bluuebunny/crossref_metadata_2025 huggingface dataset:
Racial differences in cardiovascular disease mortality among cancer survivors.
Authors: Sung Hyuna , Hyun Noorie , Siegel Rebecca , Jemal Ahmedin
Published: June 2022

12075

Background: Cancer survivors have an elevated risk of death from cardiovascular disease (CVD). Whether the risk differs by race/ethnicity and cancer type has not been fully explored in the U.S. Methods: Data from survivors of top 23 cancers diagnosed at ages 20 to 64 years during 2000-2018 were obtained from 17 Surveillance, Epidemiology, and End Results registries. Risks for CVD death among survivors relative to the general population were calculated using standardized mortality ratios (SMRs) in each racial/ethnic group: Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Hispanic, Non-Hispanic Asian or Pacific Islander (API), and Non-Hispanic American Indian (AI). Among survivors, the risks were compared by race/ethnicity using cause-specific proportional hazards models for competing risks, controlling for year of diagnosis, age at diagnosis, sex, stage (when appropriate), and the first course of treatment receipt (surgery, radiotherapy, chemotherapy). Results: Among 2,806,515 survivors (NHW, 68%; NHB, 13%; Hispanic, 12%; API, 7%; AI, 0.5%), 57,883 CVD deaths occurred during 6.4 person-years of mean follow-up (32 per 10,000). Cancer survivors overall were at increased risk of CVD death compared to their general population counterpart with an SMR of 1.76 among API (95% CI = 1.69-1.84; 8.7 excess deaths per 10,000), 1.49 among AI (95% CI = 1.33-1.68; 11.9 excess deaths per 10,000), 1.46 among Hispanic (95% CI = 1.41-1.50; 7.4 excess deaths per 10,000), 1.30 among NHB (95% CI = 1281-1.33; 14.9 excess deaths per 10,000), and 1.13 among NHW (95% CI = 1.12-1.14; 3.4 excess deaths per 10,000) survivors. Compared with NHW survivors, the adjusted hazard of CVD death was statistically significantly higher among NHB survivors for 23/23 cancers and among AI survivors for 9/18 cancers but was statistically significantly lower among Hispanic survivors for 5/23 cancers and among API survivors for 10/23 cancers, with no significant difference otherwise. The highest hazards ratios (HRs) were among NHB survivors of melanoma (HR = 3.19, 95% CI = 2.11-4.83); breast (HR = 2.73, 95% CI = 2.57-2.89); pancreatic (HR = 2.63, 95% CI = 2.19-3.16); and testicular (HR = 2.59, 95% CI = 1.62-4.14) cancers, whereas the lowest HRs were among API survivors of head and neck (HR = 0.53, 95% CI = 0.44-0.63) and cervical (HR = 0.57, 95% CI = 0.41-0.80) cancers and Hispanic survivors of cervical cancer (HR = 0.59, 95% CI = 0.46-0.75). Conclusions: The risk of CVD death differs considerably among cancer survivors by race/ethnicity and cancer types, highlighting the need for targeted prevention and surveillance in primary care. Future studies are needed to identify factors that contribute to this variation in order to inform efforts towards mitigating risk.
Body weight (BW) response timing to anamorelin (ANAM) in advanced non–small cell lung cancer (NSCLC)–associated cachexia.
Authors: Skipworth Richard J.E. , Walsh Declan , Rotaru Daniela D. , Ballinari Gianluca , Currow David C.
Published: June 2022

12110

Background: BW loss and anorexia are key clinical manifestations of cancer cachexia, a multifactorial syndrome affecting around 80% of patients (pts) with advanced cancer. BW loss is associated with reduced tolerance and response to cancer therapy, and shorter survival. ANAM is a novel, oral selective ghrelin receptor agonist. In ROMANA 1 and 2 (NCT01387269, NCT01387282) studies in pts with NSCLC and cachexia, ANAM treatment significantly increased BW and improved anorexia symptoms and concerns compared with placebo (PBO), with rapid responses occurring at wk 3 and sustained at wk 6, 9, and 12. In this post-hoc analysis, we report the timing of BW responses to assess the effects of ANAM treatment at and beyond wk 3. Methods: In ROMANA 1 and 2, pts with advanced NSCLC and BMI <20 kg/m2 or BW loss ≥5% in the past 6 mo received ANAM or PBO for 12 wk. BW responses were grouped on the basis of BW change from baseline (BW gain 0 to <5% or ≥5%, and BW loss); pts were classified according to the timing of first BW response as early responders (at wk 3), late responders (at wk 6, 9, or 12), and non-responders. Missing values were not imputed. Categorical variables are presented as number and percentages, with statistical comparisons performed using the chi-square test. Results: In total, 552 pts in the ANAM arm and 277 in PBO were included in the analysis for all time points; at wk 3/6/9/12, data were available for 534/520/461/412 pts in the ANAM arm and 270/262/229/206 in PBO. The non-cumulative rate of pts with BW gain ≥5% was significantly higher with ANAM compared with PBO at wk 3 (13 vs 6%, p=.0030), wk 6 (26 vs 8%, p<.0001), wk 9 (28 vs 9%, p<.0001), and wk 12 (31 vs 11%, p<.0001); conversely, the rate of BW loss was significantly lower with ANAM at all time points (p<.0001). There were no significant differences between ANAM and PBO in the rate of pts with BW gain 0 to <5% at wk 3, 6, 9, and 12 (p≥.0500). The timing of first occurrence of ≥5% BW gain response is shown in the table. The rates of early and late responders were significantly higher with ANAM compared with PBO, with 28% of ANAM-treated pts first responding beyond wk 3; a larger proportion of responses with ANAM were sustained over time. Conclusions: ANAM significantly increased the rates of ≥5% BW gain and reduced BW loss rates compared with PBO at all time points; the proportion of first responders at wk 3 and beyond wk 3 was higher with ANAM, with the most significant increase seen at wk 6. Continuing ANAM treatment beyond wk 3 results in a clinically significant benefit. Clinical trial information: NCT01387269, NCT01387282. [Table: see text]
Intravenous amisulpride as rescue treatment of postoperative nausea and vomiting in patients undergoing oncologic surgical procedures.
Authors: Elliott Amber , Minkowitz Harold , Ashburn Claudine , Fox Gabriel
Published: June 2022

