bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitigating the risk of transfusion-transmitted bacterial infections in hematology oncology patients.
Authors: Alvarez Harold , Lanteri Marion , Koehne Guenther
Published: June 2021

e19047

Background: Hospital acquired infections create major logistical, financial, and patient safety concerns within the healthcare system. Bacterial contamination (BC) of platelet components (PCs) can lead to transfusion-transmitted bacterial infections (TTBI), central line-associated bloodstream infections, and sepsis, with long-term complications and/or death. In the US, hematopoietic stem cell transplant (HSCT) recipients require transfusion support until engraftment and together with hematology/oncology (hemonc.) patients receive the highest number of PCs/patient. FDA’s Guidance recommends approaches to reduce BC risk including the use of enhanced bacterial culture screening (EBSC) or pathogen reduction (PR) of platelets. Methods: The Miami Cancer Institute (MCI) implemented PR-PCs for all allogeneic HSCT patients. Irradiation, CMV testing, and bacterial screening have been discontinued for PR-PCs. Transfusion outcomes are being monitored using active hemovigilance (HV) reporting. Results: Considering the fatality risk associated with BC of PCs (1:200,000 – 1:1,000,000) despite the use of optimal skin cleansing, initial sample diversion, and primary bacterial culture, 1/2,880 PCs are still contaminated (Bloch et al.); further steps towards BC mitigation are needed. As the UK and US reported a residual BC risk of 5.4-9.4/million PCs after implementation of EBSC, PR may represent an alternative approach with other cumulative benefits. Indeed, national HV data from France, Switzerland and Belgium reported no sepsis transfusion reactions since PR implementation (Benjamin et al.). In addition, the risk of TA-GVHD and other TTI including emerging infectious diseases (EID) may be decreased after the inactivation of pathogens and leukocytes (Lanteri et al.). At MCI, the percentage of transfused PR-PCs has been increasing steadily from 7.9% in July 2019 to 22.2% in January 2021. Over a 19 month-period, a total of 9,296 PC were transfused including 1,677 PR-PCs. While non-PR-PCs were all irradiated and bacterially screened, PR-PC were neither irradiated nor bacterially screened. No cases of TA-GVHD or TTI were reported. A total of 27 mild, non-life-threatening platelet transfusion reactions were reported including 22 (81.5%) after non-PR PCs transfusion and 5 (18.5%) after PR-PC transfusion. In addition, the early release of transfusion-ready fresh PR-PCs 24-48 hours after collection has proven invaluable in providing clinicians and patients with blood continuity during the COVID-19 pandemic. Conclusions: Though certain measures have improved blood safety, the risk of TTI associated with PC transfusion remains a concern for vulnerable hemonc. patients. Using PR-PC is especially important to consider when patients undergo extensive life-saving therapies such as bone marrow transplants.
Tislelizumab (BGB-A317) for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL): Long-term follow-up efficacy and safety results from a phase 2 study.
Authors: Song Yuqin , Gao Quanli , Zhang Huilai , Fan Lei , Zhou Jianfeng , Zou Dehui , Li Wei , Yang Haiyan , Liu Ting , Wang Quanshun , Lv Fangfang , Guo Haiyi , Yang Liudi , Huang Jane , Novotny William F. , Wang Yidi , Zhu Jun
Published: June 2021

e19507

Background: Tislelizumab is a humanized IgG4 monoclonal antibody with high affinity/specificity for programmed cell death protein 1 (PD-1). It was engineered to minimize binding to Fc-γ receptors on macrophages, thereby decreasing antibody-dependent phagocytosis, a potential mechanism of T-cell clearance and resistance to anti–PD-1 therapy. Tislelizumab therapy was highly active in autologous stem cell transplant (ASCT)-failed or ineligible patients with R/R cHL ( Leukemia. 2020;34:533). Here we report results from up to 3 years follow-up. Methods: This asingle-arm, multicenter phase 2 study (NCT03209973) of 200 mg tislelizumab administered intravenously to patients (pts) with R/R cHL every 3 weeks until progressive disease (PD) or unacceptable toxicity. Patients were eligible if they: failed to achieve a response or progressed after ASCT, or: received ≥2 lines of prior systemic chemotherapy for cHL and were ineligible for ASCT. Primary endpoint was overall response rate (ORR) assessed by an independent review committee (IRC) per Lugano criteria ( J Clin Oncol. 2014;32:3059). Secondary endpoints were progression-free survival (PFS), duration of response (DOR), complete response (CR) rate, and time to response (TTR) per IRC, safety, and tolerability. Results: Pts (N=70) from 11 centers in China were enrolled and treated; characteristics have been previously reported. As of the data cutoff date (Nov 2, 2020), median follow-up was 33.8 months (range, 3.4-38.6). Pts still on treatment at the end of study (n=33; 47.1%) entered a long-term extension study. Efficacy data is presented in the Table below. In the 13 pts who received prior ASCT, 11 (84.6%) achieved CR. The most common treatment-emergent adverse events (AEs; ≥30%) were pyrexia (57.1%), upper respiratory tract infection (38.6%), hypothyroidism (37.1%), and increased weight (34.3%). Treatment-related grade ≥3 AEs (≥2 pts) were pneumonitis, hypertension, neutropenia, lipase increased, weight increased, and increased creatine phosphokinase (CPK; 2.9% each). Immune-related AEs were reported in 32 pts (45.7%), with grade ≥3 AEs in 8 pts (11.4%): pneumonitis (4) and skin adverse reactions, nephritis, lipase increased, and blood CPK increased (1 each). AEs led to treatment discontinuation in 6 pts (8.6%). Conclusions: Long-term follow-up of R/R cHL pts treated with tislelizumab further demonstrated the substantial therapeutic activity and continued PFS benefit. There were no new safety concerns identified for long-term treatment with tislelizumab. Clinical trial information: NCT03209973. [Table: see text]
Secondary hemophagocytic lymphohistiocytosis (HLH): Five years’ experience at the UTHealth McGovern Medical School at Houston, Texas.
Authors: Cervoni-Curet Frances Natalia , Rios Adan , Yohannan Binoy , Miao Hongyu
Published: June 2021

