Virtual Pooled Registry-Cancer Linkage System: an improved method for ascertaining cancer diagnoses.

BACKGROUND: The National Cancer Institute funds many large cohort studies that rely on self-reported cancer data requiring medical record validation. This is labor intensive, costly, and prone to underreporting or misreporting of cancer and disparity-related differential response. US population-based central cancer registries identify incident cancer within their catchment area, yielding all malignant neoplasms and benign brain and central nervous system tumors with standardized data fields. This manuscript describes the development, implementation, and features of a system to facilitate linkage between cohort studies and cancer registries and the release of cancer registry data for matched cohort participants. METHODS: The Virtual Pooled Registry-Cancer Linkage System (VPR-CLS) provides an online system to link cohorts with multiple state cancer registries by 1) securely transmitting a study file to registries, 2) providing an optimized linkage algorithm to generate preliminary match counts, and 3) providing a streamlined process and templated forms for submitting and tracking data requests for cohort participants who matched with registries. RESULTS: In 2022, the VPR-CLS launched with 45 registries, covering 95% of the US state populations and Puerto Rico. Registries have linked with 15 studies having 14 273-10.9 million participants. Except in 1 study, linkage sensitivity ranged from 87.0% to 99.9%. Numerous registries have adopted the VPR-CLS templated institutional review board-registry application (n = 39), templated data use agreement (n = 25), and central institutional review board (n = 16). CONCLUSIONS: The VPR-CLS markedly improves ascertainment of cancer outcomes and is the preferred approach for determination of outcomes from cohort studies, postmarketing surveillance, and clinical trials.

NCI SEER-Linked Virtual Tissue Repository Pilot.

BACKGROUND: The Surveillance, Epidemiology, and End Results (SEER) Program with the National Cancer Institute tested whether population-based cancer registries can serve as honest brokers to acquire tissue and data in the SEER-Linked Virtual Tissue Repository (VTR) Pilot. METHODS: We collected formalin-fixed, paraffin-embedded tissue and clinical data from patients with pancreatic ductal adenocarcinoma (PDAC) and breast cancer (BC) for two studies comparing cancer cases with highly unusual survival (≥5 years for PDAC and ≤30 months for BC) to pair-matched controls with usual survival (≤2 years for PDAC and ≥5 years for BC). Success was defined as the ability for registries to acquire tissue and data on cancer cases with highly unusual outcomes. RESULTS: Of 98 PDAC and 103 BC matched cases eligible for tissue collection, sources of attrition for tissue collection were tissue being unavailable, control paired with failed case, second control that was not requested, tumor necrosis ≥20%, and low tumor cellularity. In total, tissue meeting the study criteria was obtained for 70 (71%) PDAC and 74 (72%) BC matched cases. For patients with tissue received, clinical data completeness ranged from 59% for CA-19-9 after treatment to >95% for margin status, whether radiation therapy and chemotherapy were administered, and comorbidities. CONCLUSIONS: The VTR Pilot demonstrated the feasibility of using SEER cancer registries as honest brokers to provide tissue and clinical data for secondary use in research. Studies using this program should oversample by 45% to 50% to obtain sufficient sample size and targeted population representation and involve subspecialty matter expert pathologists for tissue selection.

Reporting tumor genomic test results to SEER registries via linkages.

BACKGROUND: Precision medicine has become a mainstay of cancer care in recent years. The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program has been an authoritative source of cancer statistics and data since 1973. However, tumor genomic information has not been adequately captured in the cancer surveillance data, which impedes population-based research on molecular subtypes. To address this, the SEER Program has developed and implemented a centralized process to link SEER registries' tumor cases with genomic test results that are provided by molecular laboratories to the registries. METHODS: Data linkages were carried out following operating procedures for centralized linkages established by the SEER Program. The linkages used Match*Pro, a probabilistic linkage software, and were facilitated by the registries' trusted third party (an honest broker). The SEER registries provide to NCI limited datasets that undergo preliminary evaluation prior to their release to the research community. RESULTS: Recently conducted genomic linkages included OncotypeDX Breast Recurrence Score, OncotypeDX Breast Ductal Carcinoma in Situ, OncotypeDX Genomic Prostate Score, Decipher Prostate Genomic Classifier, DecisionDX Uveal Melanoma, DecisionDX Preferentially Expressed Antigen in Melanoma, DecisionDX Melanoma, and germline tests results in Georgia and California SEER registries. CONCLUSIONS: The linkages of cancer cases from SEER registries with genomic test results obtained from molecular laboratories offer an effective approach for data collection in cancer surveillance. By providing de-identified data to the research community, the NCI's SEER Program enables scientists to investigate numerous research inquiries.

