bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1 study (DRAGON) of SRK-181 (linavonkibart), a latent TGFβ1 inhibitor, combined with pembrolizumab in patients with anti-PD1 resistant advanced solid tumors: Updated results of expansion part.
Authors: Vaishampayan Ulka N. , Sweis Randy F. , Kilari Deepak , Tarhini Ahmad A. , Gainor Justin F. , Barve Minal A. , Sonpavde Guru P. , McKean Meredith , Park David J. , Babu Sunil , Ju Yawen , Liu Lan , Henry Susan , Gan Lu , Yap Timothy A.
Published: June 2024

2507

Background: Linavonkibart (LKT), also known as SRK-181, a fully human IgG4 monoclonal antibody, selectively inhibits latent transforming growth factor-beta isoform 1 (TGFβ1). TGFβ1 drives tumor immune escape by promoting an immunosuppressive pro-tumor microenvironment, including reducing antigen presentation, impairing T-cell infiltration, and tumor-killing activity. Previously, results from the dose escalation phase (3+3 design) of the ongoing open-label, phase 1 DRAGON study (NCT04291079) have showed antitumor activity with LKT + pembrolizumab (P). The combination was well tolerated with no dose limiting toxicity and the recommended dose for LKT is 1500mg q3W. Methods: In the Part B (expansion phase), LKT (1500mg q3w) + P were administered in melanoma (MEL), urothelial carcinoma (UC), and non-small cell lung cancer (NSCLC) pts, who were non-responders to prior anti-PD-1; and in ccRCC and HNSCC pts, with disease progression on the most recent prior anti-PD-1.Biomarker analyses include immunohistochemistry and flow cytometry. Results: As of 12 Jan 2024, 72 pts (29% females, median age of 65 years) were enrolled in Part B. All pts received at least one anti-PD-1 therapy with median prior lines of therapies of 3 (range 1-9). All ccRCC and all but 2 HNSCC pts had a best response of SD or PD on prior anti-PD-1. All these patients had progressed on the most recent anti-PD-1. None of the MEL, UC and NSCLC pts had a response to prior anti-PD-1. The most common treatment-related AEs (TRAE, ≥10%) of any grade were rash (23.6%), pruritus (20.8%), fatigue (19.4%) and diarrhea (12.5%). Grade 3 TRAE (≥5%) were rash (8.3%). Only 1 grade 4 TRAE (dermatitis exfoliative generalised) occurred. No grade 5 TRAE and no treatment-related SAE (≥2% [1 pt]) was observed. Efficacy results are presented in the table below. Tumor assessments were based on RECIST 1.1 criteria by PI assessment. Biomarker results showed decreased circulatory myeloid derived suppressor cell levels and increased CD8+ infiltration into tumors across multiple tumor types, indicating enhanced proinflammatory microenvironment. Conclusions: Combination treatment with LKT+P is associated with enhanced proinflammatory microenvironment with promising efficacy in anti-PD-1 resistant pts across multiple tumor types with manageable safety profile. The result supports LKT as a potential treatment to overcome immune checkpoint inhibitor-associated resistance. Clinical trial information: NCT04291079 . [Table: see text]
Examining response to immunotherapy in clear-cell renal cell carcinoma using baseline serum metabolic signatures.
Authors: Pirhaji Leila , Morris Matthew , Eaton Jonah , Zhang Min
Published: June 2024

