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ImportanceApproval by the US Food and Drug Administration of immune checkpoint inhibition (ICI) for advanced gastroesophageal cancer (aGEC) irrespective of PD-L1 status has generated controversy. Exploratory analyses from individual trials indicate a lack of meaningful benefit from ICI in patients with absent or low PD-L1 expression; however, analysis of a single variable while ignoring others may not consider the instability inherent in exploratory analyses.ObjectiveTo systematically examine the predictive value of tissue-based PD-L1 status compared with that of other variables for ICI benefit in aGEC to assess its stability.Data SourcesMEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register (2000-2022).Study Selection, Data Extraction, and SynthesisRandomized clinical trials (RCTs) were included of adults with aGEC (adenocarcinoma [AC] or squamous cell carcinoma [SCC]) randomized to anti−PD-1 or PD-L1−containing treatment vs standard of care (SOC). Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers. Of 5752 records screened, 26 were assessed for eligibility; 17 trials were included in the analysis.Main Outcomes and MeasuresThe prespecified primary end point was overall survival. The mean hazard ratio (HR) for ICI vs SOC was calculated (random-effects model). Predictive values were quantified by calculating the ratio of mean HRs between 2 levels of each variable.ResultsIn all, 17 RCTs (9 first line, 8 after first line) at low risk of bias and 14 predictive variables were included, totaling 11 166 participants (5067 with SCC, 6099 with ACC; 77.6% were male and 22.4% were female; 59.5% of patients were younger than 65 years, 40.5% were 65 years or older). Among patients with SCCs, PD-L1 tumor proportion score (TPS) was the strongest predictor of ICI benefit (HR, 0.60 [95% CI, 0.53-0.68] for high TPS; and HR, 0.84 [95% CI, 0.75-0.95] for low TPS), yielding a predictive value of 41.0% favoring high TPS (vs ≤16.0% for other variables). Among patients with AC, PD-L1 combined positive score (CPS) was the strongest predictor (after microsatellite instability high status) of ICI benefit (HR, 0.73 [95% CI, 0.66-0.81] for high CPS; and HR, 0.95 [95% CI, 0.84-1.07] for low CPS), yielding a predictive value of 29.4% favoring CPS-high (vs ≤12.9% for other variables). Head-to-head analyses of trials containing both levels of a variable and/or having similar design generally yielded consistent results.Conclusions and RelevanceTissue-based PD-L1 expression, more than any variable other than microsatellite instability-high, identified varying degrees of benefit from ICI-containing therapy vs SOC among patients with aGEC in 17 RCTs.

Repeat exposures to low oxygen (intermittent hypoxia, IH) elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans were unclear. We show acute IH results in an increase in ET-1, MSNA, and BP in healthy young men; however, the effect of IH on MSNA and BP does not occur through activation of ET-receptors in healthy young men.

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non–muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non–muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody–drug conjugates for metastatic bladder cancer.

Abstract In this secondary analysis of Hispanic adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated on Cancer and Leukemia Group B (CALGB) 10403, we evaluated outcomes and geographic enrollment patterns relative to US population data. We used demographic, clinical, and survival data on AYAs enrolled on CALGB 10403 (N = 295, 2007-2012). Surveillance, Epidemiology, and End Results registries provided overall survival (OS) for US AYA ALL by ethnicity/race. North American Association of Cancer Registries provided AYA ALL incidence overall and proportion among Hispanics by US state. Of AYAs enrolled on CALGB 10403, 263 (89%) reported ethnicity/race: 45 (17%) Hispanic, 172 (65%) non-Hispanic White (NHW), 25 (10%) non-Hispanic Black (NHB), and 21 (8%) other. Compared with NHWs, Hispanic and NHB patients had lower household income, and Hispanic patients were more likely to harbor high-risk CRLF2 aberrations. Relative to US estimates, where Hispanic patients represented 46% of newly diagnosed AYA ALL patients and experienced inferior OS compared with NHW (P < .001), Hispanic AYAs on CALGB 10403 did as well as NHW patients (3 year OS, 75% vs 74%; P = NS). Hispanic patients also had higher rates of protocol completion (P = .05). Enrollments on CALGB 10403 differed relative to the distribution of Hispanic AYA ALL in the United States: enrollment was highest in the Midwest; t and only 15% of enrollees were from states with a high proportion of Hispanic AYA ALL patients. In summary, Hispanic patients treated on CALGB 10403 did as well as NHWs and better than population estimates. Geographical misalignment between trial sites and disease epidemiology may partially explain the lower-than-expected enrollment of Hispanic AYA ALL patients.

