bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of toripalimab with anlotinib and chemotherapy as first-line therapy in patients with extensive-stage small-cell lung cancer: Preliminary results of an open-label, single-arm, phase II study.
Authors: Luo Hao , Jian Dan , Feng Yan , Zhong Li , Chen Qian , Guan Wei , Zhang Shiheng , Luo Jiamin , Yang Xueqing , Gong Kan , Xiong Yanli , Li Mengxia , Xu Mingfang , Pu Yu , Zhao Liang , Qian Chengyuan , Dai Nan , Wang Dong 
Published: June 2021

e20570 Background: Although the combination of PD-1/PD-L1 immune checkpoint inhibitors (ICIs) with platinum-etoposide chemotherapy (EP) is the preferred first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC), the survival benefit of the addition of ICIs was still modest. Recent studies supported that combination of ICIs and anti-angiogenic agents could be a promising therapeutic strategy for normalization the immunosuppressive microenvironment and overcoming the low efficacy of ICIs. We reported the efficacy and safety of toripalimab combined with anlotinib and EP in treatment-naïve ES-SCLC. Methods: The eligible ES-SCLC patients (18-75 years, ECOG PS ≤2), with measurable target lesion (RECIST v1.1) received toripalimab (240 mg, d1) combined with etoposide (100 mg/m2, d1-3) plus carboplatin (AUC = 5, d1)/cisplatin (75 mg/m2, d1) and anlotinib (12 mg QD, d1-14) of a 21-day cycle for 4-6 cycles, then patients with CR、PR or SD could continue to receive maintenance therapy with toripalimab and anlotinib until disease progression. The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: Between 2018 October and 2020 November, 16 treatment-naïve ES-SCLC patients (14 males, 2 females) were enrolled. The median age is 63 (range, 42-74) years. The median follow-up was 7.6 months. 100% (16/16) patients achieved an objective response (1 CR and 15 PR). The DCR was also 100% (16/16). The median DOR had not been reached (range, 4.8+ to 21.9+ month). 37.5% (6/16) patients had disease progression after six months of treatment, while median PFS was not reached. As of Jan 31, 2021, all patients were still alive. The median OS had not been reached. 62.5% (10/16) patients remained on-treatment. The most common adverse events (AEs) were grade 1-2 anemia (75%), decreased appetite (50%) and neutropenia (43.8%). Seven patients had Grade 3 AEs (5 neutropenia; 1 leukopenia, 1 emesis, and 1 ketoacidosis). No Grade 4/5 AEs occurred. Conclusions: Toripalimab combined with anlotinib and etoposide plus carboplatin/cisplatin showed promising anti-tumor activity and tolerable toxicities in treatment-naïve ES-SCLC. Clinical trial information: NCT04731909.
PI3K-AKT pathway alterations are revealed as a potential mechanism of chemoradiation resistance in small cell lung cancer by whole-exome sequencing.