12111

Background: Nausea and vomiting or retching after surgery can have significant adverse impacts, including increased length of stay, worse outcomes and patient dissatisfaction. Therefore, effective management remains a high priority. While more aggressive, multimodal prophylaxis has helped, options for treating those patients who fail are limited. Intravenous (IV) amisulpride has been shown to be safe and effective for the rescue treatment of Post-Operative Nausea and Vomiting (PONV) in a large, randomized, double-blind, placebo-controlled trial in a broad surgical population (Habib AS, Kranke P, Bergese SD, Chung F, et al. Anesthesiology 2019;130:203-212). We conducted a post-hoc analysis to investigate the safety and efficacy of amisulpride specifically in those patients undergoing oncologic surgery, predominantly excision of breast, gastrointestinal, or genitourinary malignancies. Methods: This subset analysis includes data from a randomized, double-blind, placebo-controlled, multicenter phase III trial of a single 10 mg dose of IV amisulpride as rescue treatment of PONV occurring in patients failing pre/peri-operative prophylaxis, generally with ondansetron and/or dexamethasone (Habib AS, Kranke P, Bergese SD, Chung F, et al. Anesthesiology 2019;130:203-212). The subset includes only those patients identified as undergoing surgery related to a specified malignancy or a mass considered likely to be malignant. The primary efficacy outcome was complete response (CR), defined as no emetic episodes (vomiting or retching) or administration of antiemetic rescue medication in the 24 hours after dosing. Results: In total, 465 patients were treated with either 10 mg amisulpride or placebo and 112 (56 in each group) underwent oncologic surgery. Of these, 43 (38%) underwent surgery for a pelvic tumor, 37 (33%) had breast or axillary surgery, 13 (12%) had colorectal, hepatic or pancreatic surgery and 19 (17%) underwent procedures for other malignancies, such as nephrectomy or thyroidectomy. The CR rate at 24 hours in the amisulpride group was 38%, compared to 23% with placebo. This was comparable with the success rates for the whole study population (42% vs 29%). The CR rate after 2 hours was 66% in the amisulpride group and 39% in the placebo group, also in line with the overall study results (70% vs 49%). Among those patients whose PONV occurred in the post-anesthesia care unit (PACU), the mean length of PACU stay from treatment to PACU discharge was 156 minutes in the amisulpride group and 230 minutes in the placebo group. Treatment-emergent adverse effects (TEAE) were comparable in nature and incidence between amisulpride and placebo. Conclusions: Amisulpride at 10 mg IV is safe and effective as rescue treatment for PONV in cancer patients undergoing surgery and is associated with a marked reduction in PACU length of stay.
Increasing the use of olanzapine in patients receiving chemotherapy in a community oncology practice.
Authors: Potugari Bindu Rani , Beekman Kathleen W. , Tolkinen Jane , Griggs Jennifer J.
Published: June 2022

12123

Background: The addition of olanzapine to high emetic risk chemotherapy regimens substantially improves nausea and vomiting within 24 hours and is recommended in the guidelines of both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN). However, the uptake of olanzapine has been low in national and institutional settings. The purpose of this project was to increase guideline-concordant prescribing of olanzapine in eligible patients in a community oncology practice. Methods: We developed a multiphase program to address the barriers to the use of olanzapine in a community oncology practice. Patients’ medical records (N = 423) were reviewed to collect baseline data. Motivational interviewing with prescribing clinicians elicited barriers to prescribing, reinforced clinical guidelines, and elicited and reinforced language that suggested a willingness to change prescribing patterns. Chemotherapy protocols were subsequently updated to include olanzapine for high emetic chemotherapy regimens, and prescriber and nurse education was provided by our pharmacists regarding the most recent ASCO and NCCN guidelines. A fellow-led educational session was provided to the infusion nursing team and care managers. At the end of a seven-month period, prescribing information was identified through a system-generated report followed by a medical record review for validation (N = 136) and was shared monthly with prescribing clinicians. Results: At baseline, the use of olanzapine was zero. Multiple barriers were identified regarding the use of olanzapine during motivational interviewing with clinicians, including lack of knowledge of the guidelines, belief that most patients do not require olanzapine, concerns about sedation with the previously recommended dose of 10 mg, and order sets that did not include olanzapine. After the interventions, there was a statistically significant increase in the use of olanzapine from 0% to 56% (p-value < 0.001). Conclusions: A combination of motivational interviewing, prescriber and nurse information support, and changes to the pre-populated order sets for chemotherapy antiemetics was highly successful in improving the uptake of guideline-concordant prescribing of antiemetics. This model of quality improvement, including motivation interview, may support quality improvement efforts across oncology.[Table: see text]
The impact of an oncology-specific shared savings agreement.
Authors: Thompson Edward , Hospodar Alexa , McLarty Sarah , Pervez Sabah , Yeon Heeseon , Hastings Kevin , Cullum Robert , Junk Christopher , Sapkota Ujwal , Mcgovern-Siembab Allendre , Perez Lady , Angelica Patricia , Jeshang Namrata , Cavers William , Johlie Melissa , Reddy Shirisha , Brito Rogelio A. , Avalos-Reyes Elisea , Johnson Kjel Andrew , Grunsfeld Tracy
Published: June 2022