2604

Background: Clear cell renal cell carcinoma (ccRCC) accounts for 80% of kidney cancer cases. While immune checkpoint blockade (ICB) is a front-line treatment, most patients do not have durable clinical benefit, and current biomarkers fail to predict response. Previous studies reported metabolic alterations in response to ICB based on profiling of 202 targeted metabolites. To identify metabolic signatures predicting response to ICB at baseline, we have developed mzLearn, a data-driven algorithm that overcomes obstacles in liquid chromatography/mass spectrometry (LC/MS) measurements of untargeted metabolomics at scale. Methods: We used baseline and post-treatment raw LC/MS data (n=1,650) from ccRCC patients in Phase I (n=91) and Phase III (n=741) trials (Workbench IDs ST001236 and ST001237), where anti-PD-1 treatment yielded a significant increase in overall survival compared to mTOR inhibitor. mzLearn detected 4,018 signals present in >60% of all samples. The identified signals have 90% accuracy in detecting targeted metabolites with 10% false positives while effectively overcoming signal drifts and batch effects. We then performed unsupervised K-means clustering of baseline metabolomic features and supervised linear and Cox proportional hazard models to find minimal subsets of those features associated with clinical benefit after adjusting for clinical variables, e.g., age and prognostic scores. We then developed logistic regression models to predict clinical benefit (CB), i.e., tumor shrinkage with ≥6 months progression-free survival (PFS). Finally, we used PIUMet (1), a network-based tool for untargeted metabolomic analysis, to identify linked mechanisms. Results: We identified three main metabolomic subtypes with distinct PFS in response to treatments. We identified a cluster of anti-PD-1 responders (n=279) with significantly higher PFS (p=2e-5, HR=0.56) and a non-responder cluster (n=261) who showed no significant effect from anti-PD-1 relative to mTOR inhibition (p=0.874, HR=1.02). Importantly, one subtype (n=201) tended to have higher PFS after mTOR inhibition (p=0.11, HR=1.27). Next, using supervised methods, we identified 97 baseline metabolite features associated with clinical benefit in the ICB arm. A smaller subset of top-scoring features predicts CB with a cross-validated AUC of 78% and the AUC=71% when tested in the independent Phase I cohort. PIUMet analysis of these features predicted their association with sphingolipid metabolism and arginine/proline metabolism. Conclusions: We showed baseline metabolic stratification of ccRCC patients can predict treatment response and discovered novel blood-based metabolic signatures of predicting response to ICB at baseline. These results establish a solid foundation for predictive biomarker discovery and potentially therapeutic recommendations after further validation. 1. Pirhaji et al. Nat. Met. 2016.
Lung-MAP S1800D: A phase II/III study of N-803 (ALT-803) plus pembrolizumab versus standard of care in participants with stage IV or recurrent non-small cell lung cancer (NSCLC) previously treated with anti-PD-1 or anti-PD-L1 therapy.
Authors: Wrangle John M. , Redman Mary Weber , Husain Hatim , Reckamp Karen L. , Stinchcombe Tom , Edelman Martin Joseph , Leal Ticiana , Faller Bryan A. , Minichiello Katherine , Borghaei Hossein , Kelly Karen , Herbst Roy S. , Gray Jhanelle E.
Published: June 2024

