National Clinical Trials Network Research Articles

Pediatric and Adolescent Hodgkin Lymphoma: Paving the Way for Standards of Care and Shared Decision Making.

Hodgkin lymphoma (HL) is a treatable cancer with an incidence peak in adolescent and young adult years. Treatment strategies have been developed to balance the intensity of therapy needed to maintain disease-free survival while simultaneously preserving overall survival. Risk-based, response-adapted frontline therapy has long used a combination of chemotherapy and radiotherapy (RT). Successive clinical trials over the past three decades have safely reduced cumulative alkylator, anthracycline, and RT exposures for many patients. The advent of checkpoint inhibitors and the CD30-targeted antibody drug conjugate, brentuximab vedotin, has provided new options for de-escalation of conventional therapies associated with late effects in survivors treated at a young age. The ability to evaluate novel agents has been accelerated in collaborative trials inclusive of children and adolescents within the US National Clinical Trials Network and between the Children's Oncology Group and the EuroNet Pediatric Hodgkin Lymphoma Consortium. With numerous treatment options, patients with HL and their clinicians have an opportunity for shared decision making from diagnosis, through cancer treatment, and into survivorship. Given excellent survival outcomes, decisions about treatment in classic HL should be collaborative and attention to long-term survivorship needs should remain a high priority. Patient-reported outcomes remain an important tool to aid clinicians working with survivors to optimize health status and related quality of life for decades after HL therapy.

Interim FDG-PET/CT for predicting response of HER2-positive breast cancer to neoadjuvant therapy: ECOG-ACRIN EA1211/DIRECT trial.

TPS614 Background: Strategies to optimize treatment decision-making in early stage HER2-positive breast cancer are a priority. Recent studies suggest that early metabolic changes on FDG-PET/CT predict response to HER2-directed therapy. The TBCRC026 trial showed that participants not obtaining a 40% reduction in SULmax by cycle 1 day 15 (C1D15) following neoadjuvant trastuzumab/pertuzumab (HP) were unlikely to obtain pCR [negative predictive value (NPV) 91%]. This trial aims to validate FDG-PET/CT as a neoadjuvant interim (niFDG-PET/CT) imaging integral biomarker in patients treated with standard HER2-directed regimens (NCT05710328). Methods: Trial design: EA1211/DIRECT is a multicenter, single-arm, primary imaging phase 2 study enrolling patients with stage II/III HER2-positive breast cancer. Patients undergo standard skull base-thigh FDG-PET/CT at baseline and C1D15 and receive standard of care pertuzumab-based neoadjuvant therapy followed by surgery. Eligibility: Age ≥18 years, ECOG performance status 0-2, stage IIa-IIIc, untreated HER2-positive breast cancer with known hormone receptor status, suitable to undergo FDG-PET/CT imaging and neoadjuvant therapy. Statistical methods: ΔSULmaxD15 will be computed as: (D15 SULmax – baseline SULmax)/baseline SULmax. The primary objective is to estimate the NPV of niFDG-PET/CT for pCR using ΔSULmaxD15 of the primary breast cancer at a threshold of 40%. NPV is defined as the probability that pCR will not be achieved by participants with ΔSULmaxD15 <40%. Secondary endpoints include evaluating sensitivity, specificity, and positive predictive value of ΔSULmaxD15 of the primary breast cancer at a threshold of 40% and ability of the niFDG-PET/CT biomarker to predict 3-year event free survival (EFS). Sample size: We expect that 50% of patients will not reach the ΔSULmax threshold of 40% and a pCR rate of 40-60%. The proposed sample size is 210 participants, adjusted to 235 to account for missing data in 10% of cases. Computation of exact, two-sided 95% confidence intervals (CI) for NPV determined the lower limit of the CI is at least 80% when the true NPV is at least 88%. The lower limit is 84% when the true NPV has the value of 91%, which was estimated in the TBCRC026 study. Current status: EA1211/DIRECT was activated in May 2023 across the NCI National Clinical Trials Network (NCTN) and is anticipated to complete in March 2025. Those interested in the clinical trial can email ea1211team@ecog-acrin.org. The EA1211/DIRECT trial is the first step in implementing a Response-Guided Treatment Strategy by validating the ΔSULmax threshold of 40% as the optimum cut point across standard of care HER2-directed neoadjuvant regimens. If EA1211/DIRECT meets its objectives, the results will be used to design clinical utility studies, thus hoping to change practice. Clinical trial information: NCT05710328 .

Abstract PR005: Final results from a Phase I trial of intravesical chemoimmunotherapy with gemcitabine and Bacillus Calmette-Guérin (BCG) for patients with BCG-exposed high-grade non-muscle invasive bladder cancer

