bluuebunny/crossref_metadata_2025 huggingface dataset:
Trajectory of aging following diagnosis of cancer.
Authors: Simons Morgan , Lyu Chen , Osman Iman , Zhong Hua
Published: June 2022

12087

Background: Aging is a nebulous concept with several definitions, but they all generally include physical and cognitive decline in function as a key component. We hypothesized that following cancer diagnosis, patients decline in physical and cognitive function would correspond with accelerated and/or accentuated aging trajectories. The magnitude of the functional changes could inform strategies to minimize impact of cancer diagnosis on trajectory of aging. Methods: We analyzed 32,935 participants >50 years enrolled between 1995-2018 in the Health and Retirement Study (HRS), a population-based, biennial longitudinal health interview survey of older adults in the United States. We assessed the changes in physical and cognitive function among cancer patients controlling for their pre-cancer trajectories and comparing it with aged population with no cancer diagnosis as control. The primary outcomes were change in physical function (Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL): range 0–11) and global cognitive function (Telephone Interview for Cognitive Status (TICS): range 0–27). The secondary outcome was change in self-rated health (SRH: range 1-5). We estimated the effect of acute change based on the immediate post-cancer outcome measurements compared to the trajectories before cancer; and the long-term effect as the per-year change in outcome decline post cancer compared to aging of cancer-free respondents adjusting covariates by linear mixed models. Results: 5,101 developed incident cancer: 1,514 in the 50-64 age group, 1,901 in the 65-74 age group, and 1,686 in the 75+ age group. 27,834 participants were cancer-free throughout. Cancer was associated with acute declines in physical function (0.06 [0.01– 0.10] and 0.25 [0.14– 0.36] points), cognitive function (0.22 [0.04–0.39] and 0.24 [0.01– 0.46] points), and SRH (0.19 [0.14–0.23] and 0.22 [0.12–0.33] points) for age of onset groups 50- and 75+ respectively. Moreover, participants with cancer demonstrated accelerated decline in physical function (0.02 [0.01–0.03], and 0.06 [0.05–0.07] points per year faster for 50-74 and 75+ age-of-onset groups respectively) compared to cancer-free participants, but not in cognitive and SRH. Lung, colorectal & breast cancer were associated with the highest acute and accelerated decline in functions, while prostate cancer was associated with moderate and insignificant decline. Conclusions: Using 24 years of nationally representative longitudinal data, this study provides, for the first time, evidence for the heterogeneous aging trajectories of cancer patients across varying age-of-onset and cancer types. Our results supported an accelerated aging trajectory of physical function with increased acceleration with increasing age-of-onset compared to the non-cancer population. It also provides evidence for accentuated aging trajectories of cognitive function and self-rated health.
Associations between DNA methylation age and chronic health conditions in survivors of childhood leukemia and CNS tumor.
Authors: Gramatges Maria Monica , LeJeune Wanda , Hernandez Evelyn , Lupo Philip , Richard Melissa A.
Published: June 2022

12088

Background: Survivors of childhood cancer are at risk for treatment related morbidities, including an early onset of chronic health conditions (CHC). Survivors are at risk for epigenetic age acceleration (EAA), i.e. when DNA methylation (DNAm)-predicted age exceeds chronologic age. EAA has been associated with treatment exposures and incidence of cardiometabolic, pulmonary, and neurologic CHC. We characterized the burden of CHCs in survivors of acute lymphoblastic leukemia (ALL) and central nervous system (CNS) tumors, two of the most common childhood cancers, and determined the association between EAA, cancer diagnosis, and burden of CHC. Methods: We included survivors of CNS tumor or ALL diagnosed at Texas Children’s Hospital (TCH) between 1992-2013, who were seen at least once in the TCH Long-Term Survivor Clinic. Demographics, diagnosis, treatment data and date of onset and type of CHC were abstracted from the electronic health record. All CHCs required subspecialty care, were present for at least 1 year, and were classified by system into one of 8 categories. Germline samples were obtained at an average of 10.5 years after diagnosis, and at an average age of 15.9 years of age. Samples were analyzed by Illumina MethylationEPIC BeadChip array on an iScan System in the Baylor College of Medicine (BCM) Laboratory for Translational Genomics. Methylation data were processed using minfi, normalized with noob, and EAA estimated using the Horvath calculator. The relationship between EAA, diagnosis, and CHCs was determined by multivariable linear regression. Results: Endocrine (65%), neuropsychiatric (78%), and sensory/motor (73%) CHCs were common in the CNS tumor group (n = 77). Metabolic (22%) and neuropsychiatric (59%) CHCs were common in the ALL group (n = 268). Survivors of CNS tumor had an earlier time of CHC onset, were more likely to have endocrine and sensory motor outcomes, and less likely to have metabolic outcomes vs. ALL survivors. On average, both survivor groups had EAA: 3.3 years (range: -12.2-15.5 years) for 138 ALL survivors and 4.4 years (range: -0.9-10.9 years) for 38 CNS tumor survivors, but EAA did not differ between diagnoses after adjustment for RT (p = 0.75). For CNS tumor survivors, EAA was 0.8 years greater for each system affected by CHC (beta = 0.8, p = 0.043) after adjustment for RT. For ALL survivors, EAA was not associated with CHCs (p = 0.33), but was associated with RT (p = 0.007). Conclusions: CHCs are prevalent in survivors of childhood ALL and CNS tumors, with patterns that differ by cancer diagnosis. In this cohort of relatively young 5 year + survivors of ALL and CNS tumor, all survivors had similar EAA but demonstrated cancer diagnosis-specific differences in associations between EAA, RT and burden of CHC.
Patient- and provider-level factors associated with telehealth utilization across a multisite, multiregional cancer practice.
Authors: Pritchett Joshua , Borah Bijan J. , Dholakia Ruchita , Moriarty James P. , Ahn Hannah , Huang Ming , Khera Nandita , Kharfan-Dabaja Mohamed , Ticku Jonathan , Leppin Aaron L. , Tilburt Jon Charles , Paludo Jonas , Haddad Tufia C.
Published: June 2022

