bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study.
Authors: Cascone Tina , William William Nassib , Weissferdt Annikka , Lin Heather Y. , Leung Cheuk Hong , Carter Brett W. , Fossella Frank V. , Mott Frank , Papadimitrakopoulou Vassiliki , Blumenschein George R. , Le Xiuning , Federico Lorenzo , Parra Cuentas Edwin Roger , Bernatchez Chantale , Wistuba Ignacio Ivan , Vaporciyan Ara A. , Gibbons Don Lynn , Swisher Stephen , Heymach John , Sepesi Boris ,   NEOSTAR Study Group
Published: March 2020

8504 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) induce major pathologic response (MPR) rates of 20 to 45% in resected NSCLCs. We report the results of NEOSTAR - a phase 2 trial of neoadjuvant N or NI for NSCLCs. Methods: Pts with stage I-IIIA (single N2) resectable NSCLC (AJCC 7th), PS 0-1, were randomized to N (3 mg/kg IV, D1, 15, 29) or N plus I (1 mg/kg IV, D1) followed by surgery (n = 44). Primary endpoint: MPR (≤10% viable tumor), hypothesized to be higher than MPR to induction chemotherapy historical controls. Tumor immune infiltrates and pre- & post-ICI tumor PD-L1 % were assessed by flow cytometry & IHC. Wilcoxon ranked sum test & Fisher’s exact test were used for comparisons. Results: 44 pts were randomized, 23 N, 21 NI: mean age 66, 64% males, 18% never smokers, 59% adenocarcinomas, stages: IA 8 (18%), IB 15 (34%), IIA 7 (16%) IIB 5 (11%); IIIA 9 (20%). Only 3 pts received < 3 doses due to TRAEs (7%). 34 pts had surgery post ICIs (7 not resected [7/41], 17%, [2 N, 5 NI], 3 pending). There were 10 MPRs in 41 pts overall (24%, 4 N, 6 NI), of which 6 were path CRs (15%, 2 N [9%], 4 NI [21%]). Among 34 resected pts, MPR rate was 29% (N 20%, NI 43%). Median % of viable tumor was lower post NI vs N (20% vs 65%, p = .097). ORR (RECIST v1.1) was 22% (8 PRs [5 N, 3 NI], 1 CR [NI]); 15% of pts had PD (3 N, 3 NI). The proportion of CR+PR in MPR+ was higher than in MPR- (6 [60%] vs 2 [7%], p < .001). Surgical complications included 2 bronchopleural fistulas (BPFs) in N & 8 air leaks (5 N, 3 NI). G3-G5 TRAEs included a death due to BPF post steroid-treated pneumonitis (G5, N); G3 pneumonia, hypoxia, hypermagnesemia (1 each, all N), G3 diarrhea (1 NI). CD3+ & CD103+ tissue resident memory CD8+ TILs were higher in NI- vs N-treated tumors (CD3+ 81.2% vs 54.4%, p = .028; CD8+ 56.2% vs 38.3%, p = .069). Median pre-treatment tumor PD-L1 was higher in responders (MPR+, CR+PR) vs non-responders (80% vs 1%, p = .024), and the % of viable tumor was lower in tumors with PD-L1 > 1% vs PD-L1 ≤1% (median 20% vs 80%, p = .046). Conclusions: Overall a 24% MPR rate to neoadjuvant ICIs was observed. NI induced a higher % of non-viable tumor and of tissue resident memory TILs vs N. Antitumor activity was associated with higher pre-treatment PD-L1 levels. Clinical trial information: NCT03158129.
Effect of trilaciclib, a CDK 4/6 inhibitor, on myelosuppression in patients with previously treated extensive-stage small cell lung cancer receiving topotecan.