1536

Background: In response to rising healthcare costs, several innovative payment strategies have emerged to improve the value and efficiency of healthcare spending. One of these strategies is a shift from volume-based to value-based care (VBC), resulting in the introduction of alternative payment models, innovative provider contracting and new value frameworks. The purpose of this study is to evaluate the impact of a VBC arrangement on total cost of care for chemotherapy patients, specifically cancer-related drug costs, daily hospital inpatient admissions and emergency room visits. Methods: This is a cohort study of chemotherapy patients, in a single state, enrolled in a large national insurer from January 18, 2021, to September 30, 2021. Oncology patients were divided into two groups; the study group consisted of chemotherapy patients receiving care in a VBC arrangement; the control group consisted of chemotherapy patients receiving care at oncology practices not engaged with the insurer in a VBC agreement. The following levers were employed to improve value: digital symptom tracking, biosimilar or lower-cost drug options and NCCN regimen concordance. We defined cancer-related drug costs as the sum of allowed costs paid for medical and pharmacy claims during the study period. Additionally, we averaged the cost per hospital inpatient day and emergency room visit and compared these by group. Results: This study included 1,574 patients, 733 patients in the study group and 841 in the control group. A reduction of 5.1% (a difference of $441) in cancer-related drug costs per member per treatment month (PMPTM) was observed among patients in the study group. Patients in the study group reported 27.8% fewer inpatient days resulting in a savings of $194 PMPTM. Similarly, patients in the study group reported 70.0% fewer emergency room visits resulting in a savings of $59 PMPTM. Conclusions: In this study, chemotherapy patients participating in a shared savings VBC spent less on cancer-related drug costs, hospital inpatient days and emergency room visits through three value levers. Further studies are needed to assess if these results are similar all types of healthcare coverage and to what degree additional value levers further reduce costs. Additionally, the long-term health outcomes of these patients should be assessed.
Does the 4R oncology model improve clinicians’ effectiveness in patient-facing planning of complex cancer care?
Authors: Trosman Julia R. , Kulkarni Swati , Baer Rachel Podrazik , Feldman Lawrence Eric , Pasquinelli Mary , Kircher Sheetal Mehta , Benson Al Bowen , Gradishar William John , Rapkin Bruce , Makower Della F. , Perez Claudia Beth , Boecher Stephanie , Ravelo Mangalindan Arliene , Yu Elaine , Weldon Christine B.
Published: June 2022

1542

Background: The 4R Oncology model was proposed within the NCI ASCO Teams Project as an approach to facilitate patient-facing care planning, team-based delivery and patient self-management. 4R (Right Info/Care/Patient/Time) enables care teams and patients to manage complex care with a novel 4R Care Sequence plan. We previously reported that 4R significantly improved patient self-management, namely patients’ ability to organize and manage their care (Trosman JCO OP 2021). Here we report the impact of 4R on effectiveness of clinicians to plan and deliver complex multidisciplinary care. Methods: We surveyed clinicians (physicians and nurses) from 8 cancer centers (4 academic, 4 community) participating in a 4R adoption program. The survey was conducted Mar 2019 to Sep 2019 prior to 4R launch (Baseline cohort), and Nov 2021 to Jan 2022 post-4R launch (4R cohort). Baseline cohort included clinicians conducting care planning with patients. 4R cohort included clinicians who used 4R in care planning with new patients. The survey focused on clinicians’ self-reported effectiveness in planning and management of guideline-based care. Descriptive statistics and Fisher’s 2-sided test were used in analyses. Results: Baseline cohort’s response rate was 79% (66/83); 4R cohort’s response rate was 86% (62/72). 4R implementation was associated with significant improvement in all 5 metrics of effective care planning between the baseline and 4R cohorts (Table). Within the 4R cohort, 87% (54/62) clinicians found 4R Care Sequences useful or very useful for care planning and management. The majority, 79% (49/62), spent 10 minutes or less on average developing and administering 4R Care Sequence to a new patient, and 58% (36/62) reported decreased overall volume of post-visit inquiries about care plan from patients who received 4R. When asked about 4R delivery format, 65% (40/62) preferred paper, 23% (14/62) electronic delivery and 12% (8/62) had no preference. Conclusions: The 4R Oncology model is a promising approach to improving clinicians’ effectiveness in patient-facing care planning and reducing the workload associated with patient inquiries. An ongoing 4R research and implementation program continues efforts to identify optimal implementation methods and integrate 4R into clinical practice across the U.S. [Table: see text]
Safety and efficacy of glasdegib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Phase Ib/II GEINO 1602 trial.
Authors: Vaz María Ángeles , Gironés Regina , Del Barco Sonia , Sepulveda Sanchez Juan Manuel , Alonso Miriam , Pineda Estela , Balana Carmen , Martínez-García María
Published: June 2022

