tbuckley/cabot-search huggingface dataset:
Lenvatinib (LEN) + pembrolizumab (PEMBRO) treatment in patients (pts) with metastatic clear cell renal cell carcinoma (RCC): Final results of a phase 1b/2 trial.
Authors: Chung-Han Lee, Amishi Yogesh Shah, James J Hsieh, Arpit Rao, Alvaro Pinto, Mehmet Asim Bilen, Allen Lee Cohn, Christopher DiSimone, David R. Shaffer, Regina Gironés Sarrió, Sara Gunnestad Ribe, Jane Wu, Emmett V. Schmidt, Peter Kubiak, Chinyere Okpara, Alan D. Smith, Robert J. Motzer
Journal: Journal of Clinical Oncology (2021)

e16542 Background: Immune checkpoint inhibitors (ICIs) are commonly used as first-line treatment for pts with advanced RCC. In the recent phase 3 CLEAR trial, LEN + PEMBRO showed improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) vs sunitinib in first-line treatment of advanced RCC (Motzer R et al. NEJM. 2021). Additional treatment options are needed for pts with disease progression on ICIs. A phase 1b trial of LEN + PEMBRO was performed in multiple tumor types and included an expansion part into a phase 2 cohort of ICI-pretreated, treatment-naïve, or previously treated ICI-naïve pts with metastatic RCC (NCT02501096). We report the final results of the RCC cohort with an extended follow-up. Methods: Eligible pts were ≥18 years old and had measurable disease. Efficacy analyses were conducted by prior therapy grouping. The primary endpoint was ORR at week 24 (ORR wk24 ) per immune-related (ir) RECIST by investigator assessment. Secondary endpoints included ORR, duration of response (DOR), PFS, OS, and safety. Exploratory endpoints included tumor response assessed per RECIST v1.1 by independent review committee (IRC). Subgroup analyses of the ICI-pretreated group will be included in the poster. Results: The recommended doses determined in phase 1b were LEN 20 mg daily + PEMBRO 200 mg once every 3 weeks (Taylor M et al. JCO. 2020). The study enrolled 145 pts (efficacy analysis, n=143; safety analysis, n=145). At data cutoff (August 18, 2020), the median follow-up time was 19.8 months. The ORR wk24 was 55.8% (95% CI 45.7–65.5) for ICI-pretreated pts (n=104), 72.7% (95% CI 49.8–89.3) for treatment-naïve pts (n=22), and 41.2% (95% CI 18.4–67.1) for previously treated ICI-naïve pts (n=17). The median OS for the previously treated ICI-naïve pts was 30.3 months and was not reached in the other groups. Additional efficacy analyses are shown in the table. Treatment-related adverse events occurred in 99.3% of pts; the most common were fatigue (58.6%), diarrhea (55.2%), and hypertension (40.0%). Most pts (69%) maintained the LEN starting dose or were reduced to LEN 14 mg daily (dose level −1). Conclusions: LEN + PEMBRO demonstrated promising antitumor activity with a manageable safety profile in pts with metastatic RCC, including pts who were ICI-pretreated. Clinical trial information: NCT02501096. [Table: see text]
Polymorphisms of Monocyte-Activating Cytokine/Chemokine Genes Affect the Susceptibility to, and Severity of Chronic ITP
Authors: Yuya Kitamura, Takayuki Saitoh, Rumi Ino, Kazuki Homma, Noriyuki Takahashi, Gotoh Nanami, Tetsuhiro Kasamatsu, Takuma Ishizaki, Hiroaki Shimizu, Makiko Takizawa, Akihiko Yokohama, Norifumi Tsukamoto, Hiroshi Handa, Hirokazu Murakami
Journal: Blood (2017)
IL-1 receptor antagonist for prevention of severe immune effector cell-associated neurotoxicity syndrome.
