bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk factors associated with brain metastases in ECOG-ACRIN E1505, a phase III randomized trial of adjuvant chemotherapy with or without bevacizumab for patients with completely resected stage IB (>/= 4 cm) - IIIA non-small cell lung cancer (NSCLC).
Authors: Varlotto John M. , Dahlberg Suzanne Eleanor , Wakelee Heather A. , Ramalingam Suresh S. , Schiller Joan H. 
Published: September 2018

8539 Background: ECOG-ACRIN E1505 was a phase III randomized trial of adjuvant chemotherapy with or without bevacizumab for patients with completely-resected Stage IB (>4CM) – IIIA non-small cell lung cancer. Prior studies have shown that the risk of brain recurrence in patients after definitive surgical resection is approximately 10%; however, covariates associated with development of brain recurrence have varied across these studies. We sought to estimate the incidence of and risk factors for brain recurrence. Methods: Among the 1501 patients enrolled to ECOG-ACRIN E1505, 121 patients developed brain metastases as their first site of recurrence and are the subject of this investigation. All 1501 patients underwent a pneumonectomy (N = 192) or (bi)lobectomy and had an R0 resection. The cumulative incidence of brain recurrence was estimated after adjusting for recurrence at other sites and death as competing events. A multivariable regression model was fitted using the methodology of Fine and Gray to evaluate the effect of covariates on the subdistribution of brain recurrence. Results: With a median follow-up of 50.3 months, a total of 121 brain metastases had been reported as the first site of recurrence. The incidence of brain recurrence at 12 months post-randomization was 3.7% (95% CI: 2.8% – 4.7%), and it increased to 8.5% (95% CI: 7.0% - 10.0%) at 3 years, and to 9.9% (95% CI: 8.0% - 11.7%) at 6 years. Risk factors for brain metastases included pneumonectomy(HR=1.8; p=0.01), and nonsquamous histology(HR=2.04; p=0.003), but bevacizumab(HR=0.64; p=0.02) was associated with potentially protective effect. Conclusions: The cumulative incidence of brain recurrence increased over time to 9.9% at 6 years in this population of patients with surgically-resected non-small cell lung cancer. Treatment, tumor histology, and type of resection appear to be associated with the risk of brain recurrence. Clinical trial information: NCT00324805.
Tolerability of veliparib (V) in combination with carboplatin (C)/paclitaxel (P): Based chemoradiotherapy (CRT) in subjects with stage III non-small cell lung cancer (NSCLC).
Authors: Kozono David E. , Salama Joseph Kamel , Stinchcombe Tom , Bogart Jeffrey , Petty William J. , Guarino Michael J. , Bazhenova Lyudmila , Larner James Mitchell , Weiss Jared , DiPetrillo Thomas A. , Feigenberg Steven J. , Xu Tu , Hu Beibei , Nuthalapati Silpa , Rosenwinkel Lindsey , Bensman Lindsey , Johnson Eric Feral , McKee Mark D. , Vokes Everett E. 
Published: September 2018

8546 Background: CRT is a standard for patients with Stage III NSCLC. V is a potent, orally bioavailable PARP1/2 inhibitor that can delay DNA repair following chemotherapy or radiation induced damage. A Phase 2 study indicated favorable efficacy of V vs placebo when added to C/P in advanced NSCLC (Ramalingam et al. Clin Cancer Res. 2016). Based on these results, a Phase 1/2 trial was initiated to study the safety and efficacy of V/C/P-based CRT in the treatment of Stage III NSCLC. Methods: Subjects without prior NSCLC therapy suitable for definitive CRT received V plus C AUC 2 + P 45 mg/m2 weekly + 60 Gy over 6-9 weeks. V was escalated from 60 mg BID to a maximum planned dose based on prior studies of 240 mg BID via 3+3 design with allowed over-enrollment followed by consolidation therapy of V 120 mg BID + C AUC 6 + P 200 mg/m2 for up to two 21-day cycles. Results: Thirty-one subjects (median age 64; 10 male) have been enrolled to date into dosing cohorts at 60 mg (7), 80 mg (9), 120 mg (7) and 200 mg (8). PK of V was dose proportional. CRT or V required dose reduction for 0 or 1 subject, respectively. Four (13%) subjects discontinued study during CRT. No DLTs have been observed and an MTD has not yet been identified. The most common any grade AEs were fatigue (16), esophagitis (15), nausea (13), neutropenia (12), thrombocytopenia (12), constipation (10) and decreased appetite (10). 21 SAEs were observed including 8 with reasonable attribution to V but outside the DLT window including G3/4 febrile neutropenia (2), G3 dehydration (1), G3 vomiting (1), G3 radiation esophagitis (1), G3 esophageal stricture (1), G3 intractable N/V (1) and G5 sepsis during consolidation (1). Of 21 subjects evaluable for tumor assessment, best response was CR (1), PR (11), SD (6), and PD (3). Conclusions: V/C/P-based CRT followed by V/C/P consolidation therapy is a tractable regimen for the treatment of Stage III NSCLC. A randomized placebo-controlled Phase 2 extension of this study is planned. Clinical trial information: NCT02412371.
Prognostic impact of PD-L1 expression in correlation with HLA class I expression status in stage I adenocarcinoma of the lung.
Authors: Yoneda Kazue , Hirai Ayako , Shimajiri Shohei , Hanagiri Takeshi , Tanaka Fumihiro 
Published: September 2018

