tbuckley/cabot-search huggingface dataset:
A real-world study of anlotinib in combination with PD-L1 inhibitors plus chemotherapy as first-line therapy for extensive-stage small cell lung cancer.
Authors: Size Chen, Yiguang Lin, Minghan Song, Jiayi Dong, Shao Lijuan
Journal: Journal of Clinical Oncology (2024)

e20135 Background: Current first-line treatment options for extensive stage small cell lung cancer (ES-SCLC) are the PD-L1 inhibitor in combination with chemotherapy. Although these regimens have improved outcomes, most patients experience disease progression (PD), and median survival remains approximately 12 months. Anlotinib represents a tyrosine kinase inhibitor targeting multiple receptor tyrosine kinases, achieved good efficacy in third-line therapy in ES-SCLC. We conducted a real-world study to explore the safety and efficacy of adding anlotinib to the current first-line therapy in ES-SCLC. Methods: This real-world study included 16 patients with ES-SCLC treated with antirotinib in combination with the PD-L1 inhibitor and etoposide and cisplatin chemotherapy at our hospital between Oct 2020 and Nov 2023. Patients received six cycles of a standard dose of the PD-L1 inhibitor (Atezolizumab; Adebrelimab; Envafolimab; Nivolumab; Pembrolizumab; Tirelizumab or Sugemalimab) in combination with cisplatin (25 mg/m 2 , day 1-3 of each cycle) and etoposide (100 mg/m 2 , day 1-3 of each cycle), and anlotinib was taken orally (4-6mg, day 1-14 of each cycle). Maintenance PD-L1 inhibitor plus anlotinib was followed in a 21-day cycle until disease progression, intolerant toxicity, or longer than 2 years of treatment. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were disease control rate (DCR), objective response rate (ORR), and adverse reactions. Treatment response and adverse events (AEs) were assessed using the RECIST 1.1 and CTCAE 5.0, respectively. Results: A total of 16 patients were recruited. The median age was 72 years (66-76). Four patients (25%) had brain metastases at baseline, and seven patients (43.8%) had liver metastases. Median PFS was 10.8 months (95% CI, 8.3-13.3 months) and the median OS was 16.4 months (95% CI, 9.6-23.2 months). Totally 15 and 1 participants showed PR and SD, respectively. ORR and DCR were 93.8% and 100%. All patients had treatment-related AEs, of which grade 3-4 AE occurred in 50% (8/16). No serious infection or treatment-related death occurred. Myelosuppression was the most common AE, such as anemia (100%), leukocytopenia (100%), lymphocytopenia (100%), neutropenia (87.5%), and thrombocytopenia (50%). Other common AEs included hypoproteinemia (68.8%); hyponatremia (62.5%); creatinine elevation (56.3%), proteinuria (43.8%); hypertension (37.5%) and hypertriglyceridemia (37.5%). No unexpected AEs were found in this study. No patient stopped treatment due to intolerable toxicity. Conclusions: The addition of anlotinib to first-line immunotherapy in combination with chemotherapy results in extended PFS and OS in patients with ES-SCLC without additional AEs. The preliminary results warrant further investigation of this treatment modality in ES-SCLC.
Lurbinectedin versus platinum rechallenge in relapsed extensive stage small cell lung cancer: A retrospective cohort study.