Abstract Background: Although retreatment with BCG is considered standard of care for patients with BCG-exposed high-grade (HG) non-muscle invasive bladder cancer (NMIBC), less than 50% of patients are expected to respond. As such, the ability to augment the efficacy of BCG in this population remains a critical unmet need. Preclinical studies suggest that intravesical gemcitabine (Gem) may demonstrate synergistic efficacy with BCG by favorably altering the tumor microenvironment. We therefore sought to evaluate the safety, tolerability, and preliminary clinical efficacy of GemBCG in patients with BCG-exposed HG NMIBC through an IRB-approved Phase I/II clinical trial. Methods: Patients with BCG-exposed papillary HG NMIBC (Ta/T1) with or without carcinoma in situ (CIS) that recurred within 24 months of BCG therapy were eligible for this trial. Exclusion criteria included BCG-unresponsive disease, contraindication to BCG therapy, or ureteral/urethral urothelial disease. Consenting patients underwent complete transurethral resection of bladder tumors followed by intravesical Gem twice weekly (weeks 1, 4, 7, 10) for a total of 8 doses. Dose escalation of Gem was performed from 50-2000 mg using a Bayesian modified continual reassessment method. Intravesical Gem instillations alternated with weekly intravesical TICE BCG therapy (weeks 2, 3, 5, 6, 8, 9) for a total of 6 doses fixed at 50 mg followed by maintenance BCG in responders. Complete response (CR) rates and progression to muscle-invasive bladder cancer (MIBC) or cystectomy were evaluated at 12 months of follow up in the Phase I cohort. Results: A total of 25 patients was enrolled (median age 70 years [IQR 64-75]), all of which have at least 12 months of follow up. Of these, 88% (22/25) were male. Median duration of bladder cancer treatment prior to enrollment was 385 days (IQR 173-634), and 28% (7/25) previously received either maintenance therapy (3/25) or >1 induction courses of BCG (4/25). Based on centralized pathology review, a total of 68% had CIS ± papillary disease (8 HGTa, 5 HGT1, and 4 Tis), while 32% had papillary-only disease (4 HGTa and 4 HGT1). No dose limiting toxicities were observed, and 14/25 patients were treated at the maximum tolerated dose. The treatment was well tolerated with no patient experiencing treatment-related Grade 3-5 toxicity. CR rates at 6 months and 12 months were 96% (24/25) and 92% (23/25), respectively. No progression to MIBC or radical cystectomy was observed. Conclusion: Combination GemBCG in BCG-exposed HG NMIBC is well tolerated and appears to provide excellent cancer control. Based on these encouraging findings and the ongoing phase II portion (NCT04179162), a prospective randomized controlled trial comparing GemBCG to BCG alone for BCG-exposed NMIBC is planned through the National Clinical Trial Network (Alliance A032303). Citation Format: Syed M. Alam, Christopher D. Gaffney, Jessica Lavery, Merve Basar, Neeta D'Souza, Christian Hernandez, Melissa McCarter, Patricia Moran, Kristen Stasi, Kara Worth, Daniel Sjoberg, Guido Dalbagni, Timothy Donahue, Sherri Donat, Dean Bajorin, Bernard H. Bochner, Alvin Goh, Judy Sarungbam, Hikmat Al-Ahmadie, Eugene J. Pietzak. Final results from a Phase I trial of intravesical chemoimmunotherapy with gemcitabine and Bacillus Calmette-Guérin (BCG) for patients with BCG-exposed high-grade non-muscle invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr PR005.

Abstract B007: Urinary cytokine profiles reflect rationale for treatment with gemcitabine and Bacillus Calmette-Guérin (BCG) in BCG-exposed high-risk non-muscle invasive bladder cancer (NMIBC)

Abstract Background: Bacillus Calmette-Guérin (BCG) remains the most efficacious and widely studied intravesical therapy for NMIBC, but less than 50% of BCG-exposed patients will respond to a second course of BCG. One mechanism of resistance to BCG is an immunosuppressive tumor microenvironment with myeloid-derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), and Tregs that abrogate the anti-tumor immune response. IL-6 is associated with MDSCs and BCG resistance. Gemcitabine (Gem), however, has been shown to selectively inhibit MDSCs, TAMs, and Tregs. This observation served as the biologic rationale for our recently completed Phase I trial of combination chemoimmunotherapy with intravesical Gem and BCG for BCG-exposed high-grade (HG) NMIBC (NCT04179162) that demonstrated excellent tolerability and preliminary efficacy (96% complete response at 6-month follow-up). We sought to evaluate immune modulation with the addition of Gem to BCG as determined by changes in urinary cytokine/chemokine levels. Methods: Patients with BCG-exposed papillary HG NMIBC (Ta/T1) +/- carcinoma in situ recurring within 24 months of BCG therapy were treated with intravesical Gem twice weekly (weeks 1,4,7,10; 8 total doses) and intravesical TICE BCG weekly (weeks 2,3,5,6,8,9; 6 total doses) followed by SWOG maintenance BCG for responders. Urine specimens were collected prior to treatment and on weeks 4, 8, 12, 24, and 52 weeks after on-trial treatment initiation. Urinary cytokines present in the supernatant were evaluated using a 96-plex immuno-oncology proximity extension assay (Olink®). Cytokines with < 75% of values below the lower limit of detection of the assay were not evaluated. We performed an exploratory analysis of select pre-specified cytokines using a linear mixed model. Mean changes and 95% confidence intervals (CI) are presented with global p-values testing for a change in cytokine levels at any timepoint. Results: Urine samples were available for all 25 patients in the Phase I study. A total of 25 proteins on the panel were excluded due to low detection. Chemokines associated with T-cell trafficking (CXCL9, CXCL10, CXCL11) increased during induction treatment through 3 months of follow up and then returned to baseline after the completion of treatment (p<0.001 for each cytokine). IL-6 decreased after initiation of treatment and remained low through 12 months of follow up (-2.7, 95% CI -3.8, -1.7; p<0.001). Notably, the one patient who had a recurrence also had a rise in IL-6 after an initial decline while on treatment. Conclusion: We found evidence that the addition of intravesical gemcitabine to BCG favorably augments the tumor microenvironment based on changes in urinary cytokine/chemokine profiles. Additional tumor and urinary correlatives are ongoing. Based on the the robust preliminary efficacy demonstrated in the ongoing phase I/II trial (NCT04179162), a prospective randomized controlled trial comparing GemBCG to BCG alone for BCG-exposed NMIBC is planned through the National Clinical Trial Network (Alliance A032303). Citation Format: Christopher D. Gaffney, Syed M. Alam, Jessica A. Lavery, Merve Basar, Neeta D'Souza, Christian Hernandez, Melissa McCarter, Patricia Moran, Kristen Stasi, Kara Worth, Daniel Sjoberg, Guido Dalbagni, Timothy Donahue, Sherri Donat, Dean Bajorin, Bernard H. Bochner, Alvin Goh, Judy Sarungbam, Hikmat Al-Ahmadie, Eugene J. Pietzak. Urinary cytokine profiles reflect rationale for treatment with gemcitabine and Bacillus Calmette-Guérin (BCG) in BCG-exposed high-risk non-muscle invasive bladder cancer (NMIBC) [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B007.