Authors: Caspian Oliai, Anna Crosetti, Sven De Vos, Herbert Eradat, Monica Diane Mead, Sarah Marie Larson, Steven Tsai, Annabel Liu, Gina Khachatrian, Christopher Hannigan, Reiko E. Yamada, Neiki Rokni, John Timmerman
Journal: Journal of Clinical Oncology (2021)

7566 Background: Progress in chimeric antigen receptor (CAR) T-cell therapy has included reduction in life-threatening toxicity. Rates of severe cytokine release syndrome (CRS) have declined from 50% in early trials to 7% in the most recent real-world experience. However, rates of severe immune effector cell-associated neurotoxicity (ICANS) associated with axicabtagene ciloleucel (Axicel) remain unchanged. IL-1 is a major driver of ICANS pathophysiology that is produced upstream of IL-6. The IL-1 receptor antagonist, Anakinra, can prevent neurotoxicity in animal models when given at fever onset. We present our early experience of the first 13 participants enrolled into a phase II trial evaluating Anakinra to prevent severe ICANS (NCT4205838). Methods: This investigator-sponsored trial included adults eligible for standard-of-care Axicel for large B-cell lymphoma after ≥2 lines of intensive chemoimmunotherapy. Participants received Anakinra 100 mg SQ q6h x 12-36 doses until ICANS returned to grade ≤1. The trigger to initiate Anakinra was any grade ICANS or grade ≥3 CRS in the absence of ICANS. A protocol modification, made after the first 3 participants were treated, changed the trigger for Anakinra to grade ≥2 CRS. In addition to Anakinra, all participants received standard-of-care interventions for CRS and ICANS. The primary objective is to estimate the efficacy of Anakinra in preventing severe ICANS (grade ≥3) according to ASTCT 2018 consensus grading. Results: To date, 13 participants have been enrolled, and 7 met criteria to initiate Anakinra and received the first dose prior to severe ICANS. Median age was 56 years (range, 23-84 years). Of the 7 participants whom received Anakinra prior to severe ICANS, only 1 of 7 (14%) developed grade 3 ICANS. The most common adverse event was injection site reaction, which peaked at grade 2. There were no unexpected toxicities. Once the protocol was amended to initiate Anakinra for grade ≥2 CRS (N = 4), no participant developed severe ICANS, and only one participant met the institutional standard to receive corticosteroids (Table). Conclusions: Anakinra is feasible to initiate in the non-prophylactic setting in patients at increased risk for severe ICANS. These early results demonstrate potential to reduce severe ICANS associated with Axicel to a rate similar to other CAR T-cell products, and to reduce corticosteroid use. Further enrollment to the pre-planned sample size of N=36 is required to demonstrate statistical efficacy. Serum IL-1 analysis is also ongoing. Clinical trial information: NCT4205838. [Table: see text]
BIOL-05. MAPK PATHWAY INHIBITION SENSITIZES TO IMMUNOTHERAPY IN BRAF-MUTANT GLIOMAS
Authors: Jong-Whi Park, Anne-Marie Barrette, Wei Wang, Stefan Grossauer, Gerald Grant, Ken Lau, Sharon Pitteri, Michelle Monje, Claudia Petritsch
Journal: Neuro-Oncology (2021)

Abstract Background BRAF alterations frequently occur in pediatric low-grade gliomas. Previously, we showed that dabrafenib and trametinib (D+T) that target MAPK pathway can mediate the antitumor effect in a preclinical model of BRAF-mutant glioma (PMC5342782). Here, we further investigate the effect of MAPK pathway inhibitors on cancer cells and tumor-infiltrating immune cells to maximize the therapeutic efficacy in malignant gliomas. Methods Drug concentrations in tumor, brain and plasma were assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RNA sequencing and Gene Set Enrichment Analysis were performed using patient-derived BRAF-mutant glioma lines upon D+T treatment. Molecular profiles of drug-resistant clones were assessed for understanding of glioma heterogeneity and exploring new therapeutic targets. Results. BRAF-mutant stem-like glioma cells were particularly resistant to BRAF or MAPK inhibitor, along with aggressive phenotype in mice. LC-MS/MS showed effective D+T drug delivery in tumor regions. The transcriptome analysis demonstrated that D+T upregulate HLA molecules and downregulate immunosuppressive factors in patient-derived BRAF-mutant glioma lines. Consistent with these molecular changes, D+T led to changes in the proportions of tumor-infiltrating immune cells, including CD8+ cytotoxic T lymphocytes and FOXP3+ regulatory T cells. Furthermore, the therapeutic effect of D+T was further enhanced in combination with immune checkpoint inhibition. Conclusions The present study highlights the immunomodulatory activity of MAPK pathway inhibitors in BRAF-mutant gliomas.
