tbuckley/cabot-search huggingface dataset:
A phase 1 study of IO102-IO103 vaccine plus pembrolizumab in patients with BCG-intolerant or unresponsive non-muscle invasive bladder cancer (NMIBC).
Authors: Sumana Veeravelli, Marc Dall'era, Shuchi Gulati, Nicholas Mitsiades, Rashmi Verma, Christopher P. Evans, Thenappan Chandrasekar, Arta Monir Monjazeb, Primo N Lara, Mamta Parikh
Journal: Journal of Clinical Oncology (2024)

TPS716 Background: Pembrolizumab, an anti-PD1 antibody, is a treatment option for high-risk BCG-unresponsive NMIBC, but has a modest complete response (CR) rate of 41% at 3 months, and a median duration of CR of 16.2 months. IO102-IO103 is a novel immune-modulating cancer vaccine that stimulates activation of T cells targeting indoleamine-2,3-dioxygenase 1 (IDO1) and PDL1-positive cells, resulting in potentially increased susceptibility to anti-PD-1 blockade. Combination IO102-IO103 with nivolumab showed encouraging clinical activity and tolerability in previously anti-PD-1 naïve metastatic melanoma patients (NCT03047928). The existing data for synergistic effects of IO102-IO103 in combination with anti-PD1 therapy and the known expression of IDO in urothelial carcinoma lend rationale to this phase I trial designed to assess the feasibility, safety, and toxicity of IO102-IO103 plus pembrolizumab in patients with BCG-intolerant or unresponsive NMIBC. Methods: This open-label, single arm, phase 1 study enrolls patients with BCG-unresponsive or intolerant high-risk NMIBC who are ineligible for or have declined cystectomy and have adequate ECOG performance status (0-2), hematologic function, and end organ function. High-risk NMIBC is defined as T1, high-grade Ta, or CIS/Tis, with predominantly urothelial cell histology. Exclusion criteria include known active autoimmune disorders requiring immunosuppressive therapy or prior checkpoint inhibitor therapy. Eligible patients will be treated with pembrolizumab 200 mg IV on Day (D) 1, and IO102-IO103 85 mcg SQ on D1 and 8 of a 21-day cycle for the first two cycles, after which IO102-IO103 dosing will be D1 only, with treatment for up to 2 years. The primary endpoints of feasibility, safety, and toxicity will be evaluated by CTCAE v5.0 criteria and will be met if ≥10 patients out of 12 are able to complete the first cycle without experiencing pre-specified treatment-limiting toxicities. Key secondary endpoints include CR rate at 3 months, median duration of response, and cystectomy-free survival at 18 months. Biopsy specimens and serial urine and blood samples will be collected to evaluate potential biomarkers of response. Clinical trial information: NCT05843448 .
Disease characteristics, survival outcomes, and tumor molecular landscape in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) harboring <i>CDK12</i> alterations (<i>CDK12a</i>) receiving intensified androgen deprivation therapy (ADTi).
Authors: Chadi Hage Chehade, Georges Gebrael, Ayana Srivastava, Nishita Tripathi, Nicolas Sayegh, Vinay Mathew Thomas, Gliceida Galarza Fortuna, Beverly Chigarira, Blake Nordblad, Patrick Campbell, Clara Tandar, Haoran Li, Benjamin L. Maughan, Neeraj Agarwal, Umang Swami
Journal: Journal of Clinical Oncology (2024)

189 Background: CDK12 is one of the homologous recombination repair ( HRR) genes involved in genomic stability. The presence of CDK12a has been associated with worse survival outcomes in pts with metastatic prostate cancer [PMID: 32988971; 32462107]. However, the impact of CDK12a on outcomes in pts with mHSPC undergoing ADTi with doublets has never been reported. Herein, we sought to assess this impact while evaluating disease characteristics and tumor molecular landscape. Methods: This was a retrospective IRB-approved study. Eligibility: pts with mHSPC undergoing ADTi with either docetaxel or an androgen receptor pathway inhibitor (ARPI) (i.e., abiraterone, enzalutamide, apalutamide) harboring pathogenic CDK12a on comprehensive genomic profiling (CGP) of primary prostate tissue, metastatic lesion, or on cell-free DNA. Descriptive statistics were used for clinical features and survival outcomes. Optimal PSA response (PSA-R) was defined as PSA ≤ 0.2 ng/ml. Progression-free survival (PFS) was defined from the start of therapy for mHSPC to progression (per PCWG-3) or death from any cause. Overall survival (OS) was defined from treatment initiation for mHSPC to death from any reason or censored at the last follow-up. Concurrent genomic alterations with a frequency ≥ 10% were reported. Results: Of 323 pts with mHSPC receiving ADTi doublet with CGP testing, 19 pts harbored CDK12a and were included. The median age at diagnosis was 66.1 (56 – 77), with 63.2% of pts receiving ADTi with an ARPI. Baseline characteristics are summarized in the Table. Overall, 7 pts (36.8%) achieved an optimal PSA-R by 6 months (mo). The median PFS was 18.8 mo (95% CI 4.2 – 33.4 mo), and the median OS was 33.1 mo (95% CI 9.5 – 56.7 mo). CGP was performed on primary tissue (84.2%), followed by metastatic lesion (10.5%) and blood (5.3%). PIK3CA and TP53 were the most frequent associated genomic alterations (15.8%), followed by ARID1A, CTNNB1, RB1, and TMPRSS2 (10.5%). Conclusions: This is the first real-world study to report outcomes of pts with mHSPC and tumor CDK12a undergoing ADTi with doublets. We show these pts to have inferior outcomes than those enrolled in the registration trials of mHSPC with ADTi. Upon external validation in larger cohorts, these hypothesis-generating data may guide future clinical trial design for these pts, their preferential selection for trials, and counseling and prognostication in the clinic. [Table: see text]
Unraveling the testicular seminoma tumor microenvironment by single-cell RNA-sequencing.
Authors: Krinio Giannikou, John T. Lafin, John P. Sfakianos, Amir Horowitz, Benjamin Hopkins, Haocheng Yu, James F. Amatruda, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2024)

522 Background: Seminomas is a malignant germ cell tumor (GCT) affecting male adults and is characterized by low somatic mutation burden, histological homogeneity, and high survival rate. It is currently unknown what drives tumorigenesis of this curable testicular cancer. Tumor/immune microenvironment (TME) has a vital role in cancer survival and progression with implications in cell death resistance and immune escape. Herein, we aimed to unravel the transcriptomic TME landscape of seminomas and better understand seminoma pathogenesis. Methods: We performed single cell RNA-sequencing (scRNA-seq; 10X-Illumina platform) on surgically resected pure seminomas from four patients. A total of ~24,000 single cells were analyzed using Seurat/Bioconductor R packages and standard means for data visualization. Key findings were validated by in situ hybridization RNA analysis (RNAscope) on histological sections from these samples. Results: T-cells and Natural-Killer cell populations were mostly predominantly enriched in this seminoma cohort, where tumor cells consisted of a distinct subpopulation with limited presence (1%). Other distinct cell populations were also identified for additional immune cell types e.g., B-cells, macrophages/monocytes, endothelial and smooth muscle cells. ScRNA-seq revealed a unique set of signature marker genes (e.g., POU5F1, KHDC3L, DPPA5, NANOS3) highly expressed in seminoma cells which are associated with pivotal cellular processes e.g., developmental pluripotency and germ cell development. Notably, this gene set was also highly differentially expressed (DE) in The Cancer Genome Atlas (TGCA) seminomas (n=73) compared to TCGA non-seminomas (n=38) (FDR&lt;0.01). Amongst top marker genes, KHDC3L, also higher expressed in seminomas compared to normal testis, was validated by RNA-scope. KHDC3L demonstrated the strongest positive correlation with DPPA5 (Spearman/Pearson; R 2 =0.8, p&lt;0.0001), top #3 ranked DE gene as well as with other top 20 DE genes identified by scRNA-seq. Remarkably, similar strong correlations among other top DE genes were also found in the testicular TGCA cohort. Top DE genes including master transcription factors (e.g., POU5F1, NANOG, SOX4) are involved in the same protein pathway/networks likely suggesting synergic effect/involvement in the same regulatory circuitry. Gene Set Enrichment (GSEA) analyses demonstrated enrichment in immune signatures and pivotal pathways e.g., Wnt/beta catenin signaling and MYC targets. Conclusions: Our analyses revealed novel marker genes and immune signatures, uniquely expressed in seminomas which consist of a homogeneous cell population across all 4 tumors analyzed, clearly distinct from other cell types identified.
