tbuckley/cabot-search huggingface dataset:
Programmed cell death ligand 1 (PD-L1) inhibitors versus programmed cell death 1 (PD-1) inhibitors for the first-line therapy of extensive-stage small cell lung cancer: A propensity score-matched study.
Authors: Yaru Tian, Shuangqing Lu, Yulan Sun, Xiaoyong Tang, Zhuoran Sun, Ke Zhao, Guochang Du, Wanjing Li, Hui Zhu
Journal: Journal of Clinical Oncology (2024)

206 Background: Addition of programmed cell death ligand 1 (PD-L1) inhibitors or programmed cell death 1 (PD-1) inhibitors to etoposide‐platinum (EP) chemotherapy has become the standard first-line regimen for ES-SCLC. The clinical efficacy and safety between the two types of immune checkpoint inhibitors (ICIs) remain controversial. We conduct the retrospective study and propensity score-matched analysis to explore the potential differences between them. Methods: Patients diagnosed with ES-SCLC and treated by EP plus PD-L1 or PD-1 inhibitors at Shandong Cancer Hospital between March 2019 and November 2022 were reviewed retrospectively. According to PD-L1 or PD-1 inhibitors, they were divided into two groups. Propensity score matching (1:1) was performed to balance the baseline characteristics of the two groups. The baseline characteristics and adverse events between the two groups were compared using the chi-squared test. The survival curves of overall survival (OS) and progression-free survival (PFS) were plotted by the Kaplan-Meier method and differences were analyzed by the log-rank test.The primary endpoints were OS and PFS. Results: As a result, 448 patients were analyzed in this study. 264 patients received PD-L1 inhibitors plus EP and 184 received PD-1 inhibitors plus EP. The median follow-up was 17.6 months. The median OS and PFS was 20.4 months and 7.8 months in the overall population. Before propensity score matching, the median OS was 20.1 months in PD-L1 inhibitor plus EP group and 20.7 months in PD-1 inhibitor plus EP group, respectively (HR 1.043, 95%CI 0.776-1.401; p= 0.781). The median PFS was 7.6 months in the PD-L1 inhibitor plus EP group and 8.5 months in PD-1 inhibitor plus EP group (HR 1.099, 95%CI 0.886-1.364; p= 0.390). After propensity score matching, the median OS and PFS were 20.4 months and 7.8months in PD-L1 inhibitor plus EP group, and those were 20.1 months and 8.6 months in PD-1 inhibitor plus EP group. There was no significant difference in OS and PFS between PD-L1 inhibitors plus EP and PD-1 inhibitors plus EP in the matched population (HR 1.104; p= 0.578 and HR 1.072; p= 0.602, respectively). The overall adverse events were comparable in the two groups. Only ≥3 grade neutropenia was more frequent in the PD-L1 inhibitors plus EP group (77.7% vs 69.0%, p= 0.040). Conclusions: In conclusion, the overall efficacy and safety profile was similar between PD-L1 inhibitors and PD-1 inhibitors for the first-line treatment of ES-SCLC.
First-line (1L) anti-PD-1 plus chemotherapy in HER2-negative advanced gastric cancer: Real-world evidence from a single Korean center.
Authors: Joosung Gabriel Shim, Minkyu Jung, Hyunwook Kim, Kyoo Hyun Kim, Taeho Kim, Youhyun Kim, Hyo Sup Shim, Hyunki Kim, Hyo Song Kim, Choong-kun Lee, Sun Young Rha
Journal: Journal of Clinical Oncology (2024)

