bluuebunny/crossref_metadata_2025 huggingface dataset:
Utilizing Drug Combo to improve the design of phase 1 trials for anticancer drugs.
Authors: Wang Lei , Zhang Shijun , Wei Lai , Owen Dwight Hall , Li Lang
Published: June 2023

1571

Background: Accurate prior knowledge of a single drug or drug combination on toxicity, pharmacokinetics (PK), maximum tolerated dose (MTD), and dose-limiting toxicity (DLT) can help oncologists and statisticians design an efficient phase 1 clinical trial. However, most of the relevant knowledge is shattered in various databases. More importantly, MTD and DLT are missing in any databases. This study constructed a comprehensive knowledge base with expert-curated MTD and DLT knowledge from published anticancer drug combination phase 1 clinical trial results. We also demonstrated the utility of the knowledgebase to design a more efficient phase 1 trial. Methods: Toxicity, pharmacology, and PK knowledge were integrated from publicly available data sources, including DrugBank, SIDER, and drug labels. An interdisciplinary team manually curated the MTD and DLT knowledge. Relevant papers were discovered by PubMed keyword search (drug name + MTD or RP2D). Details regarding patient eligibility, treatment information (dose, formula, and schedule), trial design method, dose levels, DLT definition, MTD or Recommended phase 2 dose, and DLT incident were curated in the structured data format and stored in a database. Rxnorm and MedDRA were used for normalizing drug names and DLT. Results: Currently, 2358 papers on cancer drugs phase 1 trial have been curated. Additionally, pharmacological and PK knowledge of 197 cancer drugs, ADE information from 1094 drug labels, and more than 500000 pieces of DDI evidence were integrated into the knowledge base. This knowledge base (drugcombo.info) could help researchers design an efficient phase 1 trial. For example, based on knowledge from Drug Combo, the combination of nivolumab and axitinib did not have potential PK DDI and severe overlapping toxicity. The reviewing physician considered a phase 1b study to start at a curated 5 mg maximum dose of axitinib with dose reduction to 3 and 2 mg and maintenance of a 3-mg/kg dose of nivolumab based on guidelines. With such additional preliminary knowledge, the reviewing statistician felt the adaptive statistical methods could be applied to redesign this phase I combination trial and minimize patient exposure to sub-therapeutic dose levels. Conclusions: To our knowledge, Drug Combo is the first knowledge that integrated curated MTD and DLT knowledge. It would promote applying curated knowledge to better design phase I trials to treat cancer.
Survival-inferred fragility index of FDA-approved cancer drugs using surrogate endpoints.
Authors: Ofer Jonathan , Gilboa Shai , Pras Yarden , Markel Gal , Bomze David , Meirson Tomer
Published: June 2023

1573

Background: The survival-inferred fragility index (SIFI) quantifies the robustness of positive trials by estimating the number of changes in a survival analysis that would render the results insignificant. Here, we use a variation of SIFI (SIFI-median) in which the median patient is reassigned between study groups until significance is lost. Our goal was to study the robustness of oncology randomized controlled trials (RCTs) leading to drug approval by the FDA based on surrogate time-to-event endpoints. Methods: In this cross-sectional study, we identified phase II-III RCTs between 2010 and 2020. We reconstructed individual patient data from published Kaplan-Meier plots of surrogate time-to-event endpoints and calculated the SIFI-median, i.e., the minimum number of median survivor reassignments from the intervention group to the control group that would cause the loss of statistical significance. Results: A total of 101 studies comprising 60697 patients met the inclusion criteria. The most common surrogate endpoint was PFS 86 (85.1%), followed by DFS 7 (6.9%). The SIFI-median was 23 (interquartile range [IQR], 12 to 37) and the SIFI-median as a proportion of sample size was 5.3% (IQR, 2.7% to 8.1%). Forty-five studies (44.5%) had SIFI-median less than 5% of the total sample size which was often less than the number of censored patients during early follow-up. The SIFI-median was less than 1% of the total sample size in 10 studies (9.9%). Conclusions: Low fragility indices indicates that the statistical conclusions of clinical studies could be reversed with a small number of variations. The lack of statistical robustness in multiple FDA-approved drugs suggests higher uncertainty in their clinical benefit.
Use of gender-neutral language in clinical trial protocols in select cancers.
Authors: Gupta Garima , Myint Zin , Yan Donglin , Patel Reema Anil
Published: June 2023