e19578

Background: Secondary HLH in adults is associated to infections, malignancies, and autoimmune disorders. HLH in children has been the basis for the management and treatment of HLH in adults. Despite their clinical similarities there are fundamental differences. Children’s HLH is caused by gene mutations in granule-mediated cytotoxicity while secondary HLH does not have known apparent genetic causes. This may affect the clinical outcomes based in how we approach the diagnosis and management of secondary HLH in adults. Methods: We reviewed 49 cases of secondary HLH at our institution over a five-year period. Patients median age was 47 years, with 31 males, 18 females. Fifteen were Caucasian, 10 Asians, 8 African American and 15 Hispanics. One was not specified. Results: Fever, hyperferritenemia and cytopenia correlated with 100% elevation of sCD25R, the most important biomarker of HLH. Patients with these three criteria were urgently treated with dexamethasone-etoposide (HLH-94 protocol) or dexamethasone alone (autoimmune related) while completing identification of other criteria described in the pediatric population together with treatment of the secondary cause. Conclusions: Secondary HLH is not rare. Etoposide and dexamethasone (preferred dose:40 mg total/day initially) are the most important current therapeutic approaches. Secondary HLH must be treated urgently and independently of the secondary cause. Treatment should not be delayed awaiting results of sCD25R, NK-cell activity and presence of hemophagocytosis in the bone marrow (often absent). Further work needs to be done to elucidate the physiopathology of secondary HLH.[Table: see text]
Anti-PD-1 monotherapy in patients with malignant mesothelioma: A retrospective single institution experience.
Authors: Ali Atif , Holmes Hudson , Wang Hannah , Prather Lyndsey L. , Sabichi Anita Lyn , Burt Bryan M. , Ripley R. Taylor , Lee Hyun-Sung , Wang Daniel Ying
Published: June 2021

e20564

Background: Malignant mesothelioma (MM) patients historically have poor outcomes, but immune checkpoint inhibitors have shown promising results in certain patients. We aimed to retrospectively assess efficacy and safety with use of anti-PD-1 monotherapy (aPD-1 Tx) in patients with MM at our institution from Dec 2015 to Dec 2020. Methods: We identified patients with MM treated with nivolumab or pembrolizumab. Clinical details including demographics, efficacy, and toxicity were collected. Efficacy was characterized based on overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Survival curves were generated using the Kaplan-Meier method, and intergroup comparisons were performed with the log-rank test. Univariable Cox regression analysis was used to determine whether variables were associated with survival. Results: We identified 61 patients treated with aPD-1 Tx for MM. Majority of patients (90%) had malignant pleural mesothelioma. Forty-two (69%) patients were male. The median age of initiation was 65 years (range: 30-84). Most patients (66%) had an ECOG performance status (PS) of 0-1. Known asbestos exposure was noted in 19 (31%) patients. Most patients had received prior chemotherapy (74%) and treated with nivolumab (89%). Only 66% of patients with known PD-L1 had positive expression ( > = 1%). There were 43 (70%) patients with epithelioid histology. Median follow-up was 22.2 months. ORR was 33% with stable disease in 25% of patients. In first-line aPD-1 Tx, ORR was 50%. PFS and OS at 12 months were 26% and 65%, respectively. The median PFS and OS were 5.1 and 15.6 months, respectively. PD-L1 positivity was not associated with improved PFS or OS. Univariable analysis demonstrated that ECOG PS 0-1 had significantly better OS with hazard ratio (HR) 0.40 (95% CI 0.20 – 0.83; p = 0.01). Immune-related adverse events (irAE) were seen in 33% of patients with 13 patients with grade 3 or higher (nephritis, pneumonitis, arthritis, leukocytosis, dermatitis, colitis, type 1 diabetes mellitus, tongue angioedema, and thrombocytopenia). One patient had grade 5 irAE due to severe thrombocytopenia. Patients who developed an irAE had significantly improved median OS (32.1 vs 12.1 months, p = 0.01). Conclusions: Anti-PD-1 monotherapy showed clinical efficacy and safety in malignant mesothelioma as both a first-line treatment and in pre-treated patients based on our real-world experience. The development of irAE may predict benefit, although fatal side effects can occur.
Pooled analysis of clinical activity of immune checkpoint immunotherapy in relapsing/refractory ES-SCLC.
Authors: Vosuri Venkata , McGreevy Joseph , Ghous Ghulam , Doll Donald C. , Tuncer Tolga
Published: June 2021

