bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single cell sequencing reveals T follicular helper cells as the link between combination ICI therapy and the development of increased IRAEs.
Authors: Yakhshi Tafti Rana , Hugo Willy , Drakaki Alexandra , Angell Trevor E , Lechner Melissa G 
Published: June 2024

2644 Background: Targeting multiple checkpoints via the combination of individual immune checkpoint inhibitor (ICI) therapies has increased anti-tumor effects compared to single agent ICI regimens. Despite these benefits, Dual ICI therapies have a higher risk of immune toxicity and incidence of immune related adverse events (irAEs) compared to single agent immunotherapies. Of note, T follicular helper (TFH) cells have been shown to contribute to both spontaneous and, more recently, irAE autoimmunity. Given the association of TFH cells and Tertiary Lymphoid Structures (TLS) with ICI response, a potential reason for the increased effectiveness of Dual ICI in anti-cancer therapy, TFHs may also be involved in the pathogenesis and increased incidence of irAEs seen with Dual ICI therapy. Methods: To understand the underlying mechanism by which Dual ICI therapy may increase the incidence of irAEs, we obtained thyroid fine needle aspirates from 9 individuals with ICI-thyroiditis, one of the most common irAEs. We performed single-cell RNA sequencing (scRNA-Seq) and compared immune infiltrates of patients receiving anti-programmed cell death protein 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) to Dual ICI patients who received PD-1 or PD-L1 in combination with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Results: ScRNA-Seq analyses revealed a 3-fold expansion of TFH and T peripheral helper (TPH) cells in Dual ICI therapy compared to PD-1/L1 patients. CD4T cell trajectory analysis revealed a dominant transition among Dual ICI patients from a naïve SELL+ CCR7+ phenotype to the CXCR5+ TFH and later IL21+ IFNG+ TPH phenotypes (p < 0.0001). The differentiation involved an upregulation of IL21, CD40LG, BCL6, and CXCR5 genes within CD4 T cells. Differential gene analysis showed enrichment of Tertiary Lymphoid Structure (TLS) gene sets in B and TFH cell clusters indicative of TLS formation within which CD8 T, CD4 T TFH, and GC B cells interact. CD8 T cell analysis indicated a dominant expansion and differentiation towards a CXCL13+ IFNG+ FASLG+ phenotype in Dual ICI therapy compared to PD1/PDL1 monotherapy (p < 0.0001). Cell interaction analysis showed up-regulated TFH-mediated IL21 signaling and CD8 T cell-mediated CXCL13 signaling to BANK1 B cells in Dual ICI therapy. Conclusions: Dual ICI therapy led to up-regulation of activation markers and preferential differentiation of CD4 T cells towards TFH cells in addition to upregulation of TLS signature genes and signaling pathways in TFH, CD8 T, and B cells. Given the previously established association between TFHs and the pathogenesis of autoimmune diseases and irAEs, their increased numbers and activity in Dual ICI therapy may explain the greater toxicities seen.
Response to RAF/MEK/ERK inhibitors in patients with RAS altered and wild-type tumors.
Authors: Gouda Mohamed Alaa , Lin Heather Y. , Kang Lei , Le Hung , Dumbrava Ecaterina Elena , Fu Siqing , Karp Daniel D. , Tsimberidou Apostolia Maria , Naing Aung , Piha-Paul Sarina A. , Pohlmann Paula R , Rodon Ahnert Jordi , Yap Timothy A. , Meric-Bernstam Funda , Hong David S. 
