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Background Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI. Methods We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508) or nivolumab and ipilimumab (INITIATE, NCT03048474) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis. Results We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p<0.04). Furthermore, a high number of shared TCR clones between pretreatment tissue and in circulation was associated with improved survival (p=0.01). To potentially select antitumor clusters, we filtered for clusters that were (1) not found in healthy controls, (2) recurrent in multiple patients with mesothelioma, and (3) more prevalent in post-treatment than pretreatment samples. The detection of two-specific TCR clusters provided significant survival benefit compared with detection of 1 cluster (HR<0.001, p=0.026) or the detection of no TCR clusters (HR=0.10, p=0.002). These two clusters were not found in bulk tissue RNA-seq data and have not been reported in public CDR3 databases. Conclusions We identified two unique TCR clusters that were associated with survival on treatment with ICI in patients with pleural mesothelioma. These clusters may enable approaches for antigen discovery and inform future targets for design of adoptive T cell therapies.

e19530 Background: In large B-cell lymphoma (LBCL) trials, racial and ethnic representation is difficult to determine due to underreporting in some regions, or because some patients may not provide data. It is difficult to understand the full extent of any underrepresentation of specific races or ethnicities in these trials relative to the prevalence of LBCL in clinical practice. The objective of this study was to characterize racial and ethnic representation in LBCL real-world databases and recently published LBCL studies. Methods: Analyses of the distribution of different racial and ethnic categories were conducted across 6 real-world clinical practice databases from the United States (US): SEER-Medicare, COTA, Medicare, Optum Market Clarity, Optum CDM, and ConcertAI RWD. In addition, a targeted review of recently published studies in patients with LBCL was conducted to identify reported race and ethnicity distributions. Distributions were described using counts and percentages for each race (Asian, Black, White, and other/unknown/not reported) and ethnicity (Hispanic, non-Hispanic, and other/unknown/not reported) category. Results: Patients with LBCL from the databases included: COTA (N=5848), SEER-Medicare (N=102,548), Medicare (N=136,466), Optum Market Clarity (N=19,649), Optum CDM (N=22,175), and ConcertAI (N=1828). Race and ethnicity distributions are reported in the table. Across databases, Asian (2–6%) and Black (5–8%) races were substantially lower than White race (69–88%). Across various lines of therapy, distributions were similar: 3–5% Asian, 3–5% Black, and 78–82% White. Hispanic ethnicity (5–22%) was substantially lower than non-Hispanic ethnicity (70–91%). In the targeted review, 14 publications of LBCL therapies were identified; of these, 10 did not report racial/ethnic composition. In 4 publications (Salles et al, 2020; Sehn et al, 2020; Bannerji et al, 2022; and a real-world study by Shenoy et al, 2011), Asian, Black, White, and other/unknown/not reported represented 2–13%, 0–7%, 71–89%, and 1–11%, respectively. Conclusions: Information on racial and ethnic distributions in LBCL studies is underreported, particularly in global trials. If this information was reported and reflective of LBCL in clinical practice in the US, the numbers of Asian and Black patients would be low at ≤8%, and most patients would be expected to be White and non-Hispanic. [Table: see text]

7520 Background: With goal of simplifying clinical trials in lymphomas, we reported that bone marrow biopsies are irrelevant for response assessment in most patients (pts) with follicular lymphoma (FL) on trials (Rutherford JCO 2023). We then investigated impact of imaging frequency in FL clinical trials. We hypothesized that progression free survival (PFS) would not be different when imaging is performed less frequently than required by trials. Methods: We identified all trials through Alliance for Clinical Trials in Oncology that enrolled untreated pts with FL from 2008-2016. We considered 2 imaging schedules: protocol specified (control) vs relaxed (X) in which response assessments at every other required time point were omitted. For each trial, we estimated PFS using Kaplan Meier methods for the 2 schedules then determined difference in PFS between schedules as % change from control schedule in 2 year (yr) PFS rate. We performed simulation studies to approximate impact of less frequent imaging on PFS estimation using 50901 (low-intermediate risk FL) and 50904 (intermediate-high risk FL, control arm). We assumed exponential distribution for PFS, where rate parameter was calculated based on observed median PFS with uniform censoring distribution. Protocols for 50901 and 50904 mandated imaging every 4 months (mos) for 2 yrs then every 6 mos (S0). We ran 1000 iterations of 100 observations using 3 tumor assessment follow up schedules: every 6 mos for 2 yrs then yearly (S1), every 8 mos for 2 yrs then yearly (S2), or yearly (S3) for simulated progression times. We calculated deviation of PFS using simulated schedules from truth (S0). Results: Across 5 FL trials, median percent change of schedule X from control schedule in estimated 2yr PFS was 2.1% (0.0-30.8%) and in estimated 4yr PFS was 0.9% (-8.6-25.7%). Disparate result in 50901 is due to small shift in events with low number of pts at risk for progression. Simulation study results by trial were: for 50901, true median PFS 1.9 yrs and average median PFS for S1, S2, and S3 of 2.05, 2.11, and 2.21 yrs; for 50904 (control arm), true median PFS 4.1 yrs and average median PFS for S1, S2, and S3 of 4.16, 4.12, and 4.05 yrs. Conclusions: Our findings support decreased frequency of imaging studies in FL clinical trials, which would improve resource use and decrease pt burden. We plan a larger analysis to confirm results. https://acknowledgments.alliancefound.org . Clinical trial information: NCT00553501 , NCT01145495 , NCT01190449 , NCT01286272 , NCT01829568 .[Table: see text]