Authors: Chen Ming , Jin Ying , Chen Yamei , Hu Xiao , Tang Huarong , Li Qian , Li Pansong , Lv Xinze , Xia Xuefeng , Zhang Jianjun 
Published: June 2021

e20573 Background: Although small-cell lung cancer (SCLC) is sensitive to chemotherapy and radiotherapy initially, nearly all patients recur often with treatment-resistant disease. Comparing genomic profiles and clonal architecture of paired treatment-naïve and recurrent tumors may provide novel insights into mechanisms underlying recurrence and susceptibility to further treatment. Methods: Paired tumor samples procured at diagnosis and relapse were collected from 11 patients (pts) with limited-stage SCLC treated with concurrent chemoradiation (CCRT). All tissues underwent whole exome sequencing (WES). Genomic landscape including somatic mutations, somatic copy number alterations (SCNAs), and clonal architecture were compared between treatment-naïve and paired recurrent tumor samples. Baseline and paired recurrent plasma samples from another 9 pts with SCLC treated with CCRT were performed deep sequencing using a targeted panel containing 1021 cancer related genes. Results: We observed TP53 and RB1 alterations including mutations and SCNAs in the majority of treatment-naïve ( TP53 in 10 of 11, RB1 in 7 of 11 pts) and relapse samples ( TP53 in 8 of 11, RB1 in 8 of 11 pts). Tobacco exposure related mutational signature was most or second predominant in 11 pre-treatment and 9 recurrent samples, respectively. Compared with primary tumors, relapsed tumors showed significantly increased number of mutations (220 vs 210, p = 0.016). A high proportion of shared mutations between baseline and PD samples ranging from 39% to 94% was observed. More than half (n = 6) of the 11 pts had increased chromosomal instability in recurrent tumors. A total of 687 relapse-specific also called acquired mutations in 633 genes were identified, in which 158 mutations with cancer cell fraction (CCF) > 0.6. These genes were enriched in PI3K-ATK signaling pathway and covered 73% (8/11) pts. Of the 9 paired plasma samples performed by targeted sequencing, genes with specific mutations and mutations with increased CCF in relapsed plasma samples were also enriched in PI3K-ATK pathway. In vitro proliferation assay indicated that PI3K inhibitor gave rise to a marked decrease in proliferation after combined with cisplatin, implying the potential mechanism of chemoradiation resistance. The number of clones in recurrent samples was higher than that in pre-treatment samples (13 vs 12, p = 0.004), indicating that new clones emerged under the treatment and tumor heterogeneity increased. Patients characterized by weakening of the major treatment-naïve clone tended to exhibit relatively longer PFS than those with sustaining major clone in both b baseline and relapsed tumors (p = 0.034). Conclusions: PI3K-ATK pathway alterations are frequent in recurrent SCLCs, which may be a candidate resistant mechanism after chemoradiation. PFS is probably associated with clonal evolutionary pattern.
Real-world treatment patterns, clinical outcomes, and health care resource utilization in extensive-stage small cell lung cancer in Canada.
Authors: O'Sullivan Dylan E. , Brenner Darren , Syed Iqra , Shanahan Mary Kate , Moldaver Daniel , Sit Christina , Bebb D. Gwyn , Cheung Winson Y. , Boyne Devon J. 
Published: June 2021

e20575 Background: Extensive stage small cell lung cancer (ES-SCLC) patients face a high risk of recurrence and a uniformly poor prognosis. Real-world evidence related to treatment patterns, clinical outcomes, and healthcare resource utilization is needed to highlight the unmet clinical need and demand for novel therapies within this patient population. Methods: A population-based, retrospective, longitudinal study of adult ES-SCLC patients diagnosed in the province of Alberta, Canada between January 2010 and December 2018 was conducted using provincial electronic medical records and administrative claims data. Results: A total of 1,941 ES-SCLC patients were included of which 1,465 (75%) initially presented with ES-SCLC and 476 (25%) had recurrent disease. Among newly diagnosed ES-SCLC patients, front-line therapy was as follows: 523 (35.7%) chemotherapy and radiotherapy, 280 (19.1%) chemotherapy alone, 133 (9.1%) radiotherapy alone, and 529 (36.1%) best supportive care. The primary sites of radiation were the chest (67.1%) and the brain (45.7%). Median age at diagnosis was 70 years (range: 39-94) and 50.2% were men. In contrast to the de novo patients, the majority of recurrent cases (71.6%) received no front-line therapy. In the full cohort (de novo and recurrent cases), 46.5% of patients initiated first-line, 8.7% second-line, and 1.4% third-line chemotherapy. The majority of patients received either carboplatin plus etoposide (49.5%) or cisplatin plus etoposide (43.0%) in first-line. Median overall survival was higher for patients who were treated with chemotherapy and radiotherapy (10.59 months; 95% CI: 10.03-11.61) compared to patients who received chemotherapy alone (5.65 months; 95% CI: 5.06-6.12), radiotherapy alone (3.02 months; 95% CI: 2.47-4.01), or best supportive care (0.82 months; 95% CI: 0.72-0.92; log-rank p-value < 0.001). Among patients who received first-line systemic therapy, the 1-year, 2-year and 5-year survival was 29.1% (95% CI: 26.3-32.3), 7.3% (95% CI: 5.7-9.2) and 2.9% (95% CI: 1.8-4.5), respectively and the average time spent in hospital was 17, 11, and 10 days per patient within years 1, 2, and 3, respectively. Conclusions: In a Canadian real-world setting, the initiation of first-line treatment in ES-SCLC was low with significant attrition in subsequent lines. It was evident that patients who received treatment had greater survival compared to those who do not. Collectively, these results underscore the need for effective front-line therapeutic options and highlight the potential for novel therapies to improve patient outcomes.
