bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical modeling of the AKT inhibitor MK2206 and topotecan in small cell lung cancer (SCLC).
Authors: Holland William S. , Chinn Danielle C. , Lara Primo , Gandara David R. , Mack Philip C , Kelly Karen 
Published: March 2020

e17537 Background: Extensive-stage small cell lung cancer (SCLC) is an aggressive and lethal tumor. Despite its exquisite chemosensitivity, median survival is only 9-11 months. Topotecan is the only approved drug for relapsed SCLC and new treatments with demonstrated antitumor activity are urgently needed. Defects in PTEN and PI3KCA are common to SCLC (identified in 10-15% of tumor specimens), suggesting that inhibitors of the PI3K/AKT pathway should be evaluated. MK-2206 is a first- in-class oral allosteric AKT inhibitor that is both potent and highly selective against all AKT isoforms. Our aim is to determine if MK-2206 plus topotecan has superior anticancer activity compared to either agent alone in SCLC cell lines. Methods: Three SCLC cell lines (H526- PTEN/PI3K wild type; H69- PTEN wild type/PI3K mutated; H2196- PTEN mutated/PI3K wild type) were treated with MK2206, topotecan or the combination. Median Effect Analysis was conducted using proliferation assays to test the combination for synergy. Immunoblotting was performed to explore the targeted effect on the PI3K/AKT pathway while flow cytometry was used to determine cell cycle effects. Results: H526 cells were refractory to selective AKT inhibition, but sensitive to topotecan. In contrast, H69 cells were responsive to single-agent MK2206, but two orders of magnitude less sensitive to topotecan. The H2196 cell line was sensitive to both agents. All cell lines showed decreased phosphoAKT (S473) with MK2206. In the combination experiments, additive to moderately synergistic interactions were detected in all cell lines with the greatest synergism observed in the H69 cells. Increased PARP cleavage was observed in response to the combination treatment compared to single-agent topotecan suggesting that AKT inhibition improved the activity of topotecan. In H69, a prolonged G1/S-phase arrest was observed in the combination compared to single-agent treatment. Conclusions: MK2206 demonstrated antitumor activity in SCLC cell lines harboring PI3K or PTEN mutations and enhanced the activity of topotecan in wild type and mutant cell lines. Based on this data, a SWOG clinical trial of topotecan plus MK2206 versus topotecan in relapsed SCLC is in development.
Multicenter institutional experience of surgically resected thymic epithelial tumors (TETs): An observational report.
Authors: Genestreti Giovenzio , Burgio Marco Angelo , Ampollini Luca , Rolli Luigi , Sanna Stefano , Scarpi Emanuela , Burgio Salvatore Luca , Amadori Dino 
Published: March 2020

e17546 Background: Thymic epithelial tumors (TETs) consist of a series of neoplasm arising from the anterior mediastinum. Due to its rarity, large-scale prospective trials have been lacking. This retrospective multicenter analysis aimed to evaluate clinical outcome and clinico-pathological features of TETs after surgery resection and adjuvant treatments as chemotherapy and/or radiotherapy. Methods: All medical records about TETs surgically resected between 2000 and 2007 and eventually treated with adjuvant therapies (chemotherapy and/or radiotherapy) were reported. Surgical procedures included complete removal of thymic, mediastinal fat tissue and any suspicious lesions. Histological classification has been made in according to WHO criteria and Masaoka staging system was adopted. Adjuvant chemotherapy was represented by anthracycline and platin-based regimen whereas adjuvant radiotherapy was delivered on irradiation field covered primary tumor bed. Overall survival was calculated from the date of diagnosis until patient death or last follow-up visit. Disease free-survival was defined the interval from operation until date of recurrence. Results: Overall 32 patients were analyzed of whom 12 (37%) male and 20 (63%) female. Median age was 61 years (range: 33 - 86). At the beginning of their oncologic history 14 (42%) patients had miastenia. Overall at clinical staging there were 19 (60%) stage I, 4 (12%) stage II, 4 (12%) stage III, and 5 (16%) stage IVb at radiological staging. The histological exam reported: 5 (16%) A tumor type, 11 (34%) AB type, 3 (10%) B1 type, 3 (10%) B2 type, 8 (24%) B3 type, 2 (6%) C type. At pathological staging there were: 18 (56%) stage I, 7 (22%) stage II, 2 (6%) stage III and 5 (16%) stage IVb. Post-surgical therapies were represented by chemotherapy in 2 (6%) patients and radiotherapy in 13 (41%) patients. Disease relapse was recorded in 1 (3%) patient after 27 months from diagnosis. Overall survival rate at 78 months is 86% (CI: 66-100). Conclusions: TETs are rare and indolent cancer. Surgery offers the good perspectives eventually improved with adjuvant therapies like chemotherapy and/or radiotherapy. Supported by GIPO.