Published: June 2024

3099 Background: The MAPK pathway is frequently activated in different cancers. Inhibitors of different molecules across this pathway have been developed and approved including BRAF, MEK, and ERK inhibitors. However, limited data are available regarding response in patients with upstream RAS alterations. The interplay between RAS and downstream RAF/MEK/ERK has been commonly noted; although distinct conclusions have been debated. In this study, we aimed to explore possible associations between RAS status and therapeutic outcomes to RAF/MEK/ERK inhibition in patients with advanced solid tumors. Methods: We used MD Anderson Cancer Center (MDACC) CHIMERA platform to extract data of patients with advanced solid tumors who were treated with investigational protocols including RAF, MEK, and/or ERK inhibitors in the department of investigational cancer therapeutics at MDACC as part of early phase-clinical trials. We included only patients who had molecular testing annotated by MD Anderson Precision Oncology Decision Support (PODSS) team. Patients who did not complete 30 days of therapy and those who were unevaluable for response were excluded from analysis. Treatment given at cycle 1 day 1 was manually checked to exclude patients who received other drugs in combination protocols that are not inclusive of RAF, MEK, and/or ERK inhibitors, patients who received non-selective RAF, MEK, and/or ERK inhibitors, and patients who received RAS inhibitors. Results: We included 219 patients (107 males and 112 females) who received treatment with investigational RAF, MEK, and/or ERK inhibitors. The majority of patients (58%, n=127) had RAS wild type status. Patients without RAS mutations had higher response rate compared to patients with RAS alterations (18.1% vs 2.2%, p<0.001) (Table). Disease control rate (PR or SD) was also higher in patients with RAS wild-type status compared to patients with RAS alterations (70.1% vs 52.2%, p=0.007). Additionally, progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS) were significantly longer in patients without RAS mutations (median PFS 18 weeks vs 9 weeks, p<0.001; median TTF 19 weeks vs 10 weeks, p<0.001; and median OS 58 weeks vs 42 weeks, p=0.027). Conclusions: RAS alterations are associated with lower efficacy of RAF/MEK/ERK inhibitors. This can be further validated while controlling for potential confounding factors in multivariable analysis. Additional studies are needed to investigate if RAS mutations might confer inherent resistance to treatment with RAF/MEK/ERK inhibition. [Table: see text]
MyTACTIC: Activity of targeted therapy in patients (pts) with advanced solid tumors harboring specific biomarkers.
Authors: Schwartzberg Lee S. , Spigel David R. , VanderWalde Ari , Zuniga Richard Michael , Hong Jason , Szado Tania , Yoo Bongin , Passler Luke , Wang Yong , Darbonne Walter C. , Daniel Davey 
Published: June 2024

3100 Background: MyTACTIC (NCT04632992) is a tumor-agnostic, non-randomized, open-label phase II basket trial evaluating the activity of targeted therapies, alone or in combination, in pts with advanced solid tumors carrying potentially actionable molecular alterations. We report pt outcomes across all arms of the MyTACTIC trial. Methods: Eligible pts were ≥18 years old, had an ECOG PS ≤2, and measurable or evaluable lesions per RECIST v1.1 with one or more of these actionable oncogenic biomarkers: ROS1, PIK3CA, ALK, AKT, PTEN, TMB, MSI/dMMR, ERBB2,and RET. Alterations were identified prior to enrolment using local testing, typically by next-generation sequencing. Pts who had previously received the study drug or had symptomatic or active CNS metastases were excluded. Prior targeted therapy other than trial agents was allowed. Pts were assigned to 1 of 15 treatment arms to receive single-agent or combined targeted therapy according to positive biomarker results. The primary outcome was investigator-assessed confirmed objective response rate (cORR). Safety was assessed in all treated pts. Results: At data cut-off (Jan 12, 2024), 252 pts were enrolled into one of 14 arms; no pts were enrolled into arm A (entrectinib in ROS1fusion-positive tumors). Overall, pts had a median age of 65 years (range 34–90) and 93% of them had an ECOG PS ≤1. Median follow-up was 8.3 months (range 0.7–32.0). Responses were observed across 7 arms, with a cORR ranging from 11.5% to 66.7% (Table); no responses were seen in arms G, H, J, K, and L. Further efficacy outcomes including progression-free survival, duration of response, and disease control rate will be reported for each arm. The safety profile of each drug or drug combination was as expected based on prior reports. Conclusions: Targeted therapies yielded responses across tumor types in most treatment arms; testing for actionable molecular alterations is warranted for pts with limited treatment options. Clinical trial information: NCT04632992 . [Table: see text]
First-in-human phase 1/2a study of the first-in-class, next-generation CDK4-selective inhibitor PF-07220060 + endocrine therapy (ET): Updated safety data in patients with HR+/HER2− mBC.
Authors: Giordano Antonio , Sharma Manish , Williams Anja , Schmid Peter , Flores Diaz Diana Fabiola , Magallanes Manuel , Xu Binghe , Yan Min , Howell Sacha Jon , Hamilton Erika P. , Basu Cynthia , Park Jennifer , Neumann Heather , Delioukina Maria , Yap Timothy A. 