8548 Background: Programmed death-ligand 1 (PD-L1) and human leukocyte antigen (HLA) class-I, expressed on tumor cells (TCs), are important regulators in cancer immunity. The current study was conducted to assess prognostic impact of PD-L1 status in correlation with HLA class-I status in lung adenocarcinoma. Methods: A total of 94 patients with completely resected pathologic stage I lung adenocarcinoma were retrospectively reviewed. PD-L1 expression on TCs was evaluated with immunohistochemistry, in correlation with several clinicopathological and molecular features including HLA class-I expression on tumor TCs. Results: Seventeen patients (18.1%) had tumor with positive PD-L1 expression (percentage of TCs expressing PD-L1, ≥ 5%), and the incidence was higher in smokers with higher smoking index and in poorly differentiated tumor. There was no significant correlation between HLA class-I expression and PD-L1 expression. PD-L1-positivity was a significant factor to predict a poor survival (5-year survival rate, 66.7% versus 85.9%; P = 0.048), which was enhanced in tumor with normal HLA class-I expression (p = 0.029) but disappeared in tumor with reduced HLA class-I expression. Conclusions: The prognostic impact of PD-L1 expression on TCs in early-stage resectable lung adenocarcinoma was distinct according to HLA class-I expression on TCs.
Differential expression of immune inhibitory markers in association with HLA class I and the immune microenvironment in resected lung adenocarcinomas.
Authors: Zhang Mingjuan Lisa , Kem Marina , Mooradian Meghan , Eliane Jean-Pierre , Huynh Tiffany , Iafrate A. John , Gainor Justin F. , Mino-Kenudson Mari 
Published: September 2018

8551 Background: Similar to programed death ligand 1 (PD-L1), indoleamine 2,3-Dioxygenase 1 (IDO1) is known to exert immunosuppressive effects and be variably expressed in human lung cancer. However, IDO1 expression has not been well-studied in lung adenocarcinoma (ADC). Methods: PD-L1 and IDO1 expression were evaluated in 261 resected ADC using tissue microarrays and H-scores (cutoff 5). We compared IDO1 with PD-L1 expression in association with clinical features, tumor-infiltrating lymphocytes (TILs), HLA class I (β-2 microglobulin; B2M) expression, molecular alterations, and patient outcomes. Results: There was expression of PD-L1 in 89 (34.1%) and IDO1 in 74 (28.5%) cases, with co-expression in 49 (18.8%). Both PD-L1 and IDO1 were significantly associated with smoking, aggressive pathologic features, and abundant CD8+ and T-bet+ (Th1 marker) TILs. PD-L1 expression and abundant CD8+ were inversely associated with a loss of B2M membranous expression (p = 0.0019 and p < 0.001, respectively). Compared to PD-L1+/IDO1+ and PD-L1+ only cases, significantly fewer IDO1+ only cases had abundant CD8+ and T-bet+ TILs (p < 0.001, respectively). PD-L1 expression was significantly associated with EGFR wild-type (p < 0.001) and KRAS mutants (p = 0.021), whereas there was no difference in IDO1 expression between different molecular alterations. As for survival, PD-L1 was significantly associated with decreased progression-free (PFS) and overall survival (OS), while IDO1 was associated only with decreased OS. Interestingly, there was a significant difference in the 5-year PFS and OS (p = 0.004 and 0.038, respectively), where cases without PD-L1 or IDO1 expression had the longest survival, and those with PD-L1 alone had the shortest survival. Conclusions: While PD-L1 +/- IDO1 expression is observed in association with B2M expression, CTL/Th1 microenvironments, EGFR wild-type, and KRAS mutations, isolated IDO1 expression does not demonstrate these associations, suggesting that IDO1 may serve a distinct immunosuppressive role in ADC. Thus, blockade of IDO1 may represent an alternative and/or complementary therapeutic strategy to reactivate anti-tumor immunity.
Tremelimumab in combination with durvalumab in first or second-line mesothelioma patients: Safety analysis from the phase II NIBIT-MESO-1 study.
Authors: Calabro Luana , Morra Aldo , Giannarelli Diana , Amato Giovanni , Bertocci Erica , D'Incecco Armida , Danielli Riccardo , Brilli Lucia , Giannini Fabio , Altomonte Maresa , Di Giacomo Anna Maria , Maio Michele 
Published: September 2018