Authors: Michael Libre, Matthew Lu, Spencer Lessans, Jenny Wu, Shreya Bhatia, Wade Thomas Iams
Journal: Journal of Clinical Oncology (2024)

e20110 Background: Outcomes in small cell lung cancer (SCLC) remain exceptionally poor. Although patients typically have an excellent initial response to platinum doublet chemotherapy, relapse occurs quickly. Despite multiple available therapeutic options for patients with relapse after first-line treatment, there remains limited evidence indicating a preferred second-line therapy. We present findings from a retrospective cohort study comparing lurbinectedin with platinum rechallenge in a real-world setting. Methods: Patient records were identified from Vanderbilt Ingram Cancer Center between 2000 and 2023. The study cohort included extensive-stage (ES) SCLC patients treated with second-linelurbinectedin or platinum rechallenge following initial platinum-based chemotherapy.Primary outcomes included overall survival (OS) and progression-free survival (PFS). Secondary outcomes were drug-related adverse events including hospitalization, neutropenic fever, and laboratory abnormalities by CTCAE definitions. Analysis was done in R using Kaplan-Meier estimates and Cox proportional hazards models. Results: 57 patients met inclusion criteria, with 21 receiving lurbinectedin and 36 receiving platinum rechallenge. Cohorts were similar for sex, race, comorbidities, and performance status. The platinum rechallenge group skewed younger with longer chemotherapy-free interval (CTFI) (median 9.71 months vs. 2.59 months for lurbinectedin). Median PFS was 4.37 (1.53, 5.94) vs. 2.63 months (1.68, 4.40) (p = 0.030) and median OS was 8.61 (4.91, 14.26) vs. 4.70 months (2.63, 6.73) (p = 0.001) for platinum rechallenge and lurbinectedin, respectively. In a Cox proportional hazard analysis, OS and PFS hazard ratios for lurbinectedin compared to platinum rechallenge were 4.43 (1.89-10.4, p &lt; 0.001) and 2.03 (0.87-4.8) (p = 0.102) after adjusting for age, sex, race, comorbidities, and CTFI. Notably, the OS and PFS hazard ratios for CTFI alone were 0.96 (0.9-1.0) and 0.99 (0.98-1.0). There was no statistically significant difference in hospitalizations, neutropenic fever, anemia, or transaminitis between groups, although 7 (29%) of platinum rechallenge patients discontinued due to tolerability compared to 0 (0%) with lurbinectedin. Conclusions: This retrospective cohort study suggests that second-line platinum rechallenge in patients with relapsed ES-SCLC may be associated with improved OS and PFS compared to lurbinectedin. While time since last platinum was notably different between cohorts, CTFI alone did not appear to explain the observed difference in outcomes. Drug-related safety events were similar, although tolerability led to greater discontinuation with platinum chemotherapy. Although a small, single-center retrospective study, these results support further research to identify an optimal therapeutic strategy in second-line treatment of ES-SCLC.
Quantifiable TCR repertoire changes in prediagnostic blood specimens among patients with high-grade ovarian cancer
Authors: Xuexin Yu, Mingyao Pan, Jianfeng Ye, Cassandra A. Hathaway, Shelley S. Tworoger, Jayanthi Lea, Bo Li
Journal: Cell Reports Medicine (2024)

High-grade ovarian cancer (HGOC) is a major cause of death in women. Early detection of HGOC usually leads to a cure, yet it remains a clinical challenge with over 90% HGOCs diagnosed at advanced stages. This is mainly because conventional biomarkers are not sensitive enough to detect the microscopic yet metastatic early lesions. In this study, we sequence the blood T cell receptor (TCR) repertoires of 466 patients with ovarian cancer and controls and systematically investigate the immune repertoire signatures in HGOCs. We observe quantifiable changes of selected TCRs in HGOCs that are reproducible in multiple independent cohorts. Importantly, these changes are stronger during stage I. Using pre-diagnostic patient blood samples from the Nurses' Health Study, we confirm that HGOC signals can be detected in the blood TCR repertoire up to 4 years preceding conventional diagnosis. Our findings may provide the basis for future immune-based HGOC early detection criteria.
Efficacy and safety of CalliSpheres drug-eluting beads for bronchial arterial chemoembolization combined with intravenous chemotherapy for extensive-stage small cell lung cancer.