Authors: Hart Lowell L. , Andric Zoran Gojko , Hussein Maen A. , Ferrarotto Renata , Beck J. Thaddeus , Subramanian Janakiraman , Radosavljevic Davorin Z. , Jovanovic Dragana , Pachipala Krishna Kishore , Samarzija Miroslav , Zaric Bojan , Hanna Wahid Tewfik , Aljumaily Raid , Owonikoko Taofeek Kunle , Malik Rajesh K. , Morris Shannon R. , Johnson Misha L. , Yang Zhao , Adler Steven , Spigel David R. 
Published: March 2020

8505 Background: Multi-lineage myelosuppression is an acute toxicity of cytotoxic chemotherapy leading to hematologic adverse events and dose reductions and delays. Current therapies are lineage specific and administered after chemotherapy damage.Trilaciclib (T), a highly selective, reversible CDK4/6 inhibitor, is designed to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation). We have shown that T mitigates myelosuppression in patients with newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) receiving 1st-line chemotherapy. Methods: In this blinded, placebo-controlled, multicenter Phase 2 study, patients with previously treated ES-SCLC were randomized to T (240 mg/m2) + 0.75 mg/m2 topotecan, T (240 mg/m2) + 1.5 mg/m2 topotecan, or placebo (P) + 1.5 mg/m2 topotecan IV on days 1-5 of 21-day cycles. Patients had access to standard supportive care, except in cycle 1 where prophylactic growth factors were not allowed. Eligible patients had adequate organ function, measurable disease, ECOG PS 0-2, and disease progression during or after prior 1st/2nd-line chemotherapy. Objectives included safety, tolerability, measures of myelosuppression and tumor efficacy. Results: 91 patients were randomized: 30 patients received T + 0.75 mg/m2 topotecan, 32 patients received T + 1.5 mg/m2 topotecan and 28 patients received P + 1.5 mg/m2 topotecan. In patients receiving 1.5 mg/m2 topotecan, T treatment reduced occurrence [40.6% (T) vs 75.6% (P), p = 0.016], and duration in cycle 1 [2 days (T) vs 8 days (P), p = < 0.0001] of severe neutropenia. T-treated patients had fewer RBC transfusions on/after 5 weeks on study, GCSF administrations, and all-cause dose reductions. Chemotherapy efficacy was comparable in both arms (P and T) treated with 1.5 mg/m2 topotecan (median PFS (T) 4.2 months vs (P) 4.2 months, HR = 0.83). OS data is immature. Conclusions: T combined with topotecan mitigated chemotherapy-induced myelosuppression and improved tolerability of topotecan vs P. Results suggest the addition of T to cytotoxic chemotherapy for the treatment of ES-SCLC is clinically beneficial. Clinical trial information: NCT02514447.
Biomarker driven phase II umbrella trial study of AZD1775, AZD2014, AZD2811 monotherapy in relapsed small cell lung cancer.
Authors: Park Sehhoon , Shim Joonho , Jung Hyun Ae , Sun Jong-Mu , Lee Se-Hoon , Park Woong-Yang , Ahn Jin Seok , Ahn Myung-Ju , Park Keunchil 
Published: March 2020

8514 Background: Recent progress in genomic profiling of small cell lung cancer (SCLC) has demonstrated that a high proportion of SCLC harbor mutations in cell cycle-related genes and RICTOR amplification. With the recent introduction of cell-cycle altering small molecules, AZD1775 (WEE1 inhibitor), AZD2811 (aurora kinase B inhibitor) and mTOR1/2 inhibitor (AZD2014), biomarker-driven umbrella study is being conducted in relapsed SCLC. Methods: This is a phase II umbrella trial study with multiple monotherapy arms in resistant SCLC who has failed prior platinum-based chemotherapy and known genomic profile from pre-designed screening study of SUKSES-S (Small cell lung cancer Umbrella Korea StudiES, NCT02688894). Patients with MYC family amplification or co-alteration in CDKN2A and TP53 were allocated to SUKSES-C (AZD1775 arm, NCT02593019); RICTOR amplification to SUKSES-D (AZD2014 arm, NCT03106155). Otherwise, patients were randomly assigned to non-biomarker specific arms, SUKSES-N1 (AZD1775 arm, NCT02593019) or SUKSES-N3 (AZD2811 arm, NCT03366675). Each cohort was designed as Simon 2-stage scheme. Results: Patients allocated to SUKSES-C (n = 7) & N1 (n = 24) showed no objective response rate and stable disease was observed in 3 patients (42.9%) and 6 patients (25.0%), respectively. The median progression-free survival (PFS) was 1.28 months (95% confidential interval [CI] 1.18–not available [NA]) and 1.21 months (95%CI 1.15-2.33), respectively. SUKSES-D (n = 4) showed no objective response as well as no stable disease with PFS of 1.25 months (95%CI 0.98-NA). SUKSES-N3 (n = 15) showed no objective response with 5 stable disease (33.3%) and PFS of 1.61 months (95%CI 1.18-NA). For the safety record, adverse events (AEs) grade≥3 were observed as follows: SUKSES-C & -N1 (n = 1, 3.2%), -D (n = 3, 75.0%), -N3 (n = 9, 60%). Notably, neutropenia (grade≥3) was frequently observed (n = 8, 53.3%) in AZD2811 arm including a case of septic shock. Conclusions: SUKSES is the first biomarker-driven umbrella study with the largest cohort of genomic profile pre-screened in resistant SCLC patients (n = 275). However, it does not support further development of the current regimens of AZD1775, AZD2811, AZD2014. Altered administration schedule or combination regimen is under development. Clinical trial information: NCT02593019, NCT03106155, NCT03366675.
A feasibility study of induction pemetrexed plus cisplatin followed by pleurectomy/decortication for malignant pleural mesothelioma (Japan Mesothelioma Interest Group 1101 Trial).
Authors: Hasegawa Seiki , Yokoi Kohei , Okada Morihito , Tanaka Fumihiro , Shimokawa Mototsugu , Daimon Takashi , Nakano Takashi 
Published: March 2020

8518 Background: Although pleurectomy/decortication (P/D) has become a preferred surgical technique for malignant pleural mesothelioma (MPM), only a few prospective, multi-center clinical trials have been conducted. Here we present final results of a nationwide, prospective, multi-institutional study to evaluate the feasibility of induction chemotherapy followed by P/D. Methods: Eligibility criteria: a histologically confirmed diagnosis of MPM; clinical T1–3, N0–2, M0 disease; no prior treatment for the disease; age between 20 and 75 years; ECOG performance status of 0 or 1; and written informed consent. Treatment methods: Induction chemotherapy of pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 for 3 cycles, followed by P/D. Intraoperative conversion from P/D to extrapleural pneumonectomy (EPP) was permitted. Pulmonary function tests were performed at 3, 6, 12, 24, and 36 months after surgery. Primary endpoint was macroscopic complete resection (MCR) rate regardless of the surgical technique. Results: Of 24 patients enrolled, 20 patients were eligible: median age 66 (48–74); M/F: 17/3, Clinical stage I/II/III: 8/9/3; Histology epi/sar/bi: 19/1/0. Two discontinued protocol before surgery due to deteriorated FEV1 or adverse effect (AE) of chemotherapy, and the remaining 18 patients completed surgery with MCR: P/D in 15 patients and EPP in 3. The trial met the primary endpoint with MCR rate of 90% (18/20). There was no treatment-related 30- and 90-day mortality. There were two cases of chemotherapy-related grade 4 AEs, but no surgery-related grade 4 AE occurred. The overall survival rates at 1 and 2 years and median survival time (MST) after registration were 95.0% (95% CI, 69.5 to 99.3), 70.0% (45.1 to 85.3), and 41.4 months (19.7 to NA), respectively. The progression-free survival rates at 1 and 2 years and MST after registration were 84.7% (60.0 to 94.8), 42.4% (20.5 to 62.7), and 22.9 months (12.7 to 28.4), respectively. Recurrence occurred in 17 patients, and initial relapse sites were local in 17 (100%) and distal in 6 (35.3%). The best values of FVC and FEV1 during postoperative period were 78.0% and 82.5% of preoperative values, respectively. Conclusions: Induction chemotherapy plus P/D yielded a MST over 40 months with acceptable risks. Postoperative pulmonary function was approximately 80% of preoperative value. Clinical trial information: UMIN000009092.