83 Background: The implementation of immune checkpoint inhibitor combinations as first-line (1L) treatment has shown promising outcomes and is now the standard of care for HER2-negative advanced gastric cancer. However, real-world evidence supporting this approach as 1L treatment remains limited. Here, we present an analysis of real-world outcomes, comparing 1L anti-PD-1 combined with doublet chemotherapy to the previous standard chemotherapy. Methods: Patient from January 2005 to August 2023 were retrospectively reviewed. The study defined the molecular epidemiology cohort (M cohort) as patients with results for HER2, Epstein-Barr virus (EBV), mismatch repair (MMR), or PD-L1. HER2-negative patients who received palliative first-line chemotherapy doublet regimens with or without PD-1 inhibitor were included. Survival analysis included progression-free survival (PFS) and overall survival (OS), as well as subgroup analyses for molecular subtypes. Results: Total 3,028 were enrolled in the M cohort. The incidence rates of HER2-positive, EBV-positive, and deficient Mismatch Repair (dMMR) were 20.0% (606/3028), 3.8% (93/2432), and 4.7% (126/2660), respectively. PD-L1 testing was conducted on 1,394 patients, with 54.3% (1634/3028) having a CPS (Combined Positive Score) of ≥10, and 47.6% (664/1394) having a CPS of ≥1. Among these patients 1,527 had received chemotherapy doublet, and 153 had received chemotherapy doublet with PD-1 inhibitor as their 1L treatment. During a median follow-up of 56.5 months (95% CI,49.9-66.2), patients who had received PD-1 inhibitor combination therapy showed improved PFS (7.1 vs. 6.1 months; Hazard Ratio [HR], 0.77; 95% Confidence Interval [CI], 0.64–0.93) and OS (18.1 vs. 14.6 months; HR 0.80; 95% CI, 0.63–1.01) compared to those without it. The benefits in PFS from PD-1 inhibitor combination therapy were particularly notable in patients with deficient MMR status (HR, 0.22 vs. 0.80 in those without PD-1 inhibitor combination; p for interaction &lt;0.05) and in patients with signet ring cell carcinoma histology (HR, 0.58 vs. 0.92 in those without PD-1 inhibitor combination; p for interaction &lt;0.05). Conclusions: We observed real-world efficacy of the combination of PD-1 inhibitor and chemotherapy doublet as 1L treatment for HER2-negative advanced gastric cancer, consistent with previous clinical trials. [Table: see text]
Effect of pancreatobiliary reflux on macrophage-secreted IL-8, PI3K/NFκB pathway, and promotion of cholangiocarcinoma progression.
Authors: Tingting Wu, Ruiqian Gao, Xiaowei Wang, Dong Guo, Yuwei Xie, Bingzi Dong, Xiwei Hao, Chengzhan Zhu
Journal: Journal of Clinical Oncology (2024)

73 Background: Persistent pancreaticobiliary reflux (PBR) is associated with a high risk of biliary malignancy. This study aimed to evaluate the proportion of PBR in biliary tract diseases and mechanisms by which PBR promoted cholangiocarcinoma progression. Methods: Overall, 227 consecutive patients with primary biliary tract disease participated in this study. The amylase levels in the collected bile were analyzed. The mechanisms underlying the effect of high-amylase bile on bile duct epithelial and cholangiocarcinoma cells progression were analyzed. The source of interleukin-8 (IL-8) and its effects on the biological functions of cholangiocarcinoma cells were investigated. Results: The bile amylase levels in 148 of 227 patients were higher than the upper serum amylase limit of 135 IU/L. PBR was significantly correlated with sex, pyrexia, and serum gamma-glutamyl transferase (GGT) levels in the patient cohort. High-amylase bile-induced DNA damage and genetic differences in the transcript levels of the gallbladder mucosa and facilitated the proliferation and migration of bile duct cancer cells (HUCCT1 and QBC939 cells). The concentration of many cytokines increased in high-amylase bile. IL-8 is secreted primarily by macrophages via the mitogen-activated protein kinase pathway and partially by bile duct epithelial cells. IL-8 promotes the progression of HUCCT1 and QBC939 cells by regulating the expression of epithelial-mesenchymal transition-associated proteins and activating the phosphatidylinositol 3-kinase/nuclear factor kappa-B pathway. Conclusions: PBR is one of the primary causes of biliary disease. IL-8 secreted by macrophages or bile duct epithelial cells stimulated by high-amylase bile promotes cholangiocarcinoma progression.
A pan-tumor description of the genomic, transcriptomic, and immunological landscape of sodium-glucose cotransporter-2 (SGLT2) and association with clinical outcomes.
Authors: Heng Tan, Samuel A. Kareff, Harris Benjamin Krause, Andrew Elliott, Stephen V. Liu, Patrick C. Ma, Fernando Gerchman, Bernardo Spiazzi, Emmanuel S. Antonarakis, Ari M. Vanderwalde, Milan Radovich, Gilberto Lopes
Journal: Journal of Clinical Oncology (2024)

