineteen patients achieved a CR or PR to AMR according to the RECIST assessment and 21 did not. Patients with tumor response had a significantly lower Topo-II level than those without (p=0.0465, Wilcoxon test), although there was no association between tumor response and the level of CBR-I (p=0.3229, Wilcoxon test). We did not find any significant association between the levels of the two enzymes and toxicity. Conclusions: Topo-II may be a potential predictor of response in the treatment of AMR for second-line SCLC. Further investigations in larger patient materials are warranted. No significant financial relationships to disclose.
Complete remissions with weekly dosing of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in a phase I dose-escalation study in patients with relapsed or refractory Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL)
Authors: Bartlett N. , Forero-Torres A. , Rosenblatt J. , Fanale M. , Horning S. J. , Thompson S. , Sievers E. L. , Kennedy D. A. 
Published: August 2020

8500 Background: A defining feature of HL and sALCL is CD30 expression on malignant cells. The ADC SGN-35 comprises an anti-CD30 antibody conjugated to the antitubulin agent monomethyl auristatin E (MMAE). SGN-35 causes cell cycle arrest and apoptosis by binding to CD30 on the tumor cell surface, internalizing, and releasing MMAE into the cell. In a previous phase 1 study with q3 wk dosing, 54% of pts achieved an objective response (CR/PR) at SGN-35 doses ≥1.2 mg/kg [ASH 2008 abstract 1006]. Methods: To assess if more frequent dosing might maximize anti-tumor activity with acceptable tolerability, a multicenter, phase 1, weekly dosing, dose-escalation study (3+3 design) was conducted in pts with refractory or recurrent HL or sALCL. SGN-35 was administered weekly at doses of 0.4–1 mg/kg (2-hr IV infusions). Pts with stable disease or better (Cheson 2007) after two 28-day cycles (6 doses) were eligible to continue SGN-35 treatment. Results: In 17 pts, median age was 38 yrs (range 25–67). Pts received a median of 4 prior therapies; 65% received an autologous SCT. MTD has not been defined. One related G3 event (diarrhea) and no related G4 events occurred. The most common related adverse events were G1/G2 rash, nausea, and peripheral neuropathy. Exposure to SGN-35 (AUC) increased relative to dose level. Multiple CRs were observed at higher doses ( table ); observed time to response in the 1 mg/kg dose group was approximately 8 wks. The 7 pts with CRs all remain on treatment. Enrollment to SGN-35 monotherapy continues at 1.2 mg/kg; combination therapy will be subsequently explored. Conclusions: SGN-35 was generally well tolerated and induced CRs in 7 of 8 evaluable pts at the two highest doses in heavily pretreated patients. Pivotal trials of this antibody-drug conjugate will initiate in early 2009. [Table: see text] [Table: see text]
A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin's lymphoma
Authors: Cunningham D. , Smith P. , Mouncey P. , Qian W. , Pocock C. , Ardeshna K. M. , Radford J. , Davies J. , McMillan A. , Linch D. 
Published: August 2020

8506 Background: The addition of rituximab to standard therapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP21) has resulted in improved survival outcomes in the treatment of diffuse large B-cell non-Hodgkin's lymphoma (DLBC NHL). In addition, the administration of CHOP as a 14 day cycle (CHOP14) has shown benefit over standard CHOP21 chemotherapy. This randomised study was designed to evaluate the toxicity and survival outcomes achieved with the addition of rituximab to CHOP14 (R-CHOP14), as compared to standard therapy (R-CHOP21) in newly diagnosed DLBC NHL. Methods: Patients were randomised to receive either eight cycles of standard R-CHOP21 or six cycles of R-CHOP14 (+ G-CSF) with two additional cycles of single agent rituximab. Randomisation was stratified by age (≤60 vs >60), WHO performance status (0–1 vs 2) and LDH level (normal vs raised). The primary endpoint is overall survival. The study was powered to detect an improvement in 2-year survival in the R-CHOP14 arm of 8% (70% to 78%) with 5% significance and 90% power (2-sided). Results: Recruitment is complete with 1080 patients randomised. Patient characteristics in the R-CHOP21 and R-CHOP14 arms are; IPI score of ≥4 17%:15%, stage III/IV disease 63%:62%, B symptoms 44%:47%, bulk disease 51%:48%. Median age is 61 years in both arms. 82% of patients in the R-CHOP21 arm completed study therapy as compared to 89% in the R-CHOP14 arm. Reported grade III/IV toxicities in the R-CHOP21 and R-CHOP14 arms are; neutropenia 57%:31%, thrombocytopenia 5%:9%, Infection 22%:17%, cardiac 1%:2%, nausea & vomiting 8%:8%, mucositis 2%:3%. The radiological complete response rate (CR/CRu) is 47% in both treatment arms. With a median follow-up 14 months 805 patients remain alive. Conclusions: Results indicate that R-CHOP14 can be delivered as effectively as R-CHOP21 with comparable levels of acute toxicity. Final analysis will be performed when 330 deaths have occurred. No significant financial relationships to disclose.