MAIN-CAV: Phase III randomized trial of maintenance cabozantinib (CABO) and avelumab (Av) vs Av after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001).
Authors: Shilpa Gupta, Karla V. Ballman, Andrea B. Apolo, Srikala S. Sridhar, Ronald C. Chen, Yujia Wen, Aihua Edward Yen, Petros Grivas, Alan Tan, Shiva Baghaie, Matt D. Galsky, Michael J. Morris, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2024)

TPS714 Background: 1st-line induction platinum-based chemotherapy followed by switch maintenance Av is the current preferred standard of care in patients (pts) with aUC who do not progress after platinum-based chemotherapy. There is an significant need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. CABO is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitor. We hypothesized that CABO-Av combination would improve survival vs Av alone and have an acceptable safety profile as switch maintenance therapy in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for pts with locally advanced/metastatic UC (including cN3M0 only)) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adults are randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or Av and CABO 40 mg daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of anti-PD(L)1, no CNS metastases, no major surgery within 4 wks, no uncontrolled hypertension or cardiovascular disorders. Pts are stratified based on 1) best response to 1L chemotherapy: complete vs partial response vs stable disease and 2) presence vs absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of 1-sided alpha 0.025, power 80%, median OS 21 months (mo) with Av and hazard ratio 0.75, thus hypothesizing median OS 28 mo on CABO-Av. Key secondary endpoints include progression-free survival, safety, tolerability, and efficacy of CABO-Av vs Av alone based on RECIST 1.1 and iRECIST criteria (and PD-L1 status).Quality of life (QOL) are assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-Av vs Av alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test the correlation of established and new radiomic signatures with survival, adverse events and QOL and incorporate both radiologic and biologic features to assess their potential association with outcomes. This trial would be the first to systematically address whether adding the multitargeted TKI, CABO, to Av improves survival vs Av alone as 1L maintenance therapy. https://acknowledgments.alliancefound.org . Support: U10CA180821, U10CA180882; U24CA196171, U10CA180863 (CCTG); Clinical trial information: NCT05092958 .
Evaluating intermediate endpoints (IE) for overall survival (OS) in metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI): An IMDC study.
Authors: Renee Maria Saliby, Wanling Xie, J Connor Wells, Eddy Saad, Marc Eid, Chris Labaki, Karl Semaan, Evan Ferrier, Audreylie Lemelin, Cristina Suárez, Jose Manuel Ruiz-Morales, Thomas Powles, Lori Wood, Hedyeh Ebrahimi, Guillermo de Velasco, Kosuke null Takemura, Neeraj Agarwal, David A. Braun, Daniel Yick Chin Heng, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2024)

400 Background: In Ph3 trials, assessment for primary endpoint of OS necessitates extended follow-up (f/u) periods, larger pool of events, and higher associated costs. We sought to determine if shorter IEs like Time to Treatment Failure (TTF) and Time to Next Therapy (TTNT) are associated with OS in patients (pts) receiving ICI-based trt. Methods: We included all International mRCC Database Consortium (IMDC) pts who received contemporary approved first line(1L) ICI from 2013 to 2023. IEs were defined from ICI start until drug cessation or death for TTF, and initiation of next line or death for TTNT, or censored at date of last f/u. Associations of OS with TTF and TTNT status at 6-mo landmark were assessed using Cox regression adjusting for IMDC risk groups, metastatic sites, histology, age, and prior nephrectomy, stratified by treatment (trt) and yrs of ICI start. Endpoint associations across all f/u time were evaluated using Kendall’s Tau (KT) correlation by Clayton copula. A KT &gt;0.49 indicates a strong correlation ( Wicklin R., 2023). Results: The cohort consisted of 1667 pts with a median f/u of 15.4 mo (IQR: 7.1-28.6). Median age at 1L start was 63 yrs (IQR: 56-70), with 73% being male and 65% undergoing nephrectomy before starting 1L. 1132 patients received dual ICI, while 535 received an ICI+TKI combination. Pts who discontinued their 1L regimen within the 6-mo landmark demonstrated poor OS, with a hazard ratio (HR) of 2.74 (95% CI: 2.15-3.49). Additionally, those who transitioned to a 2L therapy within the first 6 mo showed worse OS, reflected by an HR of 2.82 (2.22-3.59). KT correlation with OS across all follow up was 0.49 (0.45, 0.52) for TTF and 0.67 (0.64, 0.69) for TTNT. Consistent results were seen across all subgroups with the strongest association in the ICI+TKI group (Table). Conclusions: TTNT demonstrated the strongest association with OS, particularly in the ICI+TKI subgroup, making it a potentially clinically meaningful intermediate endpoint for evaluating efficacy in ICI-based regimens.[Table: see text]
Primary sarcoma of prostate: A genomic landscape study.