Durvalumab improves long-term outcome in TNBC: results from the phase II randomized GeparNUEVO study investigating neodjuvant durvalumab in addition to an anthracycline/taxane based neoadjuvant chemotherapy in early triple-negative breast cancer (TNBC).
Authors: Sibylle Loibl, Andreas Schneeweiss, Jens Bodo Huober, Michael Braun, Julia Rey, Jens U. Blohmer, Jenny Furlanetto, Dirk Michael Zahm, Claus Hanusch, Jörg Thomalla, Christian Jackisch, Peter Staib, Theresa Link, Kerstin Rhiem, Christine Solbach, Peter A. Fasching, Nicole Burchardi, Carsten Denkert, Michael Untch
Journal: Journal of Clinical Oncology (2021)

506 Background: The GeparNuevo trial investigated the addition of durvalumab, an anti-PD-L1 checkpoint inhibitor (CPI), to standard neoadjuvant chemotherapy (NACT) in patients with early TNBC. Durvalumab increased the pathological complete response (pCR) rate particularly in patients treated with durvalumab alone before start of chemotherapy (Loibl et al. Ann Oncol 2019). Methods: GeparNuevo randomized patients with cT1b-cT4a-d tumors and centrally confirmed TNBC to durvalumab (D) 1.5 g i.v. or placebo every 4 weeks. D/placebo monotherapy (0.75 g i.v.) was given for the first 2 weeks (window phase), followed by D/placebo plus nab-paclitaxel 125 mg/m² weekly for 12 weeks, followed by D/placebo plus epirubicin/cyclophosphamide (EC) q2 weeks for 4 cycles. Randomization was stratified by stromal tumor infiltrating lymphocytes (sTILs) (low (≤10%), intermediate (11-59%), high (≥60%)). The primary objective was pCR (ypT0 ypN0). Secondary time-to-event endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). Results: A total of 174 patients were enrolled between June 2016 and September 2017. The pCR rate with durvalumab was 53.4% versus placebo 44.2% (OR 1.45, 95% CI 0.80–2.63, unadjusted Wald p = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR 2.22, 95% CI 1.06–4.64, p = 0.035; interaction p = 0.048). After a median follow-up of 42.2 months, 34 events occurred in 174 patients. 3-year iDFS in pCR vs non pCR was 92.0% vs 71.9% (log-rank p = 0.002). 3-year iDFS was 84.9% with durvalumab vs 76.9% with placebo (HR 0.54, 95%CI 0.27-1.09, stratified log-rank p = 0.0559); 3-year DDFS 91.4% vs 79.5% (HR 0.37, 95%CI 0.15-0.87, p = 0.0148); 3-year OS 95.1% vs 83.1% (HR 0.26, 95%CI 0.09-0.79, p = 0.0076). No difference was seen in iDFS, DDFS and OS between the window and no window cohort. Conclusions: Durvalumab added to neoadjuvant chemotherapy in TNBC significantly improved long-term outcome despite a small pCR increase and no continuation after surgery. It needs to be questioned whether adjuvant therapy with CPI is needed at all. Clinical trial information: NCT02685059.
Investigating survivin as a novel target in black women with breast cancer.