7500 Background: The Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib +/- anti-CD20 antibody obinutuzumab (IO) is a standard frontline regimen for older adults with CLL. BTKi alone do not often lead to complete response (CR) or undetectable minimal residual disease (uMRD), thus are given indefinitely. Smaller trials showed that IO plus venetoclax (IVO) can induce uMRD CRs which may allow successful discontinuation. Methods: Alliance for Clinical Trials in Oncology A041702 is a multicenter trial designed to evaluate if IVO with response-guided discontinuation of I improves progression free survival (PFS) versus IO with indefinite I in treatment-naïve, older CLL pts. IO is given in standard fashion, and in the IVO arm V is added at C3D1 and continued until C14D28. After 14 cycles, pts undergo response evaluation including CT scans and bone marrow biopsy with central MRD assessment by flow cytometry. Pts in IVO arm with uMRD CR discontinue I; all others continue I until progression or unacceptable toxicity. Eligible pts were age ≥70 years (amended to ≥65). Pts had CrCl ≥ 40 mL/min, bilirubin ≤ 1.5 x ULN, and no other life-limiting intercurrent illness. Pts were stratified based on Rai stage and +/- del17p13.1 by FISH, and randomized 1:1 to IO:IVO. With 431 evaluable pts, the trial had 90% power to detect significant improvement in PFS using a one-sided log-rank test with one-sided type 1 error rate of 2.5%. The Alliance DSMB approved release of data on Nov 4, 2022 after meeting the protocol defined futility threshold at the second planned event-driven interim analysis. Data were locked on December 15, 2022. Results: Between January 4, 2019 and July 15, 2022, 465 pts were registered (IO:232, IVO:233). Median age was 74; 67% of pts were men. Rai stage 3-4 was seen in 55% and del17p in 13%. With median follow-up of 14 months, PFS of IO was 87.5% compared to 85% on IVO. Events were observed in 29 pts on IO (4 progressions, 23 deaths, 2 pts started other therapy) and 35 on IVO (7 progressions, 28 deaths). The predefined futility boundary was crossed, with a hazard ratio (HR) of 1.20 (95% CI: 0.73-1.97) in favor of IO. COVID-19 was the leading cause of death in both arms, (11 COVID-19 deaths on IO, 19 on IVO), with 13 and 11 additional deaths from other causes, respectively. Censoring pts with COVID-19 related deaths, PFS HR is 0.82 (95% CI: 0.44-1.53) in favor of IVO. Grade 3+ toxicity and discontinuation in year 1 of therapy were similar between arms. Conclusions: This study demonstrates that PFS for IVO is not superior to IO for treatment-naive older CLL pts in the setting of the COVID-19 pandemic. Study treatment is ongoing, and long-term follow-up will determine if there are advantages to IVO, with special attention to MRD and therapy discontinuation. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03737981 .

4004 Background: Immune checkpoint inhibitor (ICI) studies have shown an association between the occurrence of imAEs and outcomes. In the Phase 3 HIMALAYA study (NCT03298451) in uHCC, STRIDE (Single T Regular Interval D) significantly improved overall survival (OS) vs sorafenib (S), and D monotherapy was noninferior to S. STRIDE and D had manageable safety (Abou-Alfa et al. NEJM Evid 2022). STRIDE is approved for uHCC in the United States and Japan and recommended for approval by the European Medicines Agency; D is approved in Japan. This exploratory analysis assessed the association between imAEs and outcomes in HIMALAYA. Methods: Safety was assessed in participants (pts) who received ≥1 dose of STRIDE (T 300 mg [one dose] plus D 1500 mg once every 4 weeks [Q4W]) or D (1500 mg Q4W). imAEs were AEs of special interest associated with drug exposure and consistent with an immune-mediated mechanism of action with no found alternate etiology. Median OS (