tbuckley/cabot-search huggingface dataset:
Pharmacology and Precision Medicine—Preparing for the Next Era in Clinical Medicine—Editorial
Authors: Rhian M Touyz
Journal: Pharmacological Reviews (2024)

For almost 15 years I have been working, as an associate editor, with the editorial leadership of Pharmacological Reviews . Not only has it been an honor and privilege to work with three outstanding and visionary editors-in-chief over the years (David Sibley, Eric Barker, and Lynette Daws), but it
Efficacy and safety of anti-angiogenic therapy plus immunotherapy as later-line treatment for small cell lung cancer: A real-world study.
Authors: Tong Chen, Mingzhao Wang, Yanchao Chen, Yang Cao, Yutao Liu
Journal: Journal of Clinical Oncology (2024)

e20125 Background: Small cell lung cancer (SCLC) is an highly aggressive malignancy with a poor prognosis, and current therapeutic options for relapsed SCLC are limited. This study aims to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with antiangiogenic agents in patients (pts) with previously treated SCLC, and to initially explore biomarkers for the response prediction of combination therapy. Methods: In this single-center study, medical records and follow-up data of pts with SCLC who received antiangiogenic therapy plus immunotherapy (combination therapy) or antiangiogenic monotherapy as second or later-line treatment were retrospectively analyzed. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Additionally, plasma was collected from pts in the combination therapy cohort before and after two cycles of treatment. The samples were tested for extracellular vesicles (EVs) membrane protein expression profiles. Potential biomarkers for the therapeutic effect were screened and then evaluated for their predictive performance. Results: A total of 61 pts were enrolled, including the combination therapy group (n = 40) and the antiangiogenic monotherapy group (n = 21). Baseline characteristics of the two groups were comparable. Kaplan-Meier (K-M) curve demonstrated superior PFS in combination therapy group than in monotherapy group (mPFS: 4.0 vs.2.7 months, P = 0.029). Both univariate (HR 0.634, 95%CI: 0.420-0.959, P = 0.031) and multivariate Cox regression (HR 0.554, 95%CI: 0.345-0.888, P = 0.014) proved that combination therapy, compared to antiangiogenic monotherapy, was correlated with markedly improved PFS. The combination group had higher DCR than the monotherapy group (77.5% vs. 52.4%, P = 0.044). No significant difference in the incidence of AEs between the two groups was observed. Plasma EV membrane protein detection and differential expression analysis suggested that IL-12 served as a prognostic marker for adverse outcomes in combination therapy. The Receiver Operating Characteristic (ROC) curve and K-M curve showed that IL-12 possessed favorable efficacy prediction performance (Area Under Curve, AUC = 0.85), and pts with high IL-12 expression exhibited significantly shorter PFS in contrast to those with low expression (P &lt; 0.0001). In pts experiencing progression within 3 months, higher levels of IL-12 were detected compared to those who did not (P = 0.002). Conclusions: ICIs plus antiangiogenic therapy has demonstrated superior efficacy in disease control and delayed progression over antiangiogenic monotherapy as later-line treatment in pts with SCLC. Serum EV membrane proteins showed promising predictive value for the efficacy of combination therapy.
Meta-analysis of the efficacy and safety of anlotinib combined with chemotherapy in the treatment of small cell lung cancer.
Authors: Ting Gao, Peiwen Zhao, Juanzhi Li, Yingjie Li, Xinxin Li, Xiaopeng He
Journal: Journal of Clinical Oncology (2024)