104 Background: SGLT2 has been identified as being overexpressed in a diverse set of cancers. Retrospective data has demonstrated a correlation between the use of SGLT2 inhibitors and a reduced incidence of lung cancer. We explored the association of SGLT2-coding gene SLC5A2 with the transcriptomic, genomic, immunological landscape and outcomes in a subset of solid tumors. Methods: Breast ([N = 5623], HR+HER2- [6044] or TNBC [3040]), Colorectal carcinoma (CRC, 15425), NSCLC ([21603], Adenocarcinoma [AC, 8180] or Squamous Cell Carcinoma [SCC, 3579]), Pancreatic (Panc: 5488) and Prostate (PC: 5500) tumors were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or whole exome) and RNA (whole transcriptome). PD-L1+ (22C3: TPS 1% for lung or SP142: 2+, 5% all other), Her2/Neu (+: ≥3+ and &gt; 10%) and HR (ER or PR+: ≥1+ and ≥1%) expression was assessed by IHC. Mutations were defined as pathogenic SNVs/indels (-Mt). SLC5A2-H and -L expression (transcripts per million, TPM) was defined by cancer type as top and bottom quartile, respectively. Cell infiltration was estimated by QuantiSEQ. A transcriptomic signature predictive of response to immunotherapy was applied (T cell-inflamed). The Mann-Whitney U test was applied as appropriate (p &lt; .05, adjusted for multiple comparisons). Real-world overall survival (OS) was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined patients. Results: SLC5A2 expression varied across cohorts (TNBC: 1.2 TPM, HR+HER2-BC: 1.7, CRC: 2.2, AC: 1.8, SCC: 1.3, Panc: 1.7, PC: 1.7, p &lt; .05). SLC5A2-H had a higher prevalence of FGF3 amplifications in HR+HER2- BC (17.4% -H v 10.4 -L), CRC (1.4 v .45) and PC (4.4 v .89, p &lt; .05 all). KRAS-Mt was more prevalent in SLC5A2-L CRC (41% v 53) as was BRAF-Mt (6 v 14, p &lt; .05 all). There was a lower prevalence of PDL1+ in SLC5A2-H for HR+HER- BC (14% -H v 24 -L), CRC (2 v 6), AC (47 v 68), SCC (50 v 66) and Panc (10 v 19, p &lt; .05 all). All SLC5A2-H tumors had increased Neutrophil, B, NK cell infiltrate (Table) and an increased prevalence of T cell-inflamed tumors (p &lt; .05, all). SLC5A2-H had longer OS v -L in CRC (HR .82 [.76-.88], p &lt;.001), PC (HR .85 [.74-.99], p =.03), HR+HER2- BC (HR .79 [.68-.91], p &lt; .001) and AC (HR .79 [.73-.85], p &lt; .001). Conclusions: SCL5A2-H across all investigated tumors was associated with increased immune infiltrate and a T cell-inflamed phenotype in addition to improved survival in multiple cancer types. Future research on SGLT2 should delineate its role in cancer formation versus its association as a potential positive prognostic marker. [Table: see text]
Avelumab plus axitinib for first-line treatment of advanced renal cell carcinoma: A real-world ambispective RAVE-Renal study.
Authors: Viacheslav Chubenko, Olga Baklanova, Alexey Kalpinskiy, Sufiia Safina, Andrey Lebedinets, Alexey Shkurat, Elvira Parsadanova, Maria Turganova, Vladislav Petkau, Natalya Tovbik, Elena Tkacheva, Yulia Anzhiganova, Olga Novikova, Varvara Bragina, Ruslan Zukov, Ilya Tsimafeyeu
Journal: Journal of Clinical Oncology (2024)

117 Background: In a phase 3 JAVELIN Renal 101randomized study, the combination of avelumab and axitinib demonstrated a significant improvement in progression-free survival (PFS; median 13.9 months) and objective response rate (ORR; 59.3%) among patients with metastatic clear-cell renal cell carcinoma (mRCC), leading to FDA approval as a first-line therapy. In our ambispective observational RAVE-Renal study, real-world data were gathered to assess the practical application and outcomes associated with the use of avelumab and axitinib in clinical settings. Methods: Patients were recruited from 13 sites, with data collected anonymously online. Key inclusion criteria were untreated mRCC and a minimum age of 18 years. Safety and efficacy assessments were conducted in all patients who received at least one dose of avelumab and axitinib. The primary endpoints included ORR and PFS, while secondary endpoints encompassed overall survival (OS) and the incidence of treatment-related adverse events (TRAEs). Results: At the time of data cutoff (February 03, 2024), a total of 125 patients were enrolled and treated. Median age was 61 years (range, 37-74). Patients were predominantly men (74.3%), previously nephrectomised (81.4%), had 2 and more metastatic sites (77.1%) including bone (24.3%), liver (15.7%), and brain (3%) metastases. IMDC risk was evaluated in 102 patients. Among these patients, 36 (35.3%) were categorized as having favorable risk, 50 (49%) as intermediate risk, and 16 (15.7%) as poor risk. The median number of avelumab infusions was 7 (range, 1-29). Table summarizes efficacy and safety data. Conclusions: The real-world study of first-line avelumab and axitinib therapy reveals comparable ORR and PFS to those observed in the pivotal clinical trial among patients with mRCC. The combination was well tolerated. Further follow-up of patients in the study is ongoing. Clinical trial information: KCRB01012022 . [Table: see text]
An investigator-initiated trial to evaluate safety and tolerability of YSCH-01 in patients with recurrent glioblastoma.
Authors: Hafiz Khuram Raza, Kang-jian Zhang, Zanyi Wu, Xian-long Fang, Xue-ping Cao, Shan Jiang, Zhi-feng Shi, Yanqiu Liu, Ruimei Li, De-zhi Kang
Journal: Journal of Clinical Oncology (2024)