1574

Background: Around 21% of Generation Z Americans self-identify as lesbian, gay, bisexual, transgender (LGBT), nearly double the proportion of millennials. Despite Affordable Care Act Section 1557 in 2020, transgender individuals continue to have poor access to quality cancer care, including clinical trials. The National Institutes of Health (NIH) recognizes that using gender-neutral language in healthcare is one of many ways to improve sexual and gender minorities (SGM) related health disparities. This study examines use of gender-neutral language in clinical trial protocols in select cancers. Methods: Data was collected from clinicaltrials.gov, a commonly used resource for patients and providers. Phase III clinical trials with all recruitment statuses in the US from 2017 to 2022 were included. Cancer types were limited to those with highest risk of using gender-biased language: breast, ovarian, endometrial, fallopian tube, cervical, prostate, testicular, and penile. For each trial, frequency of use of following terms was recorded by searching under study details section: male, female, she, her, he, his, him, man/men, woman/women, breastfeeding/nursing/lactating/pregnant mother or female or woman. Mean frequency was compared between 2017-19 and 2020-22 using Wilcoxon signed-rank test. Funder type, eligible sex, gender-based eligibility and gender eligibility description were also collected. Data were compared between 2017-19 (pre-1557) and 2020-22 (post-1557) using Fisher exact test. Results: 243 studies were included in the analysis; 130 were pre- and 113 were post-1557. 103/130 (80%) studies between 2017-19 and 78/113 (70%) between 2020-22 included at least one gender-biased term or “male/female” outside of eligible sex description ( p = 0.05), depicting a trend towards improvement; stronger improvement was noted in non-NIH funded studies versus NIH-funded studies. Mean frequency of gender-biased terms was higher in 2017-19 compared to 2020-22 (2.25 vs 1.88, p = 0.02). 27/130 studies (21%) between 2017-19 and 21/113 (19%) of studies between 2020-22 required gender-based eligibility ( p = 0.40). Amongst these, 100% of studies between 2017-19 and 95% of studies between 2020-22 either provided no description or used this clause incorrectly, commenting on sex assigned at birth and not gender identity. This indicates lack of awareness regarding difference between sex assigned at birth and gender identity. While it is evident to investigators during registration on clinicaltrials.gov that eligible sex refers to biological sex, it is not to anyone reviewing the trial for enrollment, resulting in implicit bias. Conclusions: Our study highlights the dire need to address SGM-related health disparities and brings attention towards paucity of gender-neutral language in clinical trial protocols. This step is critical in providing more inclusive care and capturing the rising population of LGBT individuals.
Quantifying the growth of clinical actionability in precision oncology using OncoKB.
Authors: Suehnholz Sarah P. , Kundra Ritika , Nandakumar Subhiksha , Nissan Moriah H , Zhang Hongxin , Lu Calvin , Dhaneshwar Amanda , Fernandez Nicole , Carrero Stephanie , Arcila Maria E. , Ladanyi Marc , Berger Michael F. , Syed Aijazuddin , Brannon Angela Rose , Levine Ross L. , Dogan Ahmet , Drilon Alexander E. , Solit David B. , Schultz Nikolaus , Chakravarty Debyani
Published: June 2023

1577

Background: OncoKB ( www.oncokb.org ), Memorial Sloan Kettering's (MSK) precision oncology knowledge base, contains curated information about the oncogenic effect and therapeutic implications of somatic alterations in cancer and is the first cancer variant database to be partially recognized by the US-FDA. Individual mutations and structural alterations in OncoKB are assigned a level of evidence based on whether the alteration is a predictive biomarker of response or resistance to a genomically matched standard care or investigational drug in a specific cancer subtype. As of February 2023, OncoKB includes annotations for >6200 alterations in >700 cancer-associated genes, including 50 level 1 or 2 standard care genes (specified in the FDA drug label or professional guidelines) as well as 9 level 3A and 12 level 4 genes (predictive of drug response based on well-powered clinical studies or compelling biological evidence, respectively). OncoKB data is used internally to annotate >15,000 MSK patient sequencing reports annually, and its content is integrated into the cBioPortal for Cancer Genomics. Methods: To quantitate the expansion of the clinical actionability landscape in precision oncology, we annotated the clinical sequencing results of 47,271 solid tumor samples from the AACR Project GENIE cohort (GENIE 11.0 - public) using two versions of OncoKB, the first from March 2017 and the second from November 2022. Results: From 2017 to 2022, we observed a 22.7% increase in the fraction of samples with a standard care biomarker (levels 1 and 2), and a 21.4% decrease in the fraction of samples with a driver alteration that was not clinically actionable. The tumor agnostic approvals of the anti-PD1 antibody pembrolizumab in microsatellite instability high (MSI-H) and tumor mutational burden high (TMB-H) solid tumors resulted in a 11.1%increase of samples with a level 1 biomarker. In sum, of the 38,722 samples across 66 cancer types with limited to no actionability in 2017 (levels 3B, 4 or no level), 21.7% became clinically actionable (levels 1, 2 or 3A) by November 2022. This is an upper bound estimate as it includes samples that may have been eligible for an FDA-approved precision oncology therapy based on cancer subtype alone. Conclusions: Our analysis highlights the significant expansion of precision oncology-based therapeutic options for patients with cancer over the past 5 years, as well as the ongoing unmet need for novel precision oncology approaches designed to address oncogenic but not currently actionable drug targets. [Table: see text]
Clinical pathways innovation: A lesson on the value of clinician based feedback and collaboration with Flatiron Health.
Authors: Davella Christopher , Bange Erin Mary , Singh Aditi Puri , Dougherty David W. , Gabriel Peter Edward , Maniago Rebecca Lawrence , Miao Jennifer , Harvey Colin , Ricottone Marcello , Shulman Lawrence N.
Published: June 2023