Abstract PO1-01-01: ECOG-ACRIN EA1211: Interim FDG-PET/CT for predicting response of HER2-positive breast cancer to neoadjuvant therapy (DIRECT Trial)

Abstract Background: Strategies to optimize treatment decision-making in early stage HER2-positive breast cancer are a current priority for the oncology and patient advocacy community. Recent studies suggest that early metabolic changes on FDG-PET/CT (imaging biomarker) predict response to HER2-directed therapy. The TBCRC026 trial showed that participants not obtaining a 40% reduction in SULmax by cycle 1 day 15 (C1D15) following neoadjuvant trastuzumab/pertuzumab (HP) were unlikely to obtain pCR [negative predictive value (NPV) 91%]. The ECOG-ACRIN EA1211/DIRECT trial aims to validate FDG-PET/CT as a neoadjuvant interim (niFDG-PET/CT) imaging integral biomarker in patients treated with standard HER2-directed regimens (NCT05710328). Design: EA1211/DIRECT is a multicenter, single-arm, primary imaging phase 2 study enrolling patients with stage II/III HER2-positive breast cancer. Patients undergo standard skull base-thigh FDG-PET/CT at baseline and C1D15 and receive standard of care pertuzumab-based neoadjuvant therapy followed by surgery. Eligibility: Age ≥18 years, ECOG performance status 0-2, stage IIa-IIIc, untreated HER2-positive breast cancer with known hormone receptor status, suitable to undergo FDG-PET/CT imaging and neoadjuvant therapy. Methods: ΔSULmaxD15 will be computed as: (D15 SULmax – baseline SULmax)/baseline SULmax. The primary objective is to estimate the NPV of niFDG-PET/CT for pCR using ΔSULmaxD15 of the primary breast cancer at a threshold of 40%, in patients treated with neoadjuvant HER2-directed therapy. NPV is defined as the probability that pCR will not be achieved by participants with ΔSULmaxD15 < 40%. Secondary endpoints include evaluating the sensitivity, specificity, and positive predictive value of ΔSULmaxD15 of the primary breast cancer at a threshold of 40% and the ability of the niFDG-PET/CT biomarker to predict 3-year event free survival (EFS). Sample Size: We expect that 50% of patients will not reach the ΔSULmax threshold of 40% and a pCR rate of 40-60%. The proposed sample size is 210 participants, adjusted to 235 to account for missing data in 10% of cases. Computation of exact, two-sided 95% confidence intervals (CI) for NPV determined the lower limit of the CI is at least 80% when the true NPV is at least 88%. The lower limit is 84% when the true NPV has the value of 91%, which was estimated in the TBCRC026 study. Current Status: EA1211/DIRECT was activated in May 2023 across the NCI National Clinical Trials Network (NCTN), and accrual is anticipated to complete in March 2025. Those interested in the clinical trial can email ea1211team@ecog-acrin.org. Conclusion: The EA1211/DIRECT trial is the first step in implementing a Response-Guided Treatment Strategy by validating the ΔSULmax threshold of 40% as the optimum cut point across standard of care HER2-directed neoadjuvant regimens. If EA1211/DIRECT meets its objectives, the results will be used to design clinical utility studies, and thus hoping to change practice. Citation Format: Heather Jacene, Constantine Gatsonis, Roisin Connolly, Brian Burnette, Erica Stringer-Reasor, Maeve Hennessy, Justin Romanoff, Alexander Taurone, Ciara O'Sullivan, H. T. Carisa Le-Petross, Courtney Lawhn Heath, Vered Stearns, Amy Fowler, Shou-Ching Tang, Karla A Sepulveda, Angela DeMichele, David Mankoff, Antonio Wolff. ECOG-ACRIN EA1211: Interim FDG-PET/CT for predicting response of HER2-positive breast cancer to neoadjuvant therapy (DIRECT Trial) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-01.

The Status and Challenges for Prostate Stereotactic Body Radiation Therapy Treatments in United States Proton Therapy Centers: An NRG Oncology Practice Survey

PurposeTo report the current practice pattern of the proton stereotactic body radiation therapy (SBRT) for prostate treatments. Materials and MethodsA survey was designed to inquire about the practice of proton SBRT treatment for prostate cancer. The survey was distributed to all 30 proton therapy centers in the United States that participate in the National Clinical Trial Network in February, 2023. The survey focused on usage, patient selection criteria, prescriptions, target contours, dose constraints, treatment plan optimization and evaluation methods, patient-specific QA, and image-guided radiation therapy (IGRT) methods. ResultsWe received responses from 25 centers (83% participation). Only 8 respondent proton centers (32%) reported performing SBRT of the prostate. The remaining 17 centers cited 3 primary reasons for not offering this treatment: no clinical need, lack of volumetric imaging, and/or lack of clinical evidence. Only 1 center cited the reduction in overall reimbursement as a concern for not offering prostate SBRT. Several common practices among the 8 centers offering SBRT for the prostate were noted, such as using Hydrogel spacers, fiducial markers, and magnetic resonance imaging (MRI) for target delineation. Most proton centers (87.5%) utilized pencil beam scanning (PBS) delivery and completed Imaging and Radiation Oncology Core (IROC) phantom credentialing. Treatment planning typically used parallel opposed lateral beams, and consistent parameters for setup and range uncertainties were used for plan optimization and robustness evaluation. Measurements-based patient-specific QA, beam delivery every other day, fiducial contours for IGRT, and total doses of 35 to 40 GyRBE were consistent across all centers. However, there was no consensus on the risk levels for patient selection. ConclusionProstate SBRT is used in about 1/3 of proton centers in the US. There was a significant consistency in practices among proton centers treating with proton SBRT. It is possible that the adoption of proton SBRT may become more common if proton SBRT is more commonly offered in clinical trials.

Increasing diversity in clinical trials: demographic trends at the National Cancer Institute, 2005-2020.