Authors: Daxia Cai, Jianfei Tu, Yonghui Wang
Journal: Journal of Clinical Oncology (2024)

e20137 Background: We aim to explore the efficacy and tolerability of Drug-Eluting Bead Bronchial Arterial Chemotherapy Embolization (DEB-BACE) combined with intravenous chemotherapy in the treatment of patients with initially diagnosed extensive-stage small cell lung cancer (SCLC). Methods: We collected data from 24 patients with extensive-stage small cell lung cancer who received DEB-BACE combined with intravenous chemotherapy (DEB-BACE-V) and initially diagnosed at our hospital between 2013 and 2022. Among them, nine patients received BACE combined with intravenous chemotherapy from the first-line (first-line DEB-BACE-V), ten patients from the third-line (third -line DEB-BACE-V), and five patients from the second-line (second -line DEB-BACE-V). Then, the treatment response (objective response rate and rate of cancer regression) and tumor marker levels were evaluated at the first month and third month after treatment. The quality of life was assessed using the EORTC QLQ-C30 scale. Overall survival (OS) was also evaluated. First, compare the first-line DEB-BACE-V group with the second-line DEB-BACE-V group. Then, compare the first-line DEB-BACE-V group with third-line DEB-BACE-V group. Lastly, compare the second-line DEB-BACE-V group with the third-line DEB-BACE-V group. Results: In initially diagnosed extensive-stage SCLC patients treated with DEB-BACE combined with intravenous chemotherapy, first and third month post treatment, the objective response rates were 58.33% and 79.17%, respectively; and the rates of cancer regression were 75% and 91.67%, respectively. In addition, the neuron-specific enolase (NSE) and progastrin-releasing peptide levels were reduced at the third and sixth month. Quality of life assessed by EORTC QLQ-C30 scale, which included subscales of general health status, functional domains, symptom domains, and single domains except for financial difficulty, was markedly improved in first and third month of post treatment. Adverse reactions were mild and manageable, the most common being chest pain and low fever. Median values of OS in first-line DEB-BACE-V, second -line DEB-BACE-V and third -line DEB-BACE-V were 15.7 (95% CI: 9.1595-20.759) months, 29.63 (95% CI: 20.5684-36.268) months 16.92 (95% CI: 10.4044-21.871) months, and respectively. Conclusions: Due to its favorable therapeutic response, quality of life, survival benefits, and safety profile, DEB-BACE combined with intravenous chemotherapy may become a treatment option for patients with extensive-stage SCLC, particularly as second-line therapy.
Real world outcomes in extensive stage small cell lung cancer (ES-SCLC) treated with consolidative thoracic radiation (cTRT) and chemoimmunotherapy (CIT): A population level study.
Authors: Amanda Williams Gibson, Michelle Liane Dean, Marc Kerba, Vishal Navani
Journal: Journal of Clinical Oncology (2024)

e20111 Background: Despite recent survival improvements from the combination of immune checkpoint inhibitors (ICI) with chemotherapy for patients with ES-SCLC, outcomes remain limited for the majority of patients. Addition of cTRT may elicit a synergistic response and contribute to improved disease control and survival, but there is limited data supporting routine use from either the trial or real world contexts. This study aims to investigate the safety and time-to-event outcomes of patients treated with CIT and cTRT. Methods: Demographic, clinical, treatment and outcome details were extracted from the Glans-Look Lung Cancer Research Database, a province-wide real-world outcomes registry of patients treated in routine practice. A population-level cohort of ES-SCLC patients receiving CIT and cTRT between 2019 and 2023 were identified. Results: 30 patients were identified. Median age was 68y. At CIT initiation; 63% had ECOG performance status ≤ 1, 17% had brain metastases; 20% received prophylactic cranial irradiation. CIT was comprised of platinum-etoposide and ICI: durvalumab (67%) or atezolizumab (33%), followed by maintenance ICI (median 5.8 months). cTRT was administered a median 4.8 months after CIT initiation; n=13 (43%) received 30Gy/10, n=2 (7%) received dose escalation to 40-45Gy in 14-20 fractions, and n= 15 (50%) received 20Gy-25Gy over 5-10 fractions. Reasons for discontinuation of CIT were primarily to progressive disease (n=18, 75%); with n=16 patients receiving second line systemic treatment (94% chemotherapy, 6% durvalumab rechallenge), and n=1 receiving additional thoracic stereotactic ablative body radiation. Post-cTRT pneumonitis was recorded in n=3 (10%) of patients, ranging from (CTCAE v5.0 Grade 1-3 severity), requiring hospitalization + treatment break (n=1), ICI termination (n=1), or resolving without intervention (n=1). Time-to-event outcomes are presented in the table. Receiving durvalumab as opposed to atezolizumab did not impact either mPFS (10 vs. 12 months, log rank=0.4; HR: 1.3 [95% CI: 0.8 - 5.9], p=0.12) or OS (17 vs. 13.2 months, log rank p=0.87; HR: 2.2 [95% CI: 0.4 – 4.4], p=0.67). Conclusions: ES-SCLC treatment comprised of both CIT and cTRT appears feasible and effective in among real-world patients. Pneumonitis, a potential complication of combined ICI and thoracic radiation, was infrequently observed in this cohort. Use of cTRT in addition to CIT appears to numerically surpass the ~13-month mOS observed within clinical trials which used first-line CIT without additional cTRT for ES-SCLC. [Table: see text]
Socioeconomic disparities in survival outcomes of patients with SCLC with brain metastases: A nationwide analysis.
