bluuebunny/crossref_metadata_2025 huggingface dataset:
Vandetanib versus erlotinib in patients with advanced non-small cell lung cancer (NSCLC) after failure of at least one prior cytotoxic chemotherapy: A randomized, double-blind phase III trial (ZEST)
Authors: Natale R. B. , Thongprasert S. , Greco F. A. , Thomas M. , Tsai C. M. , Sunpaweravong P. , Ferry D. , Langmuir P. , Rowbottom J. A. , Goss G. D.
Published: August 2020

8009

Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. This phase III study compared the efficacy of vandetanib vs erlotinib in patients (pts) with advanced, previously treated NSCLC. Methods: Eligible pts (stage IIIB/IV NSCLC, PS 0–2, 1–2 prior chemotherapies; all histologies permitted) were randomized 1:1 to receive vandetanib 300 mg/day or erlotinib 150 mg/day until progression/toxicity. The primary objective was to show superiority in progression-free survival (PFS) for vandetanib vs erlotinib. Secondary endpoints included overall survival (OS), objective response rate (ORR), time to deterioration of symptoms (TDS; EORTC QoL Questionnaire) and safety. Results: Between Oct 06-Nov 07, 1240 pts (mean age 61 yrs; 38% female; 22% squamous) were randomized to receive vandetanib (n=623) or erlotinib (n=617). Baseline characteristics were similar in both arms. Median duration of follow-up was 14 months, with 88% pts progressed and 67% dead. There was no difference in PFS for pts treated with vandetanib vs erlotinib (hazard ratio [HR] 0.98, 95.22% CI 0.87–1.10; P=0.721), and no difference in the secondary endpoints of OS (HR 1.01, 95.08% CI 0.89–1.16; P=0.830), ORR (both 12%) and TDS (pain: HR 0.92, P=0.289; dyspnea: HR 1.07, P=0.407; cough: HR 0.94, P=0.455). A preplanned non-inferiority analysis for PFS and OS demonstrated equivalent efficacy for vandetanib and erlotinib. The adverse events (AEs) observed for vandetanib were generally consistent with previous NSCLC studies with vandetanib 300 mg. There was a higher incidence of some AEs (any grade) with vandetanib vs erlotinib, including diarrhea (50% vs 38%) and hypertension (16% vs 2%); rash was more frequent with erlotinib (38% vs 28%). The overall incidence of CTCAE grade ≥3 AEs was also higher with vandetanib (50% vs 40%). The incidence of protocol-defined QTc prolongation in the vandetanib arm was 5%. Conclusions: The study did not meet its primary objective of demonstrating PFS prolongation with vandetanib vs erlotinib in pts with previously treated advanced NSCLC. However, vandetanib and erlotinib showed equivalent efficacy for PFS and OS in a preplanned non-inferiority analysis.

[Table: see text]
S0536: Carboplatin, paclitaxel, cetuximab, and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small cell lung cancer (NSCLC): A SWOG phase II study
Authors: Gandara D. , Kim E. S. , Herbst R. S. , Moon J. , Redman M. W. , Dakhil S. R. , Hirsch F. , Mack P. C. , Franklin W. , Kelly K.
Published: August 2020

8015

Background: Cetuximab (CX) plus platinum-based chemotherapy improves overall survival (OS) in advanced NSCLC (FLEX). SWOG previously showed that EGFR FISH is associated with efficacy outcomes in patients (pts) receiving CB/P/CX (S0342). Bevacizumab (B) plus chemotherapy also increases survival (E4599) in eligible pts. Given the biologic rationale for combining EGFR and VEGFR targeted agents, S0536 investigated the safety and efficacy of carboplatin (CB), paclitaxel (P) and CX plus B. Methods: Eligibility: treatment-naïve advanced stage non-squamous cell NSCLC, no requirement for EGFR positivity, PS 0–1, no brain metastases or hemoptysis. Treatment: CB AUC 6, P 200 mg/m2, B 15 mg/kg IV day 1 every 3 weeks, CX 400 mg/m2 day 1 then 250 mg/m2 weekly for up to 6 cycles; then B 15 mg/kg every 3 weeks and CX 250 mg/m2 weekly until progression. Primary endpoint: feasibility defined by the frequency and severity of ≥grade 4 hemorrhagic toxicities. Secondary endpoints: response rate, progression-free survival (PFS), OS and toxicity. Results: 110 pts enrolled from August 2006 to September 2007; 104 assessable. Pt characteristics: median age 64 years (42–78), Male/Female 52/52, PS 0/1 43/61, stage IIIB/IV 9/95, adenocarcinoma: 81, current/former smoker: 82. Overall toxicities were acceptable and comparable to S0342 and E4599. Primary endpoint was met: grade ≥4 hemorrhage: 2% (95% CI: 0–7%). There were 4 treatment-related deaths: lung hemorrhage (2), infection (1), unknown (1). Partial response (PR): 51/95 assessable (54%; 43%-64%); Stable disease (SD): 22/95 (23%). Disease control rate (PR+SD): 77%. With median follow up of 15 months (mos), PFS is 7 mos (18 pts remain progression-free) and OS is 14 mos. 1 year survival is 57% (47–67%). EGFR IHC by H score (>0 vs 0) showed a nonsignificant trend toward improved survival: 15 vs 11 mos (p=0.14). Conclusions: CB/P, CX plus B demonstrates safety, tolerability and efficacy in advanced NSCLC and is the most active regimen studied to date in SWOG. Additional S0536 biomarker studies including EGFR FISH will be presented. S0819, a Phase III trial of CB/P ± CX (plus B in eligible pts) is under development and is designed to validate EGFR FISH as a predictive biomarker.