1512

Background: In response to the COVID-19 pandemic, many cancer practices adopted telehealth, including telephone and video appointments. Following a period of initial expansion that began in March 2020, sustained telehealth integration has emerged across the Mayo Clinic Cancer Practice (MCCP) in 2021. The primary objective of this study was to identify factors associated with utilization of telehealth appointments. Methods: A cross-sectional, multi-site, retrospective analysis was conducted across MCCP – a multisite, multiregional cancer practice with tertiary referral campuses in Minnesota, Florida, and Arizona, as well as rural, community-based hospitals and clinics throughout the Upper Midwest. Multivariable models were used to examine the association of patient- and provider-level variables with telehealth utilization. Results: Outpatient appointments conducted in July – August 2019 (n = 32,932) were compared with those from 2020 (n = 33,662) and 2021 (n = 35,486). The rate of telehealth appointment utilization increased from <0.01% in 2019 to 11.0% in 2020 and 14.0% in 2021. The strongest provider-level predictor of telehealth utilization was female physician provider type (OR 1.06, 95% CI 1.01 to 1.11; P = 0.0297), a trend consistently observed across career stages, practice locations and settings in 2020 and 2021. Additionally, while the rate of telehealth utilization was not significantly different at referral and community-based campuses in 2020, providers at referral campuses were significantly more likely to utilize telehealth than community-based campuses in 2021 (OR 1.1, 95% CI 1.01 to 1.12; P = 0.0289). Regarding patient-level factors, rural residence (defined by Rural-Urban Commuting Area codes), which accounted for 44.2% of the patient population, was significantly associated with lower telehealth utilization as compared to patients with urban residences, particularly for video appointments (OR 1.04, 95% CI 1.02 to 1.07; P < 0.0001). Notably, the disparity in telehealth utilization between rural and urban populations was found to be less pronounced in 2021 as compared to 2020. Conclusions: Multivariable analysis across a multi-site, multi-regional cancer practice identified several factors associated with increased telehealth utilization. These included female physician provider type, referral-based campuses, and patients residing in urban settings. A detailed understanding of the factors that influence telehealth utilization – a method of care delivery which represents a “new normal” across many cancer practices – will be essential to enable continued equitable access to high-quality, high-impact, patient-centered cancer care.
Electronic research consents for complex early-phase I-II clinical trials integrated with telemedicine visits compared with in-person encounters.
Authors: Buckley Michael T. , O'Shea Molly , Lipitz-Snyderman Allison , Kuperman Gilad , Shah Suken , Redelman-Sidi Yael , Lengfellner Joseph M. , Terzulli Stephanie Lucia , Houston Collette , Sabbatini Paul
Published: June 2022

1514

Background: Based on our previous research with patient satisfaction for electronic consenting (95% of 940 respondents would recommend it another patient), we hypothesized that telemedicine (telemed) would be received as well as or better than in-person clinical research (CR) consent encounters for complex early-phase clinical trial (Phase I-II) and clinical genetic consent discussions by patients. Oncologist experiences to date have shown that telemed works well for uncomplicated clinical scenarios, but its performance alongside increased care complexity is less clear from the patient perspective. Methods: We conducted a one-time survey of adult patients having a telemed consent visit between 8/31/21 and 2/13/22 and an in-person clinic visit. Nine CR specific questions covered visit preference and empowerment across 6 high value consent agency domains. Results: 513 patients completed the survey and consented across 96 Clinical trials (CT), including genetic, therapeutic, diagnostic, and quality of life. Consent discussions were performed by 75 clinicians and 41 non-clinicians, with the majority (64%) for clinical genetic and Phase I-II CTs. Most patients (52%) preferred telemed over in-person clinic visits (19%) when all visit related factors (time, cost, convenience, quality of care, healthcare team interaction) were considered ( P<.05) (Table). Comparing their last in-person visit with telemed, patients reported feeling either less stressed/overwhelmed (16%) for their consent discussion or about the same (39%) using telemed, and 6% were more stressed ( P<.05). Patients expressed equal comfort taking agency-supported action across 6 domains regardless of consent setting. Conclusions: Electronic consenting via telemed is the preferred method for consent in complex early-phase clinical trials when all visit factors are considered and performs as well across 6 key agency domains when compared with in-person visits. Telemed does not contribute additional stress to consent appointments for most patients and performs well across complex clinical genetic and Phase I-II clinical trial discussions. Our findings suggest telemed and electronic consent should be offered as an option for patients throughout their treatment continuum. Beyond MSK, our data support a broader call for organizations to offer telemed platforms for CT discussions to increase overall patient satisfaction and potentially increase participation. [Table: see text]
Ancillary treatment referrals and visits after breast cancer surgery in a sociodemographically diverse population.
Authors: Chan Vernice Hui Yan , Heller Danielle R. , Berger Elizabeth Rapp , Capozza Scott , Greenup Rachel Adams , Sanft Tara B.
Published: June 2022