1578

Background: Clinical pathways have emerged as a strategy to provide value-based care by reducing treatment variation across oncology practice. Despite evidence for cost reduction and improved patient outcomes, adoption of clinical pathways has met resistance in the oncology community given concerns regarding the impact on workflow, and cost. Flatiron Assist, an EMR based pathways tool, is a promising solution to minimizing workflow friction by proving a novel, streamlined user interface. Methods: The Abramson Cancer Center at the University of Pennsylvania and Flatiron Health conducted a pilot study from August 2021-December 2022 to test the use of Flatiron Assist within its thoracic oncology practices. The goal of the pilot was to increase utilization as well as usability of the pathways tool over time through clinician and developer iterative collaboration. Penn’s clinical pathways were incorporated into the tool and integrated into the EMR. An education program trained clinicians on the tool’s functionality. Based on clinician feedback, the Penn team identified two areas of improvement for the tool: speed and organization of the tool keys and prompts. Changes made over time included: 1) increasing the speed of the tool 2) restructuring the organization of keys and prompts, and 3) creation of a “hot button” for three common clinical scenarios in order to increase efficiency. Speed of the application (session length in seconds), utilization of the hot button (number of sessions/overall sessions) and overall physician adoption (treatment ordering with Flatiron Assist/total thoracic orders) were calculated during the pilot. Results: Provider utilization of the pathways tool increased over time with a baseline adoption rate of 29% in August 2021 and a peak of 74% in April 2022. Median session length decreased over time from 106.4 seconds (August 2021) to 39.9 seconds (December 2022). Peak performance for session length was 38.2 seconds (November 2022). Usage of the hot button introduced in August 2022 has increased over time from 27.6% of sessions to 41.8 % in November 2022. Thoracic providers ordered, on average, 1.7 new treatment plans per week, resulting in less than 1.5 extra minutes of work per week with optimal use of the pathways tool. Conclusions: Collaboration between Penn and Flatiron Health effectively reduced specific areas of friction associated with the use of Flatiron Assist. Changes made to the speed, button organization and functionality of the tool contributed to increased clinician utilization over time. Future development of EMR based pathway tools should incorporate clinician engagement and feedback.
The Tempus TIME trial portal and clinical trial enrollment.
Authors: Rao Amol , Miller Kevin , Huynh Chanh Trung , Luedtke Rachel , Anderson Mary Alice , Harris Melissa , Johnstone Michael , Murphy Lauren , Morgan Nicholas , Harmon Rachel , Ward AnnaJane , Donovan Blathnaid , Rice Christie , Sherrin Scott , Darmofal Annie , Skelly Danielle , Cooney Matthew M.
Published: June 2023

1583

Background: The TIME Trial Program is a research network that screens > 1 million patients daily via EMR integrations and NGS testing through an automated trial matching platform and human review. There are enormous complexities following patients longitudinally as their clinical status changes while accurately matching them with hundreds of studies. The TIME Trials Portal, which stores both clinical trial documents and patient status updates, allows for real-time communication between the TIME team and Clinical Sites. Methods: After both an automated and nursing review, eligible trial patients are uploaded into the TIME Trials Portal. This database tracks the patient’s name, date of birth, biomarkers, clinical status, trial matches, free text comments, and upcoming physician, radiology, and laboratory appointments. To protect Personal Health Information, each Clinical Site can only view their own patients. Patient status is classified as Needs Review, Monitoring, Enrolled, Inactive. Each update is time-stamped and tracked. Enrolled patients have the trial name, consent date, and other pertinent information documented. Results: The data from 2020 to 2022 includes 71 TIME Sites. Over this period, 6,816 patients were added to the TIME Trials Portal for an average of 219 per month. Of these, 1,891 patients were no longer eligible due to worsening performance status, trial closure, death, and other causes. The TIME team provided 8,643 patient updates compared to 7,442 Clinical Site updates. Clinical Sites spent 1,231.7 hours using the TIME Therapies Portal resulting in 623 total consents. Data from 2022 alone, demonstrated that 30 (42.3%) Clinical Sites with EMR integrations were responsible for 4,491 (76.3% of the total) patient updates translating into 288 (82.1%) of all consents. Also in 2022, of the 27 (38%) Clinical Sites that updated their patient’s status > 50 times consented 291 (82.9% of the total) patients. Conclusions: By 2022, the TIME Trials Portal was averaging approximately 400 new patients monthly resulting in a 13.1X increase in patients added from the program’s inception. Clinical Sites updated the patient status over 7,400 times spending over 1,200 hours using the TIME Trials Portal. The highest-performing Clinical Sites, which enrolled approximately 80% of the total patients, included those with EMR integrations and/or > 50 patient updates yearly. The TIME Trials Portal enabled patient tracking and communication to facilitate clinical trial enrollment.[Table: see text]
Comparison of publications between cancer sites in high impact factor journals.
Authors: Sinha Nikita , McDonald Amanda , Barry Danika , Barber Emma Longley
Published: June 2023

1588

Background: Prior studies have shown disparities in federal funding allocation by cancer site after accounting for mortality, incidence, and person-years of life lost. Whether disparities exist in publications in high impact factor journals is unknown. The aim of this study is to analyze research publications in high impact factor journals by cancer site relative to their burden from 2000 to 2018. Methods: Abstracts from the top 55 impact factor journals from 2000 to 2018 were extracted from PubMed. We developed an algorithm to search the title of the abstract to determine whether the abstract was about cancer and identify the cancer type. The algorithm was validated against the gold standard of human review in 1143 abstracts and yielded a sensitivity and a specificity of >95%. An article proportion for each cancer site was calculated (abstracts for a cancer site / total cancer abstracts). Article proportion was compared to cancer site-specific incidence, mortality and lethality from NCI’s SEER database using scatter plots and non-parametric Wilcoxon signed rank test. Results: We identified 128,377 articles; 31,045 (24%) were about cancer. Cancers with the most publications in high impact factor journals were breast (22%), lung (11%), and colorectal (10%) cancer. Breast, lung and colorectal cancer were also well represented in high impact factor journals compared to their incidence, mortality, and lethality. Gynecologic (ovarian, cervical, and endometrial), pancreatic, hepatobiliary, and prostate cancers were poorly represented in all 3 metrics. Breast, lung, and colorectal cancer ranked in the top half of Article to Lethality scores, while the gynecologic, pancreatic, and hepatobiliary cancers were in the bottom half (p <0.05 for all comparisons). Comparison of rankings by lethality versus by funding indicates relative underfunding of the gynecologic, pancreatic, hepatobiliary, and prostate cancers. Conclusions: Research publications in high impact factor journals by cancer site are not proportionate to individual societal cancer burden. Significant disparities exist between breast, lung, and colorectal cancer when compared to gynecologic, pancreatic, hepatobiliary, and prostate cancers relative to their disease burden. Underfunding of these cancer sites likely contributes to this publication gap.[Table: see text]
Cost-effectiveness of trastuzumab deruxtecan in HER2 low metastatic breast cancer.
Authors: Dickerson James , Moen Marcus , Nielsen Perry , Tran Edward , Suen Wesley , Goldhaber-Fiebert Jeremy D , Alarid-Escudero Fernando
Published: June 2023