2060

Background: Hedgehog signaling through Smoothened (SMO) protein in gliomas promotes cell cycle progression and leads to glioma stem cells (GSCs) maintenance, which constitutes one of the key hallmarks for glioblastoma (GB) resistance against anticancer therapies. Glasdegib, a SMO inhibitor, may disrupt GSCs and lead to enhanced efficacy of the Stupp scheme. Methods: Newly diagnosed GB pts received glasdegib with standard radiotherapy (RT)/ temozolomide (TMZ) followed by maintenance with glasdegib monotherapy. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3+3 dose escalation (DE) strategy in phase Ib and overall survival (OS) in phase II. Secondary objectives included progression-free (PFS) according to RANO criteria, safety, changes in performance status, and exploratory biomarker analysis. Results: Between 2018 and 2020, 79 GB pts were enrolled and 78 received at least one dose of glasdegib. In DE, 4 pts received Glasdegib at 100 mg/QD and 6 pts received 75 mg/QD. DLTs were reported in 3/4 pts in 100 mg dose level, and 1/6 pts in 75 mg dose level, declaring 75 mg/QD of glasdegib as RP2D. For phase II, 68 additional pts were treated at 75 mg/QD dose. The median age was 55 years (range: 28-78), 54% were male, 45% were MGMT unmethylated, and 1 pts had an IDH1/2 mutation. Glasdegib treatment lasted a median of 6 m (range: 0.5-21.9). Overall, 72 (97.3%) pts completed concomitant therapy, 65 (87.8%) started adjuvant therapy, 28 (37.8%) completed adjuvant therapy, and 23 (31.1%) continued glasdegib monotherapy. Treatment combination was discontinued due to treatment-related adverse events (TRAEs) in 9 (12.2%) pts. For those pts that received RT/TMZ combined with glasdegib at 75 mg/QD dose, 7 (9.5%) presented grade (G) ≥3 hematological TRAEs during concomitant treatment and 2 (3.1%) during the adjuvant treatment. There were no G≥3 TRAEs of any type during the maintenance phase. Neutrophil count decrease G≥3 was reported in 6 (8.1%) pts and platelet count decrease G≥3 in 7 (9.5%) pts. Cutaneous events G≥3 were reported in 3 (4.1%) pts. ECOG, Minimental and Barthel indexes, were maintained when comparing baseline with end of treatment (p = 0.181, 0.25 and 0.346 respectively). Stabilization was the most common response, reported in 60 (81.1%) pts. After a median follow up of 7.8 m (range 0.7-25.9), median PFS was 6.9 m (95% CI: 6.1-8.5). The 6-m PFS rate was 62.1% (95% CI: 50.9-75.8) and the 18 m OS rate was 63.3% (95% CI: 47.5-84.4). Conclusions: The addition of glasdegib to standard RT and TMZ was safe. Glasdegib monotherapy showed no G ≥3 TRAEs. Most patients had disease stabilization, with a promising preliminary PFS and OS for newly diagnosed GBM. Final survival results are awaited. Clinical trial information: NCT03466450.
Impact of systemic therapy regimen on survival of PCNSL.
Authors: Janopaul-Naylor James , Voloschin Alfredo Daniel , Patel Jimmy S , Rupji Manali , Hoang Kimberly B. , Olson Jeffrey J. , Shu Hui-Kuo George , Zhong Jim , Neill Stewart G. , Eaton Bree R.
Published: June 2022

2070

Background: Primary CNS Lymphoma (PCNSL) is a rare and often fatal disease. Treatment includes multi-agent systemic therapy with a backbone of high-dose methotrexate (HD-MTX). Despite multiple drug and radiotherapy combinations for induction and consolidation treatment there remains no clear standard of care. The purpose of this analysis is to evaluate how varying treatment approaches impacted clinical outcomes at our institution. Methods: Data retrospectively collected for 95 consecutive patients with PCNSL pathologically confirmed from 2002 to 2021. Primary endpoint was OS with secondary endpoints of PFS and LC. Progression based on RANO criteria. Kaplan-Meier analyses, Log-rank test and Cox proportional hazard models used for time to event endpoints. MVA by backward selection applying an alpha of 0.2 for associations with 1st line chemo agents, number of cycles of HD-MTX (>6 or 0-5), size of enhancing tumor at presentation, CSF cytology, type of surgery (biopsy, STR, or GTR), and use of WBRT. Results: Most patients had KPS >70 (64.2%), were HIV negative (89.5%), and had no history of solid organ transplant (95.8%). Diagnosis was made by biopsy (73.7%) or resection (GTR 13.7%, STR 12.6%). 54.3% had <14 cc contrast-enhancing tumor volume (median 12.6 cc, range 0.5 - 67.8 cc) and 48.6% had single enhancing lesion. Of the 62 patients treated first line with at least 1 cycle of HD-MTX, 61.3% were treated with HD-MTX + Rituximab (R) and 33.9% with HD-MTX + R + temozolomide (TMZ). With or after induction HD-MTX, 1-3 patients received one or a combination of cytarabine, thiotepa, procarbazine, vincristine, carmustine, or ASCT. Of the 60 patients with evaluable CSF, 30.0% had positive cytology. IT chemotherapy (ITc) was administered to 12 patients (5 with + cytology, 4 with - cytology, 3 with unknown cytology). WBRT for consolidation after chemotherapy used for 3 patients and as monotherapy for 9 patients. 2-year OS and PFS rate was 50.1% (95% CI 38.6%-60.5%) and 38.5% (95% CI 27.9%-49.0%). On MVA, > 6 cycles of MTX was associated with superior OS, PFS, and LC. For patients receiving any chemotherapy, addition of R was associated with inferior OS while ITc was associated with improved OS, PFS, and LC (Table). There was no OS association on MVA with TMZ, GTR, consolidation WBRT, or size or number of initial lesions (p>0.05). Conclusions: Completion of induction HD-MTX and use of ITc was associated with better outcomes in this population. Incorporation of R into 1st line therapy was associated with worse OS. Survival remained poor throughout the study period, underscoring importance of further innovation. [Table: see text]
Auto-reactive antibodies as predictive markers for immune checkpoint–induced pneumonitis.
Authors: Altan Mehmet , Wang Qi , Li Quan-Zhen , Zhu Chengsong , Tran Hai T. , Sheshadri Ajay , Gandhi Saumil , Antonoff Mara , Swisher Stephen , Vokes Natalie I , Spelman Amy R. , Lee J. Jack , Zhang Jianjun , Heymach John
Published: June 2022