1533

Background: Ancillary therapies by rehabilitative, palliative, and survivorship specialists mitigate breast cancer surgery's physical and emotional effects. Existing data suggest that patients from disadvantaged backgrounds may be less likely to receive such care. We investigated provider referrals and patient visits at a high-volume urban cancer center to identify associated sociodemographic factors and characterize which populations may not be maximally benefiting from ancillary services. Methods: Data was culled from electronic health records of surgically-treated breast cancer patients at Yale-New Haven Health System between 2010-2017. Post-operative provider referrals to Physical/Occupational Therapy, Palliative Medicine, and Survivorship Program were evaluated for associations with demographic and disease variables in univariable and multivariable logistic regression analyses. Patient utilization of referrals, defined as attending at least one consultation, were analysed similarly. Results: Among 5,496 patients identified, 2,288 (41.6%) were referred for ancillary treatments and 1,572 (28.6%) attended at least one consultation. Provider referrals were highest among patients of Hispanic and Black ancestry (57.5% and 54.9%, respectively), no health insurance (57.6%), lowest percentage high school degree for zip code (50.5%), and lowest median income for zip code (50.7%). These associations remained significant in multivariable analysis [all p<0.050]. In contrast, referral utilization was greatest among patients with private insurance (70.7%), highest percentage high school degree (72.8%), and highest median household income (72.2%), in addition to Hispanic ethnicity (73.5%). In multivariable analysis, highest median household income (OR 1.45, p = 0.019) and Hispanic ethnicity (OR 1.50, p = 0.048) remained associated. Conclusions: In a large urban health system serving a diverse population, traditional markers of poor healthcare access were positively associated with provider referral for ancillary services after breast cancer surgery. However, referral did not translate to utilization, suggesting that access remains a critical barrier to therapies that target post-operative morbidity and elevate quality of life.[Table: see text]
Impact of cancer diagnosis, stage, and systemic therapies on immunogenicity after COVID-19 vaccination in patients with cancer: A systematic review and meta-analysis.
Authors: Nader Marta Guilherme , Spilleboudt Chloe , Martins-Branco Diogo , Tecic Vuger Ana , Debien Veronique , Ameye Lieveke , Brandão Mariana , Punie Kevin , Loizidou Angela , Willard-Gallo Karen , Awada Ahmad , Piccart-Gebhart Martine J. , de Azambuja Evandro
Published: June 2022

1537

Background: Patients (pts) with cancer are at increased risk of severe COVID-19. Both underlying malignancy and anti-cancer treatments influence the immune system, potentially impacting the level of vaccine protection achieved. Methods: A systematic literature search of PubMed, Embase, CENTRAL and conference proceedings (ASCO annual meetings and ESMO congress) up to 28/09/21, was conducted to identify studies reporting anti-SARS-CoV-2 spike protein immunoglobulin G seroconversion rates (SR) at any time point after complete COVID-19 immunization (mRNA- or adenoviral-based vaccines) in cancer pts. Complete immunization was defined as 1 dose of JNJ-78436735 vaccine or 2 doses of BNT162b2, mRNA-1273 or ChAdOx1 nCoV-19 vaccines. Subgroup analyses were performed to examine the impact of cancer diagnosis, disease stage, and anticancer therapies on the SR. Overall effects were pooled using random-effects models and reported as pooled SR with 95% confidence intervals (CI). Results: Of 1,548 identified records, 64 studies were included in this analysis reporting data from 10,511 subjects. The Table shows the SR in the overall population and specific subgroups. In pts with solid malignancies (SM), disease stage and primary site did not significantly impact the SR. In pts with hematologic malignancies (HM), SR were significantly lower in pts with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) compared to acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), and multiple myeloma (MM). Concerning the impact of cancer therapies on SR, pts with SM undergoing chemotherapy had numerically lower SR (N = 1,234, SR 87%, CI 81-92) compared to those treated with immune checkpoint inhibitors (N = 574, SR 94%, CI 88-97) or endocrine therapy (N = 326, SR 94%, CI 86-97) with or without another targeted therapy. Pts with HM treated with anti-CD20 therapy (within the last 12 months: N = 360, SR 7%, CI 2-20; or more than 12m: N = 175, SR 59%, CI 35-80), immune-modulating agents (BTK or BCL2 inhibitors) (N = 462, SR 47%, CI 32-64%) or other immunotherapies (anti-CD19/CART or anti-CD38) (N = 293, SR 37%, CI 23-53) had lower SR compared to pts treated with autologous (N = 353, SR 77%, CI 67-85) or allogenic stem cell transplantation (N = 509, SR 77%, CI 68-84). Conclusions: SR varies between cancer types and anticancer therapies with some cancer pts having low protection against COVID-19 even after complete vaccination. [Table: see text]
Characteristics associated with functional resilience versus functional decline among adult patients with advanced non–small cell lung cancer.
Authors: Tang Joy , Janse Sarah A. , Carbone David Paul , Shields Peter G. , Wong Melisa L. , Arrato Nicole A , Andersen Barbara L. , Presley Carolyn J
Published: June 2022

1538

Background: As more treatment options become available for advanced non-small cell lung cancer (NSCLC), oncologists still have difficulty predicting functional resiliency versus functional disability throughout treatment. Functional resiliency refers to the ability to recover baseline functional status in the face of an intervening health care event. This study aims to identify characteristics associated with resilience among adults with advanced NSCLC. Methods: In a prospective cohort of participants with newly diagnosed stage IV NSCLC, resilience was evaluated based on three functional disability items in the EQ-5D-5L (modified: mEQ-5D-5L) through 12 months of follow-up compared to baseline scores. This included patients treated with chemotherapy, immunotherapy, targeted agents and no treatment. Participants were classified into four groups: functional decline, maintenance, resilient, or variable. Resilience was determined based on improvement in disability scores, with a 1-point increase in functional status score representing a 0.5 standard deviation change on the mEQ-5D-5L. Patient characteristics included demographics, comorbidities, ECOG performance status, presence of brain or bone metastases, mood (GAD-7, PHQ-9), and lung cancer-specific symptoms (QLQ-LC13). Treatment toxicity and toxicity grades were also recorded. Differences between groups were determined through Fisher’s exact test or ANOVA. Results: Among 207 participants, 87 (42.0%) maintained functional status, 78 (37.7%) experienced functional decline, 22 (10.6%) were classified as resilient and 20 (9.7%) were variable. Characteristics associated with higher resilience (p < 0.1) included being employed (p = 0.02) and living in a metro setting (p = 0.10). Characteristics not associated with resilience included age, education level, smoking status, presence of brain metastases, ECOG performance status, or psychological symptoms. Approximately half the participants (n = 105, 50.7%) who received treatment experienced toxicities. One third (33.8%) experienced ≥ grade 3 toxicities. There was no significant association between toxicity grade and resilience grouping. Conclusions: Characteristics associated with functional resilience included employment status and living setting. At least half of adults with advanced NSCLC experience treatment-related toxicities. It is important to determine characteristics of resilience to better understand which patients will tolerate cancer treatments.
Enabling community-led integrated women health care models for women cancers screening and early detection through EMPOWER (Enabling and Motivating Partnerships Owned by Women who Engage and Reclaim their lives) project.
Authors: Nyongo Dorothy Ogada , Wambua Jacqueline
Published: June 2022

