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Treating Biliary Tract Cancers: New Targets and Therapies

Ho, Joseph; Fiocco, Constance; Spencer, Kristen
Biliary tract cancers (BTCs) are rare and aggressive tumors that typically present at an advanced stage when surgical resection is no longer considered a therapeutic option. While gemcitabine and cisplatin have been the mainstay of treatment, unique chemotherapy combination strategies, targeted therapies, and immunotherapies have had some clinical efficacy and remain promising areas for clinical research. The use of molecular profiling of BTCs has facilitated the development and subsequent clinical application of novel targeted therapy compounds. Among the many genomic alterations identified in BTCs, molecular abnormalities in the fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH), human epidermal growth factor receptor 2 (HER2), and BRAF have been successfully targeted therapeutically in clinical trials. Furthermore, the expanded use of new chemotherapy combinations, targeted therapies, and immunotherapies into alternate clinical settings such as in the neoadjuvant and adjuvant spaces is an area of active investigation. The management of BTCs is rapidly evolving. In this article, we review the emerging targets and therapies in BTC.
PMID: 36441502
ISSN: 1179-1950
CID: 5373872

First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors

Davis, Elizabeth J; Martin-Liberal, Juan; Kristeleit, Rebecca; Cho, Daniel C; Blagden, Sarah P; Berthold, Dominik; Cardin, Dana B; Vieito, Maria; Miller, Rowan E; Hari Dass, Prashanth; Orcurto, Angela; Spencer, Kristen; Janik, John E; Clark, Jason; Condamine, Thomas; Pulini, Jennifer; Chen, Xuejun; Mehnert, Janice M
BACKGROUND:OX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949. METHODS:Phase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7-1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics. RESULTS:Eighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1-9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs. CONCLUSION:No safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors. TRIAL REGISTRATION NUMBER:NCT02923349.
PMCID:9628691
PMID: 36316061
ISSN: 2051-1426
CID: 5358222

A phase Ib dose-escalation study of troriluzole (BHV-4157), an oral glutamatergic signaling modulator, in combination with nivolumab in patients with advanced solid tumors

Silk, Ann W; Saraiya, Biren; Groisberg, Roman; Chan, Nancy; Spencer, Kristen; Girda, Eugenia; Shih, Weichung; Palmeri, Marisa; Saunders, Tracie; Berman, Robert M; Coric, Vlad; Chen, Suzie; Zloza, Andrew; Vieth, Joshua; Mehnert, Janice M; Malhotra, Jyoti
BACKGROUND:Glutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors. METHODS:Patients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy. RESULTS:We enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested. CONCLUSION/CONCLUSIONS:The combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors. Trial Registration ClinicalTrials.gov Identifier NCT03229278.
PMCID:9250196
PMID: 35780243
ISSN: 2047-783x
CID: 5278302

Pembrolizumab for previously treated advanced anal squamous cell carcinoma: results from the non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study