2554

Background: Certain immune-related adverse events (irAEs) that emerge with immune checkpoint blockade share clinical features of autoimmune conditions. Preexisting auto-reactive antibodies and their contribution to irAEs have not been well defined, and observations are limited. Methods: We longitudinally collected patient plasma samples from a clinical trial that combines immune checkpoint inhibitors, Ipilimumab, and Nivolumab (I+N) with subsequent radiation therapy (Lonestar, NCT03391869). Plasma samples were collected at baseline, after 12 weeks of I+N (induction), and at the time of Grade ≥ 2 pneumonitis (CTCAEv5.0). Auto reactive antibody profiles were analyzed using a fluorescence-based assay system that measures more than 130 antigens and is capable of assaying antibody reactivity for IgG and IgM fractions, including nuclear-cytosolic and tissue-specific antigens. Selected antibodies had a reportable result range, reference intervals, and reproducibility with quality controls. A paired t-test was used to compare the mean of longitudinally collected baseline and toxicity samples. An unpaired t-test was used to compare differences between groups. The False Discovery Rate was used to control the Type I error rate of multiple comparisons. Results: In the study cohort, G≥2 pneumonitis was observed in 11 patients out of 194 (5.6%). Serum was collected at baseline for all 11 patients, and 9 of the 11 patients had a serum sample collected at the time of pneumonitis event. Longitudinal serum samples (baseline and post-induction) collected from 32 patients without any irAEs were used as control. At baseline AChR3 and calmodulin antibodies were elevated in patients who developed pneumonitis, compared with baseline samples from controls (p≤0.05). At the time of pneumonitis IgM antibodies against AChR3, CXCL10, NSE, BAFF, CA242, Cytokeratin 19 were noted to be elevated in serum for pneumonitis cases compared with post induction samples from control (p≤0.005). Conclusions: We identified auto reactive antibodies associated with a higher risk of immunotherapy associated pneumonitis in patients treated with ipilimumab and nivolumab. These included auto reactive antibodies against proteins associated with lung injury (AChR3), lung inflammation (BAFF, CXCL10) and against alveolar epithelium (Cytokeratin 19). Future studies are warranted to determine if auto-reactive antibodies can be used as pre-treatment risk markers or to diagnose pneumonitis and may offer insights into to mechanisms that predispose toward pneumonitis.
Assessment of a 4-chemokine signature in prediction of T-cell inflammation and response to immune checkpoint inhibition across tumor types.
Authors: Romero Joan Miguel , Titmuss Emma , Wang Yifan , Vafiadis James , Pacis Alain , Jang Gun Ho , Zhang Amy , Golesworthy Bryn , Lenko Tatiana , Williamson Laura , Grunwald Barbara , O'Kane Grainne M. , Wilson Julie , Gallinger Steven , Laskin Janessa J. , Zogopoulos George
Published: June 2022

2558

Background: Immune checkpoint inhibitors (ICI) are highly effective in select cancers. Novel predictors of T cell-inflammation may identify a broader subset of tumors with ICI responsiveness. Our group has identified four chemokines (CCL4, CCL5, CXCL9, CXLC10) able to predict a T cell-inflamed phenotype in primary and metastatic pancreatic tumors. Here, we test whether this 4-chemokine signature can predict T cell-inflammation across additional tumor types and response to ICI. Methods: Using matched genomic and transcriptomic data from 6,455 patients spanning 25 tumor types from The Cancer Genome Atlas, we searched for associations between the 4-chemokine signature and metrics of antitumor immunity. Further, we tested the association of this signature with markers of DNA damage repair deficiency. We also investigated the ability of this signature to predict response to immunotherapy using real-world data from a pan-cancer cohort of 82 patients in the Personalized OncoGenomics Program who had received ICI. Results: The majority of tumor types displayed sub-populations with high expression of the 4-chemokines (4-chemokinehi) and transcriptional hallmarks of the cancer-immunity cycle. Testicular germ cell tumors, cervical squamous cell carcinomas, and head and neck squamous cell carcinomas were the strongest expressors of the signature. Immunomodulatory genes, including PD-L1, PD-1, TIM3, LAG3, TIGIT, CTLA-4, and FASLG, were significantly overexpressed (p<0.05) in the 4-chemokinehi cohorts. Genesets of processes involved in the cancer-immunity cycle, including MHC I expression and cytolytic activity, were upregulated in the 4-chemokinehi cohorts (p<0.05). While a global relationship between tumor mutation burden (TMB) and 4-chemokine expression across tumor histological type was seen (rho=0.42, p=0.02), high TMB was associated with only a subset of 4-chemokinehi tumors. Among patients treated with ICIs, those with 4-chemokinehi tumors had a longer median time to progression (104 versus 71 days, p=0.013) and overall survival (391 versus 195 days, p=0.016). The 4-chemokine signature outperformed TMB for overall survival prediction. Conclusions: Sub-populations of T cell-inflamed patients exist across tumor types and may therefore respond favourably to ICI. The 4-chemokine signature has the potential to select a wider spectrum of patients that may benefit from ICIs. [Table: see text]
LB101, a conditionally tetravalent PD-L1xCD47 bispecific monoclonal antibody (mAb), combines tumor microenvironment (TME) targeted delivery (PD-L1) and a single biological high potency effector (CD47).
Authors: Finlay Jonny , Yver Antoine , Chivers Simon , Grainger David
Published: June 2022