Ethnic differences in the patterns, sources, and reasons for cannabis use among cancer patients at an NCI-Designated Cancer Center.

OBJECTIVE: This study aims to describe patterns, sources, and reasons for cannabis use among cancer patients by ethnic group. METHODS: Data are from a cross-sectional study of 416 surveys collected via RedCap anonymously from adult cancer patients seen at a National Cancer Institute-designated comprehensive cancer center within the last 5 years. A harmonized survey was created with 11 other National Cancer Institute centers to assess cannabis use patterns, sources, and reasons for use. Sociodemographics and cancer details were also collected via self-report. Descriptive statistics by ethnic group were compared using χ2 and Fisher exact tests. RESULTS: Among the sample (age mean = 50.4 [15.7] years; 53% male; 8.3% lesbian, gay, bisexual, transgender, queer; 46.7% Hispanic and Latinx individuals), 69.6% reported lifetime use of cannabis, 33.7% began cannabis use after cancer diagnosis, 48.1% of those consuming cannabis did not have a prescription for cannabis, and 29.4% of cannabis users consumed daily. The frequency of cannabis use (P = .04) and reasons for cannabis use (P = .02) varied by ethnic group. Sleep and pain were the most prevalent reasons for use among the Hispanics and Latinx populations; pain, mental health management, and neuropathy were the most prevalent reasons for cannabis use among non-Hispanic White individuals. CONCLUSIONS: Patterns and reasons for cannabis use differed among cancer patients by ethnic group in this exploratory cross-sectional study aimed to provide data for more rigorous study. Understanding these distinctions are pivotal in conducting more rigorous studies that address the unique needs of diverse populations utilizing cannabis for managing cancer-related symptoms.

Concurrent substance use among cancer patients with and without a history of cannabis use since cancer diagnosis at an NCI-Designated Cancer Center in Florida.

BACKGROUND: Although substance use may have adverse impacts on cancer outcomes, little is known regarding patterns of concurrent substance use with cannabis among cancer patients. Our objective was to examine predictors of concurrent substance use with cannabis among cancer patients since their cancer diagnosis and explore perceptions of cannabis among these patients. METHODS: Patients treated at a National Cancer Institute-designated comprehensive cancer center were invited to participate in an electronic survey regarding medical cannabis from August to November 2021. Survey data were linked to internal data resources including electronic health records and patient intake forms to obtain history of substance use (defined as within at least 3 months of cancer diagnosis) of cigarettes, injection drugs, high levels of alcohol, or clinically unsupervised prescription drugs (total n = 1094). Concurrent substance users were defined as those with any reported substance use and cannabis use at the time of cancer diagnosis. We used descriptive statistics (χ2 or exact tests) to compare groups and estimated adjusted odds ratios (AORs) with 95% confidence intervals (CIs) to identify predictors of substance use among users and nonusers of cannabis. RESULTS: Approximately 45% (n = 489) of the sample reported cannabis use since their cancer diagnosis. Of patients who reported using cannabis, 20% self-reported concurrent polysubstance use, while 8% of cannabis nonusers reported substance use (P < .001). Among patients who use cannabis, those who reported 2 or more self-reported treatment-related symptoms (eg, pain, fatigue) were more likely to have self-reported concurrent substance use (AOR = 3.15, 95% CI = 1.07 to 9.27) compared with those without any symptoms. Among nonusers, those with lower educational background were more likely to have a history of concurrent substance use (AOR = 3.74, 95% CI = 1.57 to 8.92). Patients who use cannabis with concurrent substance use were more likely to report improved sleep (P = .04), increased appetite (P = .03), and treatment of additional medical conditions (P = .04) as perceived benefits of cannabis use. CONCLUSIONS: High symptom burden may be associated with concurrent substance use with cannabis among cancer patients.