e20572

Background: ES-SCLC is an aggressive lung cancer with high rates of relapse following induction regimens. Immune checkpoint immunotherapy (ICI) seems promising in the refractory/relapsing setting based on a smaller number of studies with smaller sample sizes. Here we report a pooled estimate of clinical activity of ICI in above patients based on published phase II/III trials so far. Methods: PubMed, EMBASE, Cochrane review, and clinicaltrials.gov databases were searched for phase II/III randomized controlled trials studying immune checkpoint immunotherapy in second or third line setting for ES-SCLC treatment. Data were extracted based on Reviews and Meta- Analysis guidelines. DerSimonian-Laird (DL) random effects model was used to estimate the pooled proportion of patients achieving objective response rate (ORR), pooled proportion of patients experiencing therapy related adverse events (TRAEs grade ≥ 1), pooled median progression free survival (PFS) and pooled median overall survival (OS), and weights were estimated using inverse variance method. Statistical heterogeneity was calculated using the I2 and chi-squared test. Outcomes were calculated by using ‘Metafor’ and ‘Meta’ packages by R-Studio and “CRAN” project. Results: Five studies with a total of 698 patients who received immune checkpoint immunotherapy were analyzed. Median age of patients who received treatment was 63 yrs. The pooled proportion of patients who achieved ORR was 15% (95% CI 0.11 to 0.20). Pooled Median PFS was about 1.54 (95% CI, 1.34- 1.74) months and median OS was 6.46 (95% CI, 5.13- 7.73) months. The pooled proportion of patients who experienced adverse events during the treatment was 49% (95% CI 0.38 to 0.60). Conclusions: ICI as second or third line treatment choice offers modest improvement in progression free survival and overall survival in ES-SCLC patients who have not received ICI as first line in combination with etoposide and platinum based therapies.
Clinical utility of circulating genetically anormal cells in stage I small-cell lung cancer diagnosis.
Authors: Wang Hui , Wang Ziqi , Zheng Xiaoxuan , Sun Jiayuan , Zhang Xiaoju , Ye Xin , Chen Yanci , Huang Meng , Zhang Juncheng , Yang Xiaozheg , Bai Chunxue
Published: June 2021

e20581

Background: Small-cell lung cancer (SCLC) is an aggressive disease with rapid progression rate and high metastatic potential that accounts for 15% of all lung cancers. Early-stage SCLC is usually asymptomatic; therefore, the majority of the SCLC patients were diagnosed in advanced stages. Although some radiological features were reported with advanced stages SCLC by CT scans, diagnosis of early stages SCLC from CT images has remained challenging since the radiological features are not distinct. Neuron-specific enolase (NSE) is commonly used in the clinical setting as a biomarker for SCLC, but the sensitivity of the test did not meet the needs. Here, we proposed a study using Circulating Genetically Abnormal Cells (CAC) to improve the diagnosis rate of SCLC in the early stages. Methods: A series of 26 stage I SCLC patients were enrolled from October 2019 to October 2020. All participants were having newly discovered pulmonary nodules ≤ 30mm when enrolled in the study, with no previous cancer history. Before the histopathological examination, 10 ml of peripheral blood were collected from each patient for CAC test, by using a 4 color FISH–based assay to detect the genetic abnormalities of 3p22.1, 3q29, 10q22.3, and CEP10 in the chromosome. Besides, NSE was performed on all participants. Both tests were intended to evaluate the malignant risk of lung nodules. Results: Confirmed by histopathological exam, 69% patients were diagnosed with SCLC located on the central part of the lung, and 31% patients were found to have peripheral-type SCLC. 88% of the patients in the overall cohort were smokers or past smokers, and only 12% participants had a family history of cancer. For Immunohistochemistry tests, the numbers of participants with positive CD56, TTF-1, CgA, CK, Syn and Ki-67 ≥ 60% are 65%, 58%, 12%, 42%, 50% and 69%, respectively. For diagnostic performance, the sensitivity of CAC in the over-all cohort is 73.08% (95%CI: 52.21%-88.43%), compared with 50.00% (95%CI: 29.93%- 70.07%) for NSE. CAC has achieved 77.78% (95%CI: 52.36% - 93.59%) and 62.5% (95%CI：24.49% - 91.48%) sensitivity in the centra and peripheral group. For NSE, the sensitivity of these two groups were 55.56% (95%CI: 30.76% - 78.47%) and 37.5% (95%CI: 8.52% - 75.51%). Conclusions: Compared with NSE, CAC is more sensitive to stage I SCLC, especially for SCLC that arising in central locations. This non-invasive method can be a complementary diagnostic tool with LDCT for smokers aged ≥65 with newly discovered pulmonary nodules. Clinical trial information: ChiCTR1900026233.
Every three weekly irinotecan for refractory/relapsed small cell lung cancer.
Authors: Nutalapati Snigdha , Yan Donglin , Morgan Rachael , Chauhan Aman
Published: June 2021

e20584

Background: Current NCCN guidelines support weekly irinotecan regimen for refractory/relapsed SCLC (small cell lung cancer). Despite prior studies that used irinotecan for other solid malignancies included both weekly and three weekly regimens, NCCN do not acknowledge three weekly regimen for SCLC due to insufficient data, especially from United States patient population. We aimed to study clinical efficacy, side effect profile and cost analysis of three weekly irinotecan regimens for refractory/relapsed SCLC. Methods: Retrospective analysis of relapsed/refractory SCLC or high-grade neuroendocrine carcinoma (HGNEC) patients treated with every 3 weekly irinotecan (300 mg/m2) regimen between 2010 and 2020 at NCI-designated Markey Cancer Center/University of Kentucky healthcare was performed. Median PFS and adverse events per CTCAE 5.0 were determined. Results: A total of thirty-eight patients were included in our analysis, 32 with SCLC and 6 with HGNEC. Of 6 patients with HGNEC, primary site included bladder (n=1), prostate(n=1), gastroesophageal junction(n=1) and unknown primary (n=3). Mean age at diagnosis was 58 years. Mean prior line of therapies were 1.8 (range=1 to 4) and mean number of irinotecan cycles were 3.5 (range=1 to 12). Median progression free survival was 2.1 months (95% CI-1.6 to 8.1). Grade (G) 2, 3 and 4 adverse events were noted among 20.5%, 33.3% and 7.8% respectively. G3 and G4 neutropenia was seen in 2.6% and 5.3%; neutropenic fever was noted among 5.3%; G2 and G3 diarrhea among 7.9% and 15.8%; ileus among 5.3%; enterocolitis among 2.6%; G2 and G3 nausea and vomiting among 7.9% and 10.5%; G3 transaminitis among 2.6%; G3 and G4 acute kidney injury was seen among 5.1% and 2.6% respectively. Estimated overall costs (including infusion related expenses, cost of pre-medications and irinotecan) to deliver three 100mg/m2 doses with every weekly regimen was $661 compared to only $268 for a single 300mg/m2 dose with every three-weekly regimen. Conclusions: In previously treated patients with refractory/relapsed SCLC, every three weekly irinotecan regimen was found to have comparable efficacy and adverse event profile. Diarrhea, nausea, vomiting and neutropenia are the most common adverse events reported. Moreover, cost effectiveness of every 3 weekly regimen and reduced number of infusions should potentially benefit patients who live far from health care facility as is the case in rural Appalachia and also help reduce financial toxicity.
Short-term efficacy and long-term survival of limited-stage small cell lung cancer treated with large fractionation radiotherapy and conventional fractionation radiotherapy.
Authors: Chen Cheng , Jiang Yingying , Jiang Ning , He Kang , Chen Cheng , Zhao Lijun , Kong Cheng , Song Xue , Wang Xiaohua , He Xia , Zhu Xiangzhi
Published: June 2021