1541

Background: With the growing burden of Women cancers in East Africa, integrating cancer screening and prevention to optimize horizontal care delivery models is a paramount approach to strengthening women-centered and cost-effective primary healthcare. EMPOWER is a unique partnership with the government of Kenya, County referral hospitals, County First Ladies Association, International Cancer Institute, Patient organizations and Roche Kenya to demonstrate integrated cancer prevention and treatment within primary healthcare shared across the Kenyan Health system. Methods: EMPOWER clinics were launched with over 300 community health workers (including women living with disabilities) and HCPs were identified and trained to provide facility and community-based screening and early detection for breast cancer, cervical cancer, hypertension and diabetes through an integrated health systems strengthening approach. Mentorship was provided to HCPs through routinely held joint screenings and clinics, weekly Tumor Boards, Teleclinics, Telemedicine and Digital Pathology platforms. In addition, training support was provided through virtual preceptorships, skills-training workshops, hub-and-spoke oncological services provision and robust patient navigation. Results: 14 EMPOWER clinics have been launched across Kenya to increase community awareness of breast, cervical, and NCDs, strengthen capacity to deliver integrated Women cancer management services in County health clinics. In Kenya out of 25,502 people screened, 13,192 were screened for breast cancer with 97 abnormal findings identified; 10,349 screened for cervical cancer with 200 abnormal cervical screenings identified and 1,664 screened for prostate cancer with 32 abnormal findings. In addition, an integrated approach in Non Communicable Disease (NCD) care, diabetes and hypertension screening; 4,298 screened for diabetes and 6,116 screened for hypertension. All those diagnosed with cancers were linked to existing cancer care delivery systems and continuous support offered through the strengthened health care systems. Prostate cancer was added as more men turned up for screening events. Conclusions: This model is replicable and scalable across LMIC and recently the model inspired health providers’ from Tanzania and Nigeria to adopt the same for women’s cancers. EMPOWER has demonstrated a scalable care model in Kenya contributing to investments in pathology training and clinical treatment to improve challenges in referrals and updating guidelines to enable multi-disease tissue testing and handling and treatment with Standard of Care.
Improving first-in-human and window-of-opportunity informed consent forms through participant feedback.
Authors: Avinger Anna , Sibold Hannah Claire , Campbell Gavin Paul , Abernethy Eli Rowe , Bourgeois John , McClary Tekiah , Blee Shannon M. , Dixon Margie D. , Harvey R. Donald , Pentz Rebecca D.
Published: June 2022

1562

Background: Although patient advocates have created templates for standard consent forms, assessing patient preferences for First in Human (FIH) and Window of Opportunity (WO) trials consents is important given their unique risks. FIH trials are the first time a drug is tested in humans. In WO trials, treatment naïve patients receive a therapeutic agent in the window of time between diagnosis and standard of care (SOC) surgery. Our goal was to determine patient-preferred presentation of important information in FIH and WO consent forms. Methods: The study consisted of two phases: (1) analysis of consents for FIH and WO oncology trials open at a cancer center between 2019 and 2022; (2) interview patients who had reviewed consents for FIH or WO trials during the consent process. FIH consents were analyzed for the location(s) of information stating that the study drug has not been tested in humans (FIH info). The WO consents were analyzed for the location(s) of information stating the risk that trial may delay SOC surgery (WO info). Participants were asked about their preferred placement of the information in their own trial’s consent form and whether the consent was clear. Interviews were audio-recorded and double coded. Consent form analysis was compared to patients’ preferences. Results: 25 consents [20 FIH; 5 WO] were analyzed. 19/20 FIH consent forms included FIH info, and 4/5 WO consent forms included WO info. 42 patients were approached [19 FIH; 23 WO]; 34 [17 FIH; 17 WO] participated. 12/17 (71%) WO participants thought that the trial explanation in the consent form was clear. Conversely, only 9/17 (53%) FIH participants found it clear. Conclusions: Patients preferred that the important FIH and WO information be placed early in the consent, though exactly where varied. 82% of FIH participants wanted FIH information in the purpose, while only 19% of WO participants clearly preferred that WO information be in the purpose, and 41% preferred WO information to remain in the risks section. Using consent templates that reflect patient preferences accurately is essential for ethical informed consent; however, a one-size fits all approach may not accurately capture patient preferences, so multiple templates may be necessary. [Table: see text]
Phase 1 trial of TIM-3 inhibitor cobolimab monotherapy and in combination with PD-1 inhibitors nivolumab or dostarlimab (AMBER).
Authors: Falchook Gerald Steven , Ribas Antoni , Davar Diwakar , Eroglu Zeynep , Wang Judy S. , Luke Jason J. , Hamilton Erika P. , Di Pace Brian , Wang Tianli , Ghosh Srimoyee , Dhar Arindam , Borgovan Theo , Waszak Angela , LoRusso Patricia
Published: June 2022