e20101 Background: Immunotherapy combined with chemotherapy(CT) has become the standard treatment for SCLC. For patients who are not eligible for immune checkpoint inhibitors, CT alone has limited efficacy. Anlotinib (AL3818), an oral, small-molecular TKI, has displayed significant anti-angiogenesis and anti-tumor growth effects through the inactivation of the VEGFR, PDGFR, FGFR and c-Kit. Several study indicated that anlotinib could prolong PFS in patients with SCLC. A meta-analysis investigating the efficacy and safety of anlotinib in combination with CT for patients with SCLC is needed. SCLC is urgently demanding novel and effective strategies. Herein, this study was to evaluate the safety and efficacy of anlotinib plus CT for SCLC. This investigation of the efficacy and safety of anlotinib in combination with CT may provide a reference for the treatment selection and management of SCLC. Methods: The studies were searched through PubMed, Embase, Cochrane Library, Web of Science up to July 28, 2023, and China National Knowledge Internet (CNKI), Wanfang, and VIP databases up to July 4, 2023. The outcomes include ORR, DCR, mPFS, OS, VEGF, and AE. Subgroup analysis was performed regarding chemotherapy drug types and the number of previous treatment cycles. Results: A total of 16 studies with 1083 patients were included in the study. Anlotinib plus chemotherapy showed significantly better efficacy in improving ORR, DCR, and mPFS compared with anlotinib therapy alone or CT alone and better PFS, 1-year and 2-year OS, and lower VEGF compared with chemotherapy alone (all P &lt;0.05). The combination of anlotinib with CT had a significantly higher risk of leukopenia (RR: 1.41, 95% CI: 1.09 to 1.82, P =0.008). Based on the subgroup analyses, the anlotinib plus etoposide group and anlotinib plus irinotecan were superior to the etoposide and the irinotecan groups, respectively, in terms of ORR outcome and DCR outcome. The risk of thrombocytopenia and myelosuppression was higher in the anlotinib plus etoposide group than in the etoposide group. For patients receiving one or NA cycle of therapy before, anlotinib plus CT was superior to CT for DCR outcome, and in patients receiving more than 2 cycles of treatment before, there was a higher risk of myelosuppression outcomes in the anlotinib plus CT group than in the anlotinib group. After more than 2 cycles of treatment, a higher risk of gastrointestinal reaction outcomes in the anlotinib plus CT group than anlotinib group. Conclusions: The findings in the present study suggest that the combination of anlotinib with CT could provide improved PFS, ORR, DCR, and OS in patients with SCLC. This meta-analysis may innovate new prospects in the therapy for SCLC.
CDK7 as a biomarker to predict response to etoposide and carboplatin treatment in limited-stage small cell lung cancer with surgical resection.
Authors: Shanshi Tong, Chengbin Lin, Weiyu Shen
Journal: Journal of Clinical Oncology (2024)

e20104 Background: The etoposide and carboplatin (EC) treatment has achieved great success in the adjuvant therapy of small cell lung cancer (SCLC), but its response rate is still low. However, there are currently no good biological indicators to suggest EC treatment sensitivity in limited-stage small cell lung cancer (LS-SCLC) patient with surgical resection. We aimed to explore reliable biomarkers for EC treatment during adjuvant therapy. Methods: We chose LS-SCLC patients undergoing adjuvant etoposide and carboplatin (4 cycles) after surgical resection in Ningbo Medical Center Lihuili Hospital from Jan, 2016 to Dec, 2023. Assessments of status including complete remission (CR), partial remission (PR), disease stable (SD) and progressive disease (PD) were according to the efficacy evaluation criteria of solid tumor (RECIST) version 1.1. We collected the clinical characteristics and overall survival (OS) of LS-SCLC patients for analysis. The formaldehyde-fixed, paraffin-embedded samples were collected to conduct immunohistochemistry (IHC) of CDK7 (CST, 2916, 1:1000). The H-score was calculated by IHC Profiler. All statistical analyses were evaluated using Graphpad and Excel. P value &lt; 0.05 were considered statistically significant. Results: Clinical characteristics were displayed in table. The CDK7 expression was significantly correlated with the responsivity. Patients with higher CDK7 expression levels had lower responsivity to EC therapy, while there is no correlation between other clinical indicators (age, gender, smoke, SCLC type and ki-67 index) and EC therapy responsivity. Moreover, the expression of CDK7 and OS displayed significantly negative correlation (P &lt; 0.05). Patients were divided into two groups depends on CDK7 expression. The Kaplan-Meier curves shows that OS was significantly different (P&lt;0.01). Conclusions: Our study indicated that CDK7 acted as a promising biomarker for both EC treatment sensitivity and clinic outcome prediction in LS-SCLC patients with surgery. [Table: see text]
Treatment of relapsed small cell lung cancer in the real-world: A comparison of platinum-etoposide rechallenge and cyclophosphamide-doxorubicin-vincristine (CAV) chemotherapy.
Authors: Deepro Chowdhury, Mathieu McKinnon, Paul Wheatley-Price, Sara Moore
Journal: Journal of Clinical Oncology (2024)