1593

Background: In recent years, metastatic breast cancer treatment has been revolutionized by new therapies that improve overall survival in phase three randomized clinical trials. These drugs are often more expensive than traditional cytotoxics. In 2022, the Destiny-Breast04 trial results showed that trastuzumab deruxtecan (T-DXd) improved survival in HER2 low metastatic breast cancer patients; FDA approval shortly thereafter greatly expanded the potential market capitalization of T-DXd. While the trial demonstrated T-DXd’s clinical efficacy, its cost-effectiveness remains unknown. Methods: We developed a decision-analytic state transition Markov model to simulate a hypothetical cohort of HER2 low metastatic breast cancer patients to assess the cost-effectiveness of T-DXd compared to a physician's choice chemotherapy from a US healthcare payer perspective over a lifetime horizon. Each month, simulated patients could remain progression-free, progress, have a non-interstitial lung disease (ILD) treatment-related adverse event leading to drug discontinuation (TRAE), have ILD leading to drug discontinuation, progress after either a TRAE or ILD, or die. Patients with either a TRAE or ILD were presumed to be progression free directly after discontinuation of the offending agent, and hence eligible for a different therapy. We calibrated the model to outcome data from the Destiny-Breast04 trial, supplemented with data from other relevant metastatic breast cancer clinical trials. Health-related quality-of-life weights were derived from studies of metastatic breast cancer patients. Drug prices (2020 USD) were extracted from the Federal Supply Schedule. Outcomes included discounted (3% annual) quality-adjusted life years (QALYs), life years, lifetime costs, and incremental cost-effectiveness ratios (ICER). We varied T-DXd price and efficacy in a two-way sensitivity analysis to assess our findings’ robustness. Results: Modeled life expectancies with T-DXd and chemotherapy were 26.5 and 21.5 months, respectively (T-DXd: 1.19 QALYs; chemotherapy: 0.93 QALYs). Discounted lifetime costs were 315,000 for T-DXd and 203,000 for chemotherapy; T-DXd cost 431,000 per QALY gained, surpassing a cost effectiveness threshold of 150,000 per QALY gained. The two-way sensitivity analysis showed that, across a range of plausible efficacies, T-DXd would need a price reduction of approximately 50% to be cost-effective at the $150,000 threshold. Conclusions: While providing clinical benefits, our model-based analysis finds that at current prices, T-DXd for HER2 low metastatic breast cancer is not cost-effective at traditional thresholds. Substantial price reduction for T-DXd to a level much closer to prices of comparator cytotoxics could greatly increase the value for money T-DXd provides patients.
Association of participation in Medicare’s Oncology Care Model with spending, utilization, and quality outcomes among commercially insured and Medicare Advantage members: A national difference-in-differences analysis.
Authors: Mullangi Samyukta , Ukert Benjamin , Sylwestrzak Gosia , DeVries Andrea , Schauder Stephanie , Andreyeva Elena , Debono David Joseph , Fisch Michael Jordan , Schleicher Stephen Matthew , Navathe Amol S. , Schwartz Aaron L , Bekelman Justin E. , Parikh Ravi Bharat
Published: June 2023

1596

Background: Medicare’s Oncology Care Model (OCM) was a voluntary, episode-based model between 2016 and 2021 that provided participating practices with additional payments to fund care enhancements such as extended clinical hours and urgent care. While it resulted in net losses for traditional Medicare beneficiaries, the OCM may have had “spillover” improvements on spending, utilization, and quality for commercially insured (CM) and Medicare Advantage (MA) members who were not targeted by the program. Methods: This retrospective analysis used claims from Elevance Health, a large national payer, to identify commercially insured and Medicare Advantage members diagnosed with breast, colorectal, lung, prostate, and pancreatic cancer initiating systemic therapy between 2014 to 2021. We identified 85 OCM practices and 581 matched non-OCM practices based on episode, practice, demographic, and market factors. The exposure variable was participation in the OCM model. All outcomes were defined in 6-month episodes; the primary outcome was overall inflation-adjusted spending; secondary outcomes included hospitalization and emergency room visits, and end-of-life acute care utilization. We utilized adjusted difference-in-differences linear probability models, with state-level fixed effects to control for market price variability, to estimate the association between OCM participation and all outcomes. Results: We studied 45,296 episodes of care in OCM practices and 122,231 episodes in non-OCM practices among CM and MA members during the post-implementation period. OCM participation was associated with a $5,275 (SE $749.40) reduction in total allowed spending (p<0.001), driven by reductions in outpatient and systemic therapy spending. OCM was associated with improvements in end-of-life utilization and ED visits but none in hospitalizations and timely chemotherapy initiation. Conclusions: Participation in the OCM was associated with modest spillover spending benefit onto CM and MA members, but minimal utilization and quality benefits. Resultant practice innovations may have benefited non-targeted patients. Evaluations limited to targeted patients may have underestimated the full impact of the OCM.[Table: see text]
Telemedicine-supervised cancer therapy for patients with an aggressive lymphoma and metastatic lung cancer in the U.S. Veterans Affairs National TeleOncology Service.
Authors: Lin Chenyu , Zhou Katherine I. , Burningham Zachary R. , Rowe Kerry G. , Anglin-Foote Tori , Maddox Mark , Friedman Daphne Ruth , Halwani Ahmad Sami , Passero Vida Almario , Kelley Michael J. , Rodgers Thomas David
Published: June 2023