Authors: Osama Batayneh, Joseph M Jacob, Gennady Bratslavsky, Philippe E. Spiess, Ashish M. Kamat, Petros Grivas, Andrea Necchi, Liang Cheng, Jeffrey S. Ross, Alina Basnet
Journal: Journal of Clinical Oncology (2024)

181 Background: Primary sarcoma of prostate is exceedingly rare and not well-studied. We sought to describe the genomic landscape of this rare entity and identify potential therapy targets. Methods: From 19,057 cases of prostate cancers, only 11 (&lt;.01%) cases of primary sarcomas were identified and underwent comprehensive genomic profiling (CGP) using FDA-approved hybrid capture-based system to assess all classes of genomic alterations (GA). Genomic-based ancestry, genomic signature, gLOH, MSI and TMB status were determined by CGP. Germline status was predicted using a Somatic-Germline-Zygosity algorithm. PD-L1 expression was determined by IHC (Dako 22C3 TPC scoring). Results: The routine histology and IHC stains from all 11 cases were reviewed centrally. There were 9 stromal sarcomas, and 1 each leiomyosarcoma and rhabdomyosarcoma. All patients (median age 57) were clinically advanced stage at the time of CGP. The primary tumor site was used in 6 patients and metastatic sites (3 bone, 1 ureter and 1 lung metastasis) in 5 patients. The mean number of GA per case was 2.3 (1 to 4 GA/sample). The most frequent GA were in TP53 (36.4%), RB1 (27.3%), ATRX (18.2%). Potentially targetable GA were rare and included MTOR pathway inhibitors for GA in TSC2 and PTEN (1 case each) and PIK3CA inhibitors (GA in PIK3CA in 1 case). There were 3 cases with non “targetable” gene rearrangements including a STAT6- NAB2 fusion in a stromal sarcoma (possible solitary fibrous tumor of prostate), a BCOR- MAML3 fusion and a TMPRSS2- ERG fusion in a stromal sarcoma with an adjacent focus of Gleason 6 prostate adenocarcinoma. 1 case featured a predicted germline mutation of the FLCN gene. All cases were microsatellite stable. TMB ranged from 0 to 9.8 mutations/Mb with median of 3.4 mutations/Mb with no cases at ≥10 mutations/Mb. gLOH scores were low, ranging from 0% to 10.9% (median 2.6%). Genomic ancestry was European in 7 patients and Admixed American in 4 others. There were no specific genomic signatures identified. PD-L1 was tested in 4 cases (all negative). Conclusions: Prostate sarcoma is an exceedingly rare primary cancer of the prostate with limited opportunities for targeted therapy or immunotherapy strategies. These tumors do not appear to be driven by “targetable” gene fusions and individual “targetable” mutations are uncommon. [Table: see text]
Real-world analyses of mortality risk after androgen deprivation therapy initiation in Black vs. White patients with prostate cancer.