TPS33 Background: Glioblastoma (GBM), accounting for 55% of primary malignant brain tumors, is characterized by its highly aggressive nature, poor prognosis, and high recurrence rate. Surgical resection is the primary treatment, yet recurrence is common, and survival rates remain dismal. Recurrent GBM lacks established interventions and standardized therapies. YSCH-01 is an oncolytic adenovirus, developed based on cancer-targeting gene-viro-therapy strategy (1), that has been incorporated with an interferon-like immune anticancer gene (L-IFN). Our preclinical studies have demonstrated significant tumor inhibition by YSCH-01 in both cell-line derived xenograft and patient-derived xenograft models (2). This investigator-initiated trial aims to evaluate the safety and efficacy of YSCH-01 in subjects with recurrent GBM. Methods: Six subjects with recurrent GBM are planned to be enrolled, receiving intracranial injections of YSCH-01 via Ommaya reservoir at a dosage of 5.0×1010 VP, once every 3 weeks for a total of 5 administrations, with a dose-limiting toxicity (DLT) assessment period of 3 weeks. Ommaya reservoir implantation will precede drug administration by one day. Inclusion criteria specify pathology-confirmed recurrent GBM, age 18-75 years, expected survival ≥ 12 weeks, and Karnofsky Performance Status (KPS) score ≥ 50 points, with at least one enhanced lesion of ≥ 1 cm diameter. Safety will be evaluated based on DLT and adverse events (AEs) assessed using CTCAE 5.0. Efficacy will be assessed every 5 weeks using Response Assessment in Neuro-Oncology (RANO) criteria, with overall survival follow-up at 12 weeks for two years. Two of the planned six cases have been enrolled, completing the DLT period without DLTs. The trial is registered with Clinical Trial Registry under NCT05914935. Clinical trial information: NCT05914935 .
Trends in megestrol acetate prescription among Korean patients with biliary-pancreatic cancer and their impact.
Authors: Ju Won Kim, Hoon Ji Oh
Journal: Journal of Clinical Oncology (2024)

85 Background: Chemotherapy-induced anorexia poses a significant challenge for cancer patients, particularly in biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC), known for their poor response to treatment. Megestrol acetate (MA), a commonly prescribed appetite stimulant, is associated with concerns regarding thrombosis and polypharmacy. Understanding the trends in MA prescription and its cascade effects is essential for optimizing cancer care. Methods: We conducted a retrospective cohort study using data from the Health Insurance and Review Assessment Service (HIRA) database in South Korea. The study included patients diagnosed with BTC and PDAC between 2008 and 2017. Prescription trends for MA, thrombosis events, anticoagulant prescriptions, and total parenteral nutrition (TPN) were analyzed. Statistical analysis included Chi-square tests and Kaplan-Meier estimates. Results: In our analysis of 41,670 patients with BTC and PDAC between 2008 and 2017, MA prescriptions increased notably, with PDAC patients rising from 7.85% to 51.84%. TPN prescriptions remained consistently high, especially among patients prescribed MA. For instance, in 2008, 94.71% of BTC patients prescribed MA received TPN, compared to 70.34% without MA. Similarly, in 2017, 87.56% of those prescribed MA received TPN, compared to 61.63% without MA. Among BTC patients with long-term MA prescriptions, 16.34% received anticoagulants, compared to 4.92% without MA (p&lt;0.001). Among PDAC patients, 18.3% with long-term MA prescriptions received anticoagulants, compared to 7.12% without MA (p&lt;0.001). Conclusions: The study highlights the escalating trend in MA prescriptions among BTC and PDAC patients, along with increased thrombosis diagnoses and anticoagulant prescriptions. These findings underscore the importance of understanding and managing the cascade effects of MA use and associated polypharmacy in optimizing cancer care and improving patient outcomes.
Long-term survival after metasectomy in patients with bone or soft-tissue metastases from renal cell carcinoma.
Authors: Takashi Higuchi, Shinji Miwa, Katsuhiro Hayashi, Norio Yamamoto, Hiroyuki Tsuchiya
Journal: Journal of Clinical Oncology (2024)