Authors: Shreyas S Bellur, Diya Jayram, Shahzaib Ahmad, Vivek Bhat, Ahmad Ozair, Mohammad Arfat Ganiyani, Atulya Aman Khosla, Vivek Podder, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2024)

e20133 Background: Despite advances in the management of cancer, socioeconomic disparities have been reported to impact survival outcomes. However, recent state of disparities in SCLC patients with brain metastases (BM) remains unknown. We explored socioeconomic disparities in survival outcomes of SCLC BM patients. Methods: We conducted a retrospective cohort study and included patients diagnosed with SCLC BM in 2018-2019 in the National Cancer Database. Patients were grouped as White, Black, American Indian, Aleutian or Pacific Islander (AAPI), or Asian. Socioeconomic and survival outcomes were analyzed and reported using median overall survival (mOS) (95% CI). Cox proportional hazard models adjusted for sex, race, facility type, education, and income and reported using hazard ratios for death (HR) (95% CI). Results: Of 2369 SCLC BM patients, 85% (N=2018) were White, 11% (N=259) Black, 0.4% (N=10), and 1.8% (N=43) Asian. 58% were Medicare-insured, and 21% earned &gt;$74,063. 40% were treated at comprehensive cancer care centers (CCC). Log-rank test revealed no significant difference in survival between races. Hispanic did not have a significant survival benefit compared to non-Hispanic patients. Medicare-insured patients have a significantly worse mOS of 7.56 months (6.90-8.28) compared to 13.77 months (12.62-16.07) in private-insured patients. Cox multivariate analysis (Table) showed improved survival in Asian (HR - 0.55, 0.34-0.89, P=0.014) and Black (HR- 0.82, 0.69-0.98, P=0.029) compared to White patients. Patients treated at CCCC had worse survival (HR-1.26, 1.11-1.42, P&lt;0.001) than in academic centers. Patients who earn more reported higher survival (HR-0.82, 0.68-0.98, P=0.030). Conclusions: Race did not significantly impact survival based on unadjusted analysis. Medicare-insured patients have unfavorable outcomes. On adjusted analysis, Asian and Black patients appear to have better survival. Treatment at community centers has worse survival. Focused efforts are warranted to bridge this gap and reduce disparities due to socioeconomic factors. [Table: see text]
Neuroendocrine features in small cell lung cancer (SCLC) and associations with platinum-sensitivity, metastatic tropism, and overall survival.
Authors: Weston He, Ahmad Karkash, Yan Han, Justin Wang Shi, Julian A. A. Marin-Acevedo, Mya Tran, Misty Dawn Shields
Journal: Journal of Clinical Oncology (2024)

e20113 Background: SCLC heterogeneity can be classified into neuroendocrine (NE) subtypes (ASCL1, NeuroD1, POU2F3, YAP1) with plasticity along its NE spectrum. SCLC harbors conventional NE features on immunohistochemistry (IHC) utilized for diagnosis. In the era of chemoimmunotherapy, insight into the role of conventional SCLC NE IHC with proclivity for metastatic site tropism and therapeutic outcomes, including chemotherapy-free interval (CTFI) and overall survival (OS), has not been studied. Methods: We retrospectively reviewed patients with SCLC who received antineoplastic therapy within the Indiana University (IU) Health System Affiliates from January 2018 to January 2024. Data was stored in an institutional review board approved RedCap. Demographics, treatment, metastases, TTF-1 and NE IHC markers, CTFI, and OS were recorded. IHC expression of Chromogranin A, synaptophysin, and INSM-1 were utilized to classify tumors into NE-low (1-3 negative markers), NE-moderate ( &lt; 3 positive markers), and NE-high (3 positive markers). ANOVA, Kruskal-Wallis, Chi-square, Fisher’s Exact, and log-rank tests were applied. Results: One-hundred and fifty-three patients diagnosed with SCLC were included. Forty-six patients with limited-stage (LS-SCLC, 30.1%) and 107 patients with extensive-stage (ES-SCLC, 69.9%) were identified. Classification by conventional NE IHC included NE-low (n = 41), NE-moderate (n = 18), and NE-high (n = 