Full-dose irinotecan plus platinum (IP) with concurrent thoracic radiotherapy (C-TRT) in unresectable locally advanced non-small cell lung cancer (LA-NSCLC).
Authors: Zhang Jun , Biswas Tithi , Fried Daniel B , Rosenman Julian , Russo Suzanne M. , Salvador Wenimar , Tiley Stephen , Parent Teresa , Eubanks Susan , Nelson Zenith , Aljumaily Raid , Bowling Mark , Walker Paul R. 
Published: March 2020

e17547 Background: Weekly paclitaxel-carboplatin or cisplatin-etoposide with C-TRT is the standard of care for unresectable LA-NSCLC, with median survival time (MST) of 16-24 months and 3 year overall survival (OS) of 17-27%. Irinotecan plus platinum with C-TRT has been studied in LA-NSCLC with similar outcomes and no undue toxicities (Langer et al J Thorac Oncol 2007; Bastos et al J Thorac Oncol 2010). We reviewed our multi-disciplinary thoracic oncology program experience of full dose IP with C-TRT in LA-NSCLC. Methods: All patients with unresectable LA-NSCLC treated between January 2007 and December 2011 were searched through our program database and included. 26 patients treated with definitive IP and C-TRT were identified. Treatment consisted of irinotecan 65mg/m2, plus cisplatin 30mg/m2 or carboplatin AUC 3, on days 1 and 8, every 21 days for four cycles. C-TRT started on day 22 at 2 Gy/day for 6-7 weeks. (Total 60-70Gy.) Survival curves were estimated by Kaplan-Meier analysis. Primary end point was OS. Secondary endpoints were overall response rate (ORR), progression free survival (PFS), and toxicities. Results: Patient characteristics: Median age 61 (range 44-82); 73% males; 50% squamous, 31% adenocarcinoma, 19% other histology; 30% Stage IIIA/ 62% IIIB/8% IIB. 1 patient died early without evaluation. ORR was 69%, 5 (19%) complete response, 13 (50%) partial response, 7 (27%) stable disease. Median PFS 10.1 months. MST 31.4 months. One year OS 67.8% (95% CI 52-89) and three year OS 35.7% (95%CI 15-87). 12 (46%) patients had G3/4 hematologic toxicities: 7 neutropenia, 6 thrombocytopenia, 6 anemia, 2 lymphopenia. 9 (34.6%) patients had G3/4 non-hematologic toxicities: 4 radiation esophagitis, 3 elevated creatinine, 2 pneumonia, 2 nausea/vomiting. 1 G5 radiation pneumonitis. Two patients died of pneumonia and sepsis. 18 (69%) patients completed 4 cycles IP with concurrent TRT. Conclusions: Definitive treatment with full dose Irinotecan plus platinum and concurrent thoracic radiotherapy is effective and tolerable for unresectable LA-NSCLC with an enhanced MST of 31 months and 3 year OS of 35%.
Phase II study of ADI-PEG 20 in patients with relapsed sensitive or refractory small cell lung cancer.
Authors: Tran Sinhan , Ready Neal , Krug Lee M. , Pietanza Maria Catherine , Jungbluth Achim A , Pan Linda S. , Venhaus Ralph Rudolph , Hoffman Eric W. , Peters Ann-Marie , Dukelow Karen , Bomalaski John S. , Wu Bor-Wen , Old Lloyd J. 