e20586

Background: Hyperfractionation (1.5Gy per dose twice a day, total dose 45Gy) or conventional fractionation (2Gy per dose once a day, total dose 60-70Gy) is the recommended dose fractionation for LS-SCLC. However, the optimal segmentation mode and dose of radiotherapy have not been determined. In this study, we evaluated the short-term efficacy and toxic and side effects of macrofractionation to explore the feasibility of macrofractionation radiotherapy in the treatment of LS-SCLC patients. Methods: From May 2011 to February 2020, 52 patients with LS-SCLC admitted to Jiangsu Cancer Hospital were retrospectively analyzed. The patients were divided into two groups according to the dose separation mode, including 29 cases in the large division group (3-4Gy per dose once a day, total dose 45-60Gy) and 23 cases (2Gy per dose once a day, total dose 50-68Gy) in the conventional division group. The short-term efficacy, 1-year survival rate and some other aspects of the two groups were compared. Results: The short-term overall response rate of large segmentation group was 79.3%, and there was significant difference compared with 52.2% of conventional segmentation group ( χ2 =4.293, P<0. 05) (Table). The 1-year survival rate of the large segmentation group was similar to that of the conventional segmentation group (82.8% vs．82.6%). The median survival time of large segment group was 30 months,which was not significantly different from the 34 months of conventional segment group (χ2=0.417, P>0.05). In terms of the effect of the two fractionated dose modes on long survival, 31.0% of patients in the large fractionation group survived more than 48 months, compared with only 13% in the conventional fractionation group. In addition, in the subgroup analysis of this study, it was found that compared with conventional fractionation radiotherapy, patients aged 45-65 years with ECOG score of 0-1 and lesions less than 5cm before radiotherapy could obtain more significant survival benefit from large fractionation radiotherapy, with statistically significant difference between the two groups (χ2=4.874, P<0.05). Conclusions: Large segmentation radiotherapy in the treatment of patients with LS-SCLC can improve the therapeutic effect and prolong the survival, especially for patients aged 45-65 years with ECOG score of 0-1 and lesions less than 5cm before radiotherapy , the survival benefit is more significant. In addition, large fractionated radiotherapy showed certain advantages in the long-term survival of patients with LS-SCLC, which is worthy of further clinical application.[Table: see text]
Prevalence [P] of molecular biomarkers [MB] expression [exp] in patients [pts] with metastatic adenocarcinoma lung [MAC]: Illinois CancerCare [ILCC] analysis.
Authors: Kumar Nikhil , Gomez Patrick Leigh , Harper Jamie
Published: June 2021

e21004

Background: Treatment of MAC is guided by MB. These include Programmed Death Ligand 1 (PDL1), Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK) & ROS1. There is little information available on P of MB in US Midwestern population, a largely homogenous Caucasian group. We examined the expression (exp) of the MB in pts with MAC who presented at ILCC in 2018, one of the largest practices in US Midwest. Methods: We conducted a retrospective analysis of all MAC pts who presented at ILCC in 2018. We analyzed the exp of PDL1, EGFR, ALK, and ROS1 in these pts. PDL1 status was defined as high if PDL1 was ≥50%, low if 1- < 50% and -ve if 0- < 1%. High and low groups [all pts with > 1%] were designated +ve. Results: In 2018 there were 125 pts seen at ILCC with MAC. As of 6/2019, 57/125 [46%] pts were alive. Pts: median age 69 yrs [45-89], median PS 1 [0-3], males 62%, current/former smokers 90%, Caucasians 95%. PDL1 results were available in 104/125 pts [83%], EGFR in 95 (76%), ALK in 97 (78%), and ROS1 in 95 (76%). Previously reported papers have described PDL1+ to be as high as 58% in MAC. However, in our study only 53/104 (51%) pts were PDL1+. Though, 26/104 (25%) did have high PDL1 exp [consistent with other reports]. 27/104 (26%) had low PDL1 exp and 51/104 (49%) pts were PDL1-ve. EGFR mutation [M] was found in 11/95 (12%), ALK M was found in 5/97 (5%) pts & ROS1 M was found in 2/95 (2%), the results of these three mutations are consistent with other groups. Conclusions: Our results indicate that exp of PDL1+ pts at ILCC is lower than reported by others, yet the proportion of those with ≥50% PDL1 in our group is similar to others. Exp of EGFR, ALK, and ROS1 in our pts is similar to other studies.[Table: see text]
Platinum-based chemotherapy combined with endostar in the treatment of advanced NSCLC: A real world study.
Authors: Jiang Wei , Sun Wei , Li Wenhui , Gao Jing , Wang Hui , Zhou Wei , Liang Jing , Aa Lixiang , Zhao Changhong , Wang Luhua
Published: June 2021