2504

Background: TIM-3 expressed on tumor-infiltrating T cells is associated with T-cell suppression. AMBER (NCT02817633) is evaluating cobolimab (TSR-022/GSK4069889) monotherapy and with PD-1 inhibitors in advanced solid tumors. Methods: Multi-center, open-label study conducted with the following escalation arm (Parts 1A–C primary analysis reported here): (1A) cobolimab (IV Q2W) monotherapy at 7 doses (6 weight-based [0.03–10 mg/kg] and 1 flat [1200 mg] dose); (1B) cobolimab (1 mg/kg) + nivolumab (3 mg/kg IV Q2W); and (1C) cobolimab (100, 300, or 900 mg) + dostarlimab (500 mg IV Q3W). Primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D, monotherapy and combination). Results: 104 patients (pts) were included: 1A (n=46), 1B (n=7), or 1C (n=55); 4 pts from 1A crossed over to 1C (included in 1A and 1C safety and efficacy analyses). Most common cancers were non-small cell lung cancer (NSCLC) and melanoma (1A), NSCLC (1B), and NSCLC, skin, and peritoneal mesothelioma (1C). In 1A, 30.4% had ≥5 lines (L) of prior therapy; 42.9% had 3L in 1B; 33.3% had 2L in 1C. Treatment-related treatment-emergent adverse events (TR-TEAE) occurred in 67.4% (1A), 85.7% (1B), and 67.3% (1C); most commonly in 1A (n≥4) fatigue (13.0%) and nausea (8.7%); 1B (n≥3) diarrhea (57.1%) and nausea and vomiting (42.9% each); and 1C (n≥8) fatigue (20.0%) and rash (14.5%). Grade (Gr)≥3 TR-TEAEs occurred in 4.3% (1A), 28.6% (1B), and 14.5% (1C). There were no Gr5 TR-TEAEs or TR-TEAEs leading to dose delay. Serious TR-TEAEs occurred in 2.2% (1A), 0% (1B), and 12.7% (1C). TR-TEAEs led to discontinuation in 2.2% (1A), 28.6% (1B), and 9.0% (1C). Dose limiting toxicities (DLTs) occurred in 3.0% (1/33) in 1A (Gr3 lipase increased [10 mg/kg]); 40.0% (2/5) in 1B (Gr3 diarrhea and ALT and AST elevation); and 0% in 1C. Cobolimab serum exposure increased in a dose proportional manner at the therapeutic dose range. Preliminary mean terminal phase t1/2 ranged from 2.5–5.8 days for 0.03–0.3 mg/kg and 6.9–10.2 days for 1–10 mg/kg doses (1A), 6.9 days for 1B, and 9.5–12.3 days for 1C. Conclusions: Cobolimab + dostarlimab was well tolerated and showed preliminary anti-tumor activity, warranting further investigation of the RP2D + docetaxel in a randomized, phase 2 study. Funding: GSK (213348). Clinical trial information: NCT02817633. [Table: see text]
A phase 1 trial of the bifunctional EGFR/TGFβ fusion protein BCA101 alone and in combination with pembrolizumab in patients with advanced solid tumors.
Authors: Bedard Philippe L. , Hernando-Calvo Alberto , Carvajal Richard D. , Morris Van K. , Paik Paul K. , Zandberg Dan Paul , Kaczmar John M. , Niculescu Liviu , Bohr David , Reiners Ralf , Gharakhani Elham , Salazar Rachel , Bilic Sanela , Hanna Glenn J.
Published: June 2022

2513

Background: BCA101 is a first-in-class bifunctional fusion protein consisting of an anti-EGFR monoclonal antibody (mAb) and TGFβ receptor 2 extracellular domain (TGFβRII-ECD). Herein, we report the safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data of BCA101 as monotherapy and in combination with pembrolizumab among patients (pts) with advanced solid tumors refractory to standard therapies. Methods: Pts received BCA101 as a single agent (SA) or in combination with pembrolizumab at escalating doses in a parallel 3+3 design starting at 64 mg intravenously (IV) weekly (qw); and at 240 mg IV qw with pembrolizumab 200 mg IV q3w. Primary endpoint: safety and tolerability (CTCAE v5.0); dose limiting toxicity (DLT) period: 21 days. Secondary endpoints: overall response rate (ORR), PK/PD profile, progression-free survival (PFS), and changes in plasma and intra-tumoral TGFβ signaling assessed by SMAD2 phosphorylation. Results: As of 08-Feb-2022, 60 pts have received BCA101 (part A). Forty-five pts (colorectal, n=14; pancreatic, n=7; head and neck squamous cell carcinoma [HNSCC], n=6) received SA BCA101 at doses up to 1500 mg IV weekly. Fifteen subjects (SCC of the anal canal [SCAC], n=8; HNSCC, n=7) received BCA101 doses ranging from 240 to 1500 mg IV qw in combination with pembrolizumab. Maximum tolerated dose has not been reached. Common adverse events (AEs) attributed to BCA101 include rash (70%), fatigue (23%), pruritis and epistaxis (17% each); all grade (G)2 or less. One DLT was observed at the 1250 mg SA dose (G3 anemia, hematuria). No drug-related G4 AEs or deaths were observed. At data cutoff, best response in the SA arm was stable disease (SD) in 15/39 (39%) evaluable pts. In combination, partial response (PR) was observed in 3/11 (27%) evaluable pts (2 in SCAC, 1 in HNSCC) and a disease control rate (DCR) of 9/11 (82%). Two of 3 responders have been on study >4 months; including 1 confirmed PR in a HNSCC pt refractory to anti-PD-1 therapy and cetuximab. Saturation of the EGFR target was observed at BCA101 doses ≥750 mg. Dose proportional increase in Cmax and AUC were observed with doses of BCA101 750-1500 mg. Prolonged neutralization of plasma TGFβ1 was achieved at all doses ≥500 mg. Among paired tumor biopsies (n=23), pSMAD2 reduction up to 62% was observed at doses ≥500 mg. Conclusions: BCA101 is well tolerated and clinically active as a SA and in combination with PD-1 blockade with a predictable PK/PD profile. A recommended dose of 1500 mg both as SA and in combination has advanced to the part B expansion phase for pts with HNSCC, SCAC, and cutaneous SCC. Clinical trial information: NCT04429542.
Predictors of severe CRS in longitudinal CAR T-cell clinical trial data.
Authors: Strait Caleb , Aptekar Jacob , Kattan Michael W. , Agarwal Vibhu
Published: June 2022