6077 Background: E3311 is a phase II randomized study which showed favorable outcomes among intermediate (INT) risk HPV+ OPC patients (pts) who underwent TOS followed by pathology-guided or adapted, deintensified adjuvant treatment. Among HPV+ pts treated with definitive chemoradiation, survival outcomes are worse among those who smoked > 10 pack years (pk-yrs). Methods: We retrospectively analyzed demographics, pathologic results, and efficacy outcomes from E3311 by smoking group (current (C) vs. former (F) and > 10 vs. ≤10 pk-yrs – the latter a pre-specified stratification factor for INT patients). Binary and categorical variables were compared using a chi-square test (or Fisher’s exact test for small sample sizes). Ordinal variables were compared using a Wilcoxon rank sum test. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using a log-rank test. Results: Among 359 evaluable pts, performance status (PS) was significantly worse for pts with > 10 pk-yrs vs. ≤10 pk-yrs (15.4% vs. 7.9% with PS of 1, p = 0.034). Primary site, margin status, histologic grade, stage, and extranodal extension were not significantly different between the groups of > 10 vs. ≤10 pk-yrs. Smoking status (F vs. C) was available for 182 pts with a history of smoking. Slightly more C vs. F smokers had tonsil as primary site (79.5% vs. 65.0%, p = 0.09). Positive margins were significantly more frequent among C smokers (10.3% vs. 2.1%; p = 0.029). Overall, there were no significant differences in PFS (p = 0.55) or OS (p = 0.94), comparing those with > 10 vs. ≤10 pk-yrs, or comparing C vs. F smokers (p = 0.76, p = 0.82, respectively). Similarly, no significant differences were observed within the treatment arms. (Table 1) Conclusions: In this analysis of smoking status in E3311, INT risk HPV+ OPC pts who are C smokers or have a history of > 10 pk-yrs had favorable 3-yr PFS and OS rates that were not significantly worse than those with < 10 pk-yrs history. This data represents the first treatment approach for HPV+ OPC in which outcomes were not influenced by smoking status. Clinical trial information: NCT01898494. [Table: see text]

Summary Exploratory analysis of a phase III trial in esophageal cancer found that the patients who most contributed to an overall survival benefit from PD-1 blockade were not responders, but non-responders. The analysis has limitations but may have implications for investigating the optimal timing of immunotherapy relative to other treatments. See related article by Okada et al., p. 3277

BACKGROUND: The use of high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) for hypoxemic respiratory failure secondary to COVID-19 are recommended by critical-care guidelines; however, apprehension about viral particle aerosolization and patient self-inflicted lung injury may have limited use. We aimed to describe hospital variation in the use and clinical outcomes of HFNC and NIV for the management of COVID-19. METHODS: This was a retrospective observational study of adults hospitalized with COVID-19 who received supplemental oxygen between February 15, 2020, and April 12, 2021, across 102 international and United States hospitals by using the COVID-19 Registry. Associations of HFNC and NIV use with clinical outcomes were evaluated by using multivariable adjusted hierarchical random-effects logistic regression models. Hospital variation was characterized by using intraclass correlation and the median odds ratio. RESULTS: Among 13,454 adults with COVID-19 who received supplemental oxygen, 8,143 (60%) received nasal cannula/face mask only, 2,859 (21%) received HFNC, 878 (7%) received NIV, 1,574 (12%) received both HFNC and NIV, with 3,640 subjects (27%) progressing to invasive ventilation. The hospital of admission contributed to 24% of the risk-adjusted variation in HFNC and 30% of the risk-adjusted variation in NIV. The median odds ratio for hospital variation of HFNC was 2.6 (95% CI 1.4–4.9) and of NIV was 3.1 (95% CI 1.2-8.1). Among 5,311 subjects who received HFNC and/or NIV, 2,772 (52%) did not receive invasive ventilation and survived to hospital discharge. Hospital-level use of HFNC or NIV were not associated with the rates of invasive ventilation or mortality. CONCLUSIONS: Hospital variation in the use of HFNC and NIV for acute respiratory failure secondary to COVID-19 was great but was not associated with intubation or mortality. The wide variation and relatively low use of HFNC/NIV observed within our study signaled that implementation of increased HFNC/NIV use in patients with COVID-19 will require changes to current care delivery practices. (ClinicalTrials.gov registration NCT04323787.)