e21033

Background: Recombinant human endostatin (endostar), an angiogenesis inhibitor, has been approved for the treatment of NSCLC in combination with chemotherapy in China. This study aims to evaluate real world efficacy and safety of endostar combined with platinum-based chemotherapy in the treatment of advanced NSCLC. Methods: This study retrospectively collected electronic medical record system (EMR) information of NSCLC patients (pts) who received endostar combined with platinum-based chemotherapy regiments from June 2012 to August 2019 in 7 cancer hospitals after obtaining ethical approval. Baseline characteristics, efficacy evaluation and safety data were analyzed. Tumor response was evaluated according to RECIST 1.1. Adverse events (AEs) were graded according to NCI-CTC AE 4.0. The endpoints include objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety. Results: 512 advanced NSCLC pts who received endostar combined with platinum-based chemotherapy regiments were analyzed. The median age of pts was 59.2 years. Most pts were male, accounting for 75.2%. 63.3% pts was diagnosed at stage IV. 40.0% pts was adenocarcinoma and 35.4% pts was squamous cell carcinoma. 81.4% pts received endostar combined with chemotherapy as first-line. 292 people were included in the efficacy analysis set. The ORR, DCR and median PFS were 34%, 73% and 8.2 (95% CI 6.0-13.7) months, respectively. There were no significant differences of ORR and DCR among common platinum-based chemotherapy. The most common AEs were gastrointestinal reactions (29%), bone marrow suppression (14%), and liver damage (12%). Conclusions: The real-world data confirmed the superiority of endostar plus platinum-based chemotherapy in Chinese advanced NSCLC pts, with acceptable adverse effects. Clinical trial information: ChiCTR2000035129.
A phase II study of anlotinib plus whole brain radiation therapy (WBRT) for advanced non-small cell lung cancer with multiple brain metastases.
Authors: Zhu Xiangzhi , Tao Hua , Jiang Ming , Shi Meiqi , Kong Cheng , Song Xue , Zhang Nan , Chen Cheng , Jiang Ning , Zhao Lijun , Yan Pengwei , He Xia
Published: June 2021

e21063

Background: The prognosis of non-small-cell lung cancer (NSCLC) patients(pts) with multiple brain metastases is poor. WBRT is the main treatment for the pts, but QUARTZ study showed that the efficacy of WBRT is unsatisfactory. The synergistic effect of the antiangiogenic therapy with radiation therapy has been well established. Anlotinib, an antiangiogenic multi-target TKI, had significantly improved progression-free survival (PFS) of advanced NSCLC with Brain Metastases. This study aimed to evaluate the efficacy and safety of anlotinib combined with WBRT in pts with brain metastases ( > 3) from advanced NSCLC. Methods: Advanced NSCLC pts with brain metastases ( > 3) who were histologically confirmed to be driver gene wild type or positive and pts who had received two or more previous treatments were eligible. Pts with meningeal metastasis were excluded. All pts were treated with anlotinib (12 mg, QD, day 1 to 14 of a 21-day cycle) combined with WBRT (DT 30Gy/12f), followed by maintenance therapy with anlotinib until disease progression or treatment intolerance. The primary endpoint was intracranial progression-free survival (iPFS). Secondary endpoints were extracranial PFS (ePFS), OS and toxicity. Results: As of 25 Jan 2021, 28 pts were enrolled. The median age was 57.5 years with 46.4% male. 89.3% of pts with adenocarcinoma. 21.4% pts harbored EGFR mutation. A total of 25 pts were included in efficacy analysis. In intracranial evaluation, ORR was 64.0%, DCR was 88.0%, median iPFS was 11.1 months (95% CI 5.9 to 12.1). In extracranial evaluation, ORR was 12.0%, DCR was 84.0%, median ePFS was 6.0months (95% CI 3.2 to 8.8). Most common grade 1-2 adverse events (AEs) were hypertension (67.8%), fatigue (64.2%)，anorexia (46.4%) and hand and foot skin reaction (37.5%). The most common grade 3-4 AEs were hypertension (12.5%), hand and foot skin reaction (10.7%) and fatigue (7.2%). No intracranial hemorrhage occurred during treatment. Dose adjustment due to AE occurred in 21.4% patients. Conclusions: This prospective study shows that the combination of anlotinib and WBRT for patients with multiple brain metastases after standard treatment resistance exhibited an effective therapeutic approach and manageable AEs. For further investigation, large sample and additional clinical trials are warranted. Clinical trial information: ChiCTR1900022093.
A novel combination score based on early serum tumor markers and neutrophil-to-lymphocyte ratio dynamics predicts response to PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer.
Authors: Wang Jun , Tang Yin , Sun Yahong , Yin Beibei , Guan Yaping , Feng Dongfeng
Published: June 2021