[Table: see text]
First-line gefitinib versus first-line chemotherapy by carboplatin (CBDCA) plus paclitaxel (TXL) in non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations: A phase III study (002) by North East Japan Gefitinib Study Group
Authors: Kobayashi K. , Inoue A. , Maemondo M. , Sugawara S. , Isobe H. , Oizumi S. , Saijo Y. , Gemma A. , Morita S. , Hagiwara K. , Nukiwa T.
Published: August 2020

8016

Background: Based on our promising results of phase II studies estimating gefitinib in NSCLC pts with sensitive EGFR mutations (JCO 2006, BJC 2006), this multicenter phase III trial compared progression free survival (PFS) of first line gefitinib versus first line chemotherapy in EGFR mutation positive pts with stage IIIB/IV NSCLC. Per protocol, an analysis for safety except response, PFS and overall survival were estimated. Methods: PNA-LNA PCR clamp test, which had been developed and validated by us (Cancer Res 2005, Cancer Sci 2007), was employed to detect EGFR mutations using cytological samples or histological samples. Pts having sensitive EGFR mutations, measurable site(s), ECOG PS 0–1, age of 20–75 years, and no prior chemotherapy were randomized (1:1 ratio; balanced for institution, sex, and stage) to receive Arm A: gefitinb (250 mg/ day) orally, or Arms B: CBDCA AUC 6 and TXL 200mg/m2 in 21-day cycles until disease progression. The primary endpoint was PFS, and the sample size was calculated to be 320 in total (alpha=5%, power=80%) to confirm the superiority of Arm A (hazard ratio = 0.69). Results: From April 2006 to July 2008, 155 pts were enrolled (Arm A=80; Arm B=75). Their characteristics were well balanced between arms: median age=65 years; 64% female; 77% Stage IV; 93% adenocarcinoma, 61% non-smoker. There were several differences in toxicities between Arm A and Arm B (grade 4 neutropenia: 1% vs. 29%, grade 3–4 liver dysfunction: 24% vs. 1%, grade 3 neuropathy: 0% vs. 5%, respectively, p<0.01). But these were tolerable in both arms. Furthermore, there were no interstitial lung disease and no toxic deaths in both arms. Analyzing both arms together, preliminary response rate and PFS of the 155 pts were 53.7% and 6.5 mos, respectively. Conclusions: This is the first prospective study to compare first line gefitinib with first line chemotherapy for advanced NSCLC pts harboring EGFR mutations. Due to acceptable toxicities, the independent safety committee decided to continue this study further. At the end of 2008, 200 pts have been entered to this study, and, per protocol, an interim analysis to investigate PFS will be performed in May 2009.

No significant financial relationships to disclose.
A phase II study of erlotinib and sorafenib in chemotherapy-naive patients with locally advanced/metastatic non-small cell lung cancer (NSCLC)
Authors: Lind J. S. , Dingemans A. C. , Groen H. J. , Smit E. F.
Published: August 2020

8018

Background: This multicentre, phase II study evaluates efficacy and safety of erlotinib, an EGFR inhibitor, and sorafenib, a multi-kinase inhibitor, in advanced NSCLC. In addition circulating endothelial cell (CEC) numbers, plasma VEGF, tumor metabolic activity (18FDG-PET), and tumor blood flow (H215O-PET) were measured. Methods: Chemotherapy-naive patients (≥ 18 years; performance status 0–1) with pathologically proven irresectable stage IIIB or IV NSCLC were eligible. Pts received erlotinib (150 mg/od) and sorafenib (400 mg/bd) until disease progression or unacceptable toxicity. The planned sample size was 48. The primary endpoint was the rate of non-progression (NPR) at 6 weeks. Secondary endpoints: objective response rate (RECIST), time to progression (TTP), overall survival (OS) and adverse events (AEs). CECs, characterized by CD45neg/CD34bright, and plasma VEGF were measured in blood samples on days (D)0, 7, 21. 18FDG-PET and H215O-PET were performed on D0, 21. Results: 50 pts were enrolled: 22 females; median age 60 yrs (range 41–78); 30 PS 0; 37 stage IV; 34 adenocarcinoma; 11 never smokers; 10/33 EGFR mutations (exons 19 (n=5), 20 (n=1), 21 (n=4)); 3/33 K-Ras mutations. Median FU is 3.3 mo (range 0.2–10.8) with 20 pts on therapy. The NPR at 6 weeks was 76%: 13 PR, 25 SD, 8 PD, 4 NE. Median TTP is 4.6 mo (95% CI 2.6–6.6). Median OS has not been reached. Grade ≥ 3 AE: anorexia (n=1), acneiform rash (n=5), diarrhoea (n=6), fatigue (n=4), hand-foot skin reaction (n=6), nausea (n=2), oral mucositis (n=2), rash (n=5), vomiting (n=1) and fatal hemoptysis (n=1). Median CECs (n=24) and plasma VEGF (n=25) increased from 41cells/ml D0 to 124 D7 (p=0.001) to 148 D21 (p=0.000) and 44pg/ml D0 to 60 D7 (p= 0.024), respectively. 18FDG SUV (n=28) decreased by median 35% (p=0,000). 18FDG SUV decreased more in clinical (RECIST) responders than non-responders (-51% vs -18.5%, p=0.031). Tumor blood flow (n=14) decreased by median 11% (n.s). Relations of these biomarkers with TTP and survival will be provided. Conclusions: The combination of sorafenib and erlotinib is safe and has clinically significant anti-tumor activity in chemotherapy-naive patients with stage IIIB/IV NSCLC, with significant changes in CECs, VEGF, and metabolic tumor activity.

