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BackgroundOX40 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.MethodsPhase 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.ResultsEighty-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.ConclusionNo 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 numberNCT02923349.

Furthermore, to assess endpoints such as safety and early efficacy is difficult if one cannot judge whether toxicities are related to the burden of cancer disease, pre-existing comorbid disease, or the experimental agent. [...]strict eligibility requirements, including performance status, are needed to test novel therapies in early stages. Patients with metastatic melanoma and HIV on highly active antiretroviral therapy have reportedly tolerated immunotherapy well, with no apparent effects on HIV disease activity serologically and no adverse pharmacokinetic interactions with highly active antiretroviral therapy.7,8 Ravi and colleagues described the use of immunotherapy in nine patients with hepatitis B and C with advanced melanoma; although viral loads fluctuated in some patients during therapy, this had no apparent clinical significance.9 It must be emphasised that these anecdotal reports cannot be applied broadly in clinical practice. Jim West/Science Photo Library We declare no competing interests. 1 HH Chao, T Mayer, J Concato, Prostate cancer, comorbidity, and participation in randomized controlled trials of therapy, J Investig Med, Vol. 58, 2010, 566-568 2 D St Germain, AM Denicoff, EP Dimond, Use of the National Cancer Institute Community Cancer Centers Program screening and accrual log to address cancer clinical trial accrual, J Oncol Pract, Vol. 10, 2014,...

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 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.

Sarcomatoid hepatocellular carcinoma (SHCC) is a rare variant of liver cancer that lacks treatment options. The IMbrave trail demonstrated the efficacy of atezolizumab and bevacizumab (A + B) in patients with unresectable hepatocellular carcinoma but excluded patients with sarcomatoid variants. Herein, we describe a case of disease control achieved using the IMbrave regimen in a patient with sarcomatoid hepatocellular carcinoma.

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.

BackgroundCabozantinib, a multiple receptor tyrosine kinase inhibitor, promotes an immune-permissive environment which might enhance the activity of immune checkpoint inhibitors. COSMIC-021 (NCT03170960), a multicenter phase 1b study, is evaluating the combination of cabozantinib with atezolizumab in advanced solid tumors; here we present efficacy and safety results in patients with triple negative breast cancer (TNBC), ovarian cancer (OC), and endometrial cancer (EC).MethodsEligible patients had locally advanced or metastatic TNBC, OC, or EC and had radiographically progressed on prior systemic anticancer therapy. One or two lines of prior therapy were permitted. Patients with OC were platinum resistant or refractory. Prior treatment with anti-PD-1 or anti-PD-L1 agents was allowed for patients with TNBC. Patients received cabozantinib, 40 mg PO QD, plus atezolizumab, 1200 mg IV Q3W. The primary endpoint was objective response rate (ORR) per RECIST 1.1 as assessed by investigator. Other endpoints included safety, duration of response (DOR), progression free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter.ResultsAs of February 19, 2021, 30–32 patients were enrolled in each of the cohorts. 47% of patients with TNBC, 47% with OC, and 40% with EC had received 2 lines of prior therapy. Median follow-up was 18.7 months, 20.8 months, and 19.0 months for the TNBC, OC, and EC cohorts, respectively. Grade 3/4 treatment-related adverse events occurred in 33% of patients with TNBC, 56% with OC, and 37% with EC. One Grade 5 treatment-related adverse event of pulmonary hemorrhage occurred in the TNBC cohort and one of encephalitis occurred in the OC cohort. Cabozantinib plus atezolizumab demonstrated clinical activity in all three tumor cohorts (table 1).Abstract 531 Table 1ConclusionsCabozantinib in combination with atezolizumab demonstrated encouraging clinical activity in patients with previously treated advanced cancers.AcknowledgementsMedical writing support provided by Suvajit Sen, PhD (Exelixis, Inc.)Trial RegistrationNCT03170960Ethics ApprovalYesConsentYes