Ultrasensitive DNA hypermethylation detection using plasma for early detection of NSCLC: A validation study in Chinese patients.
Authors: Chen Chen , Huang Xiaojie , Song Mingzhe , Yin Wei , Hulbert Alicia , Brock Malcolm , Herman James , Yu Fenglei , Liu Wenliang 
Published: March 2020

8522 Background: Our previous study revealed that high diagnostic accuracy for early stage lung cancer could be obtained in plasma samples with ultrasensitive DNA hypermethylation detection methods called MOB-qMSP. In this study, we sought to validate and also improve the diagnostic accuracy of lung cancer screening with modified MOB-qMSP approach in Chinese patients. We also develop a lung cancer specific gene panel for Chinese patients. Methods: We included patients with small lung nodules (less than 3cm in diameter) on CT scan screening and conducted a case-control study. Cases (n=138) had pathological confirmation of Non-Small Cell Lung Cancer (NSCLC) lesions staged IA or IB. Controls (n=65) had pathological confirmation of non-cancerous lesions. Plasma samples were obtained pre-operatively. Promoter methylation of eight lung cancer-specific genes (CDO1, TAC1, SOX17, HOXA7, HOXA9, GATA4, GATA5 and PAX5B) was detected using nanoparticle-based DNA extraction (MOB) followed by qMSP. Results: DNA methylation was detected in plasma more frequently in cases compared to controls (p<0.001) for 5 out of 8 genes. The sensitivity and specificity for lung cancer diagnosis using the best individual gene was 64-85% and 55-79% respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 92% and 78%. Area under the Receiver Operating Curve (AUC) for this panel was 0.90, 95% CI (0.86-0.96). Cross validation combining gene methylation with clinical information correctly predicted lung cancer in 86% of subjects using plasma detection. Furthermore, we analyzed the sensitivity and specificity of the same three-gene combination in cases subgroups regarding the tumor size and the results are as follow: in subgroup with tumor size of 2-3cm, the sensitivity and specificity were 94% and 87%, and the AUC was 0.96, 95% CI (0.91-0.99); in subgroup with tumor size of 1-2 cm, the sensitivity and specificity were 92% and 80%, and the AUC was 0.90, 95% CI (0.84-0.96); in subgroup with tumor size less than 1cm, the sensitivity and specificity decreased to 66% and 87%, and the AUC was 0.77, 95% CI (0.64-0.88). Conclusions: This study validates our previous study but in Chinese patients that it is possible to obtain high diagnostic accuracy for early stage NSCLC using a panel of methylated promoter genes in plasma samples with ultrasensitive MOB-qMSP, especially in patients with tumor of larger size. These epigenetic biomarkers could potentially be used to identify patients with high risk of lung cancer development.
Randomized phase Ⅱ trial of uracil/tegafur and cisplatin versus pemetrexed and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage Ⅲ non-squamous non-small-cell lung cancer: NJLCG1001.