1602

Background: Telemedicine is increasingly used in cancer care but has mostly been applied to surveillance and oral therapy rather than parenteral treatments. In the U.S. Veterans Affairs National TeleOncology service (NTO), patients receive intravenous cancer treatments locally under remote supervision from a disease-specialized oncologist. We analyzed care delivered by the NTO for patients with an aggressive lymphoma (AL) and metastatic lung cancer (mLC). Methods: The demographics of veterans with AL and mLC enrolled in NTO between 2020-2023 were compared to patients receiving in-person care at the VA. From these NTO cohorts, two subsets of patients receiving 1st line therapy for diffuse large B cell lymphoma (DLBCL) and stage IV non-small cell lung cancer (NSCLC) were extracted and compared to control arms of in-person care matched 1:4 by stage, age, PDL1 (NSCLC), and cytogenetics (DLBCL). Fisher’s exact test was used for categorical variables, t test for continuous variables, log rank for survival, and negative binomial for count outcomes. Results: 140 patients with AL or mLC (40 DLBCL, 13 Hodgkin, 2 Burkitt, 61 NSCLC, 24 SCLC) were enrolled in NTO, spanning 12 U.S. states. Compared to in-person care ( n = 7,561), NTO had more rural (56% vs. 34%, p < 0.001) and white patients (89% vs. 77%, p = 0.002). With a median follow-up of 256 days (IQR, 154 - 415), NTO mLC and AL patients had a median of 15 and 17 telemedicine visits, respectively. 13 of 55 AL (24%) and 56 of 85 mLC (66%) patients received systemic therapy of any line, while 38 (69%) of AL were on surveillance. 7 mLC and 2 AL patients were referred externally for care. 11 patients with DLBCL and 30 patients with stage IV NSCLC started 1st line therapy while in NTO, which were compared to matched controls. NTO and matched control had similar mean time from referral to first appointment and from diagnosis to first treatment. There were no significant differences in progression-free survival between NTO and matched controls for NSCLC (HR 1.1, 95% CI 0.7-1.8) or DLBCL (HR 0.5, 95% CI 0.1-2.3). COVID infections in the first 12 months and number of ED visits in the first 3 months of treatment were not statistically different from controls. Conclusions: The NTO service demonstrates the feasibility of infusional chemoimmunotherapy administration under the direction of a remote tele-oncologist. This model has the potential to improve access to specialized oncology care for rural populations and provides a framework for decentralized clinical trials.[Table: see text]
Use and value of self-management (SM) recommendations in a real-world evidence study evaluating digital patient monitoring (DPM) of patients (pts) receiving cancer care.
Authors: Eicher Manuela , Bana Marika , Ribi Karin , Schneider Sophie , Ammann Johannes
Published: June 2023

1603

Background: SM includes pts’ abilities and activities to manage symptoms, treatment (tx), and any problems inherent to a chronic condition. Tailored SM support is recommended in cancer care. DPM enables pts to systematically self-report disease- or tx-related symptoms, communicate directly with healthcare professionals (HCPs), and access support materials. This observational study evaluated the real-world use of the Symptom Navi Program (SNP; Bern, Switzerland) SM materials on the Kaiku Health DPM platform (Helsinki, Finland) in collaboration with F. Hoffmann-La Roche Ltd (Roche; Basel, Switzerland). Methods: Adults diagnosed with locally advanced or metastatic non-small/small cell lung cancer, or any stage HER2-positive breast cancer being treated with locally approved and reimbursed drugs with an expected tx duration of >3 months, had access to a DPM solution that provided disease- and tx-tailored modules, including SNP SM recommendations for selected mild or moderate symptoms. The co-primary endpoints were DPM adoption and adherence. Here we report secondary endpoints; the perceived clinical impact, DPM module and service experience (assessed via Customer Effort Score [CES] and Customer Satisfaction Score [CSS]), and use of DPM features such as SM recommendations, via a DPM tool questionnaire. Results: Of the 89 enrolled pts, 66 had completed the DPM tool questionnaire at Week 6 of DPM use (data cutoff: June 9, 2022). Among the educational content, the symptom feedback library was accessed most. Pts spent up to a median of 12 minutes on Roche educational or SNP SM materials. The majority of pts (45/66 [68%]) considered the symptom questionnaires to cover all/most of the symptoms they experienced; 18/66 (27%) experienced only fair/partial symptom coverage; 49% (25/51) of pts whose symptoms were not covered contacted their HCP team. 34 pts (52%) took action based on the symptom questionnaire feedback; the most common action was SM recommendations applied according to symptom level (21/66 [32%]), followed by sending a message via the platform to the care team (8/66 [12%]). Half of pts found the SNP SM recommendations helpful/very helpful and 22 pts agreed that the SNP SM recommendations almost always/sometimes supported them in delaying contacting an HCP at an emergency room. At Week 6, the CES was 80%, CSS was 71%, and 48% (32/66) of pts felt that this service improved their care. Conclusions: Pt feedback showed that SNP SM recommendations were the most used action in response to the symptom questionnaire feedback and were perceived by most to be helpful/very helpful. These results support the use of SM recommendations in pts with cancer to help them self-manage tx-related symptoms experienced; future studies are needed to further explore their impact and usefulness, and to form recommendations for routine use in clinical practice.
INB-200 phase I study of gene modified autologous gamma-delta (γδ) T cells in patients with newly diagnosed glioblastoma multiforme (GBM) receiving maintenance temozolomide (TMZ).
Authors: Lobbous Mina , Goswami Trishna , Lamb Lawrence S. , Rochlin Kate , Pillay Thriumaine , Youngblood Samantha , ter Haak Mariska , Nabors Louis B.
Published: June 2023

