bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutational landscape with a focus on KRAS mutations in non-small lung cancer in Taiwan.
Authors: Tran Nguyet , Bonner Joseph D. , Chen Wei-Ju , Lin Fang-Wei , Gruber Peter J. , Lange Jeff , Lauer Andrea , Gruber Stephen B.
Published: June 2021

e20513

Background: Lung cancer is the leading cause of cancer death in Taiwan. The poor prognosis of lung cancer patients with advanced disease and recent development of precision medicine motivates the investigation of molecular targets. The purpose of the study is to estimate the prevalence of KRAS gene mutations and 15 other gene targets among non-small cell lung cancer (NSCLC) patients in Taiwan. Methods: This retrospective study included 933 NSCLC patients diagnosed between January 1992 and July 2018 at six medical centers in Taiwan, including Taichung Veteran’s General Hospital, Chung San Medical University Hospital, China Medical University Hospital, Kaohsiung Veteran’s General Hospital, Tri-Service General Hospital and National Taiwan University Hospital. Patients ≥18 years, had primary histologically confirmed NSCLC diagnosis at time before any treatment, and availability of archival tumor tissue with >30% tumor cellularity. Mutational Analysis: The Formalin-Fixed Paraffin-Embedded (FFPE) tumor blocks were analyzed for the prevalence of somatic mutations. The entire coding sequence of 16 genes was analyzed by next generation sequencing of macrodissected DNA from FFPE recut slides at a depth of greater than 300x and interrogated for somatic pathogenic variants. RNA was not available; hence this limits sensitivity to detect fusions. Results: The mean age at diagnosis was 62 years, 498/933 (53%) were women, 411/843 (49%) were smokers or former smokers, and 829/933 (89%) of adenocarcinoma histopathology. Stage was available for 723 patients with a distribution of 328/723 (45%) Stage I, 120/723 (17%) Stage II, 210/723 (29%) Stage III, and 65/723 (9%) Stage IV. EGFR mutations were identified in 327/933 (35.1%) and TP53 mutations in 179/933 (19.2%). KRAS mutations were identified in 72/933 (7.7%) patients, with KRAS G12C mutations observed in 23/933 (2.5%), KRAS G12D in 16/933 (1.7%), and KRAS G12V in 14/933 (1.5%) (Table). In addition, co-occurring mutations with KRAS were observed and are highlighted, including 14 TP53, 4 PIK3CA, 2 EGFR, 2 CTNNB1, 1 STK11, 1 BRAF and 1 PTEN. Conclusions: EGFR and TP53 were the most frequent mutations identified among all stage NSCLC in Taiwanese populations, followed by KRAS. KRAS G12C and KRAS G12D, the two most frequent KRAS mutations, were identified in 32% and 22% of the KRAS-mutant tumors. Although the prevalence of any KRAS mutation or KRAS G12C mutation is lower than typically seen in Western countries, it is similar to observations among Asian populations. These findings broaden the understanding of the mutational landscape of NSCLC patients in Taiwan to inform development of new therapeutic approaches. [Table: see text]
Investigation of immune microenvironment in EGFR mutant NSCLC.
Authors: Hu Yi , Cui Longgang , Zhao Xiaochen , Bai Yuezong , Zhang Fan
Published: June 2021

e20517

Background: Immune checkpoint inhibitor therapy has made great achievements in NSCLC, but patients with EGFR mutations have poor efficacy with immunotherapy. Previous studies have explored the expression of PD-L1, neo-antigen, co-mutation and regulatory pathways in EGFR mutate NSCLC. This work compared the immune microenvironment of EGFR mutant and wild-type NSCLC. Methods: Patients: NSCLC. Using multi-color immunohistochemistry (multi-IHC) to evaluate the expression of 2 indicators in tumors and tumor stroma, namely CD8+ T cell and macrophage. Shapiro-Wilk was used for normality test, and t-test or Mann-Whitney U test was used according to the results. Two-sided P < 0.05 was considered a significant difference. Results: The study included 119 NSCLC patients, including 59 women (49.6%) and 60 men (50.4%), with a median age of 57. There were 68 patients (57.1%) with EGFR mutations, 19 patients (16%) with KRAS mutations, and 58 patients (48.7%) with TP53 mutations. multi-IHC results showed that, EGFR mutation Vs EGFR wild type samples, (1) the number and proportion of CD8+ T cells in tumor were not statistically different. The median number of CD8+ T cells in tumor stroma was 231.5 vs 359, p = 0.05 and the proportion of CD8+ T cells was 3.92% vs 5.64%, p = 0.02; (2) The median number of macrophage in tumors was 1522 vs 110, p < 0.01, and the proportion of macrophage cells was 24.93% Vs 1.38%, p < 0.01. The median value of macrophages in tumor stroma was 617.5 Vs 208, p < 0.01, and the proportion of macrophages cells was 10.88% vs 3.03%, p < 0.01. Conclusions: Compared with EGFR wild-type patients, EGFR mutation patients have a lower proportion of CD8+ T cells and a higher proportion of macrophages in the immune microenvironment.
Outcomes of patients with unresectable stage III non-small cell lung cancer treated with durvalumab and subsequent therapies after disease progression.
Authors: Dickson Franco Adjei-Baffour , Raez Luis E. , Dumais Katerine , Powery Herman W. , Walker Damaal
Published: June 2021