Authors: Watanabe Kana , Toi Yukihiro , Nakamura Atsushi , Fukuhara Tatsuro , Chiba Ryosuke , Akiyama Masachika , Sakakibara-Konishi Jun , Tanaka Hisashi , Yoshimura Naruo , Miyauchi Eisaku , Nakagawa Taku , Igusa Ryotaro , Minemura Hiroyuki , Mori Yoshiaki , Fujimoto Keisuke , Matsushita Haruo , Takahashi Fumiaki , Inoue Akira , Sugawara Shunichi , Maemondo Makoto 
Published: March 2020

8527 Background: It is unknown which regimen is the best in concurrent chemoradiotherapy (CCRT) of locally advanced non-squamous non-small cell lung cancer (NSCLC). Our previous randomized phase Ⅱ study, NJLCG0601, showed that chemoradiotherapy with uracil/tegafur (UFT) and cisplatin achieved promising efficacy with acceptable toxicities. In this trial, this regimen was compared to a regimen with pemetrexed and cisplatin for stage Ⅲ non-squamous NSCLC. Methods: Patients with inoperable stage Ⅲ non-squamous NSCLC were randomized to UFT 400 mg/m2 on days 1–14 and 29–42, and cisplatin 80 mg/m2 on days 8 and 36 (UP), or pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on days 1, 22, and 43 (PP). Involved-field radiotherapy (IFRT) was administered from day 1 to a total dose of 66 Gy radiotherapy in 33 fractions. Consolidation chemotherapy after CCRT was not planned for this study. The primary endpoint was 2-year overall survival (OS), with expected rates of 55% and a lower limit of 35% (alfa 0.05, beta 0.2). Secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), OS, and toxicity profile. Results: From November 2010 to June 2017, 86 patients were enrolled from 11 institutions. Of the 85 eligible patients, the rate of 2-year OS was 78.6% (95% CI: 62.8–88.3%) in the UP arm and 85.5% (95% CI: 70.5–93.2%) in the PP arm. The ORR was 76.7% in the UP arm and 81.0% in the PP arm. With a median follow-up of 54 months, median PFS and OS were 12.3 and 64.2 months in the UP arm, and 26.2 months and not reached in the PP arm, respectively. Grade 3/4 febrile neutropenia was more frequent in the UP arm than in the PP arm (14.0%, 2.0%, respectively). Grade 3/4 pneumonitis occurred in 7.0% and 4.8% of patients in UP and PP arms, respectively. Conclusions: Both regimens with IFRT achieved the expected 2-year survival rate. PP had more favorable results than UP in terms of OS and PFS. We selected the PP arm for the next step.
T cell repertoire analysis of non-small cell lung cancer patients treated with neoadjuvant nivolumab alone or in combination with ipilimumab (NEOSTAR trial).
Authors: Reuben Alexandre , Zhang Jianjun , Lin Heather Y. , Little Latasha , Gumbs Curtis , Tran Hai T. , Wang Linghua , Haymaker Cara L. , Mehran Reza J. , Rice David C. , Walsh Garrett L. , Lee J. Jack , Wistuba Ignacio Ivan , Swisher Stephen , Vaporciyan Ara A. , Futreal Andrew , Sepesi Boris , Heymach John , Gibbons Don Lynn , Cascone Tina ,   NEOSTAR Study Group
Published: March 2020

8532 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) are being explored in resectable non-small cell lung cancer (NSCLC). Here, we studied the composition and changes in the T cell repertoire in a cohort of NSCLC patients (n = 44) treated with neoadjuvant nivolumab (N) alone or in combination with ipilimumab (NI) followed by surgery (NEOSTAR trial). Methods: Sequencing of the variable CDR3β chain of the T cell receptor (TCR) involved in antigen binding was performed in pre-treatment and surgical tumors, matched adjacent uninvolved lung specimens, as well as paired longitudinal blood at baseline, prior to each dose of therapy, prior to surgery, and within 8 weeks post-surgery. T cell repertoire density, diversity, and clonality (reactivity) were evaluated in addition to tumor PD-L1 expression pre- and post-neoadjuvant treatment. Results: Median T cell diversity in the blood post-therapy was 3.3-fold higher in NI- compared to N-treated patients (40,993 [NI, n = 3] vs 12,177 [N, n = 4] unique TCR rearrangements, n.s.). However, median T cell clonality in the blood was 3.5-fold higher in N- than NI-treated patients post-therapy (0.093 [N, n = 4] vs 0.026 [NI, n = 3], n.s.). Median clonality was 3.8-fold higher in the tumor post-therapy in patients receiving NI than in those receiving N (0.076 [NI, n = 7] vs 0.020 [N, n = 5], n.s.). Interestingly, diversity in the blood at baseline and in the tumor post-therapy were positively correlated ([n = 7], r = 0.82; p = 0.023), which may reflect an influx of cells from the periphery following ICIs. Importantly, higher baseline T cell clonality in the blood was associated with a lower % of viable tumor at time of surgery in both treatment arms ([n = 7], r = -0.77; p = 0.04). Conclusions: Our study is the first to assess the TCR repertoire in NSCLC patients treated with combination neoadjuvant NI and highlights potential mechanistic differences compared to N alone. Neoadjuvant NI is associated with higher clonality in tumors and lower clonality in blood post-therapy, suggesting increased T cell trafficking into the tumor. Finally, lower pre-treatment clonality in the periphery was correlated with higher % viable tumor post-neoadjuvant ICIs. Clinical trial information: NCT03158129.