2619

Background: IL-15 is a member of the IL-2 common gamma chain family of cytokines. N-803 is IL-15 administered in complex with IL-15 receptor alpha. Lung cancer, despite advances in targeted therapies and immunotherapy, remains the leading cause of cancer related death in the United States. Strategies to improve the performance of immunotherapy in advanced NSCLC is a clinical unmet need. Methods: Lung-MAP S1800D was a randomized study comparing N-803 plus pembrolizumab (NP) to investigators’ choice standard-of-care chemotherapy (SoC) for previously treated advanced NSCLC. Patients were enrolled into an Acquired Resistance Cohort (ARC) if disease progression on prior anti-PD-(L)1 occurred > 84 days from start of treatment and otherwise into a Primary Resistance Cohort (PRC). The ARC was a phase II/III study with a sample size goal of 334 patients. The PRC was a phase II with sample size of 134 patients. The first interim analysis (IA1) in the ARC evaluated futility among the first 25 patients treated with NP which required ≥1 response and ≥50% with disease control at 12 weeks to continue accrual. The primary endpoint in both cohorts was overall survival (OS). Secondary endpoints were progression-free survival (PFS), response, and toxicity. Results: Accrual in the ARC and PRC were closed at the IA1 in the ARC with 74 pts in the ARC and 8 in the PRC. Of the 74 ARC patients, 71 met eligibility (36 SoC, 35 NP), and 32 pts on each arm received treatment. With 44 events, OS was not significantly different between the two arms (HR (95%CI: 0.73(0.40-1.36), p=0.32) with a 12-month OS rate of 25% with SoC and 44% with NP. With 61 events, PFS was not significantly different but numerically worse (HR (95% CI): 1.29 (0.78-2.13, 95% CI), p=0.33). There were 3 unconfirmed partial responses and 1 confirmed complete response with NP and 3 unconfirmed partial responses and 2 confirmed partial responses with SoC. On the NP arm, there were 10 Grade 3 (1 hematologic) and 1 Grade 5 treatment-related adverse events reported as Disease Progression (34% Grade 3+ TRAE). The Grade 3+ TRAE rate on the SoC arm was 53% with 10 Grade 3+ hematologic toxicities. Conclusions: While the study failed to continue accrual past IA1, there is an indication of a subgroup that might benefit from NP with a potential OS difference at 12 months. NP was safe when compared to SoC, and responses were seen in both treatment arms, including partial and complete responses in the NP group. Evaluation of tumor and patient characteristics will be critical to define if there are those who may benefit from N-803 plus pembrolizumab. Clinical trial information: NCT05096663 .
The efficacy of immune checkpoint inhibitors in patients with cancer with pseudoprogression.
Authors: Lyadova Marina , Fedorinov Denis , Pardabekova Olesya , Nosova Margarita , Tuleiko Veronika , Lyadov Vladimir , Kuzmina Evgenia , Antonova Tatiana , Lyadov Konstantin , Galkin Vsevolod , Poddubnaya Irina
Published: June 2024

2620

Background: Pseudoprogression (PsP) is quite a common phenomenon in cancer patients undergoing therapy with immune checkpoint inhibitors (ICI). It could be defined as temporary increase of tumor volume or the number of tumor lesions after beginning of ICI treatment (immune unconfirmed progressive disease - iUPD) followed by clinical response. However, many specialists in real clinical practice are hesitant to continue ICI therapy in patients with iUPD because of medical or financial constraints. We aimed to evaluate the efficacy of ICI in patients with clinical evidence of PsP. Methods: We retrospectively analyzed 1001 cases of ICI treatment (male 58,4%, age 28-90 years) in patients with various solid malignancies: melanoma – 316, lung – 280, kidney – 247, GI cancer – 96, cervix of the uteri – 62. The patients were treated in 2 regional referral centers in Moscow and Moscow Region between June 2018 and Dec. 2022. Unconfirmed progressive disease (iUPD) according to iRECIST criteria was diagnosed in 316 patients at the first imaging control after the beginning of ICI treatment (31,6%). Results: Among 316 patients with iUPD the presence of progression (immune confirmed progressive disease – iCPD) was verified in 105 (33,2%): melanoma – 109 (34,5%), lung – 86 (30,7%), kidney – 75 (30,4%), GI cancer – 42 (43,8%), cervix of the uteri – 4 (6,5%). Stable disease was found in 144 (45,6%), partial response in 50 (15,8% - iPR), complete response in 17 patients (5,4% - iCR). Altogether, PsP was diagnosed in 211 of 1001 patients (21,1%). Overall objective response rate in 316 patients with iUPD reached 21,2%, control over disease was achieved in 66,8% of cases. Severe immune-mediated adverse events (3-4 st. according to CTC AE 5.0) were diagnosed in 9 patients (2,8%). Median overall survival in patients with iUPD and ORR was 16,85 mon (95% CI 15,1–18,5), in patients without iUPD and ORR – 14,93 mon (95% CI 13,78–16,0). Conclusions: PsP was diagnosed in 21,1% of patients getting ICI treatment in real clinical practice with median survival in PsP patients with objective response of about 17 months. Only 10,5% of patients had iCPD after their second follow-up. We feel that close adherence to iRECIST criteria to verify true progression is mandatory in patients under ICI treatment to exclude unnecessary cessation of treatment.
PD-L1 immunohistochemistry in gastric cancer: Comparison of combined positive score and tumor area positivity across 28-8, 22C3, and SP263 assays.
Authors: Klempner Samuel J. , Cowden Eric S , Cytryn Samuel Louis , Fassan Matteo , Kawakami Hisato , Shimada Hideaki , Tang Laura H. , Wagner Daniel-Christoph , Yatabe Yasushi , Savchenko Alexander , Salcius Jennifer , Johng Dorhyun , Fairchild Lauren , Chen Jing , Montenegro Giuliana , Moehler Markus H.
Published: June 2024

