Importance:CD19-directed chimeric antigen receptor (CAR) T-cell therapy induces high remission rates in relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), but relapse, which is often due to antigen loss, remains a major challenge. Dual-targeting CD19/CD22 CAR T-cell strategies may be associated with reduced antigen-negative relapse and improved remission durability. Objective:To evaluate the safety and efficacy of bicistronic CD19/CD22 CAR T-cell therapy in pediatric patients with relapsed or refractory B-ALL. Design, Setting, and Participants:This open-label, multicenter, phase 2 nonrandomized clinical trial enrolled pediatric patients with B-ALL at 5 major medical centers in China from January 2022 to August 2024, with a data cutoff of February 28, 2026. Median follow-up was 35.7 months (IQR, 29.8-41.0 months). Of 346 screened, 38 (11.0%) were excluded and 308 (89.0%) were eligible. A safety run-in established the recommended phase 2 dose, followed by cohorts with refractory disease, hematologic relapse, or isolated extramedullary relapse. Intervention:CD3-positive T cells were activated and transduced with a bicistronic lentiviral vector that encoded anti-CD19 and anti-CD22 CARs, then infused fresh after 5 to 7 days in culture. Lymphodepleting chemotherapy included fludarabine and cyclophosphamide. Consolidative transplant was reserved for patients with KMT2A- or ZNF384-rearranged acute lymphoblastic leukemia. Main Outcomes and Measures:Primary end points were safety, recommended phase 2 dose, event-free survival (EFS), and toxic effects of bicistronic CAR-T therapy in relapsed or refractory B-ALL, with or without transplant. Results:Among 261 patients (98 girls [37.6%]; mean [SD] age, 8.2 [3.8] years) with relapsed or refractory disease, 259 (99.2%) achieved complete remission with negative minimal residual disease. EFS was 70.9% (95% CI, 65.6%-76.7%) at 12 months, 63.2% (95% CI, 57.6%-69.4%) at 24 months, and 61.7% (95% CI, 55.9%-68.0%) at 36 months. Consolidative transplant was associated with improved EFS; the 24-month EFS was 57.9% (95% CI, 51.6%-65.0%) in patients without a transplant vs 85.7% (95% CI, 76.5%-96.1%) in patients with a transplant (P = .004). In 20 patients with isolated central nervous system relapse and 20 with testicular relapse, 24-month EFS was 60.0% (95% CI, 43.6%-82.6%) and 80.0% (95% CI, 64.3%-99.6%), respectively. Grade 3 to 4 cytokine release syndrome occurred in 129 patients (49.4%), and immune effector cell-associated neurotoxic effects occurred in 34 patients (13.0%). Conclusions and Relevance:In this nonrandomized clinical trial, bicistronic CD19/CD22 CAR T-cell therapy induced high rates of minimal residual disease-negative remission, with durable EFS in pediatric B-ALL. These findings support further evaluation in prospective trials. Trial Registration:Chinese Clinical Trial Register Identifier: ChiCTR2000032211.
IMPORTANCE:The combination of neoadjuvant taxanes with trastuzumab and pertuzumab remains the cornerstone treatment strategy in ERBB2-positive breast cancer. Anbenitamab (a ERBB2-biparatopic antibody that induces profound receptor clustering) and HB1801 (a solvent-free albumin-bound docetaxel), have shown promising antitumor activity and an acceptable safety profile in patients with breast cancer. OBJECTIVE:To evaluate whether neoadjuvant anbenitamab combined with HB1801 could improve efficacy without increasing toxic effects for patients with early ERBB2-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS:This multicenter, phase 3 registrational randomized clinical trial enrolled patients with stage II or III ERBB2-positive breast cancer from 61 hospitals in China between December 19, 2024, and August 29, 2025 (data cutoff: January 28, 2026). Data were analyzed from February 1 to March 20, 2026. INTERVENTIONS:Patients were randomly assigned (1:1) to receive 6 cycles of neoadjuvant anbenitamab plus HB1801, with or without carboplatin (investigational group), or trastuzumab, pertuzumab, and docetaxel, with or without carboplatin (control group). MAIN OUTCOMES AND MEASURES:The primary end point was total pathological complete response (tpCR) assessed by a blinded independent review committee. RESULTS:Among 521 included patients (median [IQR] age, 52.0 [23-79] years), 263 were randomized to the investigational group and 258 to the control group. The tpCR rate was significantly higher in the investigational group than the control group (164 patients [62.4%] vs 132 patients [51.2%]; absolute difference, 11.4 [95% CI, 3.2 to 19.6] percentage points; P = .004). Benefit was consistent across subgroups, including subgroups with hormone receptor-positive disease (77 patients [51.7%] vs 63 patients [44.4%]), hormone receptor-negative disease (87 patients [76.3%] vs 69 patients [59.5%]), early-stage disease (111 patients [63.8%] vs 87 patients [51.8%]), locally advanced disease (53 patients [59.6%] vs 45 patients [50.0%]), with carboplatin treatment (74 patients [66.7%] vs 61 patients [54.5%]), and without carboplatin treatment (90 patients [59.2%] vs 71 patients [48.6%]). Grade 3 or 4 treatment-related adverse events occurred in 77 patients (29.3%) in the investigational group and 73 patients (28.3%) of the control group. No treatment-related deaths occurred. CONCLUSIONS AND RELEVANCE:This randomized clinical trial found that neoadjuvant anbenitamab and HB1801 in patients with breast cancer significantly improved the tpCR rate compared with standard therapy with a highly manageable safety profile. This new combination may offer an improved treatment option, although long-term survival follow-up analyses are warranted. Trial Registration:ClinicalTrials.gov Identifier: NCT06747338.