Development of a prognostic risk model for small cell lung cancer: Identification of high-, intermediate-, and low-risk cohorts based on clinical-genomic data.
Authors: Ardeshir-Larijani Fatemeh , Wildey Gary , Fu Pingfu , Dowlati Afshin 
Published: March 2020

8554 Background: Although many clinical prognostic factors for SCLC outcome have been described, there are no models that incorporate the combination of clinical and genomic details into a risk model defining high and low risk patients. Methods: From a total of 791 SCLC patients seen between 2013-2018, 91 were evaluated by exome sequencing. Using the univariate Cox regression model, 19 genes were prognostic for survival and included RET, ERBB4 MAP3K1, ABL1, CCND1, TSC1, PRKCI, FGFR3, JAK3, ZNF217, BRCA1, GPR124, LRP1B, GNAS, TAF1, FGF3, STAT3, CD79A and FLT. LASSO, elastic-net Cox and traditional Cox model with stepwise selection along with traditional clinical factors (age and stage) were further used to build the final model. The final risk groups were defined based upon the prognostic index from multivariable Cox model involving age, stage (extensive/limited) and 6 genes ( MAP3K1, ABL1, CCND1, PRKCI, BRCA1, GNAS). Results: The overall survival (OS) for the entire cohort was 11.2 (95% CI: 9 – 13.4) months and the median age was 65 (range: 39 - 90) years. Eighty percent (N = 74) of evaluated patients had extensive stage (ES) disease. The HR for death of age and stage (ES/LS) was 1.06 (CI: 1.03-1.08, p < 0.0001) and 4.33 (CI: 2.23-8.41, p < 0.0001) respectively. ABL1 demonstrated the highest HR of 10.14 (2.81-36.6, p = 0.0004) followed by PRKCI (HR: 5.05, CI: 1.43-17.8 , p < 0.012), CCND1 (HR: 4.52, CI: 1.23-16.57, p < 0.023), MAP3K1 (HR: 3.38, CI: 1.37- 8.33, p = 0.008) and GNAS (HR: 2.21, CI: 1.11-4.43, p < 0.025). Interestingly, BRACA1 mutation was protective as patients with BRACA1 mutation had significantly better overall survival (HR: 0.3, CI: 0.1- 0.85, p < 0.023). Our model categorized patients into three groups of low risk ( N= 31), intermediate risk ( N= 30) and high risk ( N= 30) with significantly different survival outcomes ( p < 0.0001). Those with low risk had the median OS of 27.4 (95% CI: 16.8-55.5) months, intermediate risk with median OS of 10.8 (95% CI: 7 – 14.7) months and high risk with median OS of 5.4 (95% CI: 3.9- 9) months. Conclusions: This clinical-genomic risk group stratification represents a useful model to estimate SCLC survival outcome and may have value in future clinical trials.