2625

Background: The clinical application of programmed death-ligand 1 (PD-L1) immunohistochemistry is complicated by multiple available assays and different testing platforms, scoring algorithms, and cut-offs applied. This study assessed the analytical comparability of three commercially available PD-L1 assays (28-8, 22C3, and SP263) and two scoring algorithms used in gastric cancer (GC). Methods: Serial sections of 100 commercially procured GC samples, selected by the 28-8 assay to represent the dynamic range of PD-L1 expression, were stained with the three in vitrodiagnostic (IVD)-grade PD-L1 assays. Stained slides were blindly and independently evaluated by three trained pathologists for intra- and inter-reader assessment. Scoring was performed using the combined positive score (CPS) and tumor area positivity (TAP) methods, followed by statistical analysis. Digital image analysis (DIA) was used to objectively assess the technical performance of each assay by simulating CPS and TAP scoring methods using the HALO platform. Results: Comparable, specific, staining patterns were observed with the three PD-L1 assays. Pathologist assessment of PD-L1 positivity was reproducible in GC sample cohorts despite discernible variability in the observed staining intensity. When the same PD-L1 cut-offs were applied, inter- and intra-assay assessments of all three assays, using either CPS or TAP scoring methods, demonstrated moderate to almost-perfect (inter-assay Cohen’s kappa [κ] ranged from 0.47 to 0.83) and substantial to almost-perfect (intra-assay κ ranged from 0.77 to 1.00) agreement, respectively. Moreover, inter-pathologist evaluation showed a significant level of reproducibility (intraclass correlation coefficient (ICC) ≥0.92). DIA confirmed no difference in technical performance when specific digital algorithms were applied. Conclusions: This GC study highlights analytical concordance in PD-L1 testing among three major PD-L1 assays when TAP and CPS scoring algorithms are prospectively applied. Independently, DIA further supports the comparability of the technical performance of the assays. These observations support flexibility in cross-application of the different PD-L1 assays and scoring algorithms currently used to characterize PD-L1–positive GC samples.
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.
Correlation between multiorgan immune-related adverse events and clinical outcomes in patients with extensive-stage small cell lung cancer (ES-SCLC) treated with chemo-immunotherapy.
Authors: Monaca Federico , Gomez-Randulfe Rodriguez Martin Igor , Vita Emanuele , Cosmai Antonia , Polidori Sara , Stefani Alessio , Horn Guido , Mastrantoni Luca , Vitale Antonio , Russo Jacopo , Occhipinti Denis , Scala Alessandro , Troisi Paola , D'Argento Ettore , Di Salvatore Mariantonietta , Tortora Giampaolo , Califano Raffaele , Bria Emilio
Published: June 2024