Marabelle, Aurelien; Cassier, Philippe A; Fakih, Marwan; Kao, Steven; Nielsen, Dorte; Italiano, Antoine; Guren, Tormod Kyrre; van Dongen, Marloes G J; Spencer, Kristen; Bariani, Giovanni Mendonca; Ascierto, Paolo A; Santoro, Armando; Shah, Manisha; Asselah, Jamil; Iqbal, Syma; Takahashi, Shunji; Piha-Paul, Sarina A; Ott, Patrick A; Chatterjee, Arkendu; Jin, Fan; Norwood, Kevin; Delord, Jean-Pierre
BACKGROUND:Outcomes in advanced anal squamous cell carcinoma are poor, with few treatment options and controlled clinical trials. We evaluated the efficacy and safety of pembrolizumab in patients with advanced anal squamous cell carcinoma (cohort A) from the phase 2 KEYNOTE-158 study. METHODS:Eligible patients enrolled in the ongoing non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study, which was done across 38 centres worldwide, were aged 18 years or older; had histologically or cytologically confirmed advanced or metastatic anal squamous cell carcinoma; had previous failure of or intolerance to standard therapy or no standard therapy options; and had a PD-L1-evaluable tissue sample. Patients received pembrolizumab 200 mg intravenously every 3 weeks for 2 years, or until disease progression, unacceptable toxicity, investigator's decision to withdraw the patient from the study, or withdrawal of patient consent. The primary endpoint was objective response, as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy and safety analyses included all patients who received at least one dose of pembrolizumab. The trial is registered with ClinicalTrials.gov, NCT02628067. FINDINGS/RESULTS:Between March 3, 2016, and July 23, 2018, 163 patients were screened, of whom 112 were enrolled and treated in the anal cancer cohort. 91 (81%) patients were female, 104 (93%) had M1 disease, and 75 (67%) had PD-L1-positive tumours. The median time from first dose to data cutoff (June 27, 2019) was 34·7 months (IQR 32·5-36·4). 12 (11%, 95% CI 6-18) patients had an objective response, including 11 (15%, 8-25) of 75 patients with PD-L1-positive tumours and one (3%; 0-17) of 30 patients with PD-L1-negative tumours. 68 (61%) patients had treatment-related adverse events (20 [18%] patients had grade 3-4 adverse events), the most common of which were fatigue (17 patients), diarrhoea (13), hypothyroidism (13), and nausea (13). Serious treatment-related adverse events occurred in 12 (11%) patients. 25 (22%) patients had immune-mediated adverse events, and one (1%) had an infusion reaction. There were no treatment-related deaths. INTERPRETATION/CONCLUSIONS:Pembrolizumab monotherapy is a possible treatment option with a favourable benefit-risk ratio for patients with previously treated advanced anal squamous cell carcinoma who have no alternative satisfactory treatment options. FUNDING/BACKGROUND:Merck Sharp & Dohme.
PMID: 35114169
ISSN: 2468-1253
CID: 5180652

Standards of Care for the Health of Transgender and Gender Diverse People, Version 8

Coleman, E; Radix, A E; Bouman, W P; Brown, G R; de Vries, A L C; Deutsch, M B; Ettner, R; Fraser, L; Goodman, M; Green, J; Hancock, A B; Johnson, T W; Karasic, D H; Knudson, G A; Leibowitz, S F; Meyer-Bahlburg, H F L; Monstrey, S J; Motmans, J; Nahata, L; Nieder, T O; Reisner, S L; Richards, C; Schechter, L S; Tangpricha, V; Tishelman, A C; Van Trotsenburg, M A A; Winter, S; Ducheny, K; Adams, N J; Adrián, T M; Allen, L R; Azul, D; Bagga, H; Başar, K; Bathory, D S; Belinky, J J; Berg, D R; Berli, J U; Bluebond-Langner, R O; Bouman, M-B; Bowers, M L; Brassard, P J; Byrne, J; Capitán, L; Cargill, C J; Carswell, J M; Chang, S C; Chelvakumar, G; Corneil, T; Dalke, K B; De Cuypere, G; de Vries, E; Den Heijer, M; Devor, A H; Dhejne, C; D'Marco, A; Edmiston, E K; Edwards-Leeper, L; Ehrbar, R; Ehrensaft, D; Eisfeld, J; Elaut, E; Erickson-Schroth, L; Feldman, J L; Fisher, A D; Garcia, M M; Gijs, L; Green, S E; Hall, B P; Hardy, T L D; Irwig, M S; Jacobs, L A; Janssen, A C; Johnson, K; Klink, D T; Kreukels, B P C; Kuper, L E; Kvach, E J; Malouf, M A; Massey, R; Mazur, T; McLachlan, C; Morrison, S D; Mosser, S W; Neira, P M; Nygren, U; Oates, J M; Obedin-Maliver, J; Pagkalos, G; Patton, J; Phanuphak, N; Rachlin, K; Reed, T; Rider, G N; Ristori, J; Robbins-Cherry, S; Roberts, S A; Rodriguez-Wallberg, K A; Rosenthal, S M; Sabir, K; Safer, J D; Scheim, A I; Seal, L J; Sehoole, T J; Spencer, K; St Amand, C; Steensma, T D; Strang, J F; Taylor, G B; Tilleman, K; T'Sjoen, G G; Vala, L N; Van Mello, N M; Veale, J F; Vencill, J A; Vincent, B; Wesp, L M; West, M A; Arcelus, J
PMCID:9553112
PMID: 36238954
ISSN: 2689-5277
CID: 5361212

Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers

Palmeri, M; Mehnert, J; Silk, A W; Jabbour, S K; Ganesan, S; Popli, P; Riedlinger, G; Stephenson, R; de Meritens, A B; Leiser, A; Mayer, T; Chan, N; Spencer, K; Girda, E; Malhotra, J; Chan, T; Subbiah, V; Groisberg, R
INTRODUCTION/BACKGROUND:Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune checkpoint inhibitors. Pembrolizumab was recently approved by the Food and Drug Administration for use in TMB-high (TMB-H) tumors, regardless of histology, based on KEYNOTE-158. The primary objective of this retrospective study was real-world applicability and use of immunotherapy in TMB/MSI-high patients to lend credence to and refine this biomarker. METHODS:Charts of patients with advanced solid tumors who had MSI/TMB status determined by next generation sequencing (NGS) (FoundationOne CDx) were reviewed. Demographics, diagnosis, treatment history, and overall response rate (ORR) were abstracted. Progression-free survival (PFS) was determined from Kaplan-Meier curves. PFS1 (chemotherapy PFS) and PFS2 (immunotherapy PFS) were determined for patients who received immunotherapy after progressing on chemotherapy. The median PFS2/PFS1 ratio was recorded. RESULTS:MSI-high or TMB-H [≥20 mutations per megabase (mut/MB)] was detected in 157 adults with a total of 27 distinct tumor histologies. Median turnaround time for NGS was 73 days. ORR for most recent chemotherapy was 34.4%. ORR for immunotherapy was 55.9%. Median PFS for patients who received chemotherapy versus immunotherapy was 6.75 months (95% confidence interval, 3.9-10.9 months) and 24.2 months (95% confidence interval, 9.6 months to not reached), respectively (P = 0.042). Median PFS2/PFS1 ratio was 4.7 in favor of immunotherapy. CONCLUSION/CONCLUSIONS:This real-world study reinforces the use of TMB as a predictive biomarker. Barriers exist to the timely implementation of NGS-based biomarkers and more data are needed to raise awareness about the clinical utility of TMB. Clinicians should consider treating TMB-H patients with immunotherapy regardless of their histology.
PMCID:8717431
PMID: 34953399
ISSN: 2059-7029
CID: 5109232

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers

Yarchoan, Mark; Cope, Leslie; Ruggieri, Amanda N; Anders, Robert A; Noonan, Anne M; Goff, Laura W; Goyal, Lipika; Lacy, Jill; Li, Daneng; Patel, Anuj K; He, Aiwu R; Abou-Alfa, Ghassan K; Spencer, Kristen; Kim, Edward J; Davis, S Lindsey; McRee, Autumn J; Kunk, Paul R; Goyal, Subir; Liu, Yuan; Dennison, Lauren; Xavier, Stephanie; Mohan, Aditya A; Zhu, Qingfeng; Wang-Gillam, Andrea; Poklepovic, Andrew; Chen, Helen X; Sharon, Elad; Lesinski, Gregory B; Azad, Nilofer S
BACKGROUNDMEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition.METHODSThis open-label phase II study randomized patients with BTC to atezolizumab (anti-PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS).RESULTSSeventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35-0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination.CONCLUSIONThe combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs.TRIAL REGISTRATIONClinicalTrials.gov NCT03201458.FUNDINGNational Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN); F. Hoffmann-La Roche, Ltd.; NCI, NIH (R01 CA228414-01 and UM1CA186691); NCI's Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation.
PMCID:8670844
PMID: 34907910
ISSN: 1558-8238
CID: 5180632