No significant financial relationships to disclose.
Final safety results of BO17704 (AVAiL): A phase III randomized study of first-line bevacizumab (Bv) and cisplatin/gemcitabine (CG) in patients (pts) with advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC)
Authors: Hirsh V. , Ramlau R. , von Pawel J. , Zatloukal P. , Vera G. , Leighl N. , Mezger J. , Archer V. , Reck M.
Published: August 2020

8039

Background: AVAiL, an international placebo-controlled phase III trial, showed that Bv-based therapy significantly improved PFS and response rate in patients with advanced/recurrent NSCLC. This report summarizes overall safety findings from AVAiL. Methods: AVAiL randomized 1,043 patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC to C 80mg/m2 (d1) and G 1,250mg/m2 (d1 and d8) q3w for up to 6 cycles plus either Bv 7.5mg/kg q3w (n=331 with safety data), Bv 15mg/kg q3w (n=329) or placebo (n=326). Bv/placebo was administered until disease progression. Primary endpoint was PFS; secondary endpoints included OS, response rate, and safety. Safety was measured using NCI-CTC version 3.0 criteria for adverse events (AEs). Results: At final analysis, the median/maximum duration of Bv therapy was 4.9/28.5 mo (Bv 7.5) and 4.3/23.4 mo (Bv 15). The most common AEs overall were hematological and gastrointestinal (GI), and occurred in similar proportions of pts in the Bv and placebo arms. Grade ≥3 AEs occurred in 80%, 83%, and 77% of pts in the Bv 7.5, Bv 15 and placebo arms, respectively. The most common grade ≥3 adverse events were hematological, mainly neutropenia and thrombocytopenia. Neutropenia was reported in 43% (Bv 7.5), 40% (Bv 15) and 34% (placebo) of pts. Grade ≥3 AEs of special interest included hypertension (7%, 9% and 2%), proteinuria (2%, 3% and 0%), bleeding (4%, 5% and 2%) and hemoptysis (0.5%, 1.2% and 1.3%). The incidence of grade 5 hemoptysis was low (0.9%, 0.9% and 0% of pts, respectively). The incidence of GI perforations (<1%), thromboembolic events (≤8%), CHF (≤1%) and wound healing complications (<1%) was low and similar between treatment arms. The incidence of serious AEs was 39%, 45% and 36% in the Bv 7.5, Bv 15 and placebo arms, respectively. No new safety signals were reported. Conclusions: After E4599, AVAiL further demonstrated the efficacy of Bv in combination with platinum-based chemotherapy in the treatment of advanced NSCLC. Final safety data confirm the well established and manageable safety profile of Bv-based therapy in pts with advanced NSCLC.

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A phase II study of the halichondrin B analog, E7389, in patients (pts) with advanced non-small cell lung cancer (NSCLC) previously treated with a taxane. A California Consortium/University of Pittsburgh/University of Chicago NCI/CTEP sponsored trial
Authors: Gitlitz B. J. , Davies A. M. , Belani C. P. , Argiris A. , Ramalingam S. S. , Hoffman P. C. , Koczwas M. , Groshen S. G. , Gandara D. R.
Published: August 2020

8056

Background: E7389 is a structurally simplified synthetic macrocyclic ketone analog of halichondrin B and has a unique mechanism of microtubule binding and interaction, distinct from other agents in this class. Thus, it was our hypothesis that pts with prior taxane based therapy would respond to this agent. We conducted a phase II trial of E7389 in prior taxane-treated NSCLC pts. Methods: Eligible pts included: histologically confirmed advanced NSCLC, previous treatment with platinum-based therapy and a taxane, no more than 2 prior regimens, measurable disease, Zubrod performance status ≤ 2. Pts were classified by taxane-sensitivity status: taxane sensitive (TS) (progression >90 days after taxane) or taxane resistant (TR) (progression during or ≤90 days after taxane). Treatment: E7389 1.4 mg/m2 intravenously over 1–2 minutes on day 1 and 8 of a 21 day schedule until disease progression or unacceptable toxicity. Results: 41 pts were entered. There were 3 (15%) objective responses (7.2+, 8.5+, 10.6 mo) of 20 TS pts; and no response of 21 TR pts. Stable disease rate was 60% and 24% in TS and TR pts. respectively. Median progression free survival (PFS) is 6.3 mos TS pts. 95%CI (2.5–8.6 mos) and 1.2 mos TR pts. 95%CI (1.1–4.1 mos). Median number of cycles (range): TS 4 (1–14); TR 2 (1–7). Major toxicity included: 19 pts (46%) with grade 3 or 4 hematologic toxicity including only 1 episode of febrile neutropenia and 8 pts (20%) with grade 3 or 4 non-hematologic toxicity attributable to drug including: fatigue (1), dehydration (2), nausea (2), constipation (2). Only 1 pt developed grade 3 neuropathy (course 9). Conclusions: E7389 was well tolerated with encouraging objective response, PFS and disease control rate in the TS cohort. This cohort will be expanded, using a 2-stage design, to accrue up to another 25 pts.

No significant financial relationships to disclose.
Dermatologic infections complicating epidermal growth factor receptor inhibitor (EGFRI) therapy in lung cancer patients
Authors: Eilers R. , Gandhi M. , Patel J. , Agulnik M. , Hensing T. , Lacouture M.
Published: August 2020

8070

Background: Epidermal growth factor receptor inhibitors (EGFRIs) have shown benefit in solid tumors including non-small cell lung cancers. Despite these benefits, dermatologic toxicities are reported to affect 75–87% of those treated. These toxicities impact quality of life, and may also have implications for dose modification and tumor response. This study investigates the prevalence of infections complicating dermatologic toxicities to EGFRIs in lung cancer patients. Methods: Retrospective chart review methods were employed to analyze 90 lung cancer patients treated in the Skin and Eye Reactions to Inhibitors of EGFR and Kinases (SERIES) clinic. Cultures, biopsies, and viral stains were analyzed for pathogens and sensitivities. Selection criteria included patients treated with cetuximab or erlotinib at the time of referral. Selection was limited to initial patients and their follow-up visits in the time frame of August 2007 to June 2008. The study was approved by the institutional review board. Results: Thirty (33.3%) of 90 lung cancer patients had evidence of infection at sites of dermatologic toxicity. Twenty three (25.5%) patients were positive for bacterial infection. Six of these 23 patients had concomitant fungal or viral infection. Twenty (22.2%) patients cultured positive for Staphylococcus aureus. Of the patients with Staphylococcus aureus infections, 2 (2.2%) had tetracycline-resistant Staphylococcus aureus, 2 (2.2%) had Methicillin-resistant Staphylocccus aureus (MRSA), and 1 (1.1%) had tetracycline-resistant MRSA. Fifteen of the 23 bacterial infections were localized to the seborrheic region. Three (3.3%) patients had viral infections alone and 4 (4.4%) had fungal infections alone. All of the infected patients were followed to clinical resolution. Conclusions: The data suggests that lung cancer patients treated with EGFRIs have a high prevalence of cutaneous infections. Most notably, bacterial infections developed at anatomical sites previously affected by dermatologic toxicities. Proper recognition and management of these infections by clinicians is critical for maintaining antineoplastic dose therapy, dose intensity, quality of life, and dermatologic health in lung cancer patients treated with EGFRIs.