e20129

Background: The addition of immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy (CT-IO) has changed the first-line (1L) treatment landscape of extensive-stage small-cell lung cancer (ES-SCLC). Although ICIs improve survival, they can trigger immune related adverse events (irAEs). Notably, a correlation between irAEs and improved survival (OS) has been observed in several solid tumours including NSCLC. The impact of multiorgan irAEs in ES-SCLC treated with 1L CT-IO remains less clear. Methods: We retrospectively reviewed pts with ES-SCLC who received 1L CT-IO from November 2019 to September 2023 across 2 European centres. Demographic and clinical data were collected and analysed. We evaluated the correlation between irAEs (single and multiorgan) and OS. Results: A total of 217 pts were included. Median follow-up in censored pts was 13.2 m. Overall response rate was 75.1%, median PFS was 6.2 months (m) (95% CI, 5.8 - 6.7), and median OS 10.9 m (95% CI, 9.3 - 12.4). Single-organ any grade irAEs were reported in 58 pts (26.7%), while multi-organ irAEs occurred in 18 pts (8.3%). Clinicopathological characteristics stratified by irAEs are shown in the table. The most commonly affected organs were skin (n=25, 11.5%) and the digestive system (n=15, 6.9%). Treatment discontinuation rate due to irAEs was 11.1% (n=26). Median PFS in pts with multiorgan vs single vs no irAEs was 16.7m, 9.0m and 5.5m, respectively. Median OS was not reached, 17.9m and 8.2m, respectively. The multivariate analysis including irAEs as a time-varying covariate confirmed the association between irAEs and improved PFS (HR 0.38; 95% CI, 0.28 - 0.50, p<0.001) and OS (HR 0.37; 95% CI, 0.27-0.52, p<0.001). Conclusions: Our cohort shows that the incidence of irAEs in this setting is similar to previous real-world studies and that multiorgan irAEs were significantly associated with longer PFS and OS. Further research is needed to characterize the profile of irAEs associated with improved outcomes and to understand the role of concurrent therapeutic interventions. [Table: see text]
In-depth Microbiological Characterization of Urine From Subjects With Type 2 Diabetes
Authors: Calvigioni Marco , Biancalana Edoardo , Mazzantini Diletta , Celandroni Francesco , Rossi Chiara , Mengozzi Alessandro , Ghelardi Emilia , Solini Anna
Published: June 2024

Context

Lower urinary tract symptoms (LUTS) are common in type 2 diabetes (T2D), affecting quality of life and potentially leading to medication discontinuation. Among various factors contributing to LUTS, recent observations suggest a critical role of the urinary microbiota. Research on urinary dysbiosis in T2D remains underexplored.

Objective

We conducted a pilot study to investigate differences in the urinary microbiota between patients with T2D and healthy individuals and its potential indirect association with LUTS risk.

Methods

This case–control study included 50 patients with T2D and no LUTS, and 25 healthy controls. Microbial DNAs were extracted from urinary sediments and bacterial populations quantified by real-time quantitative polymerase chain reaction (PCR) and qualitatively investigated by 16S rRNA gene sequencing. Validation experiments with digital PCR were also performed.

Results

In patients with T2D a higher total bacterial load and an increased abundance of Bacillota were found. After stratification by gender, these results were observed only in women. However, no significant quantitative differences were observed at the genus level. Alpha diversity analysis showed no significant differences between T2D and control groups, or by gender. At the species level, a substantial qualitative and often gender-dependent shift was present in individuals with T2D.

Conclusion

The urinary microbiome of subjects with T2D was found to be different from that of healthy controls. Specifically, patients with T2D displayed higher total bacterial load and Bacillota levels, as well as qualitative changes in bacterial species. These changes suggested a dysbiotic condition of the urinary microbiota of subjects with T2D, with some gender-related differences. Although causality cannot be inferred, these findings highlight the impact of T2D on the urinary microbiota and its potential relevance in developing LUTS and, from a broader perspective, metabolic abnormalities.
Protein Arginine Methyltransferase CARM1 in Human Breast Cancer
Authors: Bacabac Megan , Liu Peng , Xu Wei
Published: June 2024

Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that deposits asymmetrical dimethylation marks on both histone and nonhistone substrates. The regulatory role of CARM1 in transcription was first identified in estrogen receptor positive (ER+) breast cancer. Since then, the mechanism of CARM1 in activating ER-target genes has been further interrogated. CARM1 is expressed at the highest level in ER negative (ER–) breast cancer and higher expression correlates with poor prognosis, suggesting an oncogenic role of CARM1. Indeed, in ER– breast cancer, CARM1 can promote proliferation and metastasis at least partly through methylation of proteins and activation of oncogenes. In this review, we summarize the mechanisms of transcriptional activation by CARM1 in breast cancer. The methyltransferase activity of CARM1 is important for many of its functions; here, we also highlight the nonenzymatic roles of CARM1. We also cover the biological processes regulated by CARM1 that are often deregulated in cancer and the ways to harness CARM1 in cancer treatment.
Neural crest development and disorders: from patient to model system and back again – the NEUcrest conference
Authors: Antonaci Marco , Kerr Amy , Lawrence Merin , Lorenzini Francesca , Narwade Nitin , Paka Chloé , Wulf Anna Magdalena
Published: June 2024

The neural crest (NC) is an embryonic multipotent and transitory population of cells that appears during late gastrulation/early neurulation in the developing embryos of vertebrate organisms. Often called “the fourth germ layer”, the NC is characterised by incredible mobility, which allows the NC cells to migrate throughout the whole embryo, giving rise to an astonishing number of different derivatives in the adult organism, such as craniofacial skeleton, adrenal gland, enteric nervous system and melanocytes. Because of these properties, neurocristopathies (NCPs), which is the term used to classify genetic diseases associated with NC developmental defects, are often syndromic and, taken all together, are the most common type of genetic disease. The NEUcrest consortium is an EU funded innovative training network (ITN) that aims to study the NC and NCPs. In March 2024, the early stage researchers (ESRs) in the NEUcrest consortium organised an in-person conference for well-established and early career researchers to discuss new advances in the NC and NCPs field, starting from the induction of the NC, and then moving on to migration and differentiation processes they undergo. The conference focused heavily on NCPs associated with each of these steps. The conference also included events, such as a round table to discuss the future of the NC research, plus a talk by a person living with an NCP. This 3-day conference aimed to bring together the past, present and future of this field to try and unravel the mysteries of this unique cell population.
Predicting Survival in Mucinous Adenocarcinoma of the Appendix: Demographics, Disease Presentation, and Treatment Methodology
Authors: McClelland Paul H. , Gregory Stephanie N. , Nah Shirley K. , Hernandez Jonathan M. , Davis Jeremy L. , Blakely Andrew M.
Published: June 2024

Background

Mucinous adenocarcinoma of the appendix (MACA) follows a complex disease course with variable survival. Large-scale predictive modeling may determine subtle yet important prognostic factors otherwise unseen in smaller cohort analyses.

Methods

Patients with MACA were identified from the Surveillance, Epidemiology, and End Results (SEER) Research Plus database (2005–2019). Primary, secondary, and tertiary outcomes were disease-specific survival (DSS), overall survival (OS), and average annual percent change (AAPC) in incidence.

Results

Among 4,258 included patients, MACA was most frequently diagnosed at 50 to 69 years (52.0%), with female preponderance (55.9%). MACA incidence AAPC was 3.8 (95% confidence interval [CI] 1.9–5.9). For patients with exclusive, first-diagnosis MACA included in survival analysis (3,222 patients), median DSS and OS were 118 and 88 months, respectively. In DSS-based multivariable analysis, worse prognosis was associated with non-Hispanic Black background (HR 1.36, 95% CI 1.02–1.82; p = 0.036), high grade (grade 3 HR 3.10, 95% CI 2.44–3.92; p < 0.001), lymphatic spread (HR 2.73, 95% CI 2.26–3.30; p < 0.001), and distant metastasis (HR 5.84, 95% CI 3.86–8.83; p < 0.001). In subcohort analysis of patients with rationale for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC, 2,387 patients), CRS-HIPEC was associated with survival benefit compared with surgery alone but only for moderate-grade tumors (median DSS/OS 138/138 vs. 116/87 months; p < 0.001).

Conclusions

Mucinous adenocarcinoma of the appendix incidence is increasing in the United States. Survival rates are affected by both demographics and classical risk factors, and CRS-HIPEC-associated survival benefit predominantly occurs in moderate-grade tumors. Further exploration of biologic and clinicopathologic features may enhance risk stratification for this disease.