Published: March 2020

e17558 Background: Small cell lung cancer (SCLC) is a rapidly progressing malignancy. The majority of patients show relapse after initial therapy. Second-line chemotherapy has limited activity, and alternative therapies are desperately needed. ADI-PEG 20 is pegylated recombinant arginine deiminase which degrades arginine, resulting in growth inhibition of SCLC tumor cells deficient in argininosuccinate synthetase (ASS) in xenografts and in vitro, and induction of sensitivity to cell autophagy. Based on ASS deficiency identified in ~50% of human SCLC, a phase II trial in patients with relapsed SCLC was initiated. Methods: This is an open label, multicenter, phase II study of ADI-PEG 20 in subjects with relapsed SCLC. The primary objective is to determine overall response rate according to RECIST. Secondary objectives are to measure safety, overall survival, pharmacodynamics, and immunogenicity. Patients with histologically documented SCLC, measurable disease, and ASS negative (by immunohistochemistry) or weakly positive (< 5%) tumor are eligible. Patients with severe comorbidities, metastatic disease of the central nervous system, prior treatment with 3 or more lines of chemotherapy, and known allergy to pegylated products are excluded. Patients are enrolled in either Cohort 1 (Sensitive disease—response to first-line therapy maintained ≥ 90 days) or Cohort 2 (Refractory disease—no response to first-line therapy or progression within 90 days, or progression after 2 lines of therapy). All patients receive weekly intramuscular injections of ADI-PEG 20 at a dose of 320 IU/m2 (36.8 mg/m2) until disease progression. The two cohorts will be analyzed separately with a two-stage design. For Cohort 1, if 3/15 patients respond, additional 13 patients will be accrued to the second stage. For Cohort 2, if 1/9 patients responds, additional 8 patients will be accrued to the second stage. Results: Cohort 1 has enrolled 2 of planned 15 patients and Cohort 2 has enrolled 7 of 9 planned patients. Conclusions: Will be published when study is complete.
Usefulness of cytological samples (CS) for the assessment of ALK rearrangements in non-small cell lung cancer (NSCLC).
Authors: Lozano Maria D. , Labiano Tania , Zudaire Maria I. , Gurpide Alfonso , Zulueta Javier , López-Picazo José María , Echeveste Jose Ignacio , Seijo Luis Miguel , Idoate Miguel A. , Martin-Algarra Salvador , Perez-Gracia Jose Luis 
Published: March 2020

e18008 Background: ALK gene rearrangements define a new molecular subtype of NSCLC with response to Crizotinib, a dual MET and ALK inhibitor. Analysis of ALK rearrangements has been performed in biopsies or surgical specimens. However, advanced NSCLC is often diagnosed by FNA cytology obtained through minimally invasive techniques, and frequently CS are the only tumour sample available. We assessed the feasibility of determining ALK rearrangements in CS. Methods: We studied prospectively ALK rearrangements in 53 CS from 53 NSCLC patients (30 M/23 F) by FISH (Vysis dual colour break apart probe). We considered positive for ALK rearrangement when > 15% of cells show splits signals. Tumor samples were obtained by bronchoscopy -FNA in 26 cases (49.1%), EBUS-FNA in 7 (13.2%), EUS-FNA in 3 cases (5.7%), CT-FNA in 3 (5.7%), and direct FNA in 6 cases (11.3%). Two cavity fluids (3.8%), 4 imprints (7.5%), and 2 cellblocks received for consultation (3.8%) were also studied. FISH was performed on non-stained ThinPrep in 28 cases (52.8%), Papanicolau stained smears in 15 cases (28.3%), cell block in 9 cases (17%), and 1 stained ThinPrep. All cases were tested for EGFR and KRAS mutations. Correlation cytological/paraffin embedded samples was performed in 4 paired cases. Results: Thirty-seven samples(69.8%) were adequate for FISH analysis. Three cases (8.1%) had ALK rearrangements: non-smoker women with adenocarcinoma, two of them with signet ring cells. One case had a concurrent EGFR mutation in exon 21. FISH study was unsuccessful in 16 cases (30.2%):10 Papanicolau stained smears (62.5%), 5 unstained ThinPrep (31.3%), and 1 cell block. Nineteen ThinPrep slides were adequate for FISH analysis (86.4%) as well as 8 out of 9 cell blocks. Concordance rate in paired cases were 100%. Conclusions: Determination of ALK gene rearrangements in CS is feasible. It is mandatory an exquisite management and care of the samples to preserve quality. ThinPrep and cell blocks are the most suitable samples for FISH analysis, while Papanicolau stained smears provide poor results. Coexistence of ALK gene rearrangements and EGFR mutations was observed in one case, indicating that such alterations are not necessarily mutually exclusive.