We described participant demographics for National Cancer Institute (NCI) clinical trials at the clinical center (NCI-CC participants) of the National Institutes of Health to identify enrollment disparities. We analyzed NCI-CC data from 2005 to 2020, calculated enrollment fractions, compared with the US cancer population represented by the Surveillance, Epidemiology, and End Results cancer incidence data (2018) and the Cancer in North America database (2018), and compared further with clinical trial disparities data from the NCI Community Oncology Research Program and National Clinical Trials Network (2005-2019), and from ClinicalTrials.gov (2003-2016). NCI-CC (38 531 participants) had higher enrollment fractions for older adults (8.5%), male (5.6%), non-Hispanic (5.1%), and Black or African American (5.3%) participants; lower women proportion across race and ethnicity; and fewer female sex-specific cancer (6.8%) than male sex-specific cancer (11.7%) participants. NCI-CC had lower median age than Surveillance, Epidemiology, and End Results (54.0 vs 65.4); more Black or African American participants (12.0% vs 11.1%); and fewer women (41.7% vs 49.5%), White (76.1% vs 80.5%), Asian or Pacific Islander (4.6% vs 6.0%), American Indian or Alaska Native (0.3% vs 0.5%), and Hispanic participants (7.1% vs 13%). NCI-CC had more Black or African American and Asian or Pacific Islander participants; fewer Hispanic participants than the NCI Community Oncology Research Program and National Clinical Trials Network; more Black or African American and Hispanic participants; fewer Asian or Pacific Islander participants than ClinicalTrials.gov data. Improvement was noted for NCI-CC (older adults, Black or African American, Asian or Pacific Islander, Hispanic participants). We found lower representation of older adults, women, Asian or Pacific Islander, American Indian or Alaska Native, and Hispanic participants vs the US cancer population and higher representation of Black or African American vs US cancer population and oncology clinical trials. Multifaceted efforts are underway to reduce disparities in cancer clinical trials at the NCI-CC.

Alliance A022101: A pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer—Evaluating radiation, ablation, and surgery (ERASur).

TPS236 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free survival and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with ≤4 sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least one lesion. Patients receive first-line systemic therapy for 4-6 months and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver and lungs in at least one site. Patients in Arm 1 will receive TAT which consists of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG). Clinical trial information: NCT05673148 .

Abstract B040: NCI 10129: A Phase 2 Study of the PARP inhibitor Olaparib (AZD2281) in IDH1 and IDH2 mutant advanced solid tumors

Abstract Introduction: Cholangiocarcinoma (CCA) is a highly aggressive malignancy with mutations in Isocitrate dehydrogenase (IDH) identified in approximately 15% of patients. Neomorphic mutations in IDH 1/2 result in accumulation of the oncometabolite 2-hydroxyglutarate (2G), which has been implicated in tumor progression via inhibitory effects on alpha ketoglutarate. Moreover, the mutant IDH dependent accumulation of 2HG results in homologous recombination deficiency (HRD) and renders these cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. NCI 10129 evaluated the efficacy of olaparib for IDH mutated solid tumors, and here we present the CCA cohort. Methods: NCI 10129 is a 3 arm, open label phase 2 clinical trial performed in the NCI National Clinical Trials Network evaluating olaparib 300 mg twice daily for IDH mutated solid tumors refractory to standard treatment. Patients with CCA were enrolled in 2 cohorts 1) IDHi pre-treated CCA and 2) IDHi untreated CCA. The primary endpoint was overall response rate (ORR) and secondary endpoints includes progression-free survival (PFS), and overall survival (OS). An exploratory analysis measured the impact of circulating 2HG levels, circulating tumor DNA, and tumor genomics on patient outcomes. Results: Thirty patients with CCA enrolled on NCI10129 (15 each IDHi pre-treated and IDHi treatment naïve), 18 patients received ≥ 2 prior systemic treatments, and 23 patients had IDH1 mutations and 7 patients IDH2 mutations. There were no objective responses seen in the first 15 CCA patients in either cohort and enrollment was closed. The median PFS was 2.4 months 95% CI (1.9 - 6.5) and median OS 12.9 months 95% CI (6.3 – not reached). The IDHi pre-treated cohort had improved median OS compared to IDHi treatment naïve (15.3 vs 7.3, P = 0.04). There were 8/30 (27%) patients with clinical benefit (CB) as defined by PFS > 6 months. Patients with CB had lower baseline mean D-2HG levels compared to those without CB (1.4 umol/L vs 5.9 umol/L, p = 0.02). Whole exome sequencing revealed the study population to be enriched for HRD by sum scores and HRD mutational signatures without alternative HRD mutations other than IDH1/2. No improvement in survival was noted based on HRD status. RNA sequencing Gene Set Enrichment Analysis revealed that cell cycle and interferon alpha pathways were activated in patients with CB (p < 0.01). Olaparib was tolerable with the majority of adverse events grade 1-2. Conclusion: Olaparib did not result in objective responses in IDH mutated CCA. However, a subgroup of patients did demonstrate prolonged PFS comparable to historical controls for refractory CCA as well that seen with targeted agents such as IDHi. Exploratory analysis revealed this subgroup to be enriched for lower baseline 2HG levels. Serial ctDNA analysis is ongoing and will be presented. Given the CB subgroup and OS data, additional clinical trials leveraging the HRD properties of IDH mutations is warranted. Future studies may benefit from DNA damage combination therapies thereby enhancing potency. Citation Format: Michael Cecchini, Mary Jo Pilat, Nataliya Uboha, Nilofer S Azad, May Cho, Elizabeth J Davis, Jordi Rodon Ahnert, Gabriel Tinoco, Geoff I Shapiro, Simon Khagi, Benjamin Powers, Roman Groisberg, Jan Drappatz, Li Chen, Biswajit Das, Xun Bao, Jing Li, Abhijit Patel, Monica Niger, Deborah Doroshow, Diane Durecki, Scott Boerner, Ranjit Bindra, Percy Ivy, Yu Shyr, Patricia LoRusso. NCI 10129: A Phase 2 Study of the PARP inhibitor Olaparib (AZD2281) in IDH1 and IDH2 mutant advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B040.