2562

Background: Anti-PD-L1 antibodies are well-established as potent immune effectors in solid tumors expressing PD-L1 and demonstrate binding to these tumor cells within the TME. By contrast, due to the ubiquitous expression of CD47 on normal cells and tissues, anti-CD47 therapeutic agents with an active antibody Fc can lead to serious dose-limiting toxicities and profound biodistribution problems. To overcome these issues, we have generated LB101, a next-generation conditionally activated PD-L1xCD47 bispecific mAb with two anti-CD47 domains blocked by two further anti-PD-L1 domains, linked by two proprietary IgG-derived hinges, which inhibit CD47 interactions in the periphery, but are degraded in the PD-L1+ TME, thereby activating CD47 blockade to induce antibody-dependent cellular phagocytosis (ADCP). Methods: An IgG1-based, conditionally activated bispecific molecule was examined in binding, phagocytosis, PD-L1 blocking and flow cytometry assays. Efficacy analyses were performed in an hPD-L1+ syngeneic model in hPD-L1+/hPD1+ C57BL/6 mice, and preliminary safety and exposure analyses were completed in monkey. Results: In its intact locked form, LB101 exhibited anti-PD-L1 assay potency similar to atezolizumab. CD47 binding was only observed for LB101 after unlocking by hinge linker cleavage, leading to strongly enhanced ADCP by human CD14+ cells. In monkey, plasma stability of the locked construct was established with a PK profile mimicking that of a typical PD-L1 mAb. In the MC38 mouse model, systemically administered LB101 monotherapy delivered at equimolar dose to atezolizumab, led to no anemia, weight-loss, or overt toxicity. Monotherapy LB101 exhibited greatly improved efficacy and durability of response (14/16 tumors eradicated) over isotype control IgG (0/16) and atezolizumab (1/16). The CD47 naked parent IgG1 mAb was not tolerated in mouse, with 100% lethality above 2mg/kg. In rechallenge experiments, all naïve mice established tumors rapidly while none of the mice from groups with prior LB101-induced regressions exhibited tumor growth. Conclusions: Single agent LB101 immunotherapy delivered systemically in a difficult to treat syngeneic mouse model resulted in PD-L1 directed, local tumor-specific CD47 effector engagement leading to significant tumor regressions as compared to atezolizumab without overt toxicity. Future developments will focus on developing LB101 as a single agent therapeutic and exploring the potential of LockBody technology in improving the therapeutic index of other anti-cancer biological effectors through conditional activation within the TME.
Micro-organospheres retain patient tumor microenvironment for precision immuno-oncology.
Authors: Ding Shengli , Natesh Naveen R. , Spiller Kassandra , Xi Rui , Nelson Daniel , Gjorevski Nikolche , Walz Antje , Marrer-Berger Estelle , Clevers Hans , Hsu Shiaowen David , Shen Xiling
Published: June 2022

2573

Background: Current patient-derived organoid (PDO) models are largely devoid of immune components. We developed a precision microfluidic and membrane platform to generate patient-derived micro-organospheres (MOS) that retain tumor-resident immune and stromal components for personalized immuno-oncology (IO) assays. Methods: MOS were generated from lung, kidney, and colorectal cancer patients. The composition and function of patient tumor-resident immune cells in MOS were characterized by flow cytometry, single-cell RNA-seq, antibody staining, and TCR-seq. High-content and longitudinal imaging with AI analyses were used to quantify tumor cell death and immune cell dynamics inside MOS in response to IO therapies including checkpoint inhibitors, T cell bispecific antibodies, and adoptive tumor infiltrating lymphocyte (TIL) therapies, followed by single-cell analyses. Results: Tumor and stromal cells quickly form tissue niches inside MOS to sustain the viability and function of encapsulated immune cells. MOS derived from lung and kidney cancer patients respond to Nivolumab, indicated by the Annexin V apoptosis marker. ESK1* (TCB antibody targeting HLA-A2/WT1) induces killing in eight lung tumor patients derived MOS. We further developed a MOS T-cell potency assay as autologous TILs or PBMC efficiently infiltrate MOS from lung, kidney and CRC patients and induce tumor cell apoptosis. Adjunctive therapies combining TCB with TILs enhanced the potency of adoptive cell therapy against lung tumor. Based on the data, three ongoing and upcoming personalize IO clinical trials will further validate the ability of the MOS assay to predict patient response to TCB, checkpoint combinations, and adoptive cell therapy. Conclusions: MOS provide a rapid and scalable personalized platform for developing and testing IO therapies such as checkpoint inhibitors, bispecific antibodies, and T cell therapies on patient tumor models that still retain the original tumor microenvironments.
Preliminary results from an early phase trial of in situ immunization of lymphoma with a virus likeparticle containing a TLR9 agonist combined with anti-PD1 therapy (NCT03983668).
Authors: Farooq Umar , Ayyappan Sabarish Ram , Yin Chaobo , Lemke-Miltner Caitlin , Smith Brian J. , Link Brian K. , Weiner George J.
Published: June 2022

2639

Background: In situ immunization involves intratumoral (IT) injection of immunostimulatory agents to modify the tumor microenvironment with the goal of inducing an anti-tumor T cell response. Here, we report preliminary results of a clinical trial exploring in situ immunization with a virus like particle (VLP) combined with systemic pembrolizumab (Pembro) in lymphoma. The VLP, known as CMP-001 or vidutolimod (Vidu), is composed of the bacteriophage Qb capsid encapsulating the TLR9 agonist G10. Preclinical studies demonstrated generation of antibodies against the Qb capsid (anti-Qb) is necessary for Vidu to induce an anti-tumor response. In other cancers, early phase clinical trials of in situ immunization with Vidu, with and without systemic anti-PD1 therapy, have revealed early promising results. Methods: This trial included patients with relapsed lymphoma that have failed at least 1 line of therapy. The first dose of Vidu is given subcutaneously to stimulate anti-Qb that opsonizes the VLP. This is followed by IT Vidu administered weekly for seven doses, then at 3-week intervals. Pembro (200 mg fixed dose) is given intravenously every 3 weeks. Subjects continue treatment if they do not experience unacceptable toxicities and in the investigator’s opinion continued treatment is in the subject’s best interest. Fine needle aspirates for flow cytometric analysis are obtained prior to therapy and 4-6 weeks following initiation of therapy. Results: Six patients have enrolled to date (1 CR, 2 PR, 1 SD, 2 PD). The first 3 patients received 5mg Vidu per dose and the second cohort 7.5 mg per dose. Common side effects included chills, rigors, mild headache, and fatigue. These typically resolved within 4 hours after receiving the injection. Conclusions: In situ immunization with Vidu plus systemic anti-PD1 is a promising therapy in lymphoma. The ability to generate anti-Qb that opsonizes the VLP appears to be necessary for Vidu to induce an immune and therapeutic response. Accrual and correlative studies are continuing with the modification that generation of functional-Qb after the first dose of Vidu is required before patients receive IT therapy. Clinical trial information: NCT03983668. [Table: see text]
Comparison of the checkpoint inhibitor pneumonitis incidence between immunotherapy alone or in combination with chemotherapy for lung cancer: An observational, retrospective pharmacovigilance study.
Authors: Xu Pei-Hang , Zheng Yi-Fan , Li Zi-mu , Kuang Yu-Kun , Tang Ke-Jing
Published: June 2022