7571 Background: In clinical trials of CAR T-cell therapies and real-world studies published to date, there is a paucity of data on outcomes by race and ethnicity. Here, we examined outcomes by race and ethnicity among LBCL pts who received axi-cel in the real-world setting. Methods: A total of 1389 pts with LBCL were identified from a non-interventional post-authorization safety study with pts receiving commercial axi-cel between 10/2017 and 08/2020. Race (African American or Asian vs White) and ethnicity (Hispanic vs non-Hispanic) were self-reported by pts. Pts with rescinded consent, enrolled in trials, having prior non-HCT cellular therapy, primary CNS lymphoma, unknown comorbidity or data in query were excluded. Median follow-up was 12.7 mo. Outcomes included ORR, CR rate, DOR, PFS and OS, grade ≥ 3 CRS (Lee 2014 criteria) and ICANS (ASTCT consensus grade). ORR and CR were evaluated in pts with ≥ 180 days of follow-up. Kaplan-Meier estimates were calculated for PFS and OS. Multivariable analyses comparing race and ethnicity were conducted via logistic and Cox regression. Results: Among all, 1127 (81%) were White, 70 (5%) African American and 81 (6%) Asian; 152 (11%) were Hispanic including 104 White, 2 Black, and 1 Asian Hispanic. African Americans, compared to White, were younger (median age 55.5 vs 62.8 years), more likely to have pulmonary impairment (41% vs 28%) and tended to have longer time from diagnosis (≥ 12 mo 71% vs 59%). Hispanic pts were younger (median age 58.5 vs 62.6 years) than non-Hispanic pts. ORR was 74% (CR 57%, 12-mo PFS and OS 48% and 63%) for White, 57% (CR 45%, 12-mo PFS and OS 36% and 62%) for African American, 67% (CR 53%, 12-mo PFS and OS 55% and 65%) for Asian and 73% (CR 55%, 12-mo PFS and OS 50% and 65%) for Hispanic pts. Grade ≥ 3 CRS and ICANS occurred in 7% and 18% of African American, 10% and 19% of Asian, and 8% and 27% of White pts, respectively. Hispanic pts had lower rates of grade ≥ 3 CRS and ICANS (4% and 15%) vs non-Hispanic (9% and 27%). African American race was associated with inferior ORR (OR 0.40; 95% CI, 0.24-0.69) and CR rate (OR 0.55; 95% CI 0.32-0.93) vs White. Asian pts had favorable DOR compared to both White (HR 0.46; 95% CI 0.24-0.87) and African American (HR 0.39; 95% CI 0.17-0.88). No statistical differences were found in OS and PFS across races, nor in any efficacy outcome between Hispanic and non-Hispanic pts. Asian (OR 0.52; 95% CI 0.29-0.96 vs White) and Hispanic pts (OR 0.51; 95% CI 0.31-0.85 vs non-Hispanic) had lower risk of grade ≥ 3 ICANS. Conclusions: Overall, axi-cel showed favorable OS, PFS and safety profile regardless of race and ethnicity in the real-world setting. No notable differences in outcomes were observed for Hispanic or Asian pts. Lower response rates in African American pts noted here warrant further investigation including any underrepresentation not explained by a lower incidence rate for DLBCL (SEER), access to care, and disease burden.

7053 Background: Mutations in isocitrate dehydrogenase 1 ( IDH1) occur in ̃3% of patients (pts) with MDS and are associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO), an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, is FDA approved for m IDH1 R/R AML and m IDH1 newly diagnosed AML in pts ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. In the first-in-human study of IVO in pts with m IDH1 advanced hematologic malignancies (NCT02074839), 12 pts with R/R MDS received IVO 500 mg once daily (QD). Based on encouraging safety and efficacy findings, including an investigator-assessed overall response rate (ORR) of 75%, with median response duration of 21.4 months, the FDA granted Breakthrough Therapy designation to IVO in m IDH1 R/R MDS and the study was amended to enroll additional pts. We report updated results. Methods: This substudy of the single-arm, open-label study of IVO evaluated pts with R/R MDS after documented failure or relapse following prior standard therapy including intensive chemotherapy and hypomethylating agents. Other key eligibility criteria included: high disease burden based on IPSS or IPSS-R risk at baseline; an Eastern Cooperative Oncology Group performance status score of 0–2; and no prior IDH1 inhibitor therapy. Pts received IVO 500 mg QD orally on days 1–28 of 28-day cycles. Results: As of 08May2021, 16 pts with R/R MDS were enrolled: 5 (31%) pts remained on treatment and free from leukemic transformation; 11 (69%) had discontinued including 6 for disease progression, 1 for allogeneic stem cell transplantation, and 1 owing to an adverse event (AE) of sepsis (the only fatal AE; reported by investigator as not related to IVO). AEs are summarized in the Table. 2 pts each experienced differentiation syndrome (grade 2) and QTcF prolongation (grade 1 and 2). 7/16 pts achieved complete response (CR, 44%; 95% CI, 20%, 70%), 1 achieved partial response (6%), and 5 achieved marrow CR (31%), resulting in an ORR of 81% (95% CI, 54%, 96%). Hematologic improvement in ≥1 lineages was achieved by 11/16 (69%) pts. The Kaplan-Meier estimate of duration of CR+PR at 12 months was 60%. 3 pts experienced CRs lasting 24.0, 63.7, and 65.4 months, which remain ongoing. 5/7 pts (71%) who were transfusion dependent at baseline became independent of red blood cell or platelet transfusions for 56 or more consecutive days on treatment. Additional translational data are being analyzed. Conclusions: In pts with m IDH1 R/R MDS, IVO monotherapy was tolerable and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for pts with m IDH1 R/R MDS. Clinical trial information: NCT02074839. [Table: see text]