Published: June 2024

3108 Background: PF-07220060 is a novel, highly selective CDK4 inhibitor with significant CDK6 sparing. Preliminary data have been reported for the monotherapy dose-escalation cohort (Part 1A) and ET combination dose-finding cohorts (Parts 1B-C) in the first-in-human study of PF-07220060 in patients (pts) with advanced solid tumors (1). Herein, we report updated safety data for PF-07220060 + ET in pts with HR+/HER2− advanced/metastatic breast cancer (mBC), including extended follow-up data for pts in dose-finding cohorts (Parts 1B-C) and first disclosure of data for pts in dose-expansion cohorts (Parts 2B-C). Methods: In Parts 1B and 1C of this Phase 1/2a study (NCT04557449),PF-07220060 + ET (letrozole [LET] or fulvestrant [FUL], respectively) was administered to pts with HR+/HER2− mBC as ≥2L therapy after prior CDK4/6 inhibitors (CDK4/6i). In dose-expansion cohort 2B, pts with HR+/HER2− mBC received 1L PF-07220060 + LET; in Part 2C, pts with progression after prior ET received PF-07220060 + FUL. Pts in Parts 2B-C were CDK4/6i-naïve. Primary objective was to evaluate safety and tolerability of PF-07220060 + ET. Results: At data cutoff (Nov 1, 2023), 33 pts received PF-07220060 (300 or 400 mg BID) + ET in Parts 1B-C; 34 pts in Part 2B and 36 pts in Part 2C received PF-07220060 (300 mg BID) with LET or FUL, respectively. Table summarizes patient characteristics in each cohort. In the pooled 1B-C cohort, the most common TEAEs were neutropenia (54.5% [18.2% G3]), diarrhea (42.4% [0% G3]), and nausea (42.4% [3.0% G3]). In Parts 2B-C, the most common TEAEs were neutropenia (61.8%/36.1% [23.5%/11.1% G3]), leukopenia (38.2%/33.3% [0%/13.9% G3]), and anemia (23.5%/27.8% [0%/2.8% G3]). No >G3 TEAEs were reported in Parts 1B-C or 2B-C. In Parts 1B-C, 2B, and 2C, TEAEs leading to discontinuation were reported in 3.0%, 5.9%, and 8.3% of pts, respectively; dose reductions due to AEs were reported in 12.1%, 5.9%, and 8.3% of pts, respectively. Median (range) relative dose intensity (RDI) of PF-07220060 was 98.3% (52.5–100) in Parts 1B-C, 99.8% (37.2–100) in Part 2B, and 99.7% (68.6–100) in Part 2C. Conclusions: PF-07220060 + ET was well tolerated in pts with HR+/HER2− mBC across post-CDK4/6i and CDK4/6i-naïve cohorts. Incidence of G3 neutropenia and other TEAEs was low, enabling high RDI and potential for continuous target coverage. 1. Yap, et al. J Clin Oncol. 2023;41(16_suppl):3009. Clinical trial information: NCT04557449 . [Table: see text]
Preclinical characterization of HBW-012-E, a novel, potent, selective, safe, and orally active KRAS G12D inhibitor with superior pharmacokinetic (PK) properties and anti-tumor efficacy.
Authors: Lee Ning , Li Yingfu , Liu Guanfeng , Li Jiang , Ren Junfeng 
Published: June 2024

3115 Background: HBW-012-E is a newly identified KRAS G12D small molecule inhibitor with improved oral bioavailability than MRTX1133, the more advanced clinical candidate with poor bioavailability. Methods: Small molecules were designed through our medicinal chemistry efforts, aiming to discover KRAS G12D inhibitors that are of good oral bioavailability. The compounds were screened via pERK and cell viability (CTG) assays in multiple cell types. The optimized compounds were further evaluated based on their PK properties and toxicity. The anti-tumor efficacy of the leads was confirmed in a mouse GP2D (with KRAS G12D) colon cancer model. Results: As shown in the table, HBW-012-E has better potency and PK characteristics than MRTX1133. In the GP2D model, comparing head-to-head with the same vehicle and protocol (50 mg/kg, BID, PO), HBW-012-E can not only inhibit tumor growth completely but also further regress tumor size by ~40%, whereas MRTX1133 can hardly inhibit tumor growth. HBW-012-E demonstrated anti-tumor efficacy in a dose-dependent manner; at a dose as low as 10 mg/kg, it achieved ~80 % tumor inhibition rate (TGI). Preliminary toxicity tests showed that HBW-012-E is safe: weak inhibition of CYP450 enzymes, negative mini-Ames test, excellent kinase selectivity, and no obvious abnormalities in the 14-day rat or mouse toxicity test. Conclusions: A new KRAS G12D inhibitor, HBW-012-E, was identified. Its preclinical profile, including potency, efficacy, and PK properties, are all superior to MRTX1133, and its safety meets the criteria of clinical development. It can potentially be used to treat intractable tumors mediated by KRAS G12D mutations, such as pancreatic cancer that still lacks effective treatments. [Table: see text]
The outcomes of atezolizumab therapy in combination with carboplatin and etoposide for small-cell lung cancer.