Fibroblast growth factor receptors (FGFR) are emerging as an important therapeutic target for patients with advanced, refractory cancers. Most selective FGFR inhibitors under investigation show reversible binding, and their activity is limited by acquired drug resistance. This review summarizes the preclinical and clinical development of futibatinib, an irreversible FGFR1-4 inhibitor. Futibatinib stands out among FGFR inhibitors because of its covalent binding mechanism and low susceptibility to acquired resistance. Preclinical data indicated robust activity of futibatinib against acquired resistance mutations in the FGFR kinase domain. In early-phase studies, futibatinib showed activity in cholangiocarcinoma, and gastric, urothelial, breast, central nervous system, and head and neck cancers harboring various FGFR aberrations. Exploratory analyses indicated clinical benefit with futibatinib after prior FGFR inhibitor use. In a pivotal phase II trial, futibatinib demonstrated durable objective responses (42% objective response rate) and tolerability in previously treated patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements. A manageable safety profile was observed across studies, and patient quality of life was maintained with futibatinib treatment in patients with cholangiocarcinoma. Hyperphosphatemia, the most common adverse event with futibatinib, was well managed and did not lead to treatment discontinuation. These data show clinically meaningful benefit with futibatinib in FGFR2-rearrangement-positive cholangiocarcinoma and provide support for further investigation of futibatinib across other indications. Future directions for this agent include elucidating mechanisms of resistance and exploration of combination therapy approaches. Fibroblast growth factor receptors (FGFR) are emerging as an important therapeutic target for patients with advanced, refractory cancers. This review summarizes the preclinical and clinical development of futibatinib, an irreversible FGFR1-4 inhibitor.