8558 Background: The anti-CTLA-4 tremelimumab at two different dose-schedules of administration showed promising activity in second-line malignant mesothelioma (MM) patients (Calabrò et al., Lancet Oncol, 2013; Calabrò et al., Lancet Respir Med, 2015). These initial results and the efficacy of targeting the PD-1/PD-L1 axis in different tumor types, prompted the NIBIT-MESO-1 study aimed at investigating the efficacy and safety of tremelimumab combined with the anti-PD-L1 durvalumab in mm patients. We report the safety analysis from the fully-enrolled NIBIT-MESO-1 study. Methods: The NIBIT-MESO-1 is a phase II, open-label, single Center study. Forty mm patients received tremelimumab at 1 mg/Kg i.v. every 4 weeks (Q4W) for 4 doses, and durvalumab at 20 mg/Kg i.v. Q4W for 13 doses. Primary objective is immune-related (ir)-objective response rate; secondary are safey, ir-disease control rate, ir-progression free survival, and overall survival. Tumor assessment per ir-modified RECIST or ir-RECIST 1.1 for pleural or peritoneal MM, respectively, was performed at baseline and q12 weeks. Adverse events (AEs) were recorded according to CTC v4.0. (ClinicalTrials.gov Id: NCT02588131). Results: From October 2015 to October 2016, 40 mm patients (38 pleural and 2 peritoneal), median age 64 years (range 41-80), ECOG performance status 0 (n = 19) or 1 (n = 21) were enrolled in the study. mm histology was epithelioid (n = 32), biphasic (n = 5), sarcomatoid (n = 2) or undefined (n = 1). As of January 2017, 12 first or 28 second-line mm patients received a median of 5.5 doses of therapy (range = 1-13). Twenty-four patients (60%) experienced any grade irAEs: 5 patients (12.5%) had grade 3-4 AEs, the most frequent being hepatotoxicity (7.5%). AEs were generally manageable and reversible per protocol guidelines. Three patients (7.5%) were discontinued due to treatment-related AEs (1 trombocytopenia, 1 limbic encephalitis, 1 liver toxicity). Conclusions: The combination of tremelimumab and durvalumab is safe and manageable in mm patients. Clinical trial information: NCT02588131.
Systemic therapy use and outcomes after relapse from accelerated hemithoracic radiation and surgery for malignant pleural mesothelioma (MPM).
Authors: Soldera Sara V. , Kavanagh John , Pintilie Melania , Feld Ronald , Leighl Natasha B. , Cho John , de Perrot Marc , Bradbury Penelope Ann 
Published: September 2018

8559 Background: The prognosis of patients (pts) with MPM remains poor. Accelerated hemithoracic radiation followed by extrapleural pneumonectomy and adjuvant chemotherapy in ypN2 disease (SMART) provides encouraging results. The ability to administer systemic therapy (Tx) and response rate (RR) after recurrence remains unclear. We therefore examined subsequent lines of Tx and outcomes following relapse after SMART. Methods: A retrospective analysis of pts diagnosed with recurrent MPM following SMART was conducted at a single institution. OS was determined from date of relapse to death and was estimated using the Kaplan-Meier method. Potential prognostic variables were tested utilizing the log-rank test. Results: Out of 86 pts undergoing SMART from 2008 to 2016, 53 (62%) developed recurrent disease of which 36% had pathological confirmation. Two cases with initial epithelial subtype on surgical specimen relapsed with different histology (sarcomatoid and small cell). In 48% of pts, relapse was unclear at first imaging (n = 42) and a median of 98 days (range 6-966) lapsed between first suspicion and final diagnosis. The median age at relapse was 66 years (range 45-79), 47% had a performance status (PS) ≥2 (n = 45) and 64% were of epithelial subtype. After a median follow up of 7.6 mo, the median OS was 5.2 mo. PS ≥2 was associated with worse OS (2.8 vs 10.7 mo, p < 0.001). Of 42 pts followed after relapse, 36% received any Tx (19% 1 line; 12% 2 lines; 5% ≥3 lines). Tx was omitted in 62% of pts due to poor PS (26/42). First line Tx consisted of platinum doublet in 93% of pts (n = 15). Of 13 pts with response evaluable disease, RR was 15% (0 CR, 15% PR). Of note, 0/13 pts had neoadjuvant Tx and 3/13 pts had adjuvant Tx (10, 13 and 38 mo lapsed between end of adjuvant Tx and start of Tx in the relapsed setting). 6/15 pts discontinued Tx due to toxicity, 5/15 due to progression and median number of cycles was 4. Conclusions: Pts with relapsed MPM following SMART have poor prognosis and low RR to first line Tx. Poor performance status at relapse is a poor prognostic factor. Earlier detection, novel diagnostic markers of relapse and consideration of maintenance strategies should be investigated in future studies.
Longitudinal monitoring of circulating tumor DNA and peripheral T cell repertoire in patients with small cell lung cancer.
Authors: Iams Wade Thomas , Almodovar Karinna , Meador Catherine , York Sally Jane , Horn Leora , Raymond Chris , Hernandez Jennifer , Shaffer Tristan , DiPasquo Dan , Lim Lee , Lovly Christine Marie 
Published: September 2018