2655

Background: Clinical trials lack direct cross-comparison in safety between immune checkpoint inhibitor (ICI) as monotherapy and in combination with chemotherapy. The adverse event of checkpoint inhibitor pneumonitis (CIP) is an important factor influencing the treatment decision making. We performed a real-world pharmacovigilance study in the US Food and Drug Administration Adverse Event Reporting System (FAERS) to determine if ICI combination therapy is superior to monotherapy for lung cancer patients in terms of CIP incidence. Methods: The database of lung cancer patients receiving ICI between 2015 and 2020 was extracted for this study. The strategy-specific durations of the pneumonitis event were compared using the Kaplan-Meier method. Reporting odds ratio (ROR), a surrogate measure in disproportionality analysis, was used to assess the signal of CIP between ICI treatment strategies. Results: A total of 27,882 lung cancer patients with reported adverse events were involved. Among them, 1763 (6.3%) CIP after ICIs therapy were identified. In general, ICI usage was associated with over-reporting frequencies of CIP, but this association was no longer significant after adjustment (ROR: 1.14, 95%CI 0.86-1.49). The median times to CIP occurred early after therapy onset, either in ICI monotherapy or in combination with chemotherapy (41 days and 37 days, log-rank p>0.05). Different reporting frequencies emerged when we further compared different ICI strategies. Combination therapy with anti-PD-1 and chemotherapy was associated with a higher CIP incidence compared with anti-PD-1 monotherapy (ROR: 1.86, 95%CI 1.37-2.51), whereas anti-PD-L1/ CTLA-4 medications had lower risks in combination with chemotherapy (ROR: 0.31, 95%CI 0.16-0.56 and ROR: 0.41, 95%CI 0.09-1.22). Subgroup analyses on those with recorded therapy duration also indicated that reports of CIP were significantly lower with combination therapy of PD-L1 and CTLA-4 (ROR: 0.52, 95%CI 0.36-0.74 and ROR: 0.22, 95%CI 0.09-0.51 respectively). Conclusions: Compared with ICI monotherapy, the combination with chemotherapy might have an acceptable risk of CIP. Anti-PD-1 medications with additional chemotherapy could increase the risk of pneumonitis, whereas the risk was lower in the combination strategy with anti-PD-L1/CTLA-4. The combination might be a better therapeutic strategy than ICI monotherapy in treating lung cancer, regarding the CIP incidence. [Table: see text]
Efficacy proof-of-concept from a phase 1 study of a novel therapeutic peptide, ST101, targeting the oncogenic transcription factor C/EBPβ in patients with refractory solid tumors.
Authors: Evans T.R. Jeffry , Lakhani Nehal J. , Arkenau Hendrik-Tobias , McKean Meredith , Symeonides Stefan N. , Iwamoto Fabio Massaiti , Rotolo Jim , Capiaux Gina , Michel Rob , Kaesshaefer Stephen , Bexon Alice Susannah , Falchook Gerald Steven
Published: June 2022

3014

Background: The oncogenic transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) promotes tumor survival and proliferation and inhibits differentiation. ST101 is a peptide antagonist of C/EBPβ, with anti-tumor activity in prostate cancer (PC), glioblastoma (GBM), breast cancer (BC), melanoma, and other pre-clinical models. Methods: This phase 1 study enrolled patients (pts) with refractory solid tumors with varying histologies. The primary objective was to evaluate safety/tolerability of ST101 and to determine the recommended phase 2 dose (RP2D). Secondary and exploratory objectives included pharmacokinetics (PK), preliminary efficacy (RECIST 1.1), and pharmacodynamic (PD) evaluation. The study used a 3+3 dose-escalation design, with once-weekly IV infusion dosing of ST101 at 0.5, 1, 2, 4, 6, 9 mg/kg or a flat dose of 500 mg. Results: Enrollment in phase 1 was completed in November 2021 with a total of 25 pts with multi-metastatic disease that were refractory to standard therapy. As of February 15, 2022, five pts remain on study with a median treatment duration of 27 weeks’ (16-77). There were no DLTs, dose modifications, or serious adverse events (SAEs) related to ST101. The only AEs of note were G1-2 histaminergic infusion-related reactions (IRRs), largely pruritis and urticaria, managed with antihistamines, montelukast, and interruption/slowing of infusion. IRRs affected 93% of pts on the first dose at ≥4mg/kg and led to prolongation of infusion time. Intensity and frequency of IRRs decrease with repeat dosing. No other AEs were consistently reported. There was no evidence of accumulation upon continued exposure of ST101 and no anti-drug antibodies. Tumor immunohistochemistry showed dose-proportionate staining for ST101 and decreased tumor proliferation in several pts represented by decreased Ki67 expression. Population PK analysis supported flat dosing in phase 2. Five pts continue on treatment with one confirmed partial response in a patient with cutaneous melanoma lasting >42 weeks and four pts with ongoing stable disease. Conclusions: ST101 demonstrated safety at all doses explored and evidence of efficacy across dose levels, particularly higher doses and in pts with melanoma. PK and PD support a dose relationship for efficacy and selection of 500 mg as the RP2D. Pts are now enrolling in phase 2 cohorts to assess response in cutaneous melanoma, GBM, castrate-resistant PC, and HR+ BC. Clinical trial information: NCT04478279. [Table: see text]
VEGF inhibitors (VEGFi) activity in liver metastases (mets) regardless of primary cancer type: Meta-analysis and systematic review.
Authors: Pires Da Silva Ines Esteves Domingues , Lo Serigne N. , Conway Jordan W. , Scolyer Richard A. , Carlino Matteo S. , Menzies Alexander M. , Long Georgina V.
Published: June 2022