2007

Background: MHC unrestricted γδ T cells target NKG2D ligands upregulated on tumor cells. IN8bio’s DeltEx chemotherapy resistant cell therapy (CRCT), is a novel γδ T cell genetically engineered to express MGMT to convey temozolomide (TMZ) resistance and allow combination therapy. NCT04165941, a Phase 1 trial assessing the safety of single and multiple infusions of autologous CRCT cells presents updated safety and efficacy data. Methods: Adult newly diagnosed GBM patients with adequate organ function and KPS≥70% are enrolled. Cells engineered from apheresis were infused through a Rickham catheter placed during surgery. Cohorts (C) 1, 2 and 3 each receive 1, 3 and6 doses of cells respectively on day (D) 1 of each 28-day maintenance cycle. Patients receive 1 x 107 γδ T cells intratumorally with 150 mg/m2 of TMZ intravenously on D1 of maintenance with the standard Stupp maintenance regimen on D2-5. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade 3 cardiopulmonary or hepatic toxicity, grade 4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. Results: 15 patients (53% male; median age 69 (range: 21-76); 80% IDH-WT, 66.7% MGMT unmethylated) were enrolled with 8 dosed (N=3 in C1, 4 in C2, 1 in C3). No patients experienced DLTs, cytokine release syndrome (CRS), or neurotoxicity (ICANS). The most common adverse events (AEs) were Grade 1/2 events including fever, fatigue, nausea, headache, platelet count decreased, incision site pain attributable to TMZ, radiotherapy or disease. One subject had Grade 3 treatment related AEs of UTI, dehydration, and thrombocytopenia. Three evaluable C1 patients have PFS of 8.3, 11.9, 7.4 months and OS of 15.6, 17.7 and 9.6 months respectively. In C2, four patients have been dosed, with no DLTs in 3 evaluable patients; 2 remain progression free at 18.9 and 14.8 months, while a third died without relapse due to pulmonary embolus at 8.7 months. One C3 patient has completed 5 of 6 planned doses without DLT. Patient recruitment continues with anticipated completion in 2023. Conclusions: Data demonstrates that single, repeat doses of CRCT gamma delta T cells have manageable toxicity with continued encouraging trend in PFS and warrants further assessment. Clinical trial information: NCT04165941 .
A genomic score to predict local control among patients with brain metastases managed with radiation.
Authors: Lamba Nayan , Cagney Daniel , Catalano Paul J. , Elhalawani Hesham Magdy Mohammad , Kim Dewey , Haas-Kogan Daphne A. , Wen Patrick Y. , Wagle Nikhil , Aizer Ayal
Published: June 2023

2011

Background: Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. As a result, radiation doses and fractionation schemes are prescribed with a “one-size-fits-all” approach. We sought to develop a DNA-based signature of radiation-based efficacy among patients with BrM, utilizing readily testable genes, to identify subpopulations at greater vs. lesser risk of recurrence. Methods: We retrospectively identified 570 patients with 1,487 distinct BrM managed with whole-brain (WBRT) or stereotactic radiation therapy (SRS/SRT) at a tertiary cancer center (2013-2020) for whom next-generation sequencing panel data (OncoPanel, 239 genes) were available on at least one tumor specimen. Local recurrence was assessed in a manner consistent with Response Assessment in Neuro-Oncology – Brain Metastases guidelines (i.e., radiographic enlargement of >20% in maximal cross-sectional diameter). Enlarging lesions managed with salvage treatment prior to >20% enlargement were considered to have recurred on the date of salvage therapy. Fine/Gray’s competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with vs. without somatic alterations of likely biological significance across 84 OncoPanel genes with a mutational frequency >0.5%. Genes with a q-value<0.10 were utilized to develop a numeric “Brain-Radiation Prediction Score” (“Brain-RPS”) to quantify local recurrence risk. Results: Genomic alterations of potential biological relevance in 11 ( ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, MDM4) and two genes ( FBXW 7 and AURKA) were associated with a decreased or increased risk of local recurrence, respectively (q-value<0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level RPS. On multivariable Fine/Gray’s competing risks regression, RPS [1.66 (1.44-1.92, p<0.001)], metastasis-associated edema [1.89 (1.38-2.59), p<0.001] and receipt of WBRT without SRS/SRT or neurosurgical resection [2.73 (1.78-4.20), p<0.001] were independent predictors of local failure. Conclusions: We developed a genomic score that can be calculated from an extracranial or intracranial site to quantify local recurrence risk following brain-directed radiation. Prior attempts to develop a biomarker-based radiation response signature have not been BrM-specific and have primarily relied on RNA-based measures of radiosensitivity, limiting their utility in clinical practice. To our knowledge, this represents the first study to systemically correlate DNA-based alterations with radiation-based outcomes among patients with BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genomic personalization of radiation treatment among patients with BrM.
Longitudinal single-cell (sc) immune profiling of cerebrospinal fluid (CSF) from melanoma patients (pts) with leptomeningeal disease (LMD) treated with intrathecal (IT) and intravenous (IV) nivolumab (N).
Authors: Morad Golnaz , Yang Yitao , Duncan Sheila , Ferguson Sherise D. , Wargo Jennifer Ann , Burton Elizabeth M. , Tawbi Hussein A. , Davies Michael A. , Liang Han , Glitza Isabella Claudia
Published: June 2023