Landscape analysis of environmental data sources for linkage with SEER cancer patients database.

One of the challenges associated with understanding environmental impacts on cancer risk and outcomes is estimating potential exposures of individuals diagnosed with cancer to adverse environmental conditions over the life course. Historically, this has been partly due to the lack of reliable measures of cancer patients' potential environmental exposures before a cancer diagnosis. The emerging sources of cancer-related spatiotemporal environmental data and residential history information, coupled with novel technologies for data extraction and linkage, present an opportunity to integrate these data into the existing cancer surveillance data infrastructure, thereby facilitating more comprehensive assessment of cancer risk and outcomes. In this paper, we performed a landscape analysis of the available environmental data sources that could be linked to historical residential address information of cancer patients' records collected by the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The objective is to enable researchers to use these data to assess potential exposures at the time of cancer initiation through the time of diagnosis and even after diagnosis. The paper addresses the challenges associated with data collection and completeness at various spatial and temporal scales, as well as opportunities and directions for future research.

Machine learning and deep learning tools for the automated capture of cancer surveillance data.

The National Cancer Institute and the Department of Energy strategic partnership applies advanced computing and predictive machine learning and deep learning models to automate the capture of information from unstructured clinical text for inclusion in cancer registries. Applications include extraction of key data elements from pathology reports, determination of whether a pathology or radiology report is related to cancer, extraction of relevant biomarker information, and identification of recurrence. With the growing complexity of cancer diagnosis and treatment, capturing essential information with purely manual methods is increasingly difficult. These new methods for applying advanced computational capabilities to automate data extraction represent an opportunity to close critical information gaps and create a nimble, flexible platform on which new information sources, such as genomics, can be added. This will ultimately provide a deeper understanding of the drivers of cancer and outcomes in the population and increase the timeliness of reporting. These advances will enable better understanding of how real-world patients are treated and the outcomes associated with those treatments in the context of our complex medical and social environment.

The SEER Program's longstanding commitment to making cancer resources available.

The Surveillance, Epidemiology, and End Results (SEER) Program, an authoritative source of cancer statistics in the United States, has been funded by the National Cancer Institute (NCI) since 1973. The goals of SEER include measuring the cancer burden in the United States, making the results available, and supporting cancer research. These goals render products that serve as resources for different audiences, such as cancer registrars, researchers, and the public. Cancer registrars have access to a dedicated tab on the SEER website for questions, assistance with cancer coding, and training and technical resources such as SEER*Rx and SEER Data Management System (SEER*DMS). For researchers, SEER provides access to databases and software such as SEER*Stat and other linked databases such as SEER-Medicare that may offer answers to emerging issues in the field of cancer outcomes, cancer burden, health disparities, healthcare access, diagnosis, and prevention. The public can access cancer materials such as the SEER Cancer Stat Facts sheets, SEER*Explorer, and Did You Know? video series to learn more about cancer. SEER continues to update its resources with and ahead of legislation such as the Plain Writing Act and 21st Century Integrated Digital Experience Act (IDEA) to improve both clarity and user experience. Moving forward, SEER continues to promote awareness of SEER resources, remains accessible and understandable across all audiences, and standardizes how new resources are shared with these groups. The longstanding commitment to making cancer resources available is fundamental to the value of SEER, as evidenced by testimonials from members of various audience types.

Cannabis and opioid perceptions, co-use, and substitution among patients across 4 NCI-Designated Cancer Centers.

Prescription opioids are used for managing pain in persons with cancer, however, there are socioeconomic and racial disparities in medication access. Cannabis is increasingly used for cancer symptom management and as an opioid alternative. Limited data are available about patterns of opioid and cannabis use among patients with cancer. We used survey data from 4 National Cancer Institute-designated cancer centers in 3 states (n = 1220) to assess perceptions, use of cannabis and opioids for pain, their substitution, and racial and ethnic differences in each outcome. Compared with White patients, Black patients were less likely to use opioids for pain (odds ratio [OR] = 0.66; P = .035) and more likely to report that cannabis was more effective than opioids (OR = 2.46; P = .03). Race effects were mitigated (P > .05) after controlling for socioeconomic factors. Further research is needed to understand cannabis and opioid use patterns and how overlapping social determinants of health create a disadvantage in cancer symptom management for Black patients.