KRAS mutational status and sensitivity to a reversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in EGFR wild type (WT) advanced non-small cell lung cancer (NSCLC) patients (pts).
Authors: Metro Giulio , Duranti Simona , Chiari Rita , Bennati Chiara , Molica Carmen , Currà Maria Francesca , Scafati Chiara , Siggillino Annamaria , Flacco Antonella , Marcomigni Luca , Ludovini Vienna , Minotti Vincenzo , Crinò Lucio 
Published: March 2020

e18023 Background: Treatment with a reversible EGFR-TKI may benefit pts with EGFR WT advanced NSCLC, though to a much lesser extent than pts carrying an activating mutation in the EGFR gene. We assessed whether KRAS mutational status would help predict sensitivity to gefitinib or erlotinib in EGFR WT advanced NSCLC pts. Methods: Sixty-seven EGFR WT, advanced NSCLC pts treated with a reversible EGFR-TKI in any line setting were included. Pts were treated from May 2005 to March 2011 at the Medical Oncology of the Perugia Hospital. EGFR (exons 18 to 21) and KRAS (codons 12, 13 and 61) genes were amplified by nested PCR and sequenced in both sense and antisense directions. Results: Median age was 60 years (39-84); 52 pts (77.6%) were PS 0 or 1; 58 pts (86.6%) belonged to the non-squamous subtype and 22 pts (32.8%) were never-smokers. Eighteen pts (26.8%) were KRAS mutant (MUT), of which 14 pts at codon 12 (COD 12 MUT) and 4 pts at codon 13 (COD 13 MUT). Overall, 11 pts (16.4%) responded to treatment and 8 pts (11.9%) achieved stable disease, for a disease control rate of 28.3%. At a median follow-up of 25.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.9 and 29.5 months, respectively. When analyzed according to KRAS status, a significantly shorter PFS was noted for the EGFR WT/KRAS MUT subgroup (N=18) compared with the EGFR WT/KRAS WT population (N=49) (1.6 vs. 3.0 months, respectively, p=0.04). However, no significant difference was observed between the two groups in terms of OS (18.0 vs. 34.8 months, respectively, p=0.42). Within the EGFR WT/KRAS MUT subrgoup a significantly longer PFS was reported for COD 12 MUT pts compared with COD 13 MUT pts (1.7 vs 0.7 months, respectively, p=0.04). Similarly, KRAS COD 12 MUT pts experienced a statistically significant superior OS compared with COD 13 MUT pts (36.2 vs 7.4 months, respectively, p=0.003). Conclusions: EGFR WT/KRAS MUT pts appear to be more resistant to treatment with a reversible EGFR-TKI, the greatest resistance occurring in COD 13 MUT pts. KRAS COD 12 MUT pts may represent a clinically distinct subgroup of KRAS mutants with a particularly favorable prognosis.
Erlotinib as frontline treatment for elderly patients (p) with advanced nonsquamous non-small cell lung cancer (nsNSCLC): GGCP044/09 study.