Importance:Industry and federal sponsors support much of the US cancer clinical trial enterprise. Industry-sponsored trials have traditionally focused on therapeutic development and regulatory approval, whereas federally sponsored trials have been viewed as addressing broader clinical and public health research questions. However, differences between these trial portfolios have not been systematically quantified. Objective:To characterize differences between federally sponsored and industry-sponsored cancer clinical trials in the US. Design and Setting:A comparative study of interventional cancer clinical trial portfolios registered on ClinicalTrials.gov and initiated between 2008 and 2024. US-based interventional cancer trials, including treatment and nontreatment interventions, were included. Exposure:Lead sponsor classified as federal or industry. Main Outcomes and Measures:Trial characteristics, including study purpose, phase, intervention type, deescalation design, rare cancer focus, and patient age category (adult vs children). Differences in trial characteristics by sponsor type were assessed using χ2 tests and described using odds ratios (ORs) with 95% CIs. Results:Overall, 11 681 federally sponsored trials (n = 2112 [18.1%]) and industry-sponsored trials (n = 9569 [81.9%]) were analyzed. Compared with industry-sponsored trials, federally sponsored trials were less likely to be single-agent drug trials conducted for the purpose of cancer treatment (48.6% vs 77.4%; OR, 0.28; 95% CI, 0.25-0.31; P < .001). In contrast, federally sponsored trials were more likely to evaluate nontreatment interventional trials, including prevention (4.7% vs 1.1%; OR, 4.43; 95% CI, 3.32-5.92; P < .001) and supportive care (2.5% vs 0.9%; OR, 2.92; 95% CI, 2.02-4.20; P < .001). Among trials conducted for the purpose of cancer treatment, federally sponsored studies were more likely to investigate multimodality regimens combining drug and biological agents (19.1% vs 7.4%; OR, 2.98; 95% CI, 2.58-3.44; P < .001) and to combine drug and/or biological agent regimens with radiotherapy (10.5% vs 1.4%; OR, 8.22; 95% CI, 6.51-10.37; P < .001) or surgery (2.5% vs 0.2%; OR, 14.09; 95% CI, 7.95-24.98; P < .001). Federal sponsorship was also associated with greater use of deescalation trial designs (3.1% vs 0.4%; OR, 8.38; 95% CI, 5.43-12.94; P < .001) and trials conducted in rare cancers (17.5% vs 12.1%; OR, 1.54; 95% CI, 1.34-1.77; P < .001) and in children (16.1% vs 5.3%; OR, 3.43; 95% CI, 2.93-4.01; P < .001). Conclusions:In this study, industry-sponsored trials were more likely to evaluate single-agent drug therapies, whereas US federally sponsored trials were more likely to evaluate nontreatment interventions, multimodality treatment strategies, treatment deescalation approaches, and therapies for rare cancers and pediatric populations. These findings provide an empirical characterization of the complementary and essential roles of federal and industry sponsors in the cancer clinical trial enterprise.