Perceptions, prevalence, and patterns of cannabis use among cancer patients treated at 12 NCI-Designated Cancer Centers.

BACKGROUND: The legal climate for cannabis use has dramatically changed with an increasing number of states passing legislation legalizing access for medical and recreational use. Among cancer patients, cannabis is often used to ameliorate adverse effects of cancer treatment. Data are limited on the extent and type of use among cancer patients during treatment and the perceived benefits and harms. This multicenter survey was conducted to assess the use of cannabis among cancer patients residing in states with varied legal access to cannabis. METHODS: A total of 12 NCI-Designated Cancer Centers, across states with varied cannabis-access legal status, conducted surveys with a core questionnaire to assess cannabis use among recently diagnosed cancer patients. Data were collected between September 2021 and August 2023 and pooled across 12 cancer centers. Frequencies and 95% confidence intervals for core survey measures were calculated, and weighted estimates are presented for the 10 sites that drew probability samples. RESULTS: Overall reported cannabis use since cancer diagnosis among survey respondents was 32.9% (weighted), which varied slightly by state legalization status. The most common perceived benefits of use were for pain, sleep, stress and anxiety, and treatment side effects. Reported perceived risks were less common and included inability to drive, difficulty concentrating, lung damage, addiction, and impact on employment. A majority reported feeling comfortable speaking to health-care providers though, overall, only 21.5% reported having done so. Among those who used cannabis since diagnosis, the most common modes were eating in food, smoking, and pills or tinctures, and the most common reasons were for sleep disturbance, followed by pain and stress and anxiety with 60%-68% reporting improved symptoms with use. CONCLUSION: This geographically diverse survey demonstrates that patients use cannabis regardless of its legal status. Addressing knowledge gaps concerning benefits and harms of cannabis use during cancer treatment is critical to enhance patient-provider communication.

Evaluation of NCI-Designated Cancer Center and Comprehensive Cancer Center Survivorship-Focused Websites: Information Provided and Accessibility.

BACKGROUND: Individuals with a history of cancer increasingly seek health information from online resources, including NCI-designated Cancer Center websites. Centers receive NCI designation because they provide excellent care and engage in cutting-edge research. However, the information presented on these webpages and their accessibility is unknown. An evaluation of the survivorship-focused webpages from NCI-designated Cancer Centers is needed to assess survivorship information and accessibility of these webpages. METHODS: We conducted an evaluation of the survivorship-focused webpages from 64 NCI-designated Cancer Centers. We evaluated where survivorship-focused webpages were housed, if there was a survivorship clinic or program, target audience of the webpage, how cancer survivor was defined, contact methods, and available resources. Accessibility outcomes included readability, font type, font size, color scheme, and alternative text (alt text) descriptors. An artificial intelligence (AI) audit was conducted to assess if the webpage was compliant with national accessibility guidelines. RESULTS: Most cancer centers had a survivorship-focused webpage, with 72% located on the cancer center's website and 28% on a health system website. Survivorship information available varied considerably and was often lacking in detail. Although three-quarters of webpages targeted patients only, variable definitions of cancer survivor were observed. Accessibility issues identified included inconsistent use of alt text descriptors, font size smaller than 15 points, and color schemes without adequate contrast. The average reading-level of information presented was above 12th grade. Only 9% of webpages were compliant with online accessibility guidelines; 72% semicompliant and 21% were noncompliant. CONCLUSIONS: Information presented on NCI-designated Cancer Center survivorship-focused webpages was inconsistent, often lacking, and inaccessible. NCI-designated Cancer Centers are role models for cancer research in the United States and have an obligation to provide survivorship information. Changes to content and website design are needed to provide better information for individuals seeking resources and health information relative to their cancer and care.

Modernizing the NCI60 Cell Line Screen for Phenotypic Drug Discovery in the 21st Century.