Overall survival throughout treatment course among patients diagnosed with small cell lung cancer.
Authors: Estrin Adina , Prince Patricia , Supina Dylan , Ben-Joseph Rami , Boccuti Anne , Asubonteng Kobby , Fridman Moshe , Rengarajan Badri , Hanvesakul Raj , Taylor Benjamin 
Published: June 2021

e20577 Background: Previous studies have investigated overall survival (OS) among small cell lung cancer (SCLC) patients with data through 2015. Using data through mid-2019, this study strives to make the body of studies more current, and to provide more recent data on the baseline characteristics and OS of treated SCLC patients, stratified by stage at diagnosis. Methods: This retrospective cohort study identified adult patients with confirmed SCLC between January 1, 2016 - December 31, 2018 that initiated anti-cancer treatment using real-world data from electronic medical records (ConcertAI, including data from CancerLinQ, an initiative of the American Society of Clinical Oncology). Exclusion criteria included evidence of other primary cancer at baseline, no initial stage recorded, death prior to diagnosis, or participation in a clinical trial. Patients entered the cohort upon receipt of their first anti-cancer treatment after SCLC diagnosis and were assigned up to three progression intervals to assess overall survival for each progression-based line of therapy. Patients were followed until death, end of data, or end of the study period (June 30, 2019). Kaplan-Meier analyses were conducted to assess median survival time as estimated by the survival curve. Results: Characteristics among the 82 limited stage (LS) and 217 extensive stage (ES) patients at 1L treatment were similar; however, LS patients were slightly older (mean age: LS = 67.5, ES = 66.4), and ES patients had a higher comorbidity score given their metastatic disease status (mean score: LS = 3.9, ES = 7.3). Both groups had very similar ECOG performance scores prior to 1L (ECOG: 0-1 ≅ 40%, 2+ ≅ 25%, Missing ≅ 35%). For the 299 patients that began 1L treatment (LS = 82, ES = 217), median OS time was 8.41 months (LS = 12.35 months, ES = 7.98 months). For the 124 of the 299 patients who progressed and were treated with 2L therapy, median OS time was 4.30 months. For the 44 of the 124 patients that progressed and were treated with 3L therapy, median OS time was 3.88 months. Of the 299 treated patients, 216 died before the end of the study period, representing 57% of the LS patients and 78% of the ES patients. Conclusions: These results reveal a difference in OS between LS and ES patients treated in 1L. The short survival time in patients with later lines of therapy highlights the need for new treatments in 2L and 3L.[Table: see text]
Comparison of molecular signatures in small cell lung cancer with or without homologous recombination associated gene mutations.