Authors: Kamishov Sergey , Tillyashaykhov Mirzagaleb , Yusupbekov Abrorjon , Niyozova Shakhnoza Khamoydinovna , Balenkov Oleg , Izrailbekova Kamila , Kobilov Odiljon , Lipartiya Meri , Rafiev Dilshod 
Published: June 2024

e20115 Background: Nearly two-thirds of patients with small-cell lung cancer (SCLC) are diagnosed at an advanced stage, associated with a poor prognosis and extremely low 5-year survival. Platinum-based chemotherapy with etoposide remains the standard treatment for such patients. In recent years, immune checkpoint inhibitors have shown improved outcomes for patients with advanced-stage SCLC. In Uzbekistan, there is currently insufficient research on atezolizumab for this oncological condition. Methods: The retrospective study included 34 patients with previously untreated stage IV SCLC and distant metastases in the central nervous system, lungs, lymph nodes, and liver. The patients underwent treatment from July 2022 to October 2023. The average age of the patients was 67.4±8.2 years, with 21 (61.8%) males and 13 (38.2%) females. The patients were divided into two groups: The 1st group comprised 14 (41.2%) individuals who received four 21-day cycles of carboplatin (AUC 5 mg/mL/min intravenously on day 1) + etoposide (100 mg/m² intravenously on days 1-3) + atezolizumab (1200 mg intravenously on day 1). Subsequently, they underwent maintenance therapy with atezolizumab until unacceptable toxicity or disease progression. The 2nd group consisted of 20 (58.8%) patients who underwent standard platinum-based chemotherapy (carboplatin + etoposide) following the same regimens. Immunohistochemical analysis was conducted using the Ventana BenchMark Ultra automatic stainer with Ventana PD-L1 SP263 monoclonal antibodies. Results: The median overall survival (OS) in the 1st patient group was 11.2 months (95% CI: 9.4-12.6), while in the 2nd group, it was 9.7 months (95% CI: 8.3-11.6). The median progression-free survival (PFS) in the 1st group was 4.8 months (95% CI: 3.9-5.3), and in the 2nd group, it was 4.1 months (95% CI: 3.1-4.6). The objective response rate in the 1st group was 41.2%, and in the 2nd group, it was 37.5%. An analysis of PD-L1 expression was conducted on both tumor cells (TC) and infiltrating immune cells (IC). The prevalence of PD-L1 expression ≥1% on TC or IC was 48.3%, while the prevalence of PD-L1 expression ≥5% was 17.4%. Among 5 patients in the 1st group with tumors showing PD-L1 expression ≥5% on TC or IC, the median OS was 15.6 months (95% CI: 11.2-17.1), compared to 8.4 months (95% CI: 7.3-9.6) in 8 patients in the 2nd group with a similar level of PD-L1 expression. The use of atezolizumab did not impact the toxicity of the administered chemotherapy. Conclusions: Adding atezolizumab to standard platinum-based chemotherapy in the first-line treatment of metastatic SCLC improves both OS and PFS in patients without increasing the toxicity of the treatment. The therapeutic benefit of atezolizumab is more pronounced in patients with elevated PD-L1 expression in tumor tissue.
Cisplatin versus carboplatin in small cell lung cancer (SCLC): Single-center experience.