Authors: Judd W. Moul
Journal: Journal of Clinical Oncology (2024)

84 Background: 2 studies found significantly longer overall survival in Black vs. White patients with metastatic castration-resistant prostate cancer (PCa): a 2019 meta-analysis of 9 phase III trials and a 2020 registry study. Our real-world data study compared all-cause mortality risk for Black vs. White PCa patients. Compared to the prior studies, our study encompasses a broader scope and is not exclusive to men with castration-resistant PCa. Methods: Data were collected from the Decision Resources Group Real World Evidence repository, which links medical and prescription claims, and US Electronic Healthcare Records. The analysis set included PCa patients who received ≥1 androgen deprivation therapy (ADT) injection between 1991-2020. Cox regression was used to compare all-cause mortality rates between White and Black patients. Multivariable regression model accounted for the following variables: baseline metastasis, BMI, oncology vs. urology setting, antagonist vs. agonist, personal major adverse cardiovascular event (MACE) history, tobacco history, baseline PSA (&gt;4 vs. ≤4 ng/mL), race (White vs. Black), statin use, increasing age per year, ethnicity (non-Hispanic vs. Hispanic), increasing ADT exposure per year, diabetes, hypertension, and family MACE history. Results: 44,439 patients were included for the all-patient analyses. 34,762 patients were included in the Black vs White analyses: 5,817 and 28,945 were Black and White, respectively. Overall, mortality risk was 2.6% and 17% at 1 and 4 years after ADT initiation, respectively. Mortality risk after ADT initiation was 1.6% and 2.6% at 1 year and 11.7% and 18.1% at 4 years for Black and White patients, respectively. Both unadjusted (HR=1.66, 95% CI 1.53-1.80, p&lt;0.05) and adjusted (HR=1.24, 95% CI 1.01-1.52, p&lt;0.05) mortality risks were higher for White vs. Black patients. Conclusions: All-cause mortality incidence was higher in White vs. Black patients. Adding to the body of evidence, our research also reveals that Black race is associated with a protective effect on survival for all-cause mortality in men undergoing ADT. Potential hypotheses for higher mortality in White vs. Black patients include survival bias to MACE (i.e., Black patients may have died from PCa before having MACE), survival bias to be diagnosed with PCa (i.e., Black patients may have higher rate of CV death and kidney failure prior to PCa diagnosis), and protective effects of higher BMI in Black patients against cancer cachexia. The large size (~45,000 patients from a database with &gt;300 million patients), long follow-up (10 years for some patients), recent clinical experience (99% from 2010-2020), and diversity of the dataset give weight to the results being an accurate representation of current clinical experience. Future studies should confirm our findings that White PCa patients have higher mortality risk and investigate the above hypotheses.
A study of blood myeloid-derived suppressor cells for predicting pembrolizumab efficacy in patients with metastatic urothelial carcinoma.
Authors: MInoru Kato, Shoma Yamamoto, Yukari Azuma, Yuji Takeyama, Junji Uchida
Journal: Journal of Clinical Oncology (2024)

658 Background: Immune checkpoint inhibitors (ICIs) are crucial for treating metastatic urothelial carcinoma (mUC) patients, yet current prognostic biomarkers fail to predict ICI efficacy. Previous preclinical models have suggested myeloid-derived suppressor cells (MDSCs) as a potential therapeutic target in bladder cancer. This study aims to evaluate the predictive value of blood MDSCs in mUC patients undergoing pembrolizumab treatment. Methods: Ninety-eight mUC patients who progressed with platinum-based chemotherapy at Osaka Metropolitan University received pembrolizumab. Among them, 30 patients were assessed for blood MDSCs. Peripheral blood samples were collected from healthy individuals (n = 6) and mUC patients (n = 30) before pembrolizumab initiation. The mononuclear cell layer was isolated using density gradient centrifugation for MDSC analysis through flow cytometry. Monocytic and polymorphonuclear MDSCs were defined as CD11b+ HLADR – CD33 high CD14 + CD15 – and CD11b+ HLADR – CD33 low CD14 – CD15 +, respectively. The neutrophil-lymphocyte ratio (NLR) in blood served as a control. Treatment response was assessed via CT images using RECICT v1.1. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, with log-rank test for between-group comparison. Results: First, blood MDSCs were significantly elevated in mUC patients compared to healthy controls (p = 0.0024, Mann Whitney test). Secondly, patients with MDSC low (≤ median, n = 15) had significantly longer PFS than those with MDSC high (&gt; median, n = 15) (17.6 vs. 1.9 months, p = 0.0126). However, no significant difference was observed in OS. In contrast, when the NLR cutoff was set at 3.5, no significant association was found for PFS and OS. Conclusions: Blood MDSCs show promise as a predictive marker for pembrolizumab therapy efficacy.