2015

Background: LMD is associated with an extremely poor prognosis in melanoma pts, who currently have very limited treatment options. Our group previously reported initial safety and efficacy results from the dose escalation portion of a first in human phase I/IB trial using IT and IV N (NCT03025256) in melanoma LMD pts. Here we present longitudinal sc profiling of immune cells in CSF from a subset of pts in this trial to better understand the immune composition of this unique microenvironment and features associated with treatment and outcomes. Methods: 39 CSF samples were collected longitudinally from 5 long survivors (LS; IT N number of doses received 10-92) and 5 rapid progressors (RP; IT N doses 2-9) and profiled by sc RNA sequencing. Raw FASTQ reads were aligned to the GRCh38 human reference genome using Cell Ranger v6.0.0 to generate the count matrix. All samples were aggregated by Seurat v4.3.0 and data integration was performed using Harmony v0.1.0. Cells were filtered by following criteria: (1) > 20% mitochondrial content, or (2) express < 100 or > 2,500-5,000 genes, according to sample specific distribution. Empty droplets and doublets were identified by EmptyDrops function from the R package DropletUtils v1.18.0 and DoubletFinder v2.0.3, respectively. We applied normalization, FindVariableFeatures (n = 2,000), scaling, PCA, UMAP and FindClusters to summarize the integrated samples and determine cell clusters. Cell types were annotated based on (1) canonical marker genes using FindAllMarkers, (2) published gene expression signatures, and (3) reference-based tool using Symphony v.0.1.0 on published data: GSE164378 and GSE158803. Statistical analysis was conducted using the Wilcoxon rank-sum test. Results: A total of 10 patients were included in this pilot analysis. Five pts were LS (2 males; IT dose 5 mg, 1 pt; 10 mg, 2 pts; 20 mg, 2 pts; 2 BRAF mutant; 5 negative CSF cytology at baseline) and 5 pts were RP (3 males; IT dose 5 mg, 1 pt; 20 mg, 2 pts; 50 mg, 2 pts; 4 BRAF mutant; 4 positive CSF cytology at baseline). At baseline [prior to cycle (C)1 of IT N], LS pts had a higher percentage of NK cells (relative to total immune cells; P = 0.036) and mucosal-associated invariant T cells (relative to total T cells, P = 0.021) than RP pts. Prior to C2, LS had a significantly higher percentage of T cells (relative to all cells; P = 0.036). The abundance of immune cells and tumor cells were not different between the two groups at C3, at which point pts have received two doses of IT N and one dose of IV N. Conclusions: Exploratory sc analysis of longitudinal CSF samples of LMD pts suggest that baseline immune features may predict outcomes with IT N. Analysis of additional pts is ongoing to provide further insights.
Long-term survival with IDH wildtype glioblastoma: First results from the ETERNITY Brain Tumor Funders’ Collaborative Consortium (EORTC 1419).
Authors: Weller Michael , Felsberg Joerg , Gramatzki Dorothee , Le Rhun Emilie , Clarke Jennifer Leigh , Soffietti Riccardo , Wick Wolfgang , Chinot Olivier L. , Ducray Francois , Roth Patrick , Hau Peter , Klein Martin , Preusser Matthias , Bendszus Martin , Golfinopoulos Vassilis , von Deimling Andreas , Gorlia Thierry , Wen Patrick Y. , Reifenberger Guido , Hertler Caroline
Published: June 2023

2016

Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and by the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumors, prognostic factors were analyzed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. Results: At the cut-off of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 not otherwise specified) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumors with O6-methylguanine DNA methyltransferase ( MGMT) promoter methylation. Median overall survival was 9.9 years (95% CI 7.9–11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p<0.001) and had a high rate of MGMT promoter unmethylated tumors. Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Never relapsing patients often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma. Clinical trial information: NCT03770468 .
ctDNA detection in patients with brain metastases arising from solid tumors.
Authors: Alder Laura , Broadwater Gloria , Green Michelle , Lipp Eric S. , Van Swearingen Amanda E.D. , Clarke Jeffrey Melson , Anders Carey K. , Sammons Sarah
Published: June 2023