2540

Background: Cytokine release syndrome (CRS) is a life-threatening toxicity of chimeric antigen receptor (CAR) T-cell therapy and there is a limited understanding of its risk factors. Known markers of severe CRS lack specificity or require central lab facilities, making them unsuitable for safety surveillance during trials. Using data from anti-CD19 CAR-T trials from the Medidata Enterprise Data Store (MEDS) we analyzed laboratory tests with repeated measurements to identify differences in trends that persist across a variety of study designs, sponsors and indications. Our aim was to capture the dynamic response to lymphodepletion (LD) and CAR-T infusion events in the time course values of laboratory markers and compare these in the severe CRS (grade 3 and higher) and non severe CRS groups. Methods: Subjects in the anti-CD19 CAR-T trials obtained from MEDS had relapsed or refractory disease in one of the following: B Acute Lymphoblastic Leukemia (B-ALL), Mantle Cell Lymphoma (MCL), Non-Hodgkin Lymphoma (NHL) and Diffuse Large B-cell Lymphoma (DLBCL). Laboratory markers with repeated measurements across all studies were included in the analysis. Response to LD, CAR-T infusion and the onset of hematologic recovery was modeled with piecewise linear splines with knots at the boundaries of the pre LD (-18d to LD), the LD - infusion and post infusion (1d to 6d and 6d to 18d) intervals using linear mixed effects regression. Results: The dataset consisted of 542 patients: 24.1% B-ALL, 44.4% NHL, 16.8% MCL, 14.6% DLBCL; mean age 54.8 (SE = 0.021) years, 67.7% males. 27.3% had CRS 3+ with a median time-to-event of 4.5 days. Average rates of change (units per day) for the severe CRS subjects in the pre LD, LD-infusion and post infusion intervals relative to the rest are shown (table). None of the markers had a significant relative rate of change prior to LD. The average change in Albumin, Platelets and Hematocrit was consistently lower in severe CRS patients. Conclusions: Longitudinal laboratory marker data may be used to derive predictors of severe CRS in patients undergoing anti-CD19 CAR-T therapy. While some of the laboratory markers discussed above corroborate earlier findings, modeling the pre and post infusion kinetics can yield novel markers with improved precision in severe CRS prediction and better patient safety. [Table: see text]
Development of B-cell maturation antigen (BCMA)-specific CD8+ cytotoxic T lymphocytes using induced pluripotent stem cell technology for multiple myeloma.
Authors: Bae Jooeun , Kitayama Shuichi , Herbert Zach , Daheron Laurence , Munshi Nikhil C. , Kaneko Shin , Ritz Jerome , Anderson Kenneth Carl
Published: June 2022

2542

Background: A strategy for reversal of T cell exhaustion is reprograming of antigen-specific CTL to early lineage memory T cells with selective anti-tumor activities. To accomplish this goal, we epigenetically reprogrammed BCMA-specific CD8+ CTL to a pluripotent state through key defined transcription factors, established “induced Pluripotent Stem Cells (iPSC)” exhibiting transcriptional and epigenetic features, re-differentiated them back into antigen-specific CTL and evaluated their properties and functional activities against multiple myeloma (MM). Methods: Functionally activeIFN-g producing HLA-A2 heteroclitic BCMA72-80 (YLMFLLRKI)-specific CD8+ CTL were applied for iPSC via transduction of four reprogramming factors (OCT3/4, SOX2, KLF4, c-MYC). Upon characterization of the BCMA-specific iPSC with high pluripotency potential, embryoid body was formed from the iPSC and further polarized into mesoderm layer development as evidenced by upregulation of transcriptional regulators (ABCA4, BMP10, CDH5, FOXF1, HAND1, PLVAP, SNAI2, TBX3). Next, BCMA-specific embryoid body-derived hematopoietic progenitor cells (HPC; CD34+ CD43+/CD14- CD235a-) were sorted and induced to undergo T cell differentiation in the presence of Fc-DLL4 signaling and rectonectin. Results: Our RNAseq analyses demonstrated unique transcriptional profiles of HPC from different iPSC clones committing to CD8+ T cells or other cell lineages (monocytes/granulocytes, B lymphocytes/NK cells). Principal component analyses demonstrated a high similarity and low variability of transcription profiles within the replicates of HPC committed to the same cell lineage. In addition, distinct genome-wide shifts and differential gene expression profiles were detected in HPC committed to each specific cell differentiation pathway. Specifically, the HPC commit to CD8+ T cells utilized a diverse repertoire of modulators promoting development of T cell maturation, specific immune response regulation, memory T cells, cytotoxicity and interferon induction, which were significantly higher than shown in HPC that differentiate to other cell lineages. In parallel, specific repression genes were identified in the HPC commit to CD8+ T cells, which develop TGF-β receptor, rearrangement of Ig heavy chain genes and inhibitory receptors. The T cells differentiated were mainly CD45RO+ memory CTL and fully rejuvenated without immune checkpoints expression and regulatory T cells and with high anti-MM activities. Conclusions: These findings identify genetic and epigenetic mechanisms and regulatory elements, which play key roles during lineage specific commitment of HPC developed in iPSC into CD8+ CTL and help to further design a next generation of regenerative medicine that provide the appropriate signals for T cell lineage commitment from progenitor cells.
Systematic review and meta-analysis evaluating the impact of antibiotic use on the clinical outcomes of patients with cancer treated with immune checkpoint inhibitors.
Authors: Zalcman Gerard , Crespin Athéna , Cervesi Julie , Le Bescop Clément , Buffet Renaud , de Gunzburg Jean , Vitry Fabien , Bandinelli Pierre-Alain
Published: June 2022