8571 Background: Advances in the treatment of small cell lung cancer (SCLC), an aggressive disease with poor prognosis, will require the development of diagnostic methods during treatment that are more sensitive and descriptive than are currently available. The emergence of “liquid biopsy” technologies coupled with comprehensive genomic information about common mutations in SCLC prompted us to implement a blood-based assay for simultaneous sequencing of circulating, cell-free tumor DNA (cfDNA) and determination of the peripheral a and b T cell receptor repertoire in patients with SCLC. Methods: Our SCLC assay uses targeted hybrid capture and next generation sequencing of cfDNA extracted from patient plasma to detect somatic mutations in 14 frequently mutated genes in SCLC. We also sequenced rearranged T cell receptor α and β genes, each with 5000 unique α and β CDR3 open reading frames per microgram of gDNA. Over 26 months we followed 27 patients with SCLC (16 with extensive stage and 11 with limited stage disease) and examined cfDNA from 141 plasma samples and T cell repertoire from 41 samples. Results: We detected somatic, disease-associated mutations in 85% of patient samples (23/27) with allele frequencies of cfDNA ranging from ≤0.5% to ≥85%. The most commonly mutated genes were TP53 (17/27 patients) and RB1 (10/27 patients) . We detected 87 unique genomic alterations in 12 different genes (in addition to TP53 and RB1 these included PTEN, NOTCH1-4, MYC, MYCL1, PIK3CA, KIT, and BRAF). The observed mutant allele frequencies in longitudinal samples tracked with treatment response, including cases in which cfDNA allele frequencies increased before clinical evidence of relapse. Longitudinal monitoring of T cell repertoire demonstrated both variability between patients and sequential changes during therapy, including one case of decreased T cell numbers accompanying disease relapse. Conclusions: As the field of immuno-oncology matures, we anticipate that coupled determination of T cell repertoire together with cfDNA monitoring will merge into a clinically useful “molecular image” of each patient’s disease status and real-time host immune response.
Efficacy of the addition of cisplatin to single-agent first-line chemotherapy in elderly patients with advanced non-small cell lung cancer (NSCLC): A joint analysis of the multicenter, randomized phase III MILES-3 and MILES-4 studies.
Authors: Gridelli Cesare , Morabito Alessandro , Cavanna Luigi , Luciani Andrea , Maione Paolo , Bonanno Laura , Piazza Elena , Leo Silvana , Cinieri Saverio , Ciardiello Fortunato , Burgio Marco Angelo , Ferrara Domenica , Cortinovis Diego , Rosetti Francesco , Montanino Agnese , Manzo Anna , Daniele Gennaro , Perrone Francesco , Gallo Ciro , Piccirillo Maria Carmela 
Published: September 2018