e20123 Background: Small-cell lung cancer (SCLC) is an aggressive malignancy, representing 15% of all diagnosed lung cancers. Initial therapy involves platinum-based chemotherapy, with recent evidence supporting the addition of immunotherapy. Despite excellent initial response to treatment, relapses are common and there is little prospective evidence available to guide second-line therapy. Depending on response to the previous regimen, second-line treatment can involve platinum-etoposide (PE) re-challenge or other therapies including CAV (cyclophosphamide-doxorubicin-vincristine), topotecan, taxanes, or immunotherapy. Methods: We reviewed all patients diagnosed with SCLC at the Ottawa Hospital from January 2014 – December 2021, and identified those treated with second-line systemic therapy. Baseline demographics, diagnostic, and treatment information were collected. The primary outcome was overall survival compared between platinum-etoposide re-challenge and CAV. Results: During the study period, 680 patients were diagnosed with SCLC, 521(76%) received first-line systemic therapy, and 161/521 (31%) went on to receive second-line systemic therapy. Baseline characteristics at initial diagnosis of this second-line cohort: median age 64, 93 (58%) female, 156 (97%) former/current smoking history, 156 (97%) extensive-stage. First-line treatment was almost exclusively platinum-based (n = 154, 96%). At the time of second-line therapy: 105 (69%) had ECOG performance status (PS) 0-1, and 103 (64%) had chemosensitive disease with a treatment-free interval (TFI) &gt; 90 days. Second-line regimens included platinum-etoposide (n =64, 43%), CAV (n =67, 41%), platinum-irinotecan (n =3, 2%), docetaxel (n =10, 6%), and other (n =12, 7%). Median overall survival from the start of second line chemotherapy was 5.7 months (95% CI 5.0-6.4). Comparing patients who received PE-re-challenge versus CAV, there were no significant differences in age, sex, smoking history, or stage at diagnosis. Patients receiving CAV were more likely to have a lower performance status (ECOG &gt;2: 40% versus 23%, p = 0.04) have a TFI &lt; 180 days (81% vs 62%, p = 0.002). PE chemotherapy led to higher physician-assessed clinical benefit (83% vs 55%, p &lt; 0.001) and median overall survival (7.3 (95% CI 5.7 – 8.8) versus 4.1 (95% CI 2.8 – 5.4 months), p &lt; 0.001) compared to those receiving CAV. In a sensitivity analysis for patients with TFI &lt; 180 days, PE-re-challenge had a higher mOS than CAV (6.2 (95% CI 5.1-7.2) versus 4.1 (95% CI 3.0 - 5.2), p &lt; 0.003). Conclusions: Patients who receive second-line systemic therapy for relapsed SCLC represent a small subset of the overall SCLC patient population. In this real-world study, platinum-etoposide re-challenge appeared to offer benefit over CAV, even in patients with PFI &lt; 180 days.
Real world outcomes of patients with small cell lung cancer (SCLC) presenting with brain metastasis at diagnosis in a single institution health system.
Authors: Julia K. Joseph, Robert M Matera, Henry Soo-Min Park, Veronica Chiang, Anne C. Chiang
Journal: Journal of Clinical Oncology (2024)