e21095

Background: Serum tumor markers (STM) are viewed as surrogate indicators of tumor burden, and neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with the systematic inflammation and immunity status of the host. The present study was designed to evaluate early STM and NLR dynamics as combined biomarkers to predict efficacy and prognosis for advanced non-small cell lung cancer (NSCLC) patients who received immunotherapy with PD-1/PD-L1 inhibitors. Methods: We retrospectively reviewed patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors. Several STM, including carcinoembryonic antigen (CEA), cytokeratin-19 fragments (CYFRA 21–1), neuron specific enolase (NSE), carbohydrate antigen 19–9 (CA19–9), and carbohydrate antigen 125 (CA125), and NLR were routinely measured or calculated at NSCLC diagnosis. Early leading STM and NLR change were evaluated between immunotherapy initiation and the first subsequent restaging. At least 20% decreases of the leading STM were considered as leading STM decrease after immunotherapy. Both pretreatment and posttreatment NLR < 5 were considered as continuous low NLR. A combination score based on the leading STM and NLR dynamics was calculated. The effects of leading STM change, NLR change, and the combination score on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were analyzed in a training cohort (n = 79) and confirmed in a validation cohort (n = 35). Results: A total of 120 patients were included in this retrospective cohort study. The median age was 63.0 years and 71.0% was male. Overall, ORR was 20.0%, and median OS and PFS were 6.2 and 4.6 months, respectively. Patients with low combination score had a significantly improved ORR (15/60) compared to those with intermediate (0/11), or high score (0/4) ( P = 0.032). In the training cohort, the combination score was significantly associated with OS ( P < 0.001) and PFS ( P < 0.001) for all patients, as well as for those with stable and progressive disease ( P < 0.001 for OS; P < 0.001 for PFS). This combination score was also further confirmed to stratify patients with different prognosis in terms of OS ( P < 0.001) and PFS ( P < 0.001) in the validation cohort. In a multivariable model, the combination score was an independent indicator for predicting OS ( P < 0.001) and PFS ( P < 0.001). Conclusions: A simple and novel combination score based on early STM and NLR dynamics representing surrogate indicators of tumor burden, and immunity status, respectively, can accurately predict efficacy and prognosis for advanced NSCLC patients with PD-1/PD-L1 blockade.
Anlotinib combined with s-1 in the third-line or later-line treatment of stage IV non-small cell lung cancer: Study for phase II clinical trial.
Authors: Yang Xiyue , Du Xiaobo
Published: June 2021

e21115

Background: At present, for stage IV non-small-cell lung cancer (NSCLC), after the failure of second-line treatment, the effective rate of third-line treatment is not very well. We designed this study to evaluate the efficacy and safety of anlotinib combined with S-1 as a third-line treatment for patients with stage IV NSCLC. Methods: According to the inclusion and exclusion criteria, 29 patients will be treated with anlotinib plus S-1 based on Simon’s optimal two-stage design.They will undergo computed tomography (CT) every two cycles to assess the therapeutic effect according to RECIST.If the efficacy is assessed as SD, PR, CR after six cycles, anlotinib will be maintained until disease progression or death. Statistical analysis of the data will be conducted using SPSS (version 22.0).The primary endpoint is the objective response rate (ORR). The secondary endpoints are disease control rate(DCR),progression-free survival(PFS), overall survival(OS), and safety. Results: Between Jan 10, 2019, and Oct 31, 2020, a total of 29 patients were enrolled for treatment.At data cutoff (Jan 11, 2021),27(93.1%) patients had discontinued the study, and 2 (6.9%) patients were still receiving treatment. The median follow-up time was 11.2 months (IQR 8.2-20.1). Objective responses were achieved in 11 (37.9%; 95%CI 20.7-57.7) of 29 patients in the intention-to-treat population,which reached this trial’s primary endpoint. Disease control was achieved in 18 patients (62.1%; 95%CI 42.3-79.3);The median overall survival was 16.7months (95%CI 14.9-18.6);the median progression-free survival was 5.8 months (95% CI 2.9-8.7). The most common grade 3 adverse events were Gastrointestinal reactions (3[10.3%]),Fatigue (2[6.9%]), and Hypertension (2 [6.9%]).No grade 4 treatment-related adverse events, or treatment-related deaths occurred. Conclusions: The combination of anlotinib with S-1 in the third-line or later-line treatment of stage IV NSCLC shows promising anti-tumour activity and manageable toxicities in patients with NSCLC, and further study in phase 3 trials will be planned in the future. Clinical trial information: ChiCTR1900020948.
The role of social determinants on overall survival in advanced-stage non-small cell lung cancer patients.
Authors: Bello Andreas , Makani Neeharika Srivastava
Published: June 2021

e21117

Background: Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. Many studies have evaluated the association of social determinants with outcomes in early-stage NSCLC. These studies have shown statistically and clinically significant associations between overall survival (OS) and other social factors (e.g marital status, educational attainment). The aim of our study was to better understand the role of various social determinants of health (SDH) on OS in advanced-stage NSCLC patients in a community oncology practice in Florida. Methods: In this retrospective study, 125 patients with stage III and IV NSCLC were recruited between January 1st, 2014 until December 31st, 2018. We performed both categorical and continuous analyses (Pearson’s chi-square and Kruskal-Wallis test, respectively) to evaluate the association between median OS and several independent variables, including; gender, race, marital status, insurance status, living status, receiving financial assistance (FA), alcohol use, and smoking histories. OS is defined as the date of diagnosis up to the date of death. Other confounders that were analyzed included histology, treatment modality, comorbidities, and performance status of the patients. Results: Of the total study population (n = 125), 60% identified as male with a mean age of 73 years for the study population. The majority of patients (89%) identified as white; 56% were married, and 81% lived with someone. 66% of patients had an HMO insurance plan, and 51% of patients obtained FA to help with treatment care costs. 47% of patients identified as former smokers and 54% denied any alcohol use. The median OS for the patient population was 0.756 years. Chi-square analyses revealed that patients who received FA were more likely to live longer than median OS as opposed to patients that did not receive FA (OR = 2.41, 95% CI [1.18, 4.96], p = 0.050). Kruskal-Wallis analyses demonstrated that patients receiving FA had nearly a two-fold increase in median OS compared to patients without financial assistance (median OS = 1.01 years vs. 0.545 years, respectively; p = 0.013). However, other social determinants evaluated did not have a significant impact on relative OS in advanced-stage NSCLC. Conclusions: Ultimately, our study concludes that receiving FA has a significant association with increased OS in advanced-stage NSCLC patients. This study highlights the importance of reducing the financial burden of advanced-stage NSCLC patients and how FA impacts patient outcomes. Future prospective cohort studies with a larger sample size are warranted to identify other SDH, as well as the underlying mechanisms affecting median OS, in patients with advanced-stage NSCLC.
Association of progression free survival with the timing of genomic testing in non-small cell lung cancer: Evidence from the GuardantInform clinic-genomic database.
Authors: Hiatt Mark D. , Yu Junhua , Zhang Nicole , McNeal Amy , Kaylor Julie , Lang Kathryn
Published: June 2021