Authors: Andrea Walens, Linnea T Olsson, Sarah Van Alsten, Lisa A. Carey, Melissa A. Troester, Yara Abdou
Journal: Journal of Clinical Oncology (2021)

594 Background: Black women with breast cancer have higher mortality than White women. Differences in tumor biology contribute to racial disparities in breast cancer outcomes. BIRC5 gene encodes survivin, an inhibitor of apoptosis protein, and an independent marker of poor prognosis in breast cancer. Cancer patients have anti-survivin antibodies and circulating survivin-specific T cells, suggesting that survivin may be targetable. Several ongoing antibody-mediated, vaccine strategies that target survivin are being developed. Nevertheless, most survivin studies were conducted in cohorts of White women. To date, the prevalence and/or role of survivin expression in breast tumors from Black women has not been studied. Methods: Associations between BIRC5 expression, clinicopathological and molecular features were measured in the population-based Carolina Breast Cancer Study (CBCS) and The Cancer Genome Atlas (TCGA) breast cancer cohort. Gene expression was measured by Nanostring RNA counting and split into BIRC5 high (4 th quartile) and low categories based on log2 gene expression values. Relative frequency differences (RFD) for the association between BIRC5 high and clinicopathologic features were estimated. RNA based p53 mutant status and homologous recombination deficiency (HRD) status were included in RFD analysis. Receiver operating characteristic (ROC) curves were used to illustrate the potential of BIRC5 expression to distinguish patients who achieved pathological complete response (pCR) after receiving neoadjuvant chemotherapy in CBCS (133 Black, 49 non-Black). Results: BIRC5 gene expression was significantly increased in tumors from 966 Black patients compared to 1,497 non-Black (p &lt; 0.00001), adjusting for stage and subtype. BIRC5 high tumors were significantly more expressed in higher stage and basal-like breast cancer subtypes. BIRC5 high tumors were also significantly enriched for expression of genes involved in p53 loss and HRD. Furthermore, in an analysis of 182 CBCS patients, BIRC5 gene expression alone predicted pCR with similar overall AUC to ROR-PT multigene signatures (AUC 0.62 vs 0.64). Conclusions: Our study shows that survivin expression is particularly high in breast tumors from Black women. This was associated with more aggressive clinicopathological features in addition to p53 mutant and HRD status. Black women with breast cancer represent an area of unmet clinical need and could potentially benefit from anti-survivin targetable treatment strategies. Further studies are needed to help close this gap which constitutes the largest disparity among cancer-specific diseases.[Table: see text]
A phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) endometrial cancer (EC).
Authors: Rebecca L. Porter, Jennifer Taylor Veneris, Nabihah Tayob, Gabriela West, Madeline Polak, Jeanette Gardner, Susana M. Campos, Carolyn N. Krasner, Elizabeth Katherine Lee, Joyce F. Liu, Elizabeth Stover, Alexi A. Wright, Ursula A. Matulonis, Panagiotis A. Konstantinopoulos
Journal: Journal of Clinical Oncology (2021)

TPS5611 Background: Folate receptor-alpha (FRα) is expressed on endometrial cancer (EC) cells and is associated with poor prognosis. Mirvetuximab soravtansine (ImmunoGen), an antibody drug conjugate (ADC) comprising a FRα-binding antibody, cleavable linker, and the tubulin-disrupting maytansinoid DM4, showed tolerability and single agent activity in a Phase 1 study with dose expansion in FRα+ advanced/recurrent EC (NCT01609556) and also when combined with chemotherapy, bevacizumab as well as pembrolizumab (NCT02606305). In addition to having direct target-mediated cytotoxicity, ADCs also stimulate the local tumor immune microenvironment. Mirvetuximab soravtansine has been shown to activate monocytes and promote phagocytosis of mirvetuximab-treated FRα-positive tumor cells through a mechanism of Fc-FcγR interaction. Further, the combination of ADCs with immune checkpoint inhibitors (ICI) can overcome primary resistance to immunotherapy in murine models. Given the low response of MSS endometrial cancers to PD-1 blockade, we hypothesized that addition of mirvetuximab may enhance response of these tumors to immunotherapy. Methods: This is a Phase 2, single cohort study of mirvetuximab soravtansine with pembrolizumab in recurrent or persistent EC. Patients must have advanced or recurrent MSS serous endometrial cancer with at least 1 and up to 3 prior lines of therapy. Confirmation of FRα expression (with PS2+ staining intensity in ≥ 50% of cells, performed centrally at Ventana Medical Systems, Inc) is required. Prior receipt of ICI is excluded. Patients will receive the combination of mirvetuximab soravtansine 6 mg/kg AIBW IV and pembrolizumab 200 mg IV administered every 21 days. The co-primary endpoint is progression-free survival at 6 months (PFS6) and objective response rate (ORR) by RECIST 1.1. Translational objectives include assessment of tumor infiltrating lymphocytes (TILs), expression of immune checkpoint markers, and whole exome sequencing (WES) for DNA repair pathway mutations, neoantigens, and polymorphisms in immunologically relevant genes. Statistical considerations are for a Simon two-stage optimal design with 16 patients in Stage 1 and 19 patients in Stage 2, to a total of 35. Prespecified activity for the first stage of accrual was met, and second stage accrual began November 2020. Clinical trial information: NCT03835819.