e20136 Background: Extensive-stage small cell lung cancer (ES-SCLC) is an aggressive lung cancer subtype with high propensity for brain metastases (mets). Despite this, there is no consensus on the treatment of brain mets especially in the setting of frontline chemoimmunotherapy and advanced radiation techniques like Gamma Knife radiosurgery (GKRS). Methods: In this single-institution retrospective study, we queried the Yale Tumor registry for all patients diagnosed with ES-SCLC in 1/2016-4/2023. Patients with brain mets at the time of presentation were identified and underwent manual chart review for abstraction of clinical information specifically pertaining to brain mets and treatment modalities. Survival outcomes including median progression free survival (mPFS), median central nervous system-progression free survival (mcPFS) and median overall survival (mOS) measured in months were also captured. Results: 423 ES-SCLC patients were identified. Of those, 92 (22%) had brain mets at initial presentation and were reviewed. 44 (48%) of patients with brain mets were treated with frontline chemotherapy (platinum doublet) while 42 (46%) were treated with chemoimmunotherapy (platinum doublet with atezolizumab or durvalumab). Patients treated with upfront chemotherapy had mPFS 6.4 (95% CI -1.2, 14.1), mcPFS 7.7 (95% CI -1.2, 17.1), and mOS 9.3 (95% CI -13.7, 36.4), compared to patients treated with chemoimmunotherapy, who had mPFS 4.9 (p=0.23; 95% CI -3.5, 15.4), mcPFS 6.7 (p=0.99; 95% CI 3.3, 20.8), and mOS 7.7 (p=0.89; 95% CI -11.4, 33.9). 63 (68%) of patients underwent upfront brain radiation. 44 (48%) had whole brain radiation (WBRT) while 19 (30%) underwent GKRS. Of the patients undergoing GKRS, 8 (42%) were symptomatic. 7 patients (37%) presented with 1 brain met, and 12 (63%) patients presented with 2-5 brain mets. For patients treated with GKRS, mPFS 6.8 (95% CI 2.3, 10.4), mcPFS 7.2 (95% CI 2.9, 12.6), and mOS 11.1 (95% CI -13.0, 40.9). For patients undergoing WBRT, mPFS 6.5 (p = 1.0; 95% CI -4.5, 20.2), mcPFS 6.5 (p = 0.96; 95% CI -3.9, 21.6), and mOS 8.6 (p = 0.21; 95% CI -17.7, 39.9). Conclusions: GKRS is a viable option for SCLC patients presenting with brain metastases, especially in those with a low number of mets. Further studies are required to determine the optimal ES-SCLC candidates for upfront GKRS. [Table: see text]
Real-world burden and treatments of chemotherapy-induced myelosuppression among patients with extensive-stage small-cell lung cancer: A retrospective real-world study in China.
Authors: Kailun Fei, Yundi Zhang, Yiting Dong, Liman Liman, Yiqi Li, Wenjing Yang, Jie Wang, Zhijie Wang
Journal: Journal of Clinical Oncology (2024)

e20102 Background: Chemotherapy-induced myelosuppression (CIM) is the major dose-limiting and severe complication for chemotherapy, particularly etoposide plus platinum-based therapy (EP), in patients with extensive-stage small-cell lung cancer (ES-SCLC). CIM adversely affects patient quality of life and imposes substantial economic burden. In China, there’s a scarcity of related studies, especially in large cohort. This study aims to summarize the burden and treatments of CIM in ES-SCLC patients using a nationally representative real-world database. Methods: Data were derived from 53 hospitals across 28 provinces, as part of the National Cancer Center (NCC) database. ES-SCLC patients receiving EP between 2018.1.1 and 2022.12.31 were included. CIM events, namely chemotherapy induced neutropenia (CIN), thrombocytopenia (CIT), and anemia (CRA) were identified based on laboratory tests and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. Incidence, treatments and impact on hospitalization cost of CIM were described. Results: 7,505 patients were included, with an average age of 61.2 years (SD = 9.02) and an average of 5.0 chemotherapy cycles (SD = 2.01). The overall incidence of CIM was 91.95%, with grade 3-4 CIM occurring in 25.09% patients. Incidence of CIN, CIT, and CRA, were 44.74%, 39.20%, and 86.48%, respectively, with febrile neutropenia at 0.72%. Among patients with CIN, 90.89% patients used granulocyte colony stimulating factor (G-CSF), and 90.56% used it prophylactically. Among patients with CIT, 17.47% used recombinant human thrombopoietin (rhTPO) and 25.49% used recombinant human interleukin-11 (rhIL-11). Among patients with CRA, 10.26% used erythropoiesis-stimulating agent (ESA). Occurrence of grade 1-2 CIM and grade 3-4 CIM may increase 9.37% and 32.36% hospitalization cost per chemotherapy cycle, respectively (¥23,316.3 vs ¥21,318.2, ¥28,217.0 vs ¥21,318.2), compared to patients without any CIM. Conclusions: Incidence of CIM is notably high among ES-SCLC patients receiving EP, and treatments like G-CSF, rhTPO, rhIL-11 and ESA are widely used. Occurrence of CIM critically escalates hospitalization cost. Innovations to protect bone marrow from chemotherapy-induced damage are promising to alleviate the burden and benefit quality of life for ES-SCLC patients.[Table: see text]
First-line immunotherapy plus chemotherapy for ES-SCLC: Comparison between PD-1 and PD-L1 inhibitors in a real-world setting.
Authors: Dahai Wang, Qin ai Gao, Yuping Sun
Journal: Journal of Clinical Oncology (2024)