[Table: see text]
Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive care (BSC) following first-line platinum-based therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Zatloukal P. , Heo D. S. , Park K. , Kang J. , Butts C. , Bradford D. , Graziano S. , Huang B. , Healey D.
Published: August 2020

8071

Background: Pts diagnosed with advanced NSCLC with good performance status typically receive platinum-based chemotherapy; however, no approved maintenance therapy exists. Tremelimumab, a fully human anti-CTLA4 mAb, is associated with durable responses in some pts with metastatic melanoma. Methods: This open-label, randomized, multicenter, phase II clinical trial evaluating efficacy and safety of tremelimumab as maintenance therapy was conducted in pts with locally advanced or metastatic NSCLC with ECOG performance status ≤1. Pts treated with ≥4 cycles of first-line platinum-based therapy resulting in either stable disease (SD) or response per RECIST were eligible and were randomized 3–6 weeks after prior therapy. Pts received 15 mg/kg IV tremelimumab Q90D or BSC until disease progression. Primary endpoint was progression-free survival (PFS) at 3 months. Secondary endpoints included safety, objective response rate, and 1-year survival. Results: Eighty-seven pts received tremelimumab (n=44) or BSC (n=43). Nine (20.9%; 90% CI: 11.4%, 33.7%) pts receiving tremelimumab and 6 (14.3%; 90% CI: 6.4%, 26.3%) pts receiving BSC were progression free at 3 months. Among pts receiving tremelimumab, there were 2 (4.8%) partial responses and 7 (16.6%) SDs, compared with 0 and 6 (14.3%) pts receiving BSC, respectively. Treatment-related adverse events (AEs) were observed in 27 (61.4%) pts receiving tremelimumab and 3 (7.0%) receiving BSC. Nine pts (20.5%) receiving tremelimumab reported grade 3 or 4 AEs compared with 0 patients receiving BSC. The most common grade 3 or 4 AEs attributed to tremelimumab were diarrhea and colitis (n=4, 9.1%). Conclusions: In pts with advanced NSCLC and good performance status receiving platinum-based first-line therapy, single-agent tremelimumab was tolerable, with safety consistent with prior studies. Although PFS analysis did not demonstrate superiority of tremelimumab over BSC, the 4.8% objective response rate seen only in the investigational arm may support future combination studies. Analysis of 1-year survival is forthcoming.

[Table: see text]
ABT-869 in non-small cell lung cancer (NSCLC): Interim results
Authors: Tan E. , Salgia R. , Besse B. , Goss G. , Gandara D. R. , Hanna N. , Steinberg J. , Steinberg J. , Qian J. , Carlson D. M. , Soo R.
Published: August 2020

8074

Background: ABT-869 is a novel orally active, potent and specific inhibitor of vascular endothelial growth factor and platelet derived growth factor receptor tyrosine kinases. Methods: This ongoing, open-label, randomized, multicenter phase 2 trial of ABT-869 at 0.10 mg/kg daily (Arm A) and 0.25 mg/kg daily (Arm B) until progressive disease (PD) or intolerable toxicity, was initiated to assess antitumor activity and toxicity of ABT-869 in patients (pts) with NSCLC. Eligibility criteria included locally advanced or metastatic NSCLC; ≥ 1 prior systemic treatment, and ≥1 measurable lesion by RECIST criteria. The primary endpoint was the progression free (PF) rate at 16 wks. Secondary endpoints were objective response rate (ORR), time to progression (TTP), progression free survival (PFS) and overall survival (OS). CT scans were assessed by the investigator and centrally; central assessment results are provided. Results: 138 patients (pts) were enrolled from 08/07–10/08 from 27 centers with interim data available for 94 pts (Arm A, n=43; Arm B; n=51). Median age was 64 years and 62 years in Arm A and B respectively. For the interim analysis population (Arm A, n=24; Arm B, n=24), 16 (33.3%) pts were PF at 16 wks: 7 (29.2%) in Arm A and 9 (37.5%) in Arm B. The ORR in Arm A (n=30) was 0% and 7.3% in Arm B (n=41). The median TTP and median PFS were 110 and 109 days, and 112 days and 108 days in Arm A and B, respectively. The most common adverse events (AEs) in Arm A were fatigue (35%), nausea (21%), and anorexia (21%), and in Arm B were hypertension (51%), fatigue (51%), diarrhea (43%), anorexia (41%), nausea (31%), proteinuria (31%) and vomiting (26%). The most common grade 3/4 toxicities in the Arm A were fatigue (7%), ascites (5%), dehydration (5%), pleural effusion (5%), and in the Arm B were hypertension (23%), fatigue (8%), PPE syndrome (8%), dyspnoea (6%) and stomatitis (6%). Most AE's were mild/moderate and reversible with interruptions/dose reduction/or discontinuation of ABT-869. Conclusions: ABT-869 demonstrates an acceptable safety profile and appears to be active in NSCLC patients.