e21143

Background: The clinical utility of ctDNA analysis for biomarker identification in advanced non-small cell lung cancer (NSCLC) has been established, supporting clinical adoption of this testing modality. All FDA-approved, immune-checkpoint inhibitor (ICI) immunotherapies require the prerequisite of negativity for ALK rearrangement and EGFR mutation, or prior toxicity or progression on oral therapies targeting mutations in these genes. Despite these recommendations and support from the American Society of Clinical Oncology and National Comprehensive Cancer Network, broad-panel marker testing for targeted therapy options in NSCLC continues to be underperformed. Data are even limited on when those tests are typically conducted and the effects of timing on the treatment outcomes. Methods: The GuardantINFORM™ clinic-genomic database was interrogated for patients over the age of 18 having a Guardant360 test positive for EGFR mutations of L858R or exon 19 after 2016 and known to have a confirmed diagnosis of lung cancer one year prior to testing. Patients had to have at least three claims prior to, and 90 days of follow-up after, their test. Patients were stratified into three groups by pre- and post-test treatment: 1) patients treated with an EGFR tyrosine kinase inhibitor (TKI) as a first-line treatment after the test, with no other chemotherapy, ICI immunotherapy (IO), or targeted therapy before the test; 2) patients with other first-line treatments prior to the test and then EGFR TKI immediately following the test; and 3) patients treated with ICI or chemotherapy after the test and before EGFR TKI or patients not treated after the test. Real-world time to next treatment (rwTTN) was defined as the index date to the treatment different than the index therapy. Progression free survival (PFS) time was defined as rwTTN or time to death, whichever came earlier. Patients who experienced adverse events (AEs) associated with chemotherapy or IO were reported as a percentage (p-value<0.001). Results: Among the 3 cohorts of patients (384 in each group who were matched on age with difference < 3, gender, and follow-up time with difference < 4 months) identified, a statistically significant difference in PFS was discovered between group 1 ( EGFR TKI as first-line treatment) and the other two groups based on the Cox proportional hazard model [hazard ratio=1.8, p-value<0.001, median survival time for group 1= 26 months (95% CI 23-29) vs. 17 months (95% CI 14-19)]. No difference existed in PFS between groups 2 and 3. The proportion of patients experiencing treatment-associated AEs was lowest in group 1 (13.5% vs 15.9% in group 2 vs 30.2% in group 3 for ICI-related AEs, 16.9% vs 23.2% vs 38.5% for chemo-related AEs, p-value<0.001). Conclusions: Performing genomic testing sooner, as early as first-line treatment, may improve the treatment response for patients with NSCLC.
Molecular testing in advanced lung adenocarcinoma: A single-center experience.
Authors: Khan Mahir , Nguyen Ryan Huu-Tuan , Pasquinelli Mary , Feldman Lawrence Eric
Published: June 2021

e21157

Background: Standard of care testing prior to first-line therapy for advanced lung non-small cell lung cancer (NSCLC) includes EGFR mutations, ALK rearrangements, and PD-L1 expression. There is limited real-world evidence on NSCLC molecular testing patterns in underrepresented racial and ethnic populations. Methods: We identified adult patients newly diagnosed with stage IV lung adenocarcinoma at the University of Illinois Hospital & Health Sciences System between January 1, 2015 and October 1, 2019. Rates of biomarker testing for EGFR, ALK, and PD-L1 were determined, as well as the median time from tissue biopsy to each result. Data were stratified by race and ethnicity. Timelines of molecular testing were studied in relation to cancer therapy initiation. Results: Among 80 patients diagnosed with advanced NSCLC, 70 (87.5%) received EGFR testing, 69 (86.3%) received ALK testing, and 40 (50%) received PD-L1 testing from 2015-2019. Thirty-one (81.6%) patients diagnosed from 2017-2019 had PD-L1 testing. Median time from biopsy to molecular test result in the overall population was 3.0 weeks for EGFR, 3.0 weeks for ALK, and 2.0 weeks for PD-L1. There was no significant difference in EGFR and ALK testing rates between Black and non-Black patients. PD-L1 testing was decreased in Black patients compared to non-Black patients ( p = 0.02) from 2015-2019, but there was no significant difference from 2017-2019. All three biomarkers had similar testing rates between White and non-White patients and between Hispanic and non-Hispanic patients. Median time from biopsy to PD-L1 result decreased from over 12 weeks in 2015 and 2016 to 2 weeks in 2018 and 2019. Six (7.5%) patients received first-line treatment before results were available. Two (2.5%) required treatment changes based on results. Conclusions: In an urban, academic center we found similar EGFR and ALK testing rates among race and ethnicity subgroups. PD-L1 testing was lower in Black patients from 2015-2019 but not after national guidelines recommended PD-L1 testing in 2017. Treatment was initiated without full biomarker data in multiple cases, sometimes leading to changes in therapy after results were obtained. Further studies are indicated to determine strategies for comprehensive, timely, and equitable biomarker testing in advanced NSCLC.[Table: see text]
Efficacy of gefitinib combined with bevacizumab versus gefitinib in advanced EGFR L858R NSCLC.
Authors: Zhao Xinmin , Wu Xianghua , Wang Huijie , Yu Hui , Sun Si , Feng Yu , Wang Jialei
Published: June 2021