BackgroundINCB086550 is an orally administered small molecule that binds PD-L1 and inhibits PD-1/PD-L1 interaction. Translational data demonstrating markers of immune activation in patients following INCB086550 were previously reported.1 Preliminary clinical data from this phase 1 study are presented below.MethodsAdult patients (≥18 years) with advanced solid tumors were enrolled into this open-label study. Patients had disease progression after standard available therapy or were intolerant of or ineligible for standard treatment. Measurable disease was required. A modified 3+3 dose-escalation design was employed, followed by dose expansions. The primary endpoints were safety and tolerability of INCB086550, identification of a pharmacologically active dose and/or MTD, and confirmation of the RP2D. Secondary endpoints included PK, pharmacodynamics, and efficacy as assessed by investigator-determined ORR and DCR (CR, PR, or SD ≥12 weeks).ResultsAs of 9Apr2021, 79 patients received treatment (Table 1); 57.0% were female, 62.0% had ≥2 prior lines of therapy, and 16% received prior IO treatment. Forty-six (58.2%) patients had treatment-related TEAEs; those occurring in ≥5% of patients are presented in Table 2. Ten patients (12.7%) had grade ≥3 treatment-related TEAEs. Immune-related TEAEs occurred in 15 patients (19.0%); the most common (>1 patient) included peripheral sensory neuropathy (n=5), pruritus (n=3), immune-mediated neuropathy (n=2), and peripheral motor neuropathy (n=2). In total, 10 (12.7%) patients had TEAEs of peripheral neuropathy; all were grade ≤3. All grade 2 or 3 TEAEs of peripheral neuropathy resolved or improved with either study drug continuation without dose modification, dose reduction, or drug interruption/discontinuation. Patients with TEAEs leading to treatment interruption were 21 (26.6%), dose reduction 5 (6.3%), and discontinuation 13 (16.5%). Five patients (6.3%) died of a TEAE (cerebrovascular accident, dyspnea, general physical health deterioration, intestinal obstruction, intracranial hemorrhage [each n=1]); all fatal TEAEs were considered unrelated to study drug. The efficacy-evaluable population included 68 patients; ORR was 11.8% (95%CI, 5.2%–21.9%; CR, 1.5%; PR, 10.3%), and DCR was 19.1% (95%CI, 10.6%–30.5%; Table 3). Eight objective responses were observed at doses ≥400 mg BID (Table 4); 3 of these were noted among the 5 IO treatment-naive patients with MSI-H tumors who received 400 mg BID.ConclusionsImmune-related AEs observed in this ongoing phase 1 study are consistent with those seen with antibody immune checkpoint inhibitors, with the exception of peripheral neuropathy. Preliminary efficacy of INCB086550 in tumor types known to be responsive to anti-PD-(L)1 therapy is encouraging and warrants further investigation.Trial RegistrationClinicaltrials.gov identifier NCT03762447ReferencesPiha-Paul S, et al. J Immunother Cancer. 2020;8(suppl 3):A255.Ethics ApprovalThe study protocol was approved by institutional review boards (IRB) or independent ethics committees at participating centers. All study participants gave informed consent before taking part. The approval numbers were: Integ Review IRB (Austin, TX), RM 598; MD Anderson Cancer Center Office of Human Subject Protection (Houston, TX), IRB ID 2018-0765; ADVARRA (Columbia, MD), IRB# 00000971; Ethisch Comité/Comité d’ Ethique Hospital (Brussels, Belgium), A2021/085; Hôpital Saint-Louis (Paris, France), Prof Le Tourneau – 2020-118/Ref. of the Promoter 0.09.22.72214; NHS Health Research Authority London - City & East Research Ethics Committee (Bristol, UK), IRAS project ID:282291/REC reference: 20/LO/1001; Comitato Etico IRCCS Pascale (Milan, Italy), ISS Validation Protocol Number 29111(2020)-PRE21-1835; Comitato Etico Della Fondazione IRCCS ”Istituto Nazionale Dei Tumori”- Milano CE150053 (Milan, Italy), INT 230/20; Comitato Etico Regione Toscana - Area Vasta Sud Est CE150047, 18064; Comitato Etico Indipendente Istituto Clinico Humanitas CE150081, 940/20; Regulatory Pharma Net (Pisa, Italy), IEC 1393.Abstract 529 Table 1Number of patients per dose levelBID, twice daily; QD, once daily.The tumor types in the study included breast, cervical, colorectal, endometrial, esophageal, gastric, hepatocellular, melanoma, mesothelioma, ovarian, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell, urothelial, adrenal, anal, cholangiocarcinoma, gall bladder, pancreatic, penile, salivary gland, sarcoma, vaginal, prostate, basal cell, pleomorphic sarcoma, fallopian, carcinoma of parotid gland, well-differentiated liposarcoma, myoepithelial, castrate-resistant prostate cancer, cancer of unknown primary, neuroendocrine, prostate adenocarcinoma with neuroendocrine differentiation, glioblastoma, anal canal, angiosarcoma, and gastroesophageal junction.Abstract 529 Table 2Treatment-related TEAEs reported by ≥5% of patients (N=79)TEAE, treatment-emergent adverse event.Abstract 529 Table 3Summary of best overall response by RECIST v1.1 or RANO*CR, complete response; DCR, disease control rate; GBM, glioblastoma; ORR, objective response rate; PR, partial response; RANO, Response Assessment of Neuro-Oncology; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.* 1 patient with GBM was assessed by RANO and had best overall response of progressive disease.† The efficacy-evaluable population included all solid tumor participants enrolled in the study who received at least 1 dose of INCB086550, completed a baseline scan, and met at least 1 of the following criteria: ≥1 postbaseline scan, participant had been on the study for a minimum of 63 days of follow-up, or participant had discontinued from treatment.‡ ”Not evaluable” indicates participants in the efficacy-evaluable population that did not have valid postbaseline overall response assessments by RECIST or RANO.§ ”Not assessed” indicates participants in the efficacy-evaluable population that did not have any postbaseline overall response assessments by RECIST or RANO.Abstract 529 Table 4Tumor types with investigator-assessed objective response per RECIST v1.1 (n=8)BID, twice daily; dMMR, deficient mismatch repair; IO, immuno-oncology; MSI-H, high microsatellite instability; RECIST, Response Evaluation Criteria in Solid Tumors.+Ongoing response.

Community college students often face complex academic, financial, and personal pressures that can negatively affect their mental health and overall wellbeing. While counseling centers provide essential clinical support, many institutions are exploring broader campus approaches to promoting student wellness. Academic libraries, as accessible and inclusive campus spaces, are increasingly recognized as important contributors to these efforts. This paper examines the role of community college libraries in supporting student wellbeing while maintaining appropriate professional boundaries.

Community college students often face complex academic, financial, and personal pressures that can negatively affect their mental health and overall wellbeing. While counseling centers provide essential clinical support, many institutions are exploring broader campus approaches to promoting student wellness. Academic libraries, as accessible and inclusive campus spaces, are increasingly recognized as important contributors to these efforts. This paper examines the role of community college libraries in supporting student wellbeing while maintaining appropriate professional boundaries.