[Table: see text]
Improving survival for metastatic non-small cell lung cancer: A SEER database analysis from 1990 to 2005
Authors: Morgensztern D. , Waqar S. N. , Gao F. , Govindan R.
Published: August 2020

8078

Background: Treatment of metastatic non-small cell lung cancer (NSCLC) has evolved over the last decade with the increased use of third-generation chemotherapy agents, established benefits from second-line chemotherapy, and the development of targeted agents. We conducted a study to evaluate whether these treatment advances translated into improved survival in a large registry database. Methods: The Surveillance Epidemiology and End Results (SEER) registry was queried for patients with NSCLC stage IV, aged 21 or older, and diagnosed between 1990 and 2005. Overall Survival (OS) rates were estimated by the Kaplan-Meier method and compared using log-rank test. Cox proportional hazard model was fitted to evaluate whether the diagnostic period is an independent predictor for OS. Demographic variables included period of diagnosis (1990–1993 or P1, 1994–1997 or P2, 1998–2001 or P3, and 2002–2005 or P4), age, gender, race, and histology. Results: There were 127,816 patients meeting eligibility criteria. Median age at presentation was 67 and most patients were male (58%), white (81%), and had adenocarcinoma (39%). Although there was no significant differences in OS between periods 1 and 2 (p = 0.18), there was a significant improvement from periods 2 to 3 (p < 0.001) and 3 to 4 (p < 0.001). 1-y and 2-y OS increased from 13.2% and 4.5% respectively in P1 to 19.4% and 7.8% respectively in P4. Predictive factors for improved survival in multivariate analyses included diagnostic period (p < 0.001), younger age (p < 0.0001), female gender (p < 0.0001), and non-black race (p < 0.0001). After adjusting for demographic factors, there were no significant differences in OS between adenocarcinoma and squamous cell from P1 to P3 (1990–2001). However, P4 showed a significant increase in OS for adenocarcinoma compared with squamous cell (p = 0.02). Conclusions: There has been a significant improvement in OS for stage IV NSCLC over the last 8 years. The recent differences in outcomes based on histology observed in P4 may reflect the increased activity of newer therapies in adenocarcinoma compared with squamous cell, including gefitinib and erlotinib.

No significant financial relationships to disclose.
Biological and clinical prognostic factors in patients with advanced non-small-cell cancer (NSCLC) treated by erlotinib: Preliminary results of the ERMETIC cohort
Authors: Cadranel J. , Beau-Faller M. , Mauguen A. , Lizard S. , Madelaine J. , Lansiaux A. , Prétet J. , Madroszyk A. , Chouaid C. , Morin F.
Published: August 2020

8079

Background: Although it has been suggested that results of EGFR-IHC, EGFR-FISH and EGFR and KRAS mutations are predictive of EGFR-TKIs efficacy, they are not used in clinical practice. ERMETIC is a French NCI granted prospective study aiming to facilitate implementation of these biomarkers in France. Methods: After a preliminary phase of validation in 16 French centers, these biomarkers were studied in available tumor specimens collected from all consecutive NSCLC patients (pts) treated by erlotinib, for the first time. Patients were followed-up until progression or death. Demographic, clinical, pathological characteristics and biomarkers were studied by Cox model as predictors of progression free survival (PFS) and overall survival (OS). Results: 493 of the 530 enrolled pts between 02/07 and 03/08 are included in this analysis, among whom at least 357 (72%) tumor specimens were collected. 88% were Caucasians, 32% females; median age was 62 (33–93); 15% were never smoker, 67% former and 15% active. 18% were PS0, 51% PS1 and 31% PS2–3. 92% pts were metastatic and 66% had adenocarcinoma (ADC). Erlotinib (150 mg in 98% of pts) was given as first-, second- and third-or-more-line in 10, 45, 42% of pts, respectively. 94% of pts had received previous platin-based chemotherapy. With a 11.5 months (mo.) median of follow-up, PFS was 2.4 mo. and OS 5.6 mo., with a 30% 1-year OS. Clinical factors independently associated with shorter OS were: PS1 and PS2–3 (HR=1.79 and 4.3, p<.0001); histology other than ADC and squamous cell (HR=1.44 and 1.03, p=.05); 2 sites of metastasis and more (HR=1.60 and 1.82, p<.0001) and former and active smoking (HR=1.49 and 2.12, p=.002). In multivariate analysis, line of treatment was not prognostic. Conclusions: The study confirmed in a large cohort of advanced NSCLC treated by erlotinib the independent value of several prognostic factors. Prognostic values of EGFR-IHC, EGFR-FISH and EGFR and KRAS mutations will be reported at the meeting.

[Table: see text]
Association between triglyceride (TG) levels, other clinical characteristics, and outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with erlotinib and bexarotene
Authors: Dragnev K. H. , Cyrus J. C. , Rigas J. R. , DiSalvo W. M. , Dmitrovsky E.
Published: August 2020

8101

Background: Studies of the nonclassical retinoid bexarotene (B) alone or in combination with chemotherapy have revealed improved survival for a subset of NSCLC patients (pts) who developed hypertrigyceridemia despite treatment with antilipid agents. It is not known if a similar association exists when B is combined with a targeted agent. We have completed 2 trials of erlotinib (E), and B, in pts with advanced NSCLC showing minimal toxicities and evidence of clinical activity. In both trials atorvastatin was begun only after elevated TG were detected. This approach differed from other studies where statin therapy was initiated concurrently with B. Methods: E 150 mg and B 400 mg/m2 were administered daily orally to pts with stage IV NSCLC, mostly as third line or higher. Atorvastatin 20 mg was started for elevated fasting TG. The dose was increased to 40 mg if hypertriglyceridemia persisted, followed by the addition of fenofibrate and/or dose reductions of B to 300 mg/m2. TG levels assessed in the first 4 weeks were correlated with overall survival. The appearance of skin rash was documented. Results: Sixty-one pts with stage IV NSCLC were enrolled, 54% women and 72% with adenocarcinoma, 15% never smokers, 20% current smokers, 15% had prior anti-EGFR therapy. Median survival time (MST) was 22 (1–274) wks (intent-to-treat). For pts with elevated TG, the MST was 24 (1–274) wks, while for pts with normal TG the MST was 21 (4–72). There was a statistically significant correlation between TG levels and survival, Spearman's correlation coefficient 0.48, p=0.0003. We will present the analysis of the association between outcomes and other clinical characteristics. Conclusions: Development of hypertriglyceridemia in the first 4 weeks of therapy with E and B in the absence of antilipid treatment is associated with increased overall survival. These findings implicate clinical benefit of dual targeting of EGFR and cyclin D1 especially in a subset of NSCLC pts with elevated TG early in therapy. Further work to identify the molecular basis for this association is needed to allow selection of pts more likely to benefit from this combined therapy.