2027

Background: While circulating tumor DNA (ctDNA) is a routine tool for therapeutics in metastatic solid tumors, data in those with stable and active brain metastases (BrMs) is limited. We assessed genomic alterations in ctDNA from patients (pts) with solid tumor BrMs in three groups: isolated BrMs/stable extracranial disease (iCNS), concurrent brain and extracranial progression (cCNS), and extracranial progression with no active BrMs at ctDNA draw (eCNS). We also compared ctDNA alterations between pts with and without BrMs. Methods: Pts with BrMs and a Guardant 360 profile (n=253) from the Duke Molecular Registry of Tumors between 01/2014 – 12/2020 were identified. Intracranial and extracranial disease status were determined via investigator assessment (RECIST and RANO-BM criteria) within 30 days of ctDNA test. Mutant allele fraction (MAF) was defined as the % of mutant alleles divided by total alleles at a given loci. Differences in mean ranks of the MAF % maximum were compared using the Kruskal-Wallis test and pairwise comparisons with the Dwass, Steel, Critchlow-Fligner multiple comparisons post-hoc procedure. We compared differences in MAF >1% using the chi-square test. Results: Among the 253 pts with BrMs: 29 (12%) had iCNS, 160 (63%) cCNS, and 64 (25%) eCNS. The two most common tumor types were breast (BC, 12.0%) and non-small cell lung cancer (NSCLC, 76.4%). Median MAF was lower in the iCNS group (1.6%) vs cCNS (4.8%) p=0.002, but eCNS did not differ (2.6%). In pts with BC BrMs, ESR1 mutations were most frequent in the iCNS group (67%), followed cCNS (54%) then eCNS (18%) (p = 0.09) as were PIK3CA mutations, iCNS(50%), cCNS (46%), and eCNS (27%), p = 0.55. In pts with NSCLC BrMs, EGFR mutations were most frequent in the iCNS followed by cCNS then eCNS (67%, 40% and 37%, p = 0.08). KRAS mutations were more frequent in cCNS followed by eCNS and iCNS (30%, 17% and 6% p = 0.031). Patients with no BrMs (n=449) included 24% breast and 76% NSCLC. In the ctDNA, ESR1 and BRCA2 mutations were more frequent in pts with BC BrMs than those without (60% vs 25%, p< 0.001) and (17% vs 5%, p=0.022), respectively. Mutations in EGFR were more frequent in pts with BrMs vs without (36% vs 17%, p<0.001). Sequencing from both BrMs tissue and ctDNA were available for 8 pts (4cCNS and 4 iCNS). 7 of these (87.5%) had identical mutations in tumor and ctDNA. Conclusions: This study illustrates the feasibility of detecting actionable mutations from ctDNA among pts with BrMs, with and without extracranial disease. A higher frequency of actionable mutations in several targetable genes was observed in ctDNA when comparing pts with and without BrMs, thus providing therapeutic opportunities. Additional studies comparing ctDNA and alterations in BrMs tissue are needed to determine if ctDNA can be considered a surrogate to support treatment decisions.
Evaluating the diagnostic performance of leptomeningeal diagnosis with CNSide compared to standard cytology.
Authors: Appel Haley , Odia Yazmin , Saxena Anshul , Roy Mukesh , Mohler Alexander , Kotecha Rupesh , Hall Matthew David , Ahluwalia Manmeet Singh , Mehta Minesh P. , Castaneda Serguei A.
Published: June 2023

2028

Background: Prior reports cited detection rates of leptomeningeal metastases (LM) using CNSide vs standard CSF cytology of 78% vs 55% in NSCLC and 84% vs 52% in various solid tumor cohorts. The objective of this study was to compare the real-world performance of the CNSide assay in diagnosing LM versus CSF cytology from lumbar puncture (LP) and established EANO-ESMD LM diagnostic criteria (EANO). Methods: We retrospectively analyzed all neuro-oncology patients from January, 2020 to December, 2022 with suspected LM who underwent LP with CSF cytology and CNSide. The CNSide assay included tumor cells (CSF-TCs) and cell-free DNA (cfDNA). LM diagnostic probability was defined by EANO criteria. Descriptive statistics and confusion matrix were calculated. Results: 87 patients (66 [76%] women) met eligibility criteria for inclusion with median age of 63 (23-87) years; 35 (40%) had uncontrolled systemic disease. The most common primary histologies were breast (45%) and lung (41%); 33% of primary lung cancers harbored molecular alterations, while primary breast cancers expressed hormone receptors in 69% and HER2 alterations in 10%. Across all primary histologies, 53 (61%) cases harbored molecular alterations, of which 27 (31%) had molecular alterations also detected by CNSide. For 7 (8%) cases with negative cytology and CNSide, CNSide detected alterations by cfDNA assays. LM was diagnosed by CSF cytology in 23 (27%) cases, consistent with confirmed LM by EANO. 36 (41%) cases had confirmed LM by CSF cytology or CNSide; all cytology positive and equivocal cases were detected by CNSide. Patients with negative CSF cytology were further defined as probable (19, 23%), possible (35, 42%), or (7, 8%) lack of evidence by EANO. Modifying EANO criteria to include both standard CSF cytology and CNSide led to 36 (41%) confirmed LM cases, an increase of 13 cases in addition to the 23 cytology positive cases (+56.5%). Compared to CNSide, standard CSF cytology had a sensitivity of 70%, but an expected 100% specificity. Compared to the established higher specificity of CNSide, EANO had 100% sensitivity, but only 18% specificity for diagnosing LM, assuming all EANO possible, probable, or confirmed cases were positive, while specificity improved to 74% with slight decrease sensitivity to 94% if only probable or confirmed cases were considered positive. Conclusions: In the largest, retrospective, single institution, real-world study, implementation of CNSide showed increased sensitivity relative to standard cytology and increased specificity relative to EANO criteria, and provided clinically relevant, cell-based molecular and cell-free DNA analyses. CNSide increased the diagnostic yield by 56.5%.