Rapid Clinical Mutation Screening for AML Using the Genexus Platform

Introduction: The promise of “precision medicine” is using therapeutic agents matched to the inferred biology of a patient's particular disease. In acute myeloid leukemia this approach demands fast and accurate assessment of the mutation and cytogenetic landscape of each AML case. The NCI Myeloid Malignancies Molecular Analysis for Therapy Choice program (“myeloMATCH”) is a precision medicine clinical trial initiative across the NCI National Clinical Trials Network for patients with newly diagnosed acute myeloid leukemia and myelodysplasia. In myeloMATCH the goal is to have cytogenetic and mutation assays performed within 72 hours of central lab receipt, allowing for a rapid assignment of the appropriate clinical trial from the myeloMATCH trial portfolio. Here we report analytic performance of rapid genomic profiling laboratory developed test based on the Thermo Fisher Genexus Oncomine Myeloid Panel GXv2 (NCI Myeloid Assay version 2, or “NMAv2”) which performs rapid sequencing of SNVs, indels, and gene fusions, capturing 1,661 hotspot variants (45 genes) and 779 fusions (35 genes) with a turnaround time of <48 hours from specimen receipt to clinical reporting. Methods: The validation testing was performed by two harmonized laboratories; NCI Molecular Characterization laboratory (MoCha) and Fred Hutch Molecular Oncology (MO). We conducted analytical validation and harmonization experiments for CLIA/CAP and FDA regulatory compliant use in this trial across both accredited clinical laboratories with harmonized workflows. Samples are extracted with AllPrep per manufacture protocol. Library preparation with the Oncomine Myeloid Assay GX v2 and the sequencing reactions are performed on the automated Ion Torrent Genexus System. Sequencing data generated by NMAv2 was analyzed using Ion Torrent Genexus system version 6.6.2.1. The default manufacturer workflow has been customized using a custom designed hotspot browser extensible data (BED) file, sequence variant baseline (SVB) file, fusion target file, torrent variant caller (TVC) version 5.18 and Oncomine extended filter chain (OEFC) version 5.16. In NMA, the default 2.5%, and 3% VAFs were set up for calling hotspot and non-hotspots SNV/indel, 1% VAF for FLT3-ITD and 100 read counts for all fusion, except 2000 read counts for KMT2A-PTD. Results: The validation set included 148 unique samples and comprised of 76 AML/MDS patients (49 peripheral blood, 27 bone marrow aspirate), 51 healthy donor blood, 6 healthy donor bone marrow, 7 cancer cell lines, 5 normal HapMap cell lines, and 3 contrived materials encompassing 364 known mutations (143 SNPs, 132 indels, 27 fusions). 180 runs were completed for this validation (106 at FH and 74 at MoCha) with 89.44% success rate in passing run level metrics. Results of the validation testing are detailed in Table 1. High reproducibility in detecting all reportable variants was observed, with overall >99% mean positive percentage agreement (PPA) across both labs (Figure 1). The limit of detection for each variant type was <0.06% for hotspot SNVs, 0.07% for non-hotspot SNVs, 0.51% for hotspot indels, ~1% for non-hotspot indels, 0.23% for FLT3-ITDs, and 50 minimum reads at 0.1% tumor content for fusions. 99.39% concordance was observed by testing 86 blinded validation sample set with analytically validated orthogonal assays. Conclusions: The NMAv2 has high specificity, sensitivity, accuracy and reproducibility (inter-lab and intra-lab) with sequencing results generated within 48 hours of assay initiation. As such, the assay is well suited for use to rapidly categorize the genomic alteration of AML to support clinical care in patients with active myeloid malignancies, including those patients potentially enrolled in the myeloMATCH program. Table 1: Results of validation experiment results for the NMAv2 Figure 1: Harmonization results for the NMAv2 between MoCha and MO labs, Right Panel = Indel; Left panel = SNV

Assessment of Outcomes of Consolidation Therapy By Number of Cycles of Blinatumomab Received in Newly Diagnosed Measurable Residual Disease Negative Patients with B-Lineage Acute Lymphoblastic Leukemia: In the ECOG-ACRIN E1910 Randomized Phase III National Clinical Trials Network Trial

Introduction: ECOG ACRIN E1910 is a randomized phase III trial that showed that adults with newly diagnosed BCR::ABL1 negative acute lymphoblastic leukemia (ALL) who become MRD negative (<0.01%) after induction chemo who receive blinatumomab with conventional chemotherapy (chemo) have improved survival compared with those who received chemo only (Litzow et al, Blood (2022) 140: Supplement 2, LBA-1). However, not all pts were able to receive all four planned cycles of blinatumomab in consolidation. In this report we assessed outcomes of pts in the blinatumomab arm of the trial who received all 4 cycles of blinatumomab compared to those who received 1-2 cycles. Methods: Patient between the ages of 30 and 70 with newly diagnosed BCR::ABL1 negative B-lineage ALL were enrolled and initially received 2.5 months of combination induction chemo utilizing a BFM-like regimen adapted from the E2993/UKALLXII clinical trial, with pegaspargase (after induction only for patients >=55 years of age) and addition of rituximab for CD20 positive patients. After remission induction (step 1) pts in morphologic complete remission (CR/CRi) received an intensification course of high dose methotrexate with pegaspargase for CNS prophylaxis (step 2). At the conclusion of step 2, remission and MRD status were determined centrally by 6-color flow cytometry with MRD negativity defined as <0.01%. In the primary analysis subset, MRD negative patients were randomized to receive an additional 4cycles of consolidation chemo or 2 cycles of blinatumomab at 28 mcg/day (flat dose) for 28 days each cycle followed by 3 cycles of consolidation chemo, another 4-week cycle of blinatumomab (3rd cycle of blinatumomab) followed by an additional cycle of chemo and then a 4th cycle of blinatumomab (step 3). Following completion of consolidation chemo +/- blinatumomab, pts were given 2.5 years of POMP maintenance therapy timed from the start of the intensification cycle (step 4). Estimates of OS were calculated using the Kaplan-Meier method. Comparison of OS between treatment arms were conducted using the stratified log-rank test and Cox proportional-hazards model with age, CD20 status, rituximab use, and whether pts intend to receive HSCT or not as stratification factors. As the number of cycles needed to optimize outcome has not been studied, an unplanned landmark analysis was used to compare OS of pts in the blinatumomab arm who received all 4 cycles o those who received 1-2 cycles. Time 0 was chosen as 9 months post step 3 randomization (the time that patients were supposed to complete 4 cycles of blina). Four pts who received blinatumomab but died within 9 months post step 3 randomization were therefore excluded from this analysis. Results: The study was activated on December 17, 2013 and closed to enrollment on October 15, 2019. 772 pts were screened for the trial and 488 were enrolled on step 1 induction therapy. The median age of the pts was 51 years (range 30-70). 224 MRD negative pts were randomized, 112 pts to each arm. In the blinatumomab arm 12 pts received 1 cycle (11%), 32 pts received 2 cycles (29%), 4 pts received 3 cycles (4%) and 63 pts received 4 cycles (57%). The OS of pts who received 1-2 cycles of blinatumomab was compared to control (Figure 1) The difference was not significant (hazard ratio 0.62, 95% CI 0.28 to 1.34, p=0.22). Fig 2 compares the survival of those who received 1-2 cycles to those who received 4 cycles ( (HR: 0.39, 95% CI 0.12 to 1.16, p=0.076). Conclusion: The addition of blinatumomab to consolidation chemotherapy resulted in a significantly better overall survival compared to chemotherapy alone in pts with newly diagnosed B-lineage ALL who were MRD negative after intensification. This represents a new standard of care for pts aged 30-70 years with BCR::ABL1 negative ALL. The optimal dose and number of cycles is however unknown. In this unplanned subgroup analysis we demonstrate that a survival benefit can only be confirmed in patients who receive the intended 4 cycles of blinatumomab during consolidation. Further studies will be needed to determine if fewer cycles can provide a similar benefit.