Authors: Firvida Perez Jose Luis , Vazquez Estevez Sergio , Casal Rubio Joaquin , Alonso Bermejo Miguel , Varela Ferreiro Silvia , Villanueva Silva Maria Jose , Afonso Afonso Francisco J. , Lazaro Quintela Martin , Areses Manrique Carmen , Campos Balea Begona , Huidobro Vence Gerardo , Fernandez Calvo Ovidio , Alvarez Gomez Elena , Grande Ventura Carlos , Fernandez Montes Ana , Castro Gomez Enrique , Mel Lorenzo Jose Manuel ,   Galician Lung Cancer Group
Published: March 2020

e18040 Background: NSCLC is primarily a disease of older people with a median age of approximately 70 years (y) at diagnosis. Platinum combination chemotherapy (CT) has shown to be more effective than single agents but it is associated with more toxicity. Erlotinib is an EGFR TK inhibitor with a favourable toxicity profile and its oral administration makes it suitable to treat elderly p. No much is known about its efficacy and toxicities in this subpopulation, often under-represented in clinical trials. This Galician study aims to evaluate the efficacy and safety of erlotinib as 1st-line treatment (Tx) for elderly p with advanced nsNSCLC. Methods: Elderly p (≥70 years old) with stage IIIB/IV nsNSCLC were included in this prospective observational study. Erlotinib was orally administered at a dose of 150 mg daily until disease progression or intolerable toxicity. PFS (primary objective) and OS were measured from time of diagnosis. Results:A total of 31 p were enrolled. Baseline characteristics: Mean age 78 y (range 70-85); female 67.7%; adenocarcinoma (including BAC) 90.3%; never/current/former smokers (%): 54.8/16.1/22.6 (6.5% unknown), stage IV 84%; ECOG PS 0/1/2 (%): 6.4/45.2/48.4. The median PFS was 6.4 and the median OS was 9.9 months. Out of 26 evaluable p, 8 had PR and 8 SD, for an ORR of 30.8% and a DCR of 61.6%. The most common adverse event was skin rash, 38.7% (9.6% grade 3-4), diarrhoea, 25.8% (3.2% gr. 3-4) and asthenia, 19.3% (no gr 3-4 were reported). 5 p (16.1%) needed dose reduction and 3 p withdrew the Tx due to grade 3 diarrhoea, eye perforation and esofaghitis, respectively. EGFR mutational status was available for 10 p (32.2%); 4 p harboured activating mutations: 3 p achieved PR and 1 p SD. SLP of 31 (ongoing), 22.4 (ongoing), 13.6 and 9.8 months. Conclusions: These results in real-life settings confirm that erlotinib is an active and well tolerated agent as frontline Tx in elderly p (≥70) in nsNSCLC. Response rate is similar to that achieved with CT in younger people; benefit in PFS is modest, but median OS is acceptable, taking into account that half of the p had a PS of 2 EGFR mutation testing should be strongly encouraged among elderly p.
Efficacy and safety of IMO-2055, a novel TLR9 agonist, in combination with erlotinib (E) and bevacizumab (bev) in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed following prior chemotherapy.
Authors: Smith David A. , Conkling Paul , Richards Donald A. , Flores Maria Regina C. , Nemunaitis John J. , Boyd Thomas E. , Mita Alain C. , de La Bourdonnaye Guillaume , Wages David , Bexon Alice Susannah 
Published: March 2020

e18047 Background: IMO-2055 is a novel TLR-9 agonist with potential to enhance the efficacy of biologics and small molecules through immune stimulation. Xenograft data show anti-tumor synergy between IMO-2055, E and bev; E-bev has been evaluated in 2nd line NSCLC. Methods: Primary objective was to determine the recommended dose (RD) of IMO-2055 (dose range 0.08-0.48 mg/kg/w s.c.) with E 150mg/day p.o. and bev 15mg/kg q3w i.v. in a standard 3+3 design. An expansion cohort at the RD further determined safety and efficacy. Pts had AJCC stage 3/4 inoperable, histologically proven NSCLC where standard chemotherapy was not an option. Treatment was until progression (PD) or toxicity. Results: 36 pts were enrolled at 10 US sites from Nov ‘07 to Mar '11. 35 were treated/evaluable for safety; 33 for efficacy. Median age was 64, 58% were men, 81% white, 81% PS 1 with 69% adenocarcinomas and median 17 months since diagnosis. 44% pts were >2nd line. Pts received a median of 4.3 3-week cycles. 19 pts entered dose-escalation: 4 at 0.08 mg/kg, 6 at 0.16 mg/kg, 6 at 0.32 mg/kg, and 3 at 0.48 mg/kg IMO-2055. Two pts had DLTs: 1 grade 3 dehydration at 0.16 mg/kg, and 1 grade 3 fatigue at 0.48 mg/kg. RD was 0.32 mg/kg based on pharmacodynamic and clinical data: 17 more pts were treated at this dose. The most common AEs were diarrhea, nausea, fatigue and rash; most frequent grade 3-4 AEs were fatigue (9%), diarrhea (9%), anemia and dyspnea (both 6%), with no clear dose-relationship to IMO-2055. G3-4 hypertension was 0%, ATE 6% and hemorrhage 3%. Five pts died of PD on or within 30 days of study drug administration. Response rate was 12% with 79% disease control (SD+PR). Median PFS was 5.6 months (95% CI 3.9-7.2) and OS 16 months (95% CI 7.5-17.8) with 55% pts alive at 1 year. Conclusions: Addition of IMO-2055 to E-bev was well tolerated with no unexpected toxicity. The RD of IMO-2055 with E-bev is 0.32 mg/kg/w s.c. Median PFS and OS in this heavily pretreated population compare favorably with published E-bev data. IMO-2055 should be further explored in NSCLC.