9002 Background: The role of platinum in first line treatment of elderly patients with advanced NSCLC is still debated. We tested its efficacy in two parallel phase 3 trials. Methods: Advanced NSCLC patients, > 70 years, ECOG performance status 0-1, were eligible. In MILES-3 (started in 2011) patients with any tumor histology were randomly assigned 1:1 to cisplatin/gemcitabine (C 60 mg/m² d1, G 1000mg/m² dd1,8) or gemcitabine (G 1200 mg/m² dd1,8). In MILES-4 (started in 2013 with a factorial design) patients with non-squamous histology were randomly assigned 1:1:1:1 to CG, G, cisplatin/pemetrexed (C 60 mg/m² d1, P 500 mg/m² d1) or pemetrexed (P 500 mg/m² d1). Six cycles were planned. In each trial, to have 80% power in detecting a HR of death 0.75 (corresponding to 3-month prolongation of median survival), with 0.05 two-tailed α, 382 events were required. The two trials were closed prematurely because of slow accrual but a joint analysis allowed to properly perform the final analysis, according to IDMC advice. Analysis was based on intention-to treat and adjusted by possible confounding factors. Results: From Mar 2011 to Aug 2016, 531 patients (MILES-3: 299, MILES-4: 232) were assigned to cisplatin-doublet (n = 263) or single-agent chemotherapy (n = 268). Median age was 75, 79% were male, 70% had non-squamous histology. Median number of cycles was 4 and 3 with and without cisplatin, respectively. With a median follow-up of 2 years, 384 deaths and 448 progression-free survival (PFS) events were reported. With and without cisplatin, median OS was 9.6 vs 7.5 months (HR 0.86, 95% CI: 0.70-1.04, p = 0.14); median PFS was 4.6 vs 3.0 months (HR 0.76, 95% CI: 0.63-0.92, p = 0.005); response rate was 15.5% vs 8.5% (p = 0.02). Significantly more severe hematologic toxicity and fatigue were reported with cisplatin. Conclusions: Although improving PFS and response rate, addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival of elderly patients with advanced NSCLC. QOL data will be reported separately. Partially supported by AIFA (grant FARM8KAJZK) and Eli Lilly. Clinical trial information: NCT01405586 and NCT01656551.
A randomized, controlled, open label phase II study of erlotinib (E) with or without the MET antibody emibetuzumab (Emi) as first-line treatment for EGFRmt non-small cell lung cancer (NSCLC) patients who have disease control after an 8-week lead-in treatment with erlotinib.
Authors: Scagliotti Giorgio V. , Moro-Sibilot Denis , Kollmeier Jens , Favaretto Adolfo G. , Cho Eun Kyung , Grosch Heidrun , Kimmich Martin , Girard Nicolas , Tsai Chun-Ming , Hsia Te-Chun , Brighenti Matthew , Schumann Christian , Wang Xuejing Aimee , Wijayawardana Sameera R. , Gruver Aaron M , Wallin Johan , Mansouri Kambiz , Wacheck Volker , Chang Gee-Chen 
Published: September 2018

9019 Background: MET expression is a mechanism of resistance to EGFR inhibition in EGFRmt NSCLC and correlated with poor prognosis. Emi (LY2875358) is a humanized IgG4 monoclonal bivalent MET antibody that blocks ligand dependent and independent HGF/MET signaling. This Phase 2 study compared the clinical activity of Emi + E versus single agent E in 1st line EGFRmt metastatic NSCLC. Methods: Stage IV, EGFRmt NSCLC pts with disease control following an 8-week lead-in E (150 mg PO QD) treatment were randomized 1:1 to receive Emi (750 mg IV Q2W) + E or E alone. Pts were stratified by ECOG PS, ethnicity, MET expression status, and response at the end of the lead-in. The primary endpoint was PFS from randomization. Additional endpoints included safety, OS, PK, and exploratory analysis of MET-expressing populations. Results: Out of181 pts enrolled, 141 pts were randomized (Emi+E: 71; E: 70). In the ITT population, median PFS for EMI+E was 9.3 months (m) compared with 9.5 m for E (HR = 0.89: 90% CI 0.64-1.23; p = 0.534). Exploratory analysis of MET-high expressing pts (MET 3+ expression in ≥90% of tumor cells; n = 24 pts) showed a 15.3 m improvement in PFS (EMI+E: 20.7 m; E: 5.4 m [HR: 0.39; 90% CI: 0.17-0.91]). No difference in PFS was observed in the complementary population (HR: 1.1 [90% CI: 0.7-1.7]). Similar frequencies of related AEs were reported for both treatment arms. Drug-related TEAEs that were more frequent ( > 10%) for Emi+E were peripheral edema and fatigue (all grade 1 or 2). Emi serum concentrations were consistent with previously obtained PK results, and no apparent exposure-response was observed. Median OS in the ITT population was not achieved (NA) for either arm. In MET-high expressing pts, median OS was 20.6 m for E (90% CI: 8.87, NA) whereas it was not achieved for Emi+E (90% CI: NA, NA). Conclusions: No statistically significant difference in PFS was noted in the ITT population.Exploratory analysis confirmed that high MET expression is a negative prognostic marker for pts treated with E and indicated that these pts may receive clinically meaningful benefit from Emi+E. Clinical trial information: NCT01897480.