Authors: Sivridemir Serife , Hasdemir Efe , Ramazanoglu Mehmet Nezir , Farzaliyeva Aydan , Rahatli Samed , Oguz Arzu , Akcali Zafer , Altundag Ozden 
Published: June 2024

e20116 Background: The current standard of care for the treatment of SCLC is concurrent chemoradiatiotherapy for patients with limited-stage and chemoimmunotherapy for extensive-stage SCLC. Cisplatin is the preferred platinum agent in both settings. Although cisplatin constitutes the standard treatment with level one evidence, carboplatin is preferred in daily practice due to its more reliable toxicity profile. Methods: To investigate carboplatin is not inferior to cisplatin in both settings we retrospectively analyzed our data between 2011-2021. The results were given HR, 95% CI, and p-value. Kaplan-Meier survival analyses with log-rank tests were performed to examine and compare OS. Results: Overall 113 patients were analyzed. 62 (54.9%) patients received carboplatin+etoposide and 51 (45.1%) patients had cisplatin+etoposide. Median age was 70 vs 59.5 in carboplatin and cisplatin patients, respectively (p < 0.001). Multivariate analyses showed that patients who received carboplatin had worse ECOG PS (p = 0.011). Median OS in both groups (Carbo vs Cis) were similar in limited stage (29.37 vs 27.77 mos p = 0.52) and extensive stage (10.79 vs 9.83 mos p = 0.64). Conclusions: Although cisplatin is still a backbone drug in both limited and extensive stage SCLC, carboplatin is a preferable drug due to its similar survival and tolerable toxicity advantage.
A phase II, open-label, efficacy and safety of olaparib with bevacizumab (SUKSES-B2) in biomarker matched relapsed or refractory small cell lung cancer.
Authors: Park Sehhoon , Kim Jiyeon , Mortimer Peter G. , Kim Heejung (Rosa) , Jung Hyun Ae , Sun Jong-Mu , Park Woong-Yang , Ahn Jin Seok , Ahn Myung-Ju , Park Keunchil , Lee Se-Hoon 
Published: June 2024

e20118 Background: The treatment of relapsed or refractory small-cell lung cancer (SCLC) remains challenging due to a paucity of effective options and its rapid proliferation coupled with a high rate of genomic alterations in the DNA damage response (DDR) pathway. The SUKSES-B2 study is designed to assess the efficacy and safety of a PARP inhibitor combined with a VEGF inhibitor within a biomarker-focused umbrella framework. Methods: In this open-label, phase II, multi-cohort umbrella trial, patients received 300mg of olaparib every 12 hours and 15mg/kg of bevacizumab on day 1 of a 21-day cycle. The biomarker based inclusion criteria for SUKSES-B2 arm were as follows: (1) SLFN11 positivity, (2) POU2F3 positivity, (3) DDR pathway alterations, or (4) ATM deficiency. A total of 25 evaluable patients were targeted for recruitment, with the primary endpoint being the objective response rate (ORR). Concurrent biomarker studies were also conducted. Results: Between August 2021 and September 2023, twenty-five patients were enrolled at Samsung Medical Center, South Korea. The median age was 67 (range: 49-80), with the cohort being predominantly male (n = 24) and smokers (n = 23). The Eastern Cooperative Oncology Group Performance Status was 0 (n = 1) or 1 (n = 24) for all participants. Patients were identified to possess following biomarkers: ATM loss (n = 1), SLFN11 expression (n = 18), POU2F3 expression (n = 1), and co-expression of SLFN11 & POU2F3 (n = 5). The ORR was 12.0%, with 3 partial responses. Median progression-free survival was 1.31 months (95% CI: 1.28-5.28) and overall survival was 7.80 months (95% CI: 5.21-9.87). All responders demonstrated 3+ SLFN11 expression with ASCL1 expression. The disease control rate was 48.0%, including nine patients with stable disease, showcasing a PFS range of 2.1 to 6.8 months. Among the patients with stable disease, four patients exhibited tumor volume reductions of 4% to 17%. Drug-related adverse events (AEs) included grade 3 anemia (n = 4) and febrile neutropenia (n = 1); however, the majority of AEs were grade 1 or 2 and were managed with standard treatments. Conclusions: The combination of olaparib and bevacizumab has shown clinical benefits in a subset of patients, particularly those with SLFN11 expression, and was generally well-tolerated. The observed extended duration of response in certain patients suggests the need for further studies. Clinical trial information: NCT04939662 .
First-line immunotherapy plus chemotherapy for ES-SCLC: Comparison between PD-1 and PD-L1 inhibitors in a real-world setting.
Authors: Wang Dahai , Gao Qin ai , Sun Yuping 
Published: June 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.