Importance:In the past 2 decades, substantial declines in national colorectal cancer (CRC) mortality rates have been observed in the US; however, it is unclear whether these improvements have happened ubiquitously across geography, race and ethnicity, sex, and age group. Objective:To assess variation in CRC mortality rates and changes over time, across county, race and ethnicity, sex, and age group (<45 years and ≥45 years). Design, Setting, and Participants:This US population-based cross-sectional study used validated small-area estimation models to estimate county-level CRC mortality rates by race and ethnicity, sex, and age group from 2000 to 2019. Data analysis was completed in May 2023. Exposures:Estimates were stratified by county, race and ethnicity (American Indian or Alaska Native, Asian or Pacific Islander, Black, Hispanic or Latino, and White), sex (female and male), and age group (<45 years and ≥45 years) as reported on death certificates. Main Outcomes and Measures:The outcome of interest was CRC mortality rates per 100 000 individuals. Estimates were corrected for race and ethnicity misclassification on death certificates and age standardized. Results:Among 3110 counties or combined county units with data from 2000 to 2019 (mean annual population, 306 million), most counties saw declines in CRC mortality among adults aged 45 years or older, from 82.5 (95% uncertainty interval [UI], 81.7 to 83.2) to 54.4 (95% UI, 53.9 to 54.9) deaths per 100 000 population among males and from 58.9 (95% UI, 58.4 to 59.3) to 39.7 (95% UI, 39.4 to 40.0) per 100 000 deaths among females 45 years or older. However, in 2019, considerable county-level variation, including within states, was observed. The largest county-level variation was observed among American Indian or Alaska Native males aged 45 years or older, ranging from 13.6 (95% UI, 8.2-20.8) to 213.5 (95% UI, 147.1-309.0) deaths per 100 000 population. Overall, 275 counties with unmasked estimates had CRC mortality rates of more than 100 deaths per 100 000 among at least 1 population (American Indian or Alaska Native females: 13 counties; American Indian or Alaska Native males: 92 counties; Black males: 182 counties; Hispanic or Latino males: 1 county; White males: 4 counties; all other populations: 0). CRC mortality rates among individuals aged younger than 45 years were stable or increased from 2000 to 2019. Conclusions and Relevance:This cross-sectional study found significant improvements in CRC mortality in adults aged 45 years or older at the national level and across all racial and ethnic populations between 2000 and 2019. However, CRC mortality rates remain extremely high in some counties and populations. These findings can help inform targeted intervention strategies for communities at highest risk.
This Viewpoint discusses the strong connection between quality improvement and leadership development.
This Viewpoint discusses recent US Food and Drug Administration (FDA) decisions regarding oncology drug trials for refractory melanoma and their potential negative impacts on the US regulatory environment.
Importance:Meningioma incidence is rising globally, yet many tumors follow an indolent course. Despite low intervention rates, surveillance imaging is extensive, and it is unclear whether current practices meaningfully influence treatment decisions. Objective:To quantify nationwide Danish trends in meningioma incidence, treatment, and surveillance and identify potentially redundant follow-up imaging. Design, Setting, and Participants:This nationwide quality improvement study integrated data from the Danish National Patient Registry and Danish Pathology Registry. All adults diagnosed with meningioma based on radiologic or histopathologic findings in Denmark between January 1, 2010, and December 31, 2023, were included. Follow-up extended through December 31, 2024. Exposure:Meningioma diagnosis and neuroimaging. Main Outcomes and Measures:The primary outcomes were trends in meningioma incidence from 2010 through 2023, treatment conversion rates (surgery or radiotherapy), and surveillance imaging volume. Secondary outcomes included intervention timing and imaging use after final treatment. Results:A total of 8134 patients with meningioma were included (median age, 66 years [range, 18-102 years]; 6002 [73.7%] women). The age- and sex-standardized incidence rate increased from 6.4 (95% CI, 5.0-7.8) to 12.6 (95% CI, 10.8-14.5) per 100 000 person-years between 2010 and 2023, yet yearly treatment rates remained stable. A total of 5307 patients (65.2%) received no treatment, while 2665 (32.8%) underwent surgery and 439 (5.4%) received radiotherapy. Histopathologic examination confirmed World Health Organization grade 1 tumors in 2379 patients who underwent surgery (89.3%). Surveillance imaging was common, with 7143 patients (87.8%) receiving 1 or more follow-up magnetic resonance imaging (MRI) scan. Of 28 736 MRI scans, 23 992 (83.5%) were not followed by treatment. Imaging beyond 5 years after diagnosis rarely led to changes in treatment but accounted for a substantial proportion of total scans. Only 78 of 5547 patients (1.4%) underwent surgery after year 5. Conclusions and Relevance:In this quality improvement study, meningioma incidence increased substantially between 2010 and 2023, while treatment rates remained stable. Most imaging did not result in intervention, suggesting that a substantial proportion of follow-up imaging could be reduced within a risk-adapted framework.