Authors: Fu Lili , Li Feifei , Ren Dandan , Mao Beibei , Chen Huan , Hao Pei , He Ji 
Published: June 2021

e20580 Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. Recently, Immune checkpoint inhibitors (ICIs) have been shown to have the potential to improve the prognosis of SCLC, but little is known about immunotherapeutic biomarkers. Homologous recombination deficiency (HRD) is demonstrated to be a response predictor to immunotherapies in gynecologic cancers, while limited studies were reported in small cell lung cancer. Herein, we analyze the mutational pattern of HRR related genes in a Chinese SCLC cohort and further analyze the relationship between HRR-gene mutations and tumor mutational burden. Methods: Target gene sequencing (543 genes) was performed in 133 Genecast cohort with small cell lung cancer. PD-L1 expression were evaluated for 90 among 133 patients using the SP142 PD-L1 immunohistochemistry assay. Results: Among 133 patients, 47 (35.3%) had HRR-gene mutations. ATM (8.3%), NBN (4.5%) and BRCA2 (4.5%) were the top 3 mutated HRR-gene in the cohort，followed by ATR (3.8%), BARD1 (3.8%), BRCA1 (3.8%), PALB2 (3.8%), RAD50 (3.8%), CHEK2 (3.0%), BLM (3.0%), BRIP1(2.3%), CHEK1(1.5%), RAD52(1.5%), and MRE11A (0.8%). Pathogenic somatic and germline mutations of HRR genes were identified in 11 (11/47, 23.4%) and 3 (3/47, 6.4%) patients, respectively. 1 (1/47, 2.1%) patient carried both germline and somatic variants. Genomic landscape revealed that TP53 and RB1 were commonly mutated genes in SCLC cohort. Mutations in KMT2D, AR and RTK-RAS pathway occurred more frequently in the HRR-Mut group, compared with the wildtype ones. Furthermore, we found that mutations in HRR-gene were associated with high TMB (Wilcoxon, p = 0.048), and patients with high TMB (≥median) showed a higher proportion of positive PD-L1 expression in 90 SCLC patients. Conclusions: Our data indicated that genomic alterations associated with HRR-genes have a positive correlation with high TMB, and detection of HRR-gene mutation status probably could help identify patients who might benefit from immune checkpoint blockade therapy. Keywords: Small cell lung cancer, Homologous recombination deficiency, Immunotherapy.
Albumin-bound paclitaxel plus PD-1/PD-L1 inhibitor versus second-line chemotherapy for patients with recurrent small cell lung cancer.
Authors: Mu Fengchun , Fan Bingjie , Li Butuo , Qin Wenru , Fan Xinyu , Wang Shijiang , Wang Chunni , Zou Bing , Wang Linlin 
Published: June 2021

e20591 Background: The main aim of this study was to evaluate the efficiency of albumin-bound paclitaxel (nab-PTX) plus PD-1/PD-L1 inhibitor versus second-line chemotherapy in small cell lung cancer (SCLC) patients who have failure to the first-line standard treatment. Methods: We retrospectively collected patients’ data from medical records between January 2015 to July 2020 in Shandong Cancer Hospital and Institute. Consecutive 42 patients who were treated with nab-PTX plus PD-1/PD-L1 inhibitor were enrolled and compared with, 126 patients who received second-line chemotherapy (1:3 matched with patient and tumor characteristics). Progress free survival (PFS), overall survival (OS), objective response rate (ORR) and disease control rate (DCR) were evaluated for each group. Results: Patients treated with nab-PTX plus immunotherapy group and second-line chemotherapy group achieved the median PFS of 5.6 months and 3.3 months ( p = 0.043), respectively. The median OS were 7.7 months and 6.3 months ( p = 0.021), respectively. The ORR and DCR were also higher in nab-PTX plus PD-1/PD-L1 inhibitor group (ORR: 33.3% vs 20.6%, p = 0.094; DCR: 61.9% vs 41.3%, p = 0.020, respectively). The most common incidences of grade ≥3 adverse events were leukopenia and neutropenia, there were no significance difference between the two groups. Conclusions: Albumin-bound paclitaxel plus PD-1/PD-L1 inhibitor conferred higher ORR and DCR, and improved PFS and OS in SCLC patients failed with first-line treatment. Further prospective and randomized trial that directly compares the treatments is urgently warranted.
An explorary analysis of a COVID-truncated REPLATINUM phase 3 trial in SCLC.
Authors: Chiappori Alberto , Fidler Mary J. , Salamat Muhammad A. , Reid Tony R. , Guo Xiaoning , Wang Xiaohui , Abrouk Nacer D. , Caroen Scott , Burbano Erica , Quinn Mary Flanagan , Williams Jeannie , Hauke Ralph J. 