DISP-15. DISPARITIES IN THE AVAILABILITY OF NEURO-ONCOLOGY CLINICAL TRIAL SUPPORTING INFRASTRUCTURE IN THE UNITED STATES

Abstract BACKGROUND Barriers to clinical trial access have significant implications for patient care and disproportionally impact rural and socioeconomically disadvantaged populations. Expanding on reported disparities in neuro-oncology trial availability, we assessed whether existing networks of clinical providers and collaboratives, including NCI’s National Clinical Trials Network (NCTN) and Community Oncology Research Program (NCORP), can effectively bridge these disparities. METHODS Locations of adult neuro-oncology trial sites, UCNS-certified neuro-oncologists, NCTN Main Members, NCORP Community Affiliates, and general oncologists reporting to Centers for Medicare/Medicaid Services were obtained, mapped to zip code tabulation areas (ZCTAs), and annotated with US Census population and geography data and the Neighborhood Atlas Area Deprivation Index (ADI). Regression and spatial analyses were conducted assessing the role of geography, socioeconomic disadvantage, and population on infrastructure accessibility. RESULTS We identified 1976 neuro-oncology trials, 586 NCTN institutions, 962 NCORP sites, 306 neuro-oncologists, and 863 general oncologists located in just 8% of all ZCTAs, inhabited by 19% of the US population. All trial-supporting infrastructure components were more likely to exist in more populated, geographically neighboring regions (OR >1, p< 0.00001). Trial sites, NCTN institutions, and neuro-oncologists served ZCTAs with less disadvantage (OR=0.99, p=0.03958; OR=0.99, p< 0.00001; OR=0.98, p< 0.00001), while NCORP served more disadvantaged areas (OR=1.01, p=0.00102) and general oncologists were distributed similarly across ADI (OR=1.00, p=0.94317). Investigating potentially underutilized infrastructure, 2 neuro-oncologists, 8 NCTN institutions, 10 NCORP sites, and 107 general oncologists were located more than 25 miles from utilized trial sites. CONCLUSION The identified disparities in neuro-oncologists and trial-supporting institutions reflect disparities in trial-site access and point to broader disparities in neuro-oncology care access. NCORP sites reach more socioeconomically disadvantaged populations, but the overall sparsity of trial-supporting networks indicates that the existing infrastructure cannot effectively bridge trial-access barriers and novel approaches including telehealth and decentralized trial designs may be necessary to promote equity.

Progression-Free Survival (PFS) and Toxicity with Nivolumab-AVD Compared to Brentuximab Vedotin-AVD in Pediatric Advanced Stage (AS) Classic Hodgkin Lymphoma (cHL), Results of SWOG S1826

Background: Approaches to therapy in pediatric and adult cHL have differed historically. Brentuximab vedotin (BV) is efficacious in pediatric patients (pts) with high-risk cHL when combined with chemotherapy and response based involved site radiation therapy (RT) ( Castellino. NEJM 2022). Inhibition of the PD-1 pathway, central to the pathogenesis of cHL, is safe and effective in children with relapsed HL but has not been evaluated in the frontline setting. Led by SWOG, the National Clinical Trials Network (NCTN) conducted the randomized, phase 3 trial S1826 to evaluate nivolumab (N)-AVD vs BV-AVD in pts ages ≥12 years (y) with newly diagnosed Stage 3-4 cHL. Methods: Eligible pts were randomized 1:1 to either 6 cycles of N-AVD or BV-AVD. At randomization enrollment was stratified by age, International Prognostic Score (IPS), and intent to use RT. Treating site of pts 12-17y, the subject of this subgroup analysis, declared intent to use RT for residual metabolically active lesions on the end of treatment PET per protocol. Recipients of BV-AVD were required to receive G-CSF prophylaxis vs optional with N-AVD. Dexrazoxane was permitted, but not mandated. Response and disease progression was assessed by investigators using the 2014 Lugano Classification. The primary endpoint was PFS; secondary endpoints included overall survival (OS), event-free survival (EFS), and safety. Results: Of 976 eligible pts enrolled (from 7/9/2019 to 10/5/2022): 24.3% (n=237) were 12-17 y and randomized to N-AVD (n=120) or BV-AVD (n=117). Median age was 15.6 y (range, 12-17.9 y), 50% of pts were male, 69% were white, 15% were black, and 18% were Hispanic. 27% had an IPS score 4-7. At the 2nd interim analysis (50% of total PFS events) the SWOG Data and Safety Monitoring Committee recommended reporting the primary results as the primary PFS endpoint crossed the protocol-specified conservative statistical boundary for the full trial. In the pediatric cohort, 6 PFS events were observed after N-AVD compared to 12 events after BV-AVD. At a median follow-up of 12.1 months, the PFS was compared between arms [HR 0.48, 95% CI 0.18-1.28, stratified one-sided logrank p=0.067) in the pediatric cohort; 1 y PFS: N-AVD, 94%, BV-AVD, 88% (Fig.1). There have been no deaths in this age group. Overall use of RT was 0.8% (2/237) and 79% of pediatric pts received dexrazoxane. The rate of grade (gr) ≥ 3 hematologic adverse events (AE) was 45% after N-AVD compared to 41% after BV-AVD, with 3% gr ≥ 3 febrile neutropenia and 1% with sepsis after either regimen, despite differences in GCSF use (59.2% N, 93.2% BV). Overall rates of immune related AEs (irAEs) (any gr) were low: pneumonitis (3.0% N vs 1% BV), and colitis (0% N vs 1% BV). Rash (any gr) was more common in BV-AVD (2% N vs 14% BV). Hypo/hyperthyroidism (any gr) was higher after N-AVD (2% N vs 0% BV). Rates of transaminitis were similar (ALT elevation: 42% N vs 54% BV). While sensory peripheral neuropathy was more frequent after BV-AVD (sensory: 18% N vs 29% BV; motor: 8% N vs 5% BV), only 1% was > grade 3. Discontinuation of N vs BV therapy occurred in 8.3% vs 2.6% of pediatric pts respectively, compared to 7.9% vs 21.1% of adults. Conclusions: In early follow-up, N-AVD and BV-AVD are well tolerated and associated with low rates of irAEs in pts ages 12-17 y. With 12.1 mos median follow-up the PFS benefit observed for N-AVD in pediatric pts mirrors that observed in the overall study. RT usage is lower, and cumulative doxorubicin dose is higher than historical pediatric cHL trials. The difference in rate of discontinuation between study arms and by age group needs further evaluation. Longer follow-up is needed to better define the roles of N-AVD and Bv-AVD for AS cHL. S1826 is a model NCTN trial, providing earlier access to novel agents and harmonization of treatment for adolescents and young adults with AS cHL. Funding: NIH/NCI/NCTN grants U10CA180888 and U10CA180819, U10CA180820, U10CA180821, U10CA180863, U10 CA180886; and Bristol-Myers Squibb. Bv provided by Seagen (Canada Only). Clinical Trial NCT03907488.