[Table: see text]
Irinotecan plus platinum analog (IP) compared to etoposide plus platinum analog (EP) in extensive stage small cell lung cancer (ED-SCLC): Systematic review with meta-analysis
Authors: Sasse E. C. , Lima J. P. , Santos L. V. , Sasse A. D.
Published: August 2020

8105

Background: Superiority of irinotecan/cisplatin over etoposide/cisplatin in ED-SCLC has been a matter of debate with contradictory findings in randomized trials. Methods: PUBMED, EMBASE, CENTRAL databases, ClinicalTrials.gov, ASCO, IASLC, ESMO Meeting sites were searched. Eligible studies were randomized trials comparing first-line IP versus EP in ED-SCLC patients. The primary outcome measure was overall survival (OS); secondary endpoints of interest were progression-free survival (PFS), response rate (RR), and toxicity. Two reviewers independently assessed eligibility, quality, and time-to-event (TTE) outcomes. Hazard ratios (HR) were derived from reported TTE outcomes or extracted using Parmar methods with 95% confidence intervals (CI). Odds Ratio (OR) was used to compare dichotomous data. A fixed effect model was used for meta-analysis. Results: Six studies were identified. Four of them had sufficient data to be included (four for OS and three for PFS). The data coming from 1,365 patients showed a HR for OS favoring IP, with significant heterogeneity (I2=50%). Sensitivity analysis identified one trial with exclusively Japanese population (144 patients). The exclusion of this trial in the meta-analysis resulted in a HR for OS of 0.86 (95% CI=0.76 - 0.97, p=0.01) still favoring IP, with no heterogeneity (I2=3%). For PFS, there was also significant heterogeneity between trials. After excluding the Japanese trial the HR for PFS was of 0.96 (95% CI=0.85 - 1.09, p=0.54) with acceptable heterogeneity. The ITT RRs were 60% for IP and 49% for EP (p<0.0001). Grade 3/4 diarrhea was more frequent in IP group while anemia, leucopenia and thrombocytopenia were more frequent in EP. Conclusions: The present meta-analysis demonstrates statistically significant OS benefit of IP over EP in westerns patients. Specific characteristics in safety profile should be taken into account when administrating IP.

No significant financial relationships to disclose.
A phase I/II (P1/P2) study of AT-101 in combination with topotecan (T) in patients with relapsed or refractory small cell lung cancer (SCLC) after prior platinum-containing first-line chemotherapy
Authors: Heist R. S. , Fain J. , Chinnasami B. , Khan W. , Molina J. , Brainerd V. , Leopold L. , Lynch T.
Published: August 2020

8106

Background: Bcl-2 family proteins are expressed in SCLC and are associated with chemotherapy resistance. AT-101 is an oral, pan Bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, and Bcl-w) and potent inducer of proapoptotic proteins. AT-101 has demonstrated activity in SCLC models, including those that express Mcl-1 and are resistant to other Bcl-2 inhibitors. The P1 portion of the study was previously reported. Methods: Pts ≥18 years of age, PS 0–1, with relapsed or refractory SCLC after first line chemotherapy with measurable disease per RECIST were eligible. Pts were stratified into 2 cohorts; cohort A ≥ 60 days and cohort B < 60 days relapse from prior chemotherapy and treated with T 1.25 mg/m2 daily and AT-101 40 mgs daily on days 1–5, q21 along with the use of myeloid growth factors. Adverse Events (AEs) were graded by the NCI CTCAE v. 3.0. Efficacy assessments (RECIST) were performed every 6-weeks. A 2-stage design was used with power/alpha of 80%/0.05 to detect a RR of > 25% and > 5%, in cohort A and B respectively. Results: 36 pts enrolled: ages 41–76; cohort A/B 23/13. The PR/SD/PD/NE rates were 17%/70%/9%/4% and 8%/54%/23%/15%, in cohorts A/B respectively. The median times to progression (TTP) were 18 and 13 weeks, respectively. The most common (>20 %) AEs (all grades): anemia (64%); neutropenia (53%); nausea (47%); fatigue (44%); thrombocytopenia (42%); dyspnoea (25%); and vomiting (22%). Most common Grade 3/4 related events (>5%): neutropenia (31%); thrombocytopenia (25%); anemia (14%); and asthenia (6%). No ileus was reported. Conclusions: AT-101 can be safely combined with T. The observed toxicities were consistent with the known rates of G4 cytopenias of T alone. The response rates observed did not meet the criteria for additional enrolment; however, many patients had a best response of SD and the median TTP in both cohorts was favorable compared to historical controls. Additional trials of AT-101 in SCLC are ongoing.

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Novel organic arsenic molecule darinaparsin: Development of IV and oral forms
Authors: Lossos I. , Craig M. D. , Tallman M. S. , Boccia R. V. , Conkling P. R. , Becerra C. , Komarnitsky P. B. , Hamilton B. L. , Lewis J. , Miller W. H.
Published: August 2020

8501

Background: Darinaparsin (ZIO-101) is a novel organic arsenical active against diverse cancers in vitro, and in vivo. Darinaparsin i.v. activity in lymphoma is being evaluated in a phase II study. Darinaparsin is orally bioavailable; the oral form is being investigated in two phase I studies in patients with advanced malignancies. Methods: Phase II trial is being conducted in patients diagnosed with advanced lymphomas who had ≥ 1 prior therapy. Patients receive 300 mg/m2/day of darinaparsin i.v. for 5 consecutive days every 28 days. Efficacy and safety are evaluated by standard criteria. Phase I oral dose escalation studies are being conducted in patients with advanced malignancies and explore safety, MTD, DLTs and preliminary efficacy of continuous and intermittent dosing schedules. Starting continuous dose is 100 mg BID for 3 weeks with 1 week rest, starting intermittent dose is 300 mg twice weekly for 3 weeks followed by 1 week rest. Results: The phase II study has accrued 28 lymphoma patients (21 non-Hodgkin's, 7 Hodgkin's); median age at baseline 61 years, ECOG ≤2, median number of prior therapies 3. Seventeen subjects have received at least 2 cycles of darinaparsin and are evaluable for efficacy. Of these, 1 subject (PTCL) has achieved a complete response, 3 - partial responses (2 marginal zone, 1 Hodgkin's), and 4 stable disease (2 PTCL, 1 DLBCL, 1 Hodgkin's). A total of 63 cycles of darinaparsin have been administered to subjects with lymphoma. No Gr. 3 or higher drug-related AEs were reported. Two SAEs were considered possibly drug-related (fall; neutropenic fever). Phase I studies accrued 35 patients; median age at baseline 58 years, ECOG ≤2, median number of prior therapies 3. Predominant tumor types include: colorectal (17), pancreatic (3), NHL (3). Current darinaparsin dose levels: continuous 200 mg BID, 2× weekly 900 mg. Of 18 patients evaluable for efficacy, 10 demonstrate SD ≥ 3 cycles. Oral darinaparsin bioavailability is 58%. Drug-related AEs include nausea/vomiting, fatigue, decreased appetite/anorexia. Conclusions: Darinaparsin is active in heavily pretreated patients with advanced lymphoma and has been very well tolerated. Oral darinaparsin is also well tolerated, and shows early activity.