e21185

Background: 60-80% of EGFR+ NSCLC could benefit from the treatment of EGFR TKIs. However, as a result of acquired resistance, median progression-free survival (PFS) associated with EGFR-TKIs monotherapy was rarely longer than 11 months. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play an important role in the angiogenesis and progression of NSCLC. The combination of EGFR-TKIs and anti-vascular drugs that inhibit the EGFR and VEGF/VEGFR pathways may be a potential therapeutic option for EGFR-mutant NSCLC. The purpose of our study was to evaluate whether gefitinib combined with bevacizumab is associated with an increased PFS benefit compared with gefitinib alone. Methods: This study is a randomized, open-controlled, single-center study. A total of 43 advanced non-squamous NSCLC patients with EGFR L858R mutations were enrolled, including 24 in the experimental group and 19 in the control group. The experimental group received gefitinib combined with bevacizumab (gefitinib 250 mg, QD+bevacizumab 7.5 mg/kg, Q3W), and the control group received gefitinib monotherapy (250 mg, QD). Response to treatment was evaluated after one month of the treatment, followed by once every two months, and adverse events were graded. The primary endpoint was PFS, and secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety and tolerability evaluation. Samples at baseline (tissue or liquid biopsy), 43 days after treatment (liquid biopsy), and disease progression were subjected to genomic (139-gene NGS panel) profiling. Results: As of December 31, 2020, 22 patients were evaluable (12 for experimental group, 10 for control group). The ORR of the experimental group and the control group were 42% vs 60%, respectively, with no significant difference (experimental group: CR = 0, PR = 5, SD = 7, PD = 0; control group: CR = 0, PR = 6, SD = 4, PD = 0). Main adverse reactions included skin rash (n = 16), diarrhea (n = 24), hypertension (n = 2), proteinuria (n = 1). Other special cases developed fever, nausea and vomiting, elevated platelets, conjunctivitis, back pain, which were manageable. 36 patients with baseline liquid biopsy samples can be evaluated (33 plasma and 3 pleural fluid samples). Of these, EGFR L858R were detectable in 86% (n = 31) of patients. The most common co-mutated gene was TP53 (57%), followed by DNMT3A (49%) and TET2 (17%). Mutation profiles were comparable between the two groups. Conclusions: Compared to gefitinib monotherapy, gefitinib combined with bevacizumab in the treatment of non-squamous NSCLC with EGFR L858R showed similar efficacy and safety profiles.
Residual of circulating tumor DNA (ctDNA) indicated therapeutic efficacy of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC).
Authors: Wang Zhehai , Han Xiao , Guo Jun , Jia Ming , Zhu Changbin , Zhu Dongyuan , Zhang Xiqin , Tang Xiaoyong , Meng Xiangjiao
Published: June 2021

e21207

Background: The synergetic effect of ICIs plus chemotherapy has been demonstrated in first line setting for patients with advanced NSCLC. As previously reported, sintilimab plus docetaxel in advanced Chinese NSCLC pts who had failed first-line chemotherapy showed encouraging efficacy and tolerable safety profile. This exploratory study aims to investigate putative biomarker(s) predicting therapeutic response and long-term outcome for eligible patients. Methods: Advanced NSCLC pts who had failed standard platinum doublet without receiving any ICIs before would receive docetaxel (75mg/m2, day 1) plus sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by sintilimab maintenance until disease progression, unacceptable toxicity, or up to 2 years. Thirty-nine eligible patients received comprehensive genomic profiling of circulating tumor DNA (ctDNA) via a 448-gene panel before treatment. ctDNA from twenty-three patients were dynamically assessed after two courses (at 6th week). Eventually, 22 patients were enrolled into analysis, one patient was lost. White blood cells were used to filter germline variants from ctDNA sequencing data. Results: Of 22 patients with paired ctDNA profiling results at 6th week, 11 patients (50%) were defined as ctDNA residual due to presence of ≥2 somatic variants; Another 11 patients (50%) who had ≤1 somatic variant were defined as non-ctDNA residual. Significant difference of best objective response rate (ORR) (63.64% vs 0%, P=0.0039, two-sided Fisher’s Exact Testing for non-ctDNA residual vs ctDNA residual patients) was observed between these two populations. And numerically higher disease control rate (DCR) was seen in non-ctDNA residual patients (100% vs 63.64%, non-ctDNA residual vs ctDNA residual). Further, patients with ctDNA residual after 2 courses of sintilimab plus docetaxel (at 6th week) displayed higher risk of disease progression [Hazard Ratio (95%CI), 9.91(2.09-46.97), P=0.0038] and inferior prognosis (median PFS, ctDNA residual vs non-ctDNA residual, 3.0 months vs NR, P=0.0007). In addition, mutations of EGFR and LRP1B were enriched in ctDNA residual group. Especially, LRP1B gene mutations associated with shorter PFS period, which should be further investigated. Conclusions: Residual of ctDNA at 6th week was able to indicate inferior response to sintilimab plus docetaxel in patients with previously treated advanced NSCLC. Further validation of ctDNA residual as a robust predictive biomarker is warranted. [Table: see text]