227 Background: Renal cell carcinoma (RCC) is reported to be associated with long-term survival, and surgical resection is now recommended in patients with metastatic lesions. This study evaluated the long-term outcome of surgery for bone or soft tissue metastases from RCC. Methods: Between 1993 and 2014, 58 patients (46 men and 12 women) underwent surgery, excluding palliative surgery, for bone or soft tissue metastatic lesions from RCC at our institution. These patients were retrospectively evaluated for factors associated with prognosis by using the log-rank test and Cox proportional hazards analysis. Results: The patients’ mean age was 60 years, and the mean follow-up period was 52 months. The surgical sites included the spine (33 patients), limb bone (10 patients), pelvis (8 patients), thoracic bone (4 patients), and soft tissue (3). The surgical procedures were total en bloc spondylectomy (TES) in 33 patients, wide excision in 13 (6 of them were also treated with prosthesis), and curettage and bone grafts in 12 (4 of them were treated with internal fixation). The 3-, 5-, 10-, and 15-year overall survival (OS) rates were 75%, 62%, 48%, and 25%, respectively. According to the surgical methods, the 5-year OS was 64% for TES, 62% for wide excision, and 46% for curettage and bone grafts. According to the surgical site, the median survival time was 127 months for the spine, 140 months for the limb bone, and 54 months for the pelvis. In multivariate analysis, preoperative lung metastasis and the pathological type, except for clear cell carcinoma, were independent risk factors for poor prognosis. However, age, performance status, Motzer classification, and abnormal blood test results were not significant risk factors. Conclusions: Our findings suggest that the surgical resection of bone and soft tissue metastatic lesions from RCC is a favorable option for improving prognosis even in patients with unfavorable conditions such as an advanced age or poor performance status. Now that treatment outcomes for renal cell carcinoma are improving, bone metastases can be treated with surgery.
Molecular basis for JAK2 inhibition with type II compounds.
Authors: Dafne Jacome, Ya Miao, Teemu Haikarainen
Journal: Journal of Clinical Oncology (2024)

176 Background: Upon prolonged exposure, the therapeutic efficiency of current clinical JAK2 inhibitors (type I inhibitors) can be attenuated, leading to drug resistance both in vitro and in vivo through non-genetic mechanisms. In contrast, type II inhibitors stabilize the inactive conformation of the kinase domain preventing the heterodimerization-mediated JAK2 activation. This confers efficacy to type I inhibitor persistent cells, improved efficacy against myeloproliferative neoplasms and other cancers such as B-cell acute lymphoblastic leukemia. Despite the advantages of type II JAK inhibitors, the discovery of type II inhibitor resistance mutation, L884P, in the kinase domain has hampered the further development of JAK2-targeted type II therapeutics. Methods: Here we use combination of protein-inhibitor binding assays, cell-based assays, X-ray crystallography, and computational tools to elucidate the resistance mechanism of JAK2-L884P mutation, to facilitate the development of type II inhibitors with activity against both wild-type and L884P mutated JAK2. Results: We have determined an atomic resolution crystal structure of JAK2-L884P mutant, revealing that mutation induces local changes in the structure but not in the ATP pocket. Furthermore, we have identified several type II compounds inhibiting. Interestingly, they show no major differences in potency in vitro against wild-type of L884P mutated JAK2. Selected compounds profiled in cell lines carrying wild-type or L884P-mutated JAK2, show differences in their cell viability, indicating that a resistance arises via allosteric effects. Conclusions: L884P mutation impacts the inhibitory potency of type II inhibitors via allosteric mechanism.Crystallographic analysis of our type II shortlisted compounds revealed that they differ in their binding modes and suggests that L884P-insensitive drugs can be developed. Preliminary cell-based experiments results confirm these findings. We will now focus on validating these observations with biomolecular simulations to clarify the molecular basis for the inhibitor resistance via L884P mutation. Our studies will facilitate the development of novel type II drugs against JAK2 in myeloproliferative neoplasms.