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Benefit of rituximab combined to ACVBP (R-ACVBP) over ACVBP in 209 poor- risk BDLC NHL patients treated with up-front consolidative autotransplantation: A GELA phase II trial (LNH 2003–3)
Authors: Mounier N. , Gisselbrecht C. , Fitoussi O. , Belhadj K. , Feugier P. , Coiffier B. , Tilly H. , Casasnovas O. , Fermé C. , Briere J. , Haioun C.
Published: August 2020

8507

Background: Rituximab (R) combined with CHOP improves survival in DLBCL pts. More intensive regimen followed by auto transplantation have been used in patients < 60y with 2–3 adverse age-adjusted International-Prognostic-Index (aa-IPI) factors, providing a 5y OS of 65% (CI 60–68%), (Haioun LNH 98–3B, ASCO 2007). The objective of the present study was to assess whether or not combining R (375 mg/m2) to the dose intense ACVBP (doxorubicin 75 mg/m2 d1, cyclophosphamide 1,200 mg/m2 d1, vindesine 2 mg/m2 and bleomycin 10 mg d1 and d5, prednisone 60 mg/m2 d1-d5) also translates into a survival benefit. Methods: From 01/2004 to 12/2005, 209 DLCBL pts < 60y with DLBCL and aaIPI 2 or 3 received 4 cycles of R-ACVBP every 15 days. CR and PR pts received a consolidative BEAM and peripheral blood stem cell rescue (LNH2003–3 trial, # NCT00144807 ). Median age was 49 years, 22 % of patients presented with aa-IPI 3, 58% with IPI 3–5 (93% with elevated LDH and 54 % with extranodal sites >1). CR rate after induction was 61%, PR rate 24% leading to an overall response rate of 84% (176 pts). Collection failure was observed in 18 pts (10%). 155 pts received auto transplantation, representing 75% of the study population. Results: With a median follow-up of 27 months, according to the updated IWC 2007, 3y PFS and OS were estimated at 76% (CI 69–81%) and 81% (CI 75–86%), respectively. A case-controlled study was performed by matching the present R-ACVBP population with ACVBP patients selected from the LNH-98–3 trial. Patients were fully matched (1:1) on histology, aa-IPI score, gender, age and follow-up duration. 3y PFS was higher in R-ACVBP than in ACVBP patients: 75% (CI 67–81%) vs 58% (CI 50–65%), p=0.0003. 3y OS were estimated at 78% (CI 71–84%) vs 67% (CI 58–74%), p=0.05. The gain in 3y OS was significant in patients who received auto transplantation: 89% (CI 81–93%) vs 77% (CI 67–84%), p=0.02. Conclusions: These results with R-ACVBP induction and consolidative auto-transplantation suggest a major survival benefit which needs confirmatory prospective study.

No significant financial relationships to disclose.
Long-term follow-up of autotransplant (AT)-supported high-dose melphalan (hdm) for multiple myeloma (MM): Update of Intergroup Francophone du Myelome (IFM), Southwest Oncology Group (SWOG), and Arkansas (ARK) Total Therapy (TT) trials
Authors: Barlogie B. , Attal M. , Crowley J. , Harousseau J.
Published: August 2020

8519

Background: Clinical trial outcomes are usually published when statistical protocol objectives have been met, with short median follow-up not exceeding 5 years. Due to treatment innovations, MM survival beyond 10 years has become more common but formal long-term results are seldom reported. Methods: IFM, SWOG and ARK provide an update of their major trials. IFM-90: 1 AT v standard therapy (STD), IFM-94: 2 v 1 AT, IFM-9902: 2AT ± THAL, IFM-9904: 2AT for high-risk MM; SWOG-9321: 1 AT v STD; TT1: 2 AT with interferon, TT2: 2AT ± THAL, TT3: 2AT + THAL + bortezomib. Results: OS clustered in 3 groups with superior outcomes for TT3/TT2/IFM-99 v TT1 v IFM-94/ IFM-90/SWOG-9321 with 5/10/15-yr estimates of 70%/50%/TE v 57%/35%/20% v 43%/25%/15% (p<0.0001). EFS also clustered in 3 groups with superior outcomes for TT3 v TT2 v remainder with estimates of 71%/TE/TE v 50%/35%/TE v 27%/ 15%/10% (p<0.0001). Among phase III trials, added THAL in TT2 increased 10-yr OS/EFS from 40%/25% to 60%/40% (p=0.04/p=0.0005); 10-yr OS was 30% v 8% with 1 v 0 AT in IFM-90 (p=0.005), 31% v 21% with 2 AT v 1 AT in IFM-94 (p=0.08), and 20% for both arms of S9321. On multivariate analysis involving 2962 patients, OS was adversely affected by B2M >=3.5mg/L (p<0.001), LDH >=ULN (p<0.001), hemoglobin <10g/dL (p=0.001) and albumin <3.5g/dL (p=0.02). 2AT (65%) and THAL (21%) both contributed independently to superior OS (p<0.001, p=0.002); among individual trials, IFM-9902 (19%) and TT2/TT3 (33%) both improved OS significantly (both p<0.001). For each of the 3 major OS clusters, 228 patients could be matched on B2M, LDH, hemoglobin and albumin, with 10-yr OS/EFS estimates of 65%/30% for the TT3/TT2/IFM-9902 group significantly exceeding 30%/15% each for the other 2 groups (p=0.001/p=0.001). Conclusions: A 15-yr EFS plateau of 10% with older trials and superior 10-yr EFS/OS estimates of 50%/35% with recent studies emphasize that cure should be a realistic trial objective in contemporary MM therapy, requiring however very long-term follow-up beyond 15 years.