94), with enrichment for the NE-high category ( P = &lt; 0.0001). No differences were observed in age, sex, smoking history, or stage across NE categories. TTF-1 positivity by IHC independently predicted NE-high ( P = 0.04). The presence of metastases did not significantly differ ( P = 0.93), but trends in enrichment of bone ( P = 0.16) and pancreatic ( P = 0.15) metastases were observed in NE-low. No difference in CTFI was identified between NE cohorts ( P = 0.28) . Median 1-year OS across the NE-low, -moderate, and -high categories was 57.2% (95% CI, 40.4-70.8%), 36.1% (13.7-59.4%), and 53.3% (42.2-63.1%), respectively (log-rank, P = 0.09). Conclusions: Conventional NE IHC fails to predict CTFI in the era of chemoimmunotherapy. SCLC significantly enriches for NE-high. TTF-1 can independently predict NE-high SCLC. Trends in metastatic tropism and shorter 1-year OS in NE-moderate SCLC were identified but limited by sample size. Enrollment expansion is ongoing. Exploration into NE subtypes and multi-omics is in process.
Effect of CDC7 inhibition and MYC degradation on neuroendocrine transformation in the lung and prostate cancer.
Authors: Alvaro Quintanal-Villalonga, Kenta Kawasaki, Esther Redin, Swanand Rakhade, Vidushi Durani, Amin Sabet, Wouter Karthaus, Samir Zaidi, Yingqian A. Zhan, Parvathy Manoj, Harsha Sridhar, Hong Zhong, Barbara Mello, Metamia Ciampricotti, Umesh Bhanot, Michael C. Haffner, Nicholas D. Socci, Helena Alexandra Yu, Joseph Minhow Chan, Charles M. Rudin
Journal: Journal of Clinical Oncology (2024)

e20105 Background: Neuroendocrine (NE) transformation occurs as a mechanism of resistance to targeted therapy in up to 14% and 30% of EGFR-mutant lung and AR-dependent prostate adenocarcinomas, respectively, leading to poor prognosis. Even if we know the tumor population at high risk of transformation ( TP53/RB1-mutated), no therapies to prevent NE relapse are currently available. Methods: To identify therapeutic vulnerabilities for tumors undergoing NE transformation, we performed an in vitro CRISPR screen in a NE-transformed lung tumor model, followed by functional validation in in vivo prostate and lung models of NE transformation, including pharmacologic as well as genetic (isogenic cell line with overexpression or knock of CDC7) validation. Results: Our screen identified CDC7, involved in DNA replication and DNA damage response, as a potential therapeutic target in this setting. Proteogenomic analyses revealed CDC7 upregulation in lung and prostate clinical samples undergoing NE transformation, detected already in pre-transformation adenocarcinomas. Importantly, TP53/RB1-inactivation induced sensitivity to the CDC7 inhibitor simurosertib, unraveling a therapeutic vulnerability in tumors at high risk of NE transformation. Thus, we tested the combination of simurosertib with targeted therapy in vivo in different lung and prostate patient-derived models of NE transformation. In these, simurosertib was able to suppress NE transformation and dramatically delay tumor relapse. Trajectory analysis on single-cell transcriptomic data for such models revealed a NE transformation transcriptional program occurring already in the untreated tumors before transformation. CDC7 inhibition led to increased proteasomal activity and degradation of MYC, a stemness transcription factor involved in NE transformation. Ectopic overexpression of MYC T58A , a proteasome degradation-resistant MYC isoform, rescued the NE phenotype in these transformation models, suggesting that CDC7 inhibition-induced MYC degradation is the mechanism by which NE transformation is prevented. Conclusions: In sum, CDC7 inhibition may suppress, or at least dramatically delay NE transformation in patients with lung and prostate adenocarcinomas at high risk of transformation, by inducing MYC proteasomal degradation. The clinical availability of CDC7 inhibitors, currently in phase II clinical trials after demonstrating tolerability and preliminary efficacy, will allow rapid translation of these results into the clinics.