e20119 Background: PD-1/PD-L1 inhibitors in combination with platinum-etoposide (EP) based chemotherapy have been approved as first-line therapy in extensive-stage small cell lung cancer (ES-SCLC). However, whether PD-1 or PD-L1 inhibitors should be preferably selected is still undetermined. Methods: The retrospective study included 367 ES-SCLC patients who received standard first-line chemoimmunotherapy from 3 cancer centers in China from May 2018 to February 2023. The efficacy, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), as well as safety were evaluated between PD-1 and PD-L1 inhibitors. Results: Among 367 ES-SCLC patients, 80 received PD-1 inhibitors plus EP, and 287 received PD-L1 inhibitors plus EP as first-line treatment. The baseline characteristics between the two groups were well balanced. Although PD-L1 inhibitors had numerically higher ORR (66.2% vs. 56.3%, P = 0.114) and DCR (93.4% vs. 87.5%, P = 0.100) compared with PD-1 inhibitors, the difference were not statistically significant. We then observed similar PFS (7.5 m vs.7.7 m; HR = 0.91[95% CI: 0.68–1.23], P = 0.547) and OS between groups. Further analysis revealed that combination of thoracic radiotherapy (TRT) with PD-1 or PD-L1 inhibitors showed similar efficacy. In addition, PD-1 or PD-L1 inhibitors had comparable efficacy in patients with different sites of metastasis. No additional immune-related adverse reactions (irAEs) were observed in the PD-1 inhibitor group compared with that in the PD-L1 inhibitor group (38.8% vs 39.7%, P = 0.875). Conclusions: PD-1 and PD-L1 inhibitors showed comparable efficacy and safety in the setting of first-line chemoimmunotherapy.
Tislelizumab combined with nab-paclitaxel single-agent chemotherapy plus bevacizumab for patients with EGFR-TKIs-resistant advanced NSCLC with ECOG PS 0-2.
Authors: Xiaohong Xie, MaoLin Zhou, YiLin Yang, Xinqing Lin, Zhanhong Xie, Yinyin Qin, Jiexia Zhang, Ming Liu, Ru Li, ChengZhi Zhou
Journal: Journal of Clinical Oncology (2024)

e20138 Background: Treatment options are limited for EGFR-TKIs-resistant advanced NSCLC. A retrospective study from our center showed that ICIs plus platinum-free, single-agent chemotherapy provided progression-free survival, overall response rate benefit, and a low rate of severe AEs in such pts. Meanwhile,there were many NSCLC patients after treatment failure with EGFR-TKIs who ECOG performance status was 2 ,they were excluded from existing prospective studies. This study was designed to further explore the efficacy and safety of Tis plus nab- paclitaxel and Beva foradvancedNSCLCpts with ECOG ps 0-2 failed to EGFR-TKIs. Methods: This is a single-arm, phase II study (NCT04310943). Pts with EGFR mutations who had failed to prior EGFR-TKIs accepted Tis (200mg, d1) ,nab-paclitaxel (100mg/m 2 , d1,8,15) and Beva (15mg/kg, d1) Q3W for up to 4 cycles, followed by Tis plus Beva (7.5mg/kg) maintenance therapy. Primary endpoints are 6m-PFS% and safety, secondary endpoints include ORR and 1-year OS rate. The planned sample size was 24 with unacceptable control of 25%, an expected value of 55%, a one-sided α of 0.05, and a power of 80%, Simon's two-stage design. Results: The median age was 57 (range: 30-70). Thirteen pts (54.2%) harbored EGFR exon 19del and 9 pts (37.5%) had exon 21 L858R at the initial diagnosis. There were 9 pts (37.5%) with ECOG ps 2 and18 pts (75%) with clinical stage IVB. Twelve pts (50%) had stable brain metastases. Fifteen pts (63.6%) progressed on both 1st/2nd and 3rd EGFR-TKIs. As of Dec30, 2023, The median follow-up time was 22.2 m (95%CI 0-51.1). Among the 21pts in the efficacy analysis set, the median PFS was 6.3 m(95%CI 5.5-7.1), the 6m-PFS % was 61.6%, the 6m-PFS% of pts with ECOG ps 2 was18.1%. The ORR was 61.9%, the median DOR was 4.4 m (95%CI 2.1-6.7), DCR was 100.0%. The median OS was 15.4 (95%CI 10.1-20.7) and 1y-OS% was 59.7%. The safety was manageable: the incidence of ≥grade 3 TRAE was 25%. Conclusions: Tislelizumab combined with nab-paclitaxel plus bevacizumab is effective with a manageable safety profile for EGFR-TKIs resistant NSCLC patients with ECOG ps 0-2. Clinical trial information: NCT04310943 . [Table: see text]