Nivolumab-AVD Is Better Tolerated and Improves Progression-Free Survival Compared to Bv-AVD in Older Patients (Aged ≥60 Years) with Advanced Stage Hodgkin Lymphoma Enrolled on SWOG S1826

Background: Survival rates in patients (pts) with classic Hodgkin lymphoma (HL) aged ≥60 years (y) are lower than younger pts. The difference is due to comorbidities, impaired performance status, decreased chemotherapy tolerance, and increased treatment-related toxicity and mortality. The frontline regimen Bv-AVD can be challenging to administer in older patients due to toxicities, particularly infection and neuropathy. The PD-1 pathway is central to pathogenesis of HL; PD-1 blockade is effective in HL. The randomized, phase 3 trial, S1826, was conducted by the National Clinical Trials Network to evaluate N-AVD vs Bv-AVD in pts with newly diagnosed advanced stage (AS) HL and enrolled 994 pts; 97 were eligible and aged ≥60y. Methods: In this subset analysis, eligible pts were ≥60y with stage 3-4 HL. Pts were randomized 1:1 to 6 cycles of N-AVD or Bv-AVD. G-CSF neutropenia prophylaxis was optional with N-AVD and required with Bv-AVD. Pre-specified pts could receive radiation therapy (RT) to residual lesions on end of treatment PET. Pts were stratified by age, international prognostic score (IPS), and intent to use RT. Response and progression were assessed by investigators using 2014 Lugano Classification. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), event-free survival (EFS), and detailed toxicity and safety events. EFS events were death without progression, progression/relapse, receipt of non-protocol systemic anti-lymphoma therapy without progression, or receipt of RT in a pt not declared eligible for RT at registration or who did not meet protocol-specified criteria for RT. Results: 97 pts aged ≥60y were enrolled from 7/9/19-10/5/22 and were randomized to N-AVD (n=48) or Bv-AVD (n=49). Median age was 66y (range, 60-83y), 62% were male, 86% were white, 3% were black, and 10% were Hispanic. 61% had stage IV disease and 47% had IPS 4-7. 69% of pts on N-AVD and 92% of pts on Bv-AVD received any G-CSF. No pts received RT per protocol. 95 pts were evaluable for safety analysis. While grade (gr) ≥3 hematologic toxicity occurred in 52% of pts on N-AVD and 38% on Bv-AVD (gr 3 neutropenia 48% vs 30%), febrile neutropenia, sepsis, and infections were lower for pts who received N-AVD vs Bv-AVD. (Table) Peripheral neuropathy was much less frequent with N-AVD than Bv-AVD in overall incidence (sensory: 31% vs 66% and motor: 8% vs 15%, respectively) and severity (grades ≥2, sensory: 10% vs 49% and motor: 0% vs 8%, respectively). (Table) The following adverse events, AEs (mainly <gr 3) were less frequent on N-AVD vs Bv-AVD: nausea (38% vs 62%), diarrhea (25% vs 45%), anorexia (15% vs 38%) and weight loss (4% vs 36%). Hypothyroidism (15% vs 0%), and rash (16% vs 2%, no gr ≥3) were more frequent on N-AVD than Bv-AVD; rates of other immune-related toxicities were similar between arms. In this subset analysis, median follow-up 12.1 months, PFS was superior in the N-AVD arm [HR 0.35 (95% CI 0.12-1.02) stratified one-sided logrank p=0.022]; 1-yr PFS was 93% (95% CI 79-98%) for N-AVD and 64% (95% CI 45-77%) for Bv-AVD. (Figure) 1-yr EFS was 93% (95% CI 79-98%) for N-AVD and 57% for Bv-AVD (95% CI 38-72%) [HR 0.19 (95% CI 0.06-0.61) stratified one-sided logrank p=0.0011]. 1-yr OS was 95% (95% CI 83-99%) for N-AVD and 83% (95% CI 67-92%) for Bv-AVD [HR 0.35 (95% CI 0.07-1.75) stratified one-sided logrank p=0.091]. On N-AVD, there were 2 deaths (due to infection/sepsis) and 3 progressions/relapses; on Bv-AVD, there were 7 deaths (5 due to infection/sepsis, 1 to pneumonitis, 1 unknown) and 8 progressions/relapses. Non-relapse mortality was 4% for N-AVD vs 14% for Bv-AVD. Treatment was discontinued early in 5 pts (10%) on N-AVD and 16 pts (33%) on Bv-AVD. N was discontinued early in 7 pts (15%) and Bv in 19 pts (39%). Reasons for discontinuation included (N vs Bv): AE (5 vs 14 pts), death (1 vs 3 pts), and disease progression (0 vs 1 pt). Conclusions: N-AVD improved PFS and EFS, and was better tolerated than Bv-AVD in pts aged ≥60 with AS HL. Substantially more pts discontinued Bv-AVD than N-AVD, primarily due to toxicity. Fewer deaths occurred on N-AVD than Bv-AVD. N-AVD is poised to become a standard of care for older AS HL pts fit for anthracycline-based combination therapy. Funding provided by the National Cancer Institute of the National Institutes of Health CA180888, CA180819, CA180821, CA180820, CA180863, CA189955 and funding/drug provided by BMS, drug provided by SeaGen for pts enrolled in Canada.