Over the past three decades, high-throughput phenotypic cancer cell line screens have revealed unanticipated small-molecule activities and illuminated connections between tumor genotypes and anticancer efficacy. Founded in 1984, the National Cancer Institute's "NCI60" screen laid the conceptual groundwork for the contemporary landscape of phenotypic drug discovery. NCI60 first operated as a primary bioactivity screen, but molecular characterization of the NCI60 cell line panel and development of a small-molecule sensitivity pattern recognition algorithm (called "COMPARE") have enabled subsequent studies into drug mechanisms of action and biomarker identification. In this issue of Cancer Research, Kunkel and colleagues report an updated version of the NCI60 screen, dubbed "HTS384" NCI60, that better aligns with current cell proliferation assay standards and has higher throughput. Changes include the use of a 384-well plate format, automated laboratory equipment, 3 days of compound exposure, and a CellTiter-Glo luminescent endpoint. To confirm that data from the HTS384 and classic NCI60 screen are comparable, the authors tested a library of 1,003 anticancer agents using both protocols and applied COMPARE to analyze patterns of cell line sensitivities. More than three dozen groups of targeted therapies showed high comparability between screens. Modernization of NCI60, and closer integration with other large-scale pharmacogenomic screens and molecular feature sets, will help this public screening service remain pertinent for cancer drug discovery efforts for years to come. See related article by Kunkel et al., p. 2403.

Toward real-time reporting of cancer incidence: methodology, pilot study, and SEER Program implementation.

BACKGROUND: A lag time between cancer case diagnosis and incidence reporting impedes the ability to monitor the impact of recent events on cancer incidence. Currently, the data submission standard is 22 months after a diagnosis year ends, and the reporting standard is 27.5 months after a diagnosis year ends. This paper presents the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program's efforts to minimize the lag and achieve "real-time" reporting, operationalized as submission within 2 months from the end of a diagnosis year. METHODS: Technology for rapidly creating a consolidated tumor case (CTC) from electronic pathology (e-path) reports is described. Statistical methods are extended to adjust for biases in incidence rates due to reporting delays for the most recent diagnosis years. RESULTS: A registry pilot study demonstrated that real-time submissions can approximate rates obtained from 22-month submissions after adjusting for reporting delays. A plan to be implemented across the SEER Program rapidly ascertains unstructured e-path reports and uses machine learning algorithms to translate the reports into the core data items that comprise a CTC for incidence reporting. Across the program, cases were submitted 2 months after the end of the calendar year. Registries with the most promising baseline values and a willingness to modify registry operations have joined a program to become certified as real-time reporting. CONCLUSION: Advances in electronic reporting, natural language processing, registry operations, and statistical methodology, energized by the SEER Program's mobilization and coordination of these efforts, will make real-time reporting an achievable goal.

Development and Application of Genetic Ancestry Reconstruction Methods to Study Diversity of Patient-Derived Models in the NCI PDXNet Consortium.

Precision medicine holds great promise for improving cancer outcomes. Yet, there are large inequities in the demographics of patients from whom genomic data and models, including patient-derived xenografts (PDX), are developed and for whom treatments are optimized. In this study, we developed a genetic ancestry pipeline for the Cancer Genomics Cloud, which we used to assess the diversity of models currently available in the National Cancer Institute-supported PDX Development and Trial Centers Research Network (PDXNet). We showed that there is an under-representation of models derived from patients of non-European ancestry, consistent with other cancer model resources. We discussed these findings in the context of disparities in cancer incidence and outcomes among demographic groups in the US, as well as power analyses for biomarker discovery, to highlight the immediate need for developing models from minority populations to address cancer health equity in precision medicine. Our analyses identified key priority disparity-associated cancer types for which new models should be developed. SIGNIFICANCE: Understanding whether and how tumor genetic factors drive differences in outcomes among U.S. minority groups is critical to addressing cancer health disparities. Our findings suggest that many additional models will be necessary to understand the genome-driven sources of these disparities.

Masking Policies at National Cancer Institute-Designated Cancer Centers During Winter 2023 to 2024 COVID-19 Surge.

This cross-sectional study examines variation in masking policies at National Cancer Institute (NCI)­designated cancer centers during the winter 2023-2024 COVID-19 surge.

Transforming patient-centered cancer care using telehealth: the MATCHES Center.