Landscape of homologous recombination-related (HRR) genes mutations in colon cancer.
Authors: Tuanjie Zhao, Chuncheng Ren, Zhiliang Zhang, Huanhuan Liu, Huina Wang, Yanrui Zhang, Yun Zhang, Xiayuan Liang, Feng Lou, Shanbo Cao, Yuru Zhang
Journal: Journal of Clinical Oncology (2021)

e15525 Background: Homologous recombination deficiency (HRD) might serve as a biomarker of immunotherapy and chemotherapy response. In addtion, HRD is associated with sensitivity to PARP inhibitor (PARPi) therapy. The HRD phenotype has been defined as the presence of a non-silent somatic mutation in homologous recombination-related (HRR) genes. Here, we focused on mutational landscape of HRR genes and the relationship between HRR-related genes and clinical outcomes in colon cancer. Methods: We prospectively sequenced 784 Chinese patients with colon cancer using next-generation sequencing techniques with 808 cancer-related genes. 290 patients with somatic mutation from the TCGA project were included. The 15 HRR genes were selected on clinical evidence of sensitivity to PARP inhibitors and immunotherapy. TCGA datasets were performed to identify the correlations between HRR gene mutations and clinical outcomes. Results: In the Chinese cohort, 11.5% (90/784) patients exhibited deleterious somatic mutation in HRR genes, including ATM (3.3%), BRCA2 (2.4%), CDK12 (2.4%), BRCA1 (1.0%), BRIP1 (1.0%), CHEK2 (0.5%), BARD1 (0.4%), RAD54L (0.4%), PALB2 (0.3%), and RAD51B (0.3%). In TCGA cohort, 28.6% (83/290) patients had at least one deleterious somatic mutation in HRR genes, including ATM (14.8%), BRCA2 (9.0%), CDK12 (7.9%), BRIP1 (3.8%), BRCA1 (3.4%), FANCL (3.1%), CHEK2 (2.4%), PALB2 (2.1%), PPP2R2A (2.1%), RAD54L (2.1%), CHEK1 (1.7%), BARD1 (1.4%), RAD51C (1.4%), RAD51B (1.0%), and RAD51D (0.3%). Overall, the mutational frequency of HRR genes in the Chinese cohort was lower than that in the TCGA cohort (p &lt; 0.001). In the TCGA cohort, colon patients with HRR-mut had significantly higher tumor mutational burden and incidence of microsatellite instability high and enhanced immune activity than patients with HRR-wt. Furthermore, In the MSK-IMPACT cohort treated by immune checkpoint inhibitor, patients with HRR-mut had significantly better OS (p = 0.009) and increased immune activities, such as infiltration of cytotoxic cells (p &lt; 0.05) and exhausted CD8+ T cells (p &lt; 0.01), and increased the IFN-γ scores (p &lt; 0.05) than patients with HRR-wt. Conclusions: Our data suggest that detection of somatic mutations in HRR genes might contribute to identify patients who might benefit from immune checkpoint blockade therapy and PARP inhibitors. In addition, the molecular features of HRR provide new opportunities to predict the tumor response to multiple treatments. Exploring other biomarkers of HRD to predict the response to PARPi and immunotherapeutic in colon cancer is necessary.