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Phase I study of an anti-CD30 Fc engineered humanized monoclonal antibody in Hodgkin lymphoma (HL) or anaplastic large cell lymphoma (ALCL) patients: Safety, pharmacokinetics (PK), immunogenicity, and efficacy
Authors: Blum K. A. , Smith M. , Fung H. , Zalevsky J. , Combs D. , Ramies D. A. , Younes A.
Published: August 2020

8531

Background: XmAb2513 is a novel 2nd-generation humanized monoclonal antibody (mAb) directed against CD30 (a cell surface antigen expressed on Reed-Sternberg cells of HL and ALCL), with an Fc region engineered to have increased binding affinity to Fcγ receptors (FcγRs) leading to improved FcγR-dependent effector cell functions. In vitro, XmAb2513 was more potent and more efficacious than 1st-generation anti-CD30 mAbs (e.g., SGN-30 & MDX-060). In cynomolgus monkeys (cynos), XmAb2513 exposure was dose-proportional with half-lives ranging from 12 - 17d in repeat dose studies, which suggested biweekly (QOW) dosing in man. A Phase 1 study has been initiated to examine the safety and efficacy of XmAb2513 in patients (pts) with relapsed HL and ALCL. Methods: Phase 1 open-label study with QOW dosing of XmAb2513; dose-escalation study design with doses of 0.3, 1, 3, 6, 9, and 12 mg/kg via IV-infusion to establish the maximum tolerated dose (MTD). Pts receive up to 4 cycles (8 infusions) with sample collections at regular intervals for safety, PK, soluble CD30 (sCD30) and detection of immunogenicity [i.e., human Abs to humanized Abs (HAHA)]. Tumor response is assessed every 2 cycles. Results: 13 HL pts have been enrolled in the 1st 4 dose levels (0.3 to 6 mg/kg). XmAb2513 has been well tolerated. The MTD has not been achieved. 1 pt with an extensive treatment history and chronic immunosuppression died due to fungal pneumonia after a single 3 mg/kg dose. The event was considered unrelated to XmAb2513. PK parameters were computed for the 1st dose alone and for the entire course of XmAb2513 treatment. PK parameters appeared non-linear across the dose range from 0.3 - 3 mg/kg. Half-life appeared to increase after multiple infusions and ranged from 5.3 - 30.2 days in the 1 and 3 mg/kg cohorts. Immunogenicity (HAHA) results have been negative. Tumor reduction has been observed in 1 pt in the 1 mg/kg cohort and 2 in the 3 mg/kg cohort. Conclusions: The MTD of XmAb2513 has not yet been reached due to its tolerability and lack of immunogenicity. PK results are on track with simulations based on PK results from cynos. XmAb2513 has demonstrated encouraging biologic activity in patients with refractory HL.

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Prognostic implications of comprehensive imaging with PET-CT, MRI, and X-rays and their biological and molecular correlates in multiple myeloma (MM) treated with total therapy 3 (TT3)
Authors: Bartel T. B. , Brown T. , Haessler J. , Shaughnessy J. , Angtuaco E. , Anaissie E. , van Rhee F. , Walker R. , Crowley J. , Barlogie B.
Published: August 2020

8532

Background: PET and MRI can reveal intramedullary focal lesions (FL) before osteolysis is detected on metastatic bone survey (MBS). Diagnostic merits, biological/molecular correlates, and outcome implications of the imaging techniques were prospectively and serially evaluated in 269 of 303 newly-diagnosed patients receiving TT3. Methods: Examined were FL number identified by PET (FDG-FL), CT portion of PET (CT-FL), MRI (MRI-FL), and MBS (MBS-FL); additionally, max-SUV of FL (SUV-FL), diffusely-involved bone marrow (SUV-DI), and extramedullary disease (EMD) on PET-CT. Results were compared, laboratory correlates examined (eg: gene expression profiling [GEP]-derived risk, molecular subgroups), and outcome implications determined. Results: Comparing anatomic sites, PET detected the highest mean FL followed by MRI and MBS (p<0.0001). Univariately significant implications on overall and event-free survival (OS, EFS) of FDG-FL, MBS-FL, and EMD may be explained by their link to other prognostic variables. Applying tertile frequency distributions of all imaging parameters, significant associations were seen for B2M with MBS-FL, FDG-FL, SUV-DI; CRP with MRI-FL, FDG-FL, CT-FL; GEP-defined high-risk with MRI-FL, FDG-FL, MBS-FL, SUV-FL; GEP low bone (LB) disease with MRI-FL, FDG-FL, SUV-FL; GEP Proliferation (PR) subgroup with MRI-FL, FDG-FL, MBS-FL, CT-FL. Yet on multivariate analysis, OS was independently adversely affected by both SUV-FL (>11) (p=0.001) and MRI >23 (p=0.043) in addition to cytogenetic abnormalities (CA) (p=0.005), B2M (>5.5mg/L) (p=0.005), and LDH ((ULN) (p=0.017). Even with GEP-defined high-risk (p=0.008), SUV-FL (>11) (p=0.009) retained independent significance in addition to CA (P<0.001) and CRP (>8mg/L) (p=0.020). Conclusions: This first prospective comprehensive imaging approach to MM showed that high SUV-FL had significant survival implications even after adjusting for powerful prognostic variables, especially GEP-defined risk. Multifaceted correlations of imaging variables also with molecular features of MM underscore the key role of bone (“soil”) for MM (“seed”) development and progression.

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