Importance:Molecular residual disease (MRD) detection has potential to transform the selection of adjuvant therapy. Most evidence is from tumor-informed assays. Tissue-free assays not requiring sequencing of the primary tumor may simplify workflows if they offer accuracy similar to that of tumor-informed assays. Objective:To evaluate tissue-free circulating tumor DNA (ctDNA) analysis in patients with triple negative breast cancer (TNBC) and compare the tissue-free assay with tumor-informed assay results. Design, Setting, and Participants:This was a prognostic and exploratory analysis of patients with TNBC at moderate to high risk of recurrence who were participating in the ctDNA surveillance period of c-TRAK TN, a multicenter phase 2 clinical study. Plasma samples were collected from participants every 3 months for up to 2 years after the completion of adjuvant therapy and analyzed prospectively with digital polymerase chain reaction (dPCR). Data for the analysis were from a database lock on September 28, 2021, with subsequent follow-up through January 18, 2023. Data were analyzed from July 2025 to May 2026. Intervention or Exposure:Tissue-free assay leverages cancer differential methylation patterns to detect ctDNA. Main Outcome and Measures:Recurrence-free survival by tissue-free ctDNA detection status. Comparison between tissue-free ctDNA detection and both dPCR and whole-exome sequencing-powered multivariant tumor-informed assays. Results:The analysis included 1026 plasma samples from 159 patients (mean [SD; range] age, 51.4 [11.4; 25.0-78.0] years; 159 females [100%]). The tissue-free assay detected ctDNA in 54 patients (34.0%), with detection strongly associated with risk of recurrence (HR, 27.2; 95% CI, 13.7-54.2; P < .001). Among patients with ctDNA detected by both the tissue-free assay and dPCR (42 patients [26%]), tissue-free detection occurred at an earlier time point in 14 patients (33.3%); dPCR detection occurred before tissue-free detection in no patients. Median lead time to recurrence was 7.9 (95% CI, 6.1-10.5) months for tissue-free vs 5.8 (95% CI, 3.3-10.0) months for dPCR (HR, 0.57; 95% CI, 0.34-0.95; P = .03). Concordance between tissue-free and multivariant tumor-informed assays was good. Among patients detected by both assays (41 of 133), 12 of 41 (29.3%) had ctDNA detected earlier by multivariant tumor-informed assay with 1 (2.4%) earlier by the tissue-free assay. Median lead times to recurrence were 7.6 (95% CI, 4.6-10.5) months with tissue-free and 7.1 (95% CI, 5.7-10.0) months with multivariant tumor-informed assay (HR, 1.46; 95% CI, 0.87-2.44; P = .15). Conclusion and Relevance:In this prognostic study, tissue-free ctDNA detection during surveillance was strongly prognostic for recurrence in patients with TNBC. Comparable lead times between the tissue-free and multivariant tumor-informed assays support tissue-free MRD detection in a clinical trial setting, permitting ctDNA testing when tissue is not available.
Importance:Metabolic syndrome (MetS) includes obesity, insulin resistance, hypertension, and dyslipidemia. While androgen deprivation therapy (ADT) is associated with an increased risk of dyslipidemia, adiposity, and MetS, evidence is limited on the occurrence and timing of metabolic dysfunction among men receiving concurrent androgen receptor pathway inhibitor (ARPI) therapy and whether patterns vary by age. Objective:To characterize the occurrence and rate of MetS during the first year following initiation of ADT-ARPI, examine associations with age and ARPI type, and evaluate component metabolic outcomes (secondary end points). Design, Setting, and Participants:This retrospective cohort study of adult patients from January 2014 to September 2025 with up to 12 months of follow-up per person used data from a national, deidentified health record dataset (Epic Cosmos) and included patients with prostate cancer who initiated treatment with ADT-ARPI (abiraterone acetate, enzalutamide, apalutamide, and darolutamide) without evidence of MetS or its components before treatment. Data were analyzed between October 2025 and January 2026 (further analyses were done with revisions through May 2026). Exposure:Concurrent ADT and ARPI use, with index date defined as the first date of overlap between therapies. Main Outcomes and Measures:New-onset MetS during the 12 months following the index date. Secondary outcomes included individual metabolic abnormalities. Results:The cohort included 16 924 men with prostate cancer (mean [SD] age, 73.1 [9.1] y; 509 [3.0%] Asian individuals, 912 [5.4%] Hispanic individuals, 3562 [21.0%] non-Hispanic Black individuals, and 11 083 [65.5%] non-Hispanic White individuals). Medical ADT use predominated, and enzalutamide was the most frequently used ARPI. During the first year following initiation of concurrent ADT and ARPI therapy, the cumulative incidence of metabolic syndrome increased steadily, reaching nearly 40%, and varied by age group. Hypertension was the most frequently documented component outcome. Metabolic associations varied by age, with the highest incidence of metabolic syndrome among patients aged 70 to 79 years (51.7 events per 1000 person-months; 95% CI, 50.7-53.9). Heterogeneity in metabolic outcomes by ARPI type was observed in exploratory analyses. Conclusions and Relevance:This study found that while ARPIs are standard of care for advanced prostate cancer, metabolic abnormalities were frequently documented shortly after initiation of concurrent ADT and ARPI therapy. This suggests that monitoring should extend beyond cancer-specific outcomes to include early detection of metabolic dysfunction, ideally through multidisciplinary care. The early burden of metabolic abnormalities highlights the need to evaluate scalable interventions addressing cardiometabolic risk in men with prostate cancer.
This Viewpoint the regulatory problem of how to design clean trials that regulators seek as the field of oncology becomes more therapeutically sophisticated.