Long-term survivors with advanced nonsquamous non-small cell lung cancer (nsNSCLC) treated with first-line (1L) chemotherapy (CT) plus bevacizumab (B) and maintenance (mtc) B.
Authors: de Castro Javier , Isla Dolores , Gonzalez Larriba Jose Luis , Vazquez Estevez Sergio , Massuti Bartomeu , Sanchez Torres Jose Miguel , Domine Manuel , Calles Antonio , Cardona Jose Vicente , Garrido López Pilar 
Published: March 2020

e18055 Background: B plus CT followed by mtc B has been shown to improve outcomes in patients (pts) with nsNSCLC. In the clinical setting, some pts are able to receive prolonged mtc treatment (Tx) with B. The aim of our research was to explore their clinical characteristics, in order to assess the behavior of these pts who benefit most from B. Methods: In 30 Spanish institutions we studied retrospectively data from 104 pts with advanced nsNSCLC receiving long-time mtc B defined by a PFS ≥ 9 months (m), which represents an increase in PFS of approximately 50%, as compared with historical data. Clinical and histological characteristics, Tx received, ORR, median PFS and OS, and safety data were recorded. Results: Pts characteristics: median age 57 years (yr); caucasian: 98%; ECOG PS 0/1/2 (%): 61/38/2; male: 61%; current/former/never smokers (%): 36/45/19; baseline hypertension (HTN)/cardiovascular disease (%): 24/9; adenocarcinoma: 82%; stage IV: 84%; 84% of pts presented ≤2 metastatic sites; central tumor location: 30%; tumor cavitation: 4%; among 40 pts tested, 8% presented activating EGFR mutations. 1L CT was: carboplatin/cisplatin doublets (%): 57/43; median no. of cycles for CT/B and mtc B was 6 and 18, respectively. Median B dose was 7.5 mg/kg. ORR: 83%. Of 71% of pts who had evidence of PD to 1L, 90% received second-line (2L) Tx. 77% of pts who progressed to 2L, received a third-line (3L). B was maintained in 26% and 24% of pts receiving 2L and 3L. Median PFS: 15 m (CI 95%:14-16); median OS: 31 m (95% CI: 22-39). 1 and 2 yrs survival rates (%): 97 (95% CI: 93 - 100) and 62 (95% CI: 51 - 73). Most frequent B related toxicities (%): gr 1/2 epistaxis (22/0), gr 1/2 HTN (12/6), grade 1/2/3 asthenia (2/6/4) and gr 1/2/3 proteinuria (3/3/1). Conclusions: To our knowledge, these are the first data reported of long-term survivors with advanced nsNSCLC treated with 1L CT/B plus long-time mtc B. Although prospective evaluation is required, the outstanding median OS (31 m) and 2-yr survival (62%) point out the importance of selecting Tx and the role of mtc B after 1LB. B was very well tolerated, without significant life-threatening toxicities. Subgroup analyses will be presented.