Modern cancer care is costly and logistically burdensome for patients and their families despite an expansion of technology and medical advances that create the opportunity for novel approaches to care. Therefore, there is a growing appreciation for the need to leverage these innovations to make cancer care more patient centered and convenient. The Memorial Sloan Kettering Making Telehealth Delivery of Cancer Care at Home Efficient and Safe Telehealth Research Center is a National Cancer Institute-designated and funded Telehealth Research Center of Excellence poised to generate the evidence necessary to inform the appropriate use of telehealth as a strategy to improve access to cancer services that are convenient for patients. The center will evaluate telehealth as a strategy to personalize cancer care delivery to ensure that it is not only safe and effective but also convenient and efficient. In this article, we outline this new center's research strategy, as well as highlight challenges that exist in further integrating telehealth into standard oncology practice based on early experiences.

Clinician-to-clinician connectedness and access to gastric cancer surgery at National Cancer Institute-designated cancer centers.

BACKGROUND: For patients with gastric cancer, the pathway from primary care (PC) clinician to gastroenterologist to cancer specialist (medical oncologist or surgeons) is referral dependent. The impact of clinician connectedness on disparities in quality gastric cancer care, such as at National Cancer Institute-designated cancer centers (NCI-CC), remains underexplored. This study evaluated how clinician connectedness influences access to gastrectomy at NCI-CC. METHODS: Maryland's All-Payer Claims Database was used to evaluate 667 patients who underwent gastrectomy for cancer from 2013 to 2018. Two separate referral linkages, defined as ≥9 shared patients, were examined: (1) PC clinicians to gastroenterologists at NCI-CC and (2) gastroenterologists to cancer specialists at NCI-CC. Multiple logistic regression models determined associations between referral linkages and odds of undergoing gastrectomy at NCI-CC. RESULTS: Only 15% of gastrectomies were performed at NCI-CC. Patients of gastroenterologists with referral links to cancer specialists at NCI-CC were more likely to be <65 years, male, White, and privately insured. Every additional referral link between PC clinician and gastroenterologist at NCI-CC and between gastroenterologist and cancer specialist at NCI-CC increased the odds of gastrectomy at NCI-CC by 71% and 26%, respectively. Black patients had half the odds as White patients in receiving gastrectomy at NCI-CC; however, adjusting for covariates including clinician-to-clinician connectedness attenuated this observation. CONCLUSION: Patients of clinicians with low connectedness and Black patients are less likely to receive gastrectomy at NCI-CC. Enhancing clinician connectedness is necessary to address disparities in cancer care. These results are relevant to policy makers, clinicians, and patient advocates striving for health equity.

Disparities in cancer clinical trials information-seeking: Findings from the National Cancer Institute's Cancer Information Service.

OBJECTIVE: To better understand cancer clinical trials (CCT) information-seeking, a necessary precursor to patient and provider engagement with CCT. METHODS: Data from the National Cancer Institute's Cancer Information Service (CIS) were used to examine CCT information-seeking patterns over a 5-year period. Descriptive and logistic regression analyses were conducted to examine characteristics of CIS inquiries and their associations with having a CCT discussion. RESULTS: Between September 2018 - August 2023, 117,016 CIS inquiries originated from cancer survivors, caregivers, health professionals, and the general public; 27.5 % of these inquiries included a CCT discussion (n = 32,160). Among CCT discussions, 35.5 % originated from survivors, 53.5 % from caregivers, 6.1 % from the public, and 4.9 % from health professionals. Inquiries in Spanish had lower odds of a CCT discussion (OR=.26, [.25-.28]), whereas inquiries emanating from the CIS instant messaging (OR=2.29, [2.22-2.37]) and email (OR=1.24, [1.18-1.30]) platforms were associated with higher odds of discussing CCT compared to the telephone. Individuals who were male, younger, insured, and had higher income and education had significantly higher odds of a CCT discussion while those who were non-Hispanic Black and living in rural locales had significantly lower odds. CONCLUSIONS: Disparities in CCT information-seeking may contribute to downstream CCT participation. PRACTICE IMPLICATIONS: Quality, language-concordant health information is needed to enable equitable awareness of - and ultimately engagement in - CCT.

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.

PURPOSE: The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor. METHODS: As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m2/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS). RESULTS: Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF-altered CNS tumors achieved stable disease >6 months. CONCLUSION: Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.