Published: June 2021

e20594 Background: RRx-001 is a small molecule immunotherapeutic in Phase 3 for the treatment of SCLC that is associated with M2-M1 tumor associated macrophage (TAM) repolarization with CD47 downregulation, vascular normalization and reversal of chemoresistance. In a controlled, multicenter clinical trial called REPLATINUM that was prematurely halted due to COVID-19, data from 17 patients with third line or beyond SCLC was analyzed. Moving forward, REPLATINUM(restarted) has added SARS-CoV-2 exclusion criteria. Our aim was to explore the efficacy of RRx-001 in REPLATINUM and to assess the statistical assumptions of the REPLATINUM(restarted) trial in order to inform future clinical development in SCLC. Methods: Patients in REPLATINUM were randomized to receive 1 of 2 arms: 1) carboplatin AUC 5 IV on day 1 or cisplatin 60 mg/m2 IV on day 1 plus etoposide 100 mg/m2 IV on days 1 through 3 every 21 days for up to 4 cycles or 2) 4 mg of RRx-001 administered sequentially with 4 cycles of a platinum doublet (cisplatin or carboplatin plus etoposide as outlined above). Progression Free Survival (PFS) was the primary efficacy endpoint based on a blinded independent central review (BICR). Results: The trial was suspended prematurely after 17 patients had been enrolled due to widespread COVID-19 exposure with the plan to restart the trial. The decision to restart the trial has provided an opportunity to examine the data for preliminary evidence of treatment efficacy. At the time that the REPLATINUM trial was halted, there were 11 patients enrolled on the control arm and 6 on the investigational arm. The BICR assessed median PFS was approximately 7.1 months for RRx-001 + platinum doublet and 3.5 months for the platinum doublet alone based on the truncated database. The BICR assessed PFS hazard ratio was approximately 0.5. OS medians were approximately 8.2 and 6.3 months for RRx-001 + platinum doublet and platinum doublet alone, respectively. Additionally, patients on the RRx-001 + platinum doublet-treated experimental arm experienced less toxicity than patients on the platinum doublet-treated control arm. Conclusions: Despite the small sample size, preliminary results from REPLATINUM suggest a trend toward a favorable primary outcome and improved safety in RRx-001-treated patients and support the validity of the statistical assumptions that underlie the REPLATINUM(restarted) trial. Pivotal evidence will emerge from REPLATINUM(restarted), which is imminently recommencing. Clinical trial information: NCT03699956.
Molecular characteristics of EGFR exon 20 uncommon R776H mutation and response to osimertinib in NSCLC patients.
Authors: An Gaili , He Li , Wang Xifang , Lei Yu , Gu Dejian , Chen Rongrong , Xia Xuefeng , Bai Jun 
Published: June 2021

e21001 Background: EGFR R776H is an uncommon exon 20 mutation in non-small cell lung cancer (NSCLC) patients. This mutation was first reported in samples after first generation EGFR TKI treatment as an acquired resistant mutation to first generation of EGFR-TKI. We further analyzed the molecular characteristics of patients with EGFR R776H mutation and its correlation with EGFR TKI therapy. Methods: In this study, a total of 16131 NSCLC patients from multiple centers with NGS data were retrospectively analyzed to study the molecular characteristics and clinical outcomes of patients with EGFR R776H mutation. Results: 44 of the 16131 patients (0.27%) had EGFR R776H mutation, and 28 of them (63.6%) were treatment-naïve while performing the mutation test. TP53 was the most common concomitant mutation in both treatment-naïve (57.1%) and treated (81.3%) patients. EGFR R776H mutation was found to coexist with multiple types EGFR mutation. The common mutations were EGFR L858R (54%) and EGFR G719A/S (25%), but It almost never coexists with 19del (2%). The coexist of EGFR R776H mutation was similar in both treatment-naïve and treated patients. In 16 of treated patients, all had received first - or second-generation EGFR TKI treatment, and the median progression-free survival (PFS) was 9 months. Interestingly, four of them found the presence of not only EGFR R776H but also EGFR T790M. It may be that EGFR R776H and T790M appear together in drug resistance, or it may be that EGFR R776H and EGFR sensitive mutation are not in the same cell clone. Two patients with EGFR R776H received treatment of Osimertinib and achieved partial response. The PFS of two patients in Osimertinib were 11 and 10 months, respectively. Moreover, EGFR C797S mutation was detected in two patients after resistant to Osimertinib. Conclusions: Presence of EGFR R776H mutation was rare in NSCLC patients and our retrospective study provides clinical evidence that Osimertinib could be of benefit and may potentially be an effective treatment strategy to improve survival outcomes in patients with EGFR R776H.
Identification of TGFBR2 mutation as a negative predictor of immunotherapy in NSCLC.
Authors: Li Teng , Wang Han , Xu Jiachen , Li Chengcheng , Zhang Yudong , Wang Guoqiang , Cai Shangli , Junling Li , Wang Zhijie 
Published: June 2021

e21002 Abstract Background: Immune adaptive resistance is one of the reasons contributing to the resistance of immune checkpoint inhibitors (ICIs). Previous studies have demonstrated the role of TGFβ-SMAD signaling in the dysfunction of immune response. We hypothesized that transforming growth factor beta receptor 2 (TGFBR2) mutation in non-small cell lung cancer (NSCLC) might be a predictor of immunotherapeutic resistance. Methods: Genomic and transcriptomic data of NSCLC patients from The Cancer Genome Atlas (TCGA) were analyzed by the in silico Pathway Activation Network Decomposition Analysis (iPNADA) to study the association between TGFBR2 mutation and intracellular signaling pathway activation. Clinical and genomic data from public cohorts with patients treated with ICIs including POPLAR/OAK, MSKCC and Van Allen cohorts were obtained and analyzed. An independent China cohort was used to demonstrate the association between TGFBR2 mutation and immunotherapeutic efficacy and we further demonstrated a case with mutated TGFBR2 treated with ICI. Results: TGF-β signaling was decreased and JAK-STAT signaling was increased in patients with mutated TGFBR2 (P < 0.05). The immune checkpoints including CD274, LAG3, TIGHT, CTLA-4, PDCD1 and PDCD1LG2 were significantly increased in patients with mutated TGFRB2 (P < 0.05). The immune dysfunction score tended to be increased in patients with mutated TGFBR2 though no significant difference was observed (P = 0.23). In the POPLAR/OAK cohort, patients with mutated TGFBR2 had shorter progression-free survival (P = 0.004; HR, 2.83; 95% CI, 1.34-6.00) and overall survival (OS) (P = 0.0006; HR, 3.46; 95% CI, 1.63-7.35) than patients with wild-type TGFBR2 when treated with ICIs. While in patients treated with chemotherapy, there was no difference in PFS (P = 0.69; HR, 0.86; 95% CI, 0.41-1.82) and OS (P = 0.61; HR, 1.21; 95% CI, 0.57-2.57) between patients with mutated and wild-type TGFBR2. In the merged MSKCC and Van Allen cohorts, similar result was observed that the OS was shorter in patients with mutated TGFBR2 (P = 0.007; HR, 2.53; 95% CI, 1.25-5.12). At last, we demonstrated a 39-year-old case with TGFBR2 mutation who was treated with 3 mg/kg nivolumab as second-line treatment. The patient progressed after three cycles of nivolumab and the PFS was only 1.3 months. Conclusions: We identified TGFBR2 mutation as a negative predictor for ICIs in NSCLC and the clinical use of ICIs needs to be cautious in those patients, highlighting the importance of genomic profiling in the treatment of ICIs. Combination ICIs and TGF-β signaling inhibitors may overcome the resistance for those patients harboring TGFBR2 mutation and need to be developed in the future.