Alliance A022101: A Pragmatic Randomized Phase III Trial Evaluating Total Ablative Therapy for Patients with Limited Metastatic Colorectal Cancer – Evaluating Radiation, Ablation and Surgery (ERASur)

For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free survival and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Further, despite the long history of treating oligometastatic CRC with local therapy, which is provider biased and not evidence based, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. A022101 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) with 4 or fewer sites of metastatic disease on baseline imaging. Liver-only metastatic disease is not permitted, and lesions must be amenable to any combination of surgical resection, MWA, and/or SBRT with SBRT required for at least one lesion. Patients receive first-line systemic therapy for 4-6 months and are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver and lungs in at least one site. Patients in Arm 1 will receive TAT which consists of treatment of all metastatic sites with SBRT ± MWA ± surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023. Recruitment is ongoing.

Defining Priorities in Value-Based Cancer Care: Insights From the Alliance for Clinical Trials in Oncology National Cooperative Group Survey.

We determine how stakeholders prioritize the importance of oncologic outcomes, patient-reported outcomes (PROs), and cancer-related health care costs. A survey was distributed to the National Clinical Trials Network Alliance for Clinical Trials in Oncology cooperative group membership from May 14 to June 30, 2022. Respondents were asked to rate (5-point Likert scale) and rank (1-9) evidence-based value domains: overall survival, treatment toxicities/complications, quality of life (QOL), financial toxicity, access to care, compliance with evidence-based care, health system performance, scientific discovery and innovation, and cost to the health care system. A total of 514 members responded, including researchers (24.7%), nurses (19.5%), medical oncologists (17.9%), administrators (9.3%), surgical and radiation oncologists (9.1%), patient advocates (3.1%), and nonphysician providers (16.4%). Participants represented various practice settings including National Cancer Institute-designated cancer centers (29.8%), university-affiliated academic cancer centers (21%), hospital-owned oncology practices (21.8%), and others (27.4%). There was agreement in how respondents prioritized value domains (W = 0.39, P < .001). Respondents ranked patient QOL (mean rank: 2.6 ± 1.9) as most important above all other metrics including survival (mean rank: 3.5 ± 0.3) and access to care (mean rank: 3.5 ± 2.1; P < .001). Members engaged in direct patient care also ranked access to care of higher importance than nonclinicians (P = .026). Cost to the health care system (mean rank: 7.5 ± 2.1) and health system performance (mean rank: 7 ± 2) were ranked as least important (P < .001). Inclusion of PROs into therapeutic assessment (59.3%) was the most frequently selected priority of future cooperative group initiatives. Oncology community stakeholders deemed patient-centered value domains as most important and considered patient QOL the highest priority. Inclusion of PROs into clinical trials was endorsed as an important component of therapeutic assessment. These findings can be taken into consideration when creating a value framework for inclusion in cancer clinical trials.

Adjuvant everolimus after surgery for renal cell carcinoma (EVEREST): a double-blind, placebo-controlled, randomised, phase 3 trial

Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.

Children's Oncology Group's 2023 blueprint for research: Hodgkin lymphoma.

The goal of therapy in pediatric Hodgkin lymphoma (HL) is to maximize overall survival while minimizing the morbidity of curative therapy. Key findings from recent Children's Oncology Group (COG) trials include: (i) superior event-free survival with the addition of brentuximab vedotin (Bv) in frontline regimens for high-risk disease, (ii) successful reduction in myeloablative regimens with demonstrated safety and efficacy of Bv and checkpoint inhibitor therapy in relapsed disease, and (ii) the potential to select a population that can be salvaged after relapse without receiving a stem cell transplant. The COG HL committee will lead a National cancer Institute National Clinical Trials Network phase 3 trial to evaluate the combination of Bv/nivolumab in early-stage disease. Ongoing advances in technology and blood biomarkers are increasing the ability to deliver biologically driven, personalized treatment for HL.

Children's Oncology Group 2023 blueprint for research: Adolescent and young adult oncology.

Over the past few decades, 5-year cancer survival has steadily improved for all adolescents and young adults (AYA, 15-39years at diagnosis) combined. While encouraging, this progress simultaneously highlights a compelling need for improving survival in higher risk AYA subsets and for addressing health outcomes and health-related quality of life (HRQoL) among long-term survivors. The Children's Oncology Group (COG), in collaboration with the National Cancer Institute (NCI) and the adult network groups within the NCI National Clinical Trials Network (NCTN), has developed a large and growing portfolio of therapeutic AYA cancer clinical trials to identify optimal treatment approaches for common AYA cancers. Additional initiatives, led by the COG AYA Oncology Discipline Committee for increasing collaboration between the COG and the adult network groups, optimizing AYA clinical trial enrollment, and standardizing the assessment of HRQoL, have been highly successful to date. Further, NCTN-wide collaborations are currently underway focused on improving survival for AYA malignancies with poor prognosis and, through development of supportive care and care delivery trials, reducing the short- and long-term toxicity caused by cancer treatment. Leveraging the research infrastructure within the NCTN and the NCI Community Oncology Research Program, the COG will continue to champion meaningful advancements in health and survival for AYAs with cancer.

President Biden Chooses Monica M. Bertagnolli, MD, to Lead the NIH

President Biden Chooses Monica M. Bertagnolli, MD, to Lead the NIH