2585

Background: In recent years, the gut microbiome has increasingly emerged as influencing the response to immune checkpoint inhibitors (ICIs) and antibiotic (ABX) exposure has repeatedly been shown to impair clinical outcomes of patients suffering from different cancer types and treated with ICIs. We published in 2020 a meta-analysis confirming that ABX use hampered survival of non-small cell lung cancer (NSCLC) patients treated with ICIs. The present study aims to determine whether ABX use also reduces survival of patients receiving ICIs for other cancers. Methods: PubMed and major oncology conferences’ proceedings were systematically searched to identify studies assessing the impact of ABX on the clinical outcomes of cancer patients treated with ICIs. Studies were included when reporting data on Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR) and Progressive Disease Rate (PD), according to ABX exposure. Pooled Hazard Ratios (HRs) for OS and PFS and Odds Ratios (ORs) for ORR and PD were calculated, as well as HRs for OS and PFS according to different cancer types and different ABX exposure time windows (TWs). Results: Overall, 94 independent cohorts were included, representing 26,174 patients suffering from various types of cancer. The pooled HRs for PFS (61 cohorts, 13,224 patients) and OS (88 cohorts, 25,480 patients) were 1.47 [95% Confidence Interval (CI) 1.31-1.66] and 1.66 [95% CI 1.50-1.83], respectively, confirming a significant harmful impact of ABX on patient’ survival, observed across all cancer types (Table). The analyses of OS and PFS based on ABX exposure TWs suggested a stronger deleterious effect of ABX when taken around ICI treatment initiation. The response to treatment among ABX users was also impaired: the pooled ORs for ORR (30 cohorts, 4,590 patients) and PD (33 cohorts, 4,972 patients) were 0.55 [95% CI 0.39-0.77] and 1.97 [95% CI 1.48-2.64], respectively. Conclusions: ABX were shown to impair the clinical outcomes of cancer patients treated with ICIs, regardless of cancer type. [Table: see text]
Updated efficacy and safety results from the phase 2 study of serplulimab, a novel anti-PD-1 antibody, in patients with previously treated unresectable or metastatic microsatellite instability-high or mismatch repair-deficient solid tumors.
Authors: Li Jin , Qin Shukui , Zhong Haijun , Jin Chuan , Chen Lili , Yuan Xianglin , Fan Qingxia , Chen Kehe , Cao Peiguo , Xiao Jianjun , Jiang Da , Zhang Tao , Zhang Hongyu , Wang Xicheng , Wang Wei , Han Lin , Wang Qingyu , Zhu Jun ,   HLX10-010-MSI201 Investigators
Published: June 2022

2592

Background: Serplulimab is a novel humanized monoclonal antibody against PD-1. At ASCO 2021, we have presented the results from the phase 2 serplulimab study (NCT03941574) in patients with unresectable/metastatic microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) solid tumors who have progressed on or been intolerant to standard therapies with a median follow-up of 7.7 months. Here, we report the updated efficacy and safety results together with the results from sensitivity analysis after another 6-month follow-up. Methods: In this single-arm, open-label, multicenter, phase 2 study, patients aged 18–75 years with histologically or cytologically confirmed unresectable or metastatic MSI-H/dMMR solid tumors were enrolled to receive 3 mg/kg of intravenous serplulimab every two weeks for up to two years. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) per RECIST v1.1. Secondary endpoints included ORR assessed by the investigators, duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of July 10, 2021, 108 patients had received at least one dose of study treatment and were included in the safety set (SS). Among them, 68 patients with confirmed MSI-H (by local sites or central lab) were included in the main efficacy analysis population (MEAP); 58 patients with confirmed MSI-H (by central lab) and had no major protocol deviations were included in the sensitivity analysis population (SAP). The median follow-up duration was 13.5 months in the MEAP and 14.0 months in the SAP. IRRC-assessed ORR per RECIST v1.1 was 39.7% (95% CI 28.0–52.3; 3 complete response [CR]) in the MEAP and 43.1% (95% CI 30.2–56.8; 2 CR) in the SAP. Investigator-assessed ORRs were 38.2% (95% CI 26.7–50.8; 1 CR) and 41.4% (95% CI 28.6–55.1; 1 CR) in the MEAP and the SAP, respectively. Median DoR, PFS, and OS were not reached; 12-month OS rate was 74.5% (95% CI 62.2–83.3) in the MEAP and 82.4% (95% CI 69.7–90.1) in the SAP. In the SS, 57 (52.8%) patients had grade ≥3 treatment-emergent adverse events, most commonly anemia (9.3%). Thirteen (12.0%) patients had grade ≥3 immune-related adverse events. Three (2.8%) deaths (2 progressive disease and 1 intestinal obstruction) that might be related to serplulimab were reported. Conclusions: The encouraging antitumor activity and the manageable safety profile sustained after a longer duration of follow-up, supporting the further development of serplulimab as a potential tissue-agnostic antitumor treatment. Clinical trial information: NCT03941574.
Predictors of immunotherapeutic benefits in patients with advanced melanoma and other malignancies treated with immune checkpoint inhibitors utilizing ORIEN “real-world” data.
Authors: Tarhini Ahmad A. , Tan Aik Choon , Xie Mengyu , El Naqa Issam , Ghasemi Saghand Payman , Dai Donghai , Chen James Lin , Ratan Aakrosh , McCarter Martin , Carpten John D. , Colman Howard , Ikeguchi Alexandra , Tripathi Abhishek , Puzanov Igor , Arnold Susanne M. , Churchman Michelle L. , Hwu Patrick , Conejo-Garcia Jose , Dalton William S. , Weiner George J.
Published: June 2022