3024

Background: Liver metastasis is a poor prognostic factor in several cancers and is associated with poor response to immunotherapy (IO) in melanoma and lung cancer. VEGFi have activity in hepatocarcinoma (HCC) and is hypothesized to be due the hypoxic microenvironment. Whether this is also true for liver mets is unknown. We sought to assess the efficacy of VEGFi in liver mets utilizing randomized-controlled clinical trials (RCTs) testing the efficacy of VEGFi, regardless of primary cancer site. Methods: Systematic searches of PubMed, Cochrane CENTRAL, and Embase were conducted from January 1, 2000, to January 1, 2022. All RCTs that compared a backbone of systemic therapy (chemotherapy [chemo] and/or IO and/or targeted therapy [TT]) or best supportive care (BSC) with vs without VEGFi in patients (pts) with liver mets from any cancer were selected. HCC trials were excluded. Study design, cancer type, number of pts, lines of treatment, study drugs and hazard ratios (HRs) with 95% CIs for overall survival (OS) and progression-free survival (PFS) were extracted. Pooled effects of VEGFi in pts with liver mets across different cancer types were estimated using random effect model with inverse variance. Heterogeneity between studies was assessed by I2 statistics. Sensitivity analyses were performed considering prespecified subgroups of trials. Results: 3170 pts with liver mets from 19 RCTs were included in this meta-analysis: 8 colorectal cancer, 4 non-small cell lung cancer, 4 renal cell cancer & urothelial cancer, 1 pancreatic cancer, 1 GIST and 1 gastric cancer. Backbone systemic therapy in these trials included: chemo (11), TT (2), IO (2), chemo+IO (1), chemo+TT (1); and 2 BSC trials. Moderate heterogeneity between studies for both PFS (I2= 55%) and OS (I2= 46%) was seen. The addition of VEGFi to standard systemic therapy or BSC was associated with superior PFS (HR = 0.61; 95% CI, 0.50-0.74; p < 0.0001) and OS (HR = 0.86; 95%CI, 0.76-0.99; p = 0.0334) in pts with liver mets, regardless of whether pts had only liver mets or concurrent other sites of mets. In the subset of RCTs with data on pts without liver mets, the benefit with VEGFi was more pronounced in patients with liver mets (HR = 0.56) vs those without liver mets (HR = 0.64) for PFS, but not for OS. Conclusions: The addition of VEGFi to standard management improved survival outcomes in pts with liver mets across different cancer types and warrants further investigation. VEGFi added to IO may be effective in pts with resistant liver mets.
A circulating miRNA-based AI prediction system to identify multiple types of cancer.
Authors: Wu Chih-Hsun , Hwang Ming-Jing , Chang Chia-Ming
Published: June 2022

3050

Background: Cancer is a major problem for human health. Development of an early diagnostic tool can increase the survival of cancer patients. Liquid biopsies have many advantages over traditional tumor tissue biopsies. Circulating microRNAs (miRNAs) are one type of liquid biopsies in part because they regulate the expression and thus functions of their target genes. Circulating miRNAs are stable, non-invasive and changes in their expression are detectable in the early stage of cancer progression, often before clear evidence of tissue biopsy/image tests. To date, there are few liquid biopsy-based tools for multiple-cancer diagnosis and their performance is unsatisfactory. The development of a non-invasive, effective early detection system for cancers is urgently needed. Methods: We integrated and investigated circulating miRNA expression data of 5046 non-cancer samples along with 3856 cancer samples of 6 major cancer types downloaded from publicly available databases. We used these expression data along with gender to establish a multiple cancer type AI prediction system. Furthermore, we built comprehensive interaction networks (miRNA-drug, miRNA-target gene) and performed functional enrichment analysis. Results: We constructed high-performance AI prediction model that can detect and differentiate 6 cancer groups from one non-cancer group. A median of sensitivity of 93.84% in test data was achieved for the multiple cancer classification task. A panel of gender and 15 most important circulating miRNAs was further shown to achieve excellent performance (sensitivity = 90.44%), with just a bit of decrease in the sensitivity of using the full set (gender and 2565 miRNAs). The 15 key circulating miRNAs worked well for the early stage (stage 1: sensitivity = 88%), much better than other liquid-biopsy results reported in the literature. This is important because these miRNAs and the AI system can be used to significantly decrease clinical cost and increase efficiency of early diagnosis, not to mention it is non-invasive. Finally, we constructed comprehensive interaction networks (drug/ target gene) for these key miRNAs to explore potential therapeutic strategies and understand the underlying biological mechanisms. Conclusions: In the study, we constructed the multiple-cancer prediction AI system to classify groups of normal individuals and cancer patients of multiple types, while finding key circulating miRNAs. As several key circulating miRNAs were shown to be potential drug targets or serve as diagnosis biomarkers to fulfill the aim of cancer precision medicine, this work represents a significant step toward achieving the goal of developing a non-invasive tool for early diagnosis of cancers.