The SHARE study: Pilot study of a communication intervention designed to elicit advanced-stage cancer patients’ preferences and goals.
Authors: Embree Thompson, Alexi A. Wright, Nancy Lynn Keating
Journal: Journal of Clinical Oncology (2021)

e24120 Background: Helping seriously-ill cancer patients identify and communicate their preferences for care can increase satisfaction, decrease anxiety and depression, and result in less intensive, hospital-based end-of-life medical care. We developed an intervention designed to elicit patients’ preferences and goals for care and share them with their family and care teams. We sought to pilot-test the feasibility and acceptability of this intervention in advanced cancer patients. Methods: We enrolled advanced-stage cancer patients and their clinicians at an academic and community oncology practice. Eligibility criteria included: patients with metastatic solid tumors and ≥2 prior lines of therapy or patients for whom oncologists indicated that they “would not be surprised” if the patient died within 6 months. Participants watched a 2.5 minute video which prompted them to think about how they define “a good day;” completed a 3-page brief questionnaire, which was shared with their care team; and were given a wallet card with question prompts. The primary outcomes were feasibility (i.e., ≥60% approach-to-consent ratio among eligible patients, ≥60% of participants rated the intervention positively) and acceptability (i.e., ≥60% of participants would recommend the intervention to patients like them). Secondary outcomes, measured pre- and post-intervention, included patient anxiety and distress, hope, quality of life, and therapeutic alliance with their care team. Results: Among 59 potentially eligible patients approached, 53 agreed to participate (90% approach-to-consent ratio). Four patients were non-evaluable because they died before study completion. Among the 49 remaining participants (mean age = 63 years, range 40-86 years), all completed the intervention. Overall, 45 of 49 patients (92%) rated their experience as excellent, very good, or good. Most participants agreed or strongly agreed that they would recommend the video (83%), brief questionnaire (88%), and wallet card (63%) to patients with cancers like theirs. However, only 34% of participants reported having an opportunity to review the questionnaire with their oncologist. There were no increases in patient anxiety or distress associated with the intervention or reductions in hope, quality of life, or therapeutic alliances with oncologists (all P &gt; 0.05). Conclusions: A communication intervention that combined a video, questionnaire, and wallet card was both feasible and acceptable for helping advanced cancer patients identify their care preferences and goals. Future studies should examine combining this with an intervention that primes clinicians to engage in goals of care discussions with advanced-stage cancer patients. Clinical trial information: NCT03392090.
Genetic subtypes, allelic effects, and convergent neurodevelopmental mechanisms
Authors: Maitreya Das, Santhosh Girirajan
Journal: Genome Medicine (2021)

High-throughput sequencing of large affected cohorts have helped uncover a plethora of risk genes for complex neurodevelopmental disorders. However, untangling complex disease etiology also involves understanding the functional consequences of these mutations in order to connect risk variants to resulting phenotypes. Here, we highlight the efforts of Mannucci and colleagues to define a novel molecular subtype of neurodevelopmental disorder associated with mutations in DHX30 and characterize location-specific mutational effects in cell culture and zebrafish models.
Abstract 13781: Urocortin-2 has Favorable Hemodynamic Effects in Acute Decompensated Heart Failure: Findings from the UNICORN Trial
Authors: Wandy Chan, Christopher Frampton, Ian Crozier, Mark Richards, Richard Troughton
Journal: Circulation (2012)

Background: Urocortin-2 (Ucn2) showed favorable hemodynamic effects in stable systolic heart failure but its actions in acute decompensated heart failure (ADHF) are unknown. We describe findings fr...