Outcomes of patients with borderline resectable and resectable pancreatic adenocarcinoma treated with neoadjuvant three-week course chemoradiotherapy using capecitabine-based versus gemcitabine-based concurrent chemotherapy

Neibart, Shane S; Mamidanna, Swati; Chundury, Anupama; Sayan, Mutlay; Alexander, H Richard; August, David A; Berim, Lyudmyla D; Boland, Patrick M; Grandhi, Miral S; Gulhati, Prateek; Hochster, Howard S; Langan, Russell C; Spencer, Kristen R; Kennedy, Timothy J; Deek, Matthew P; Jabbour, Salma K
Background/UNASSIGNED:gemcitabine (GEM)-based 3-week chemoradiation (3WCRT) with 36 Gy in 15 fractions. This study aimed to compare the odds of achieving surgical resection, time to progression (TTP), and overall survival (OS) of patients treated with 3WCRT with concurrent CAPE versus GEM. Methods/UNASSIGNED:A retrospective cohort study was conducted, examining medical records from a single center for patients with (B)RPC treated with 3WCRT between 1/2009-12/2020. Odd ratios (OR) of achieving surgical resection were estimated using logistic regression for univariable and multivariable analyses. Median TTP (mTTP) and median OS (mOS) were estimated using the Kaplan-Meier method. Cox proportional hazards analysis was conducted to estimate hazard ratios (HR) of progression and survival in univariable and multivariable analyses. Results/UNASSIGNED:4.0 months, 95% CI: 0.4-14.5; P=0.01), corresponding to a hazard ratio of 0.33 (95% CI: 0.14-0.81). Adjusting for covariates this effect persisted; the adjusted hazard ratio (AHR) for progression was 0.24 (95% CI: 0.08-0.77). Cox proportional hazards analysis also demonstrated that the CAPE group had superior OS compared to the GEM group in unadjusted (HR =0.13; 95% CI: 0.04-0.40) and adjusted models (HR =0.13, 95% CI: 0.03-0.52). Conclusions/UNASSIGNED:For neoadjuvant 3WCRT, this hypothesis-generating study suggests concurrent CAPE may be a more effective radiosensitizer than GEM for patients with (B)RPC.
PMCID:8748032
PMID: 35070387
ISSN: 2078-6891
CID: 5180642

Delayed cytokine release syndrome after neoadjuvant nivolumab: a case report and literature review

Ciner, Aaron T; Hochster, Howard S; August, David A; Carpizo, Darren R; Spencer, Kristen R
PMID: 34287029
ISSN: 1750-7448
CID: 4948192

Toward improving androgen receptor-targeted therapies in male-dominant hepatocellular carcinoma

Zhang, Hong; Spencer, Kristen; Burley, Stephen K; Zheng, X F Steven
Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and a leading cause of cancer deaths worldwide. HCC is a male-dominant cancer with a male:female ratio of up to 7:1. The androgen receptor (AR) is the male hormone receptor known as a major oncogenic driver of prostate cancer. Although AR has been linked to the sexual dimorphism of HCC, clinical trials with AR-targeted agents failed to generate survival benefits. Recent studies provide new insights into the role of AR in liver tumorigenesis and therapeutic responses. Herein, we review current understanding of AR signaling in HCC and feedback mechanisms that limit response to AR blockade. New AR-targeting strategies that might improve outcomes in HCC therapies are also discussed.
PMCID:8222101
PMID: 33561464
ISSN: 1878-5832
CID: 5180622