2618

Background: Despite the significant improvements in treating cancer with immune checkpoint inhibitors (ICIs), many patients (pts) do not achieve disease control. Using Oncology Research Information Exchange Network (ORIEN) Avatar real-world data conducted under the Total Cancer Care protocol we investigate predictive biomarkers of ICI benefits in pts with advanced malignancies. Methods: Clinical data were normalized as part of ORIEN Avatar. RNA-seq was performed on tumor samples following the RSEM pipeline and gene expressions were quantified as Transcript Per Million (TPM). Gene expressions (GE) were log2(TPM+1) transformed. Mann-Whitney U-test was used to compute differences between groups, and Kaplan-Meier survival analysis was performed. Results: Pts (n=1214) with 27 cancer types treated with ICIs were retrieved from the database, where 1143 and 875 patients were profiled by WES and RNA-seq, respectively. 804 pts had both WES and RNA-seq data. The top six cancer types were renal cell carcinoma (n=206), non-small cell lung cancer (n=173), head and neck cancer (n=157), melanoma (n=154), sarcomas (n=99) and bladder cancer (n=87). The ICI regimens included therapy with atezolizumab (n=87), avelumab (n=12), cemiplimab (n=6), ipilimumab (n=47), nivolumab (n=424), pembrolizumab (n=525) and ipilimumab+nivolumab (n=113). Median overall survival (OS) for the entire cohort was 21.9 months. Patients had significant improvement in OS if ICI was given in the first line ( P<0.0001). Previously published GE signatures were tested in the melanoma cohort. Signatures related to IFNg, effector T cells, chemokines, MHC II and Tertiary Lymphoid Structures were significantly prognostic and predictive of ICI benefits in advanced melanoma (Table). Analyses in the other cancer types are ongoing. Conclusions: GE data analyses validate the predictive value of immune related gene signatures following ICI immunotherapy in melanoma. Ongoing analyses are investigating these signatures in other malignancies and integrating the GE data with data related to TMB, somatic mutations and germline genetic variations.[Table: see text]
Automated tumor immunophenotyping and response to immunotherapy in non-small cell lung cancer using a spatial statistics approach.
Authors: Orlova Darya , Li Xiao , Eastham-Anderson Jefferey , Zou Wei , Tabatsky Evgeniy , Giltnane Jennifer M. , Patil Namrata S. , Peterson Maureen , Zijlstra Andries , Koeppen Hartmut
Published: June 2022

2626

Background: Based on the clinical success of immuno-oncology therapeutics, tissue-based, biomarker analyses have shifted from a focus on tumor cell phenotypes to spatial and functional analyses of the tumor immune environment. Distribution and composition of immune infiltrates have shown prognostic or predictive value in various studies; however, standardized approaches to categorize tumors into “Desert”, “Excluded” or “Inflamed” immunophenotypes based on the density and pattern of immune infiltrates are missing. This categorization is typically based on visual inspection of a stained tissue section; it is labor-intensive and associated with poor inter-observer concordance. To eliminate these barriers we developed an automated approach that relies on a set of derived spatial features and named this analysis pipeline LATIS (metric Learning based Automated Tumor Immunophenotyping with Spatial statistics). Methods: We used two clinical trials, POPLAR (phase II; n=258) and OAK (phase III; n=623) that compared anti-PD-L1 treatment vs chemotherapy in patients with advanced non-small cell lung cancer to develop and validate this approach. LATIS utilizes scans of slides stained immunohistochemically for CD8 and cytokeratin (CK); images were tiled and classified according to CK status (positive/negative). First, CD8 positive and CK density was calculated for each tile. Twenty six spatial features were then extracted for each tiled image scan. We used a labeled (manual immunophenotype calls) POPLAR dataset to learn a metric that separates classes of labeled data best with respect of spatial features provided for each data point. Then, to co-embed OAK dataset with POPLAR dataset into the same space, we used that learned metric as a measure of distance between new unlabeled points (OAK data set). K-means clustering in the embedded space was used to identify clusters of data points followed by QFMatch to assign class labels (“Inflamed”, “Excluded”, “Desert”) to each data point. Results: LATIS successfully relates spatial features to both, manual reads and patient response to therapy. In OAK, anti-PD-L1 treated patients experienced longer median overall survival (OS) when tumors showed intra-epithelial CD8+ cells (Inflamed) compared to tumors with a stromal pattern of CD8+ cells (Excluded) or a low density of CD8+ cells (Desert): 17.6 months vs 10.3 (Excluded) vs 12.1 (Desert) [p=0.0061]. Median progression-free survival (PFS) was 3.2 months (Inflamed) vs 2.6 (Excluded) vs 1.4 (Desert) [p=0.00058]. OS and PFS were not significantly different for the three categories in chemotherapy only arm. Conclusions: We suggest that tumor immunophenotype categories generated in an automated fashion by LATIS can serve as predictive biomarker for cancer immunotherapy.