e20531

Background: The PACIFIC trial demonstrated that durvalumab improved 3-year overall survival in unresectable Stage III non-small-cell lung cancer (NSCLC) following chemoradiotherapy (CRT). However, there is no consensus on the preferred therapy after patients progress on durvalumab. This study aimed to determine the real-world outcomes of patients treated with durvalumab and subsequent therapies after disease progression. Methods: Forty-five NSCLC patients previously treated in a large multi-site community cancer center with concurrent CRT followed by durvalumab were evaluated for progression-free survival (PFS). Subsequent lines of therapy for patients who progressed on durvalumab were also evaluated. Treatment characteristics of the patients were also reviewed. PFS was reported using the Kaplan-Meier method using a p-value of < 0.05 for statistical significance. Results: Baseline characteristics of patients included a median age of 65 years (46-90), 99% with ECOG 0 or 1, and 89% with PDL-1>50%. The median duration between the end of CRT and initiation of durvalumab was 1.3 months and the median treatment duration was 8.1 months the A total of 13 patients (29%) progressed on durvalumab; the 12-month PFS was 65.9% (49-79.7) and the 18-month PFS was 59.1% (36.7-76.1). The median PFS observed was 38.4 months (Table 1). The subsequent lines of therapy for the 14 patients that progressed were as follows: 8(62%). immunotherapy/chemotherapy combination, 2(15%) chemotherapy only, 2(15%) targeted therapy, and 1(8%) radiation therapy. Conclusions: Evaluation of consolidation durvalumab in patients with locally advanced NSCLC finds PFS in clinical practice to be consistent with trial data. Subsequent lines of therapy were consistent with guideline recommendations for newly diagnosed stage IV NSCLC. Longer follow-up will be needed to determine the PFS associated with the different subsequent therapies and how immunotherapy failure could potentially affect outcomes of subsequent chemo/immunotherapy combinations.[Table: see text]
Non-small cell lung cancer population mortality and stage shift.
Authors: Patel Parth Bhargav , Alpert Naomi , Pyenson Bruce , Taioli Emanuela , Flores Raja Michael
Published: June 2021

e20536

Background: Lung cancer population mortality has decreased over the last decade. Smoking cessation, medical therapies, CT screening, and earlier therapeutic interventions may all contribute to this decrease. We investigate the role of stage shift on population mortality of non-small cell lung cancer (NSCLC). Methods: Data from Surveillance, Epidemiology, and End Results (SEER) were queried to assess all patients from 2006-2016 with microscopically confirmed NSCLC. Incidence based mortality was evaluated by year of diagnosis. In order to assess shifts in diagnostic characteristics, stage and histology distributions were examined by year using χ2 tests. Trends were assessed by using the average annual percentage change (AAPC), calculated with JoinPoint software. Kaplan-Meier survival analysis was also performed to assess overall survival according to stage and to compare those missing any stage to those with a reported stage. Results: Between 2006-2016, 312,382 patients in SEER were diagnosed with NSCLC. Incidence based mortality within 5 years of diagnosis for NSCLC has significantly decreased over the last decade (AAPC -3.7 (95% confidence interval (CI): -4.1 - -3.4)). When assessing stage shift, there was a significant association between year of diagnosis and stage (p < 0.0001), with the percent in each year diagnosed at stage I/II increasing from 26.5% to 31.2% from 2006-2016, corresponding to a statistically significant AAPC of 1.5 (95% CI: 0.5-2.5); the percent diagnosed at stage III/IV decreased significantly from 70.8% to 66.1% (AAPC: -0.6 (95% CI: -1.0 - -0.2)). The percent missing staging information was relatively stable in this timeframe and not significant (AAPC: -1.6 (-7.4 - 4.5)). Year of diagnosis was significantly associated with tumor histology (p < 0.0001). There was a statistically significant increase in the percent of those diagnosed with adenocarcinomas, from 42.9% in 2006 to 59.0% in 2016 (AAPC: 3.4 (95% CI: 2.9-3.9)). Median survival for those with stage I/II was 57 (interquartile range (IQR): 18- - ) months; for stage III/IV was 7 (IQR: 2-19) months; and for those missing stage was 10 (IQR: 2-28) months. Patients with stage I/II had significantly better survival compared to those diagnosed with stage III/IV, or missing stage (p < 0.0001). Conclusions: Population-level mortality for NSCLC has decreased from 2006-2016. While advances in treatments, particularly targeted therapeutics have played a role in affecting mortality, our analysis suggests that decreased mortality is also due to a diagnostic shift from later to earlier stage lung cancer. Studies investigating the effectiveness of treatment on lung cancer mortality must take into account the confounding effect of stage shift on survival and mortality outcome.
Immune-related histologic phenotype in pretreatment tumor biopsy predicts pathologic response to neoadjuvant anti-PD-1 treatment in squamous lung cancer.
Authors: Yuan Pei , Guo Changyuan , Li Lin , Ling Yun , Guo Lei , Li Junling , Ying Jianming
Published: June 2021

e20540

Background: The neoadjuvant platform affords a rich and valuable resource for understanding the responses to therapy and carrying out reverse translation, including pathologic morphology. We aimed to develop a pretreatment histologic scoring system reflecting the preexisting immune response to predict the efficacy of neoadjuvant immunotherapy based on the morphological changes we mastered in the pathologic assessment after neoadjuvant immunotherapy. Methods: Surgical specimens from the 31 squamous cell lung cancer patients recruited in a phase Ib study of neoadjuvant anti-PD-1 therapy and eligible paired pretreatment biopsies from 15 of them were included in this study. The posttreatment surgical specimens were assessed according to the immune-related pathologic response criteria. Immune-related histologic phenotype assessment criteria (irHPC) were developed based on the pathologic features identified after neoadjuvant anti-PD-1 treatment. Three pathologists trained for irHPC independently scored the HE slides of the 15 pretreatment tumor biopsies according to irHPC. Results: Whether necrosis was included in the calculation of percent of residual viable tumor (%RVT) or not had almost no effect on the consistency of pathologic assessment ( P= 0.811) and the histological response grouping. The inter-pathologist variability of assessing %RVT with immune-activated phenotype was not statistically significant ( P= 0.480). Four immune-related features of pretreatment biopsies were included for calculating the predictive score, including three positive features (tumor-infiltrating lymphocytes, tumor-infiltrating eosinophils and dense plasma cells in stroma) and one negative feature (tumor-infiltrating neutrophils) according to the developed irHPC scoring system. The trained pathologist accurately predicted 6 out of 8 patients in the cPR/MPR group and 5 out of 7 patients in the non-cPR/MPR group according to irHPC. For inter-observer reproducibility using “2 points” as the cut-off point, the overall percent agreement (OPA) was 77.8%. The reliability between pathologists for a binary tumor evaluation showed “moderate” agreement (κ = 0.54). Conclusions: The irHPC scoring system reflecting the preexisting immune response could be used to predict the pathologic response of neoadjuvant immunotherapy, but still needs the larger trails to verify.
SMARCA4-mutated lung adenocarcinoma, a distinctive non-small cell lung cancer with worse prognosis.
Authors: Zhang Longfeng , Xiao Weijin , Wu Fangjun , Peng Ran , Shi Jialong , Li Chao , Lin Gen
Published: June 2021

e20548

Background: SMARCA4 gene is one of the catalytic subunits of the SWI/SNF chromosomal remodeling complex, which can regulate important cellular processes and functions and is closely associated to tumors. The clinical features, therapeutic efficacy, prognosis and pathological features of lung adenocarcinoma with this genetic variation are still unknown and controversial. Methods: The study recruited 274 patients (pts) with lung adenocarcinoma whose samples were sent to perform parallel hybridization-based next-generation sequencing. Two categories of SMARCA4 mutations were divided into Type1 mutations (frameshift mutations, nonsense mutations, splice-3 mutations, copy number amplification) and Type2 mutations (missense mutations and copy number loss) based on whether the mutation may result in defective protein. Furthermore, comparative analysis by using the clinical outcome data, the genomic and pathological characteristics were be performed in SMARCA4 Type 1 alterations corhort and Type 2 alterations corhort. Results: Among 274 pts were recruited, the mutation rate of SMARCA4 gene in lung adenocarcinoma was 9.1%. Furthermore, the presence of SMARCA4 alteration was associated with smoking (P＜0.05). Missense, nonsense, frameshift and splice were the most common types of mutations (92%). The pts with SMARCA4 Type1 alterations which probably lead to defective protein expression, had a worse prognosis compared with pts with SMARCA4 Type1 alterations (The role leading to defective protein expression is uncertain) and SMARCA4 Wild groups (P＜0.05). In addition, EGFR alterations were strongly associated with SMARCA4 Wild corhort compared to SMARCA4 Type1 alterations corhort (67% vs. 31% ), and SMARCA4 Type1 alterations was more associated with the absence of TP53, RB1, and Robo3 alterations. GO enrichment analysis suggested that the differentiated mutated genes between SMARCA4 Type1 alterations corhort and SMARCA4 Wild corhort were mainly enriched in cell cycle regulation. Pathologically, The SMARCA4 Type1 alterations was mostly poorly or moderately differentiated and strongly accompanied by the loss of expression of TTF-1(83.3%) and BRG1(80%) in immunohistochemistry. Conclusions: SMARCA4 Type1 alterations which probably lead to abnormality of protein was associated with poor prognosis and having different the genomic and pathological characteristics.
Adoption of consolidative durvalumab among patients with locally advanced non-small cell lung cancer.
Authors: Jairam Vikram , Pasha Saamir , Soulos Pamela R. , Goldberg Sarah B. , Yu James B. , Decker Roy H. , Gross Cary Philip , Park Henry S.
Published: June 2021

e20550

Background: Soon after the publication of the PACIFIC trial, the Food and Drug Administration (FDA) approved durvalumab following definitive chemoradiation in patients with unresectable stage III non-small cell lung cancer (NSCLC). However, patterns of durvalumab adoption within the United States are currently unknown. We investigated the pace of uptake of durvalumab as well as patient and tumor characteristics associated with receipt of durvalumab following FDA approval. Methods: This study used the nationwide Flatiron Health database, a longitudinal electronic health record-derived de-identified database. During the study period, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). From this de-identified database, we selected patients with stage IIIB-C NSCLC who completed at least two cycles of first-line (1L) platinum doublet chemotherapy between February 16, 2018 (FDA approval date for durvalumab) and August 16, 2019, and did not develop disease progression over a follow-up period of at least 120 days after 1L chemotherapy. In the absence of radiation therapy and surgery details in the database, these criteria served as a proxy for selecting patients who were most likely to be eligible for consolidative durvalumab. We evaluated temporal trends in the uptake of durvalumab after completion of 1L chemotherapy using the Cochran-Armitage test, clustering the time periods in 3-month intervals. We also characterized patient and tumor characteristics associated with durvalumab receipt using the chi-square test and multivariable logistic regression. Results: A total of 424 patients were included in our study sample, among whom 282 (66.5%) patients had documentation of having received durvalumab after 1L chemotherapy. Within the first 3 months after FDA approval, 60.4% of potentially eligible patients received durvalumab, while in the final 3 months of the study period, this proportion rose modestly to 68.3% (p = 0.19). On univariable and multivariable analysis, patient characteristics like age, sex, race, insurance, smoking status, performance status, and comorbidity score, as well as tumor characteristics like histology, EGFR status, and PD-L1 status, were not significantly associated with receipt of durvalumab. However, there was significant geographic variability in receipt of durvalumab, ranging from 65.7% in the South to 85.3% in the Midwest (chi-square p = 0.04). Conclusions: Early adoption of durvalumab upon completion of 1L chemotherapy for stage IIIB-C lung cancer was rapid across the United States, starting at over 60% in the first three months after FDA approval. Regional variation appears to be a more powerful driver than patient characteristics in discrepancies of durvalumab dissemination. Further exploration into these regional variations may help improve guideline-concordant care.
Association of planning target volume with disease progression in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy and concurrent and/or sequential immune checkpoint inhibition.
Authors: Taugner Julian , Karin Monika , Käsmann Lukas , Eze Chukwuka , Guggenberger Julian , Flörsch Benedikt , Tufman Amanda , Belka Claus , Manapov Farkhad
Published: June 2021

e20557

Background: The present study evaluates outcome after chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (CPI) for inoperable stage III NSCLC patients depending on planning target volume (PTV). Methods: Prospective data of thirty-nine consecutive patients with inoperable stage III NSCLC who completed CRT with sequential durvalumab (72%, 28 patients) or concurrent and sequential nivolumab (28%, 11 patients) were analyzed. Different cut offs for PTV as well as PTV as a continuous variable were evaluated for association with progression-free survival (PFS) and extracranial metastasis-free survival (eMFS). Results: All patients were treated with conventionally fractionated TRT to a total dose of at least 60 Gy (range: 60-63.6Gy), 97% (27 patients) received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 23.2 (range: 6.0-42.6) months; median overall survival (OS) and eMFS were not reached. Median Progression-free survival (PFS) was 22.8 (95% CI: 10.3-35.2) months. Age (65 years), gender and UICC stage had no significant impact on PFS. There was no significant difference between durvalumab and nivolumab patients. Patients with PTV ≥ 900ccm had a significantly shorter PFS (11.77 vs 26.3 months, p = 0.049) and eMFS (11.7 months vs not reached, p = 0.019). Furthermore, patients with PTV ≥ 900ccm and stage IIIC disease (TNM 8th Ed.) achieved a dismal median PFS of only 3.6 months (vs. 26.3 months p < 0.001). PTV as a continuous variable showed a trend for association with PFS (p = 0.064) and was a significant negative prognosticator for eMFS (p = 0.030; HR: 4.065; 95%CI: 1.148-14.397). Conclusions: PTV has a significant impact on the PFS and eMFS after CRT combined with concurrent and/or sequential CPI in inoperable stage III NSCLC. Patients with PTV ≥ 900ccm had a significantly shorter PFS and eMFS.
Prognostic impact of inflammatory profiling during and after multimodal treatment for stage III NSCLC.
Authors: Käsmann Lukas , Cabeza-Boeddinghaus Natalia Christina , Taugner Julian , Eze Chukwuka , Hofer Thomas Philipp , Pelikan Carolyn , Belka Claus , Noessner Elfriede , Staab-Weijnitz Claudia , Manapov Farkhad
Published: June 2021

e20559

Background: Immune cells have a broad impact on tumor initiation, growth, and progression, and many of these effects are mediated by proinflammatory cytokines. The prognostic impact of dynamic changes of inflammatory cytokines in non-operable stage III NSCLC patients treated with (chemo)-radiotherapy ± immune checkpoint inhibition is unknown. In a prospective analysis, pro-inflammatory cytokines including interleukin 2, 6, and 8 from peripheral blood samples were evaluated 5-10 days before treatment start (T1), on the last day of thoracic radiotherapy (T2), and 3 weeks after radiation (T3) for their impact on overall survival (OS) and progression-free survival (PFS). Methods: Twenty patients, 85% male, at a median age of 65.5 (range 33-77) years were prospectively enrolled in this study. Eighteen (90%) patients received platinum-based concurrent chemoradiotherapy (CRT); seven (35%) patients additional concurrent and/or sequential immune checkpoint inhibition (four patients nivolumab and three durvalumab); patients treated with nivolumab received induction chemotherapy. Thoracic irradiation (TRT) was applied in all patients with a median cumulative dose in equivalent 2Gy fractions (EQD2) of 64Gy (range: 52-65Gy). Results: Median follow-up achieved 25 (range 14-30) months, median OS was not reached and median PFS was 11.8 (95%CI 5.2-18.4) months. To analyze pre-treatment data, median values were used as cut-off for dichotomization. Higher IL6 levels (≥9.75pg/ml) before irradiation (T1) were associated with impaired OS (median 11 months vs. not reached; p < 0.001) and PFS (median 7.0 months vs. not reached; p = 0.041). Higher IL8 levels (≥4.62pg/ml) were also associated with shorter OS (median 16 months vs. not reached; p = 0.009) and PFS (median 7 months vs. not reached p = 0.040). Patients with a decline of ≥10% of IL8 level between T1 and T2 had a significantly shorter PFS (11.8 months vs. not reached; p = 0.028). Conclusions: High proinflammatory cytokine levels were significantly associated with deterioration of outcome regarding OS and PFS in patients enrolled in multimodal treatment for stage III NSCLC. A decline of ≥10% of IL8 level during TRT was associated with impaired PFS.
Residencial radon and small cell lung cancer: A case control study.
Authors: Rodriguez Martinez Angeles , Ruano Alberto
Published: June 2021

e20566

Background: Residential radon is the second most important risk factor for lung cancer. We aim to asses the effect of residential radon exposure on the risk of SCLC in general population. Methods: A multicentric hospital-based case-control study was designed including 10 hospitals from Spain and Portugal. Incident cases with pathological diagnosis of SCLC were prospectively recruited. Controls consisted in patients undergoing non-complex surgery unrelated to tobacco consumption. All study participants were sent a radon detector. Results: A total of 375 cases and 902 controls were recruited. 24.5% of cases were women. The median age at diagnosis was 66 for cases. 6.4% of the cases were younger than 50 years. Tobacco consumption was higher in cases compared to controls. Residential radon concentrations were higher than 147 Bq/m3 in 161 SCLC cases (42.9%). Median residential radon concentration was also higher in SCLC cases compared to controls (152.5 Bq/m3 vs 142 Bq/m3). Those people exposed to more than 147 Bq/m3 and heavy smokers showed an OR of 72,62 (95%CI 17.95 - 499.41) compared to never-smokers with less than 50 Bq/m3. Conclusions: radon exposure seems to increase the risk of small cell lung cancer. There is a significant lung cancer risk departing from 148 Bq/m3 and there is also a linear dose-response pattern. Tobacco consumption may also produce an important effect modification for radon exposure. Those individuals exposed to high radon concentrations and heavy smokers can have a very high risk of this cancer type compared with their low exposed and never-smoking counterparts. It is necessary to increase radon awareness among citizens and administrations in order they can establish the necessary protective and mitigation measures against residential radon. Effect modification between residential radon exposure and tobacco consumption on the risk of small cell lung cancer.[Table: see text]
Role of chest radiation in extensive-stage small cell lung cancer with ipsilateral pleural effusion.
Authors: Komiya Takefumi , Powell Emily , Vu Charles , Takamori Shinkichi
Published: June 2021

e20567

Background: Prognosis of extensive-stage small cell lung cancer (ES-SCLC) remains poor. Previous randomized trials suggested consolidation chest radiation (CXRT) has a modest survival benefit; however, its role in subgroups of ES-SCLC, especially ipsilateral pleural effusion (IPE) have not been reported and unknown. Methods: Using National Cancer Database (NCDB), 283,347 ES-SCLC cases diagnosed between 2004 and 2017 were screened. Eligible cases must have been staged with 7th edition of staging system and have information about clinical T and N stage, and minimum follow-up of one month. Role of CXRT was examined in M1a, M1b, and IPE subgroups. Surveillance, Epidemiology, and End Results Program (SEER) was analyzed to independently validate our results. Univariate and multivariate analyses were conducted with Cox proportional hazard models. A p-value < 0.05 was considered as statistically significant. Results: A total of 36,762 (5,511 with M1a, 31,251 with M1b, and 2,013 with IPE) cases were analyzed. In both M1a and IPE groups, use of CXRT was significantly associated with younger age, female sex, non-academic institution, and clinical T stage. Both univariate and multivariate analyses showed that use of CXRT demonstrated significantly longer overall survival in all the groups, with lower hazard ratios in the M1a and IPE groups than in the M1b group (univariate hazard ratio 0.62, 0.56, and 0.72, respectively). Propensity score analysis of the IPE group also showed a survival advantage in the CXRT group (hazard ratio 0.54). The SEER data also showed a survival advantage of CXRT in the IPE group (univariate hazard ratio of 0.40). Conclusions: This retrospective database analysis suggests M1a and in particular IPE subgroups have more survival benefit of CXRT than the M1b subgroup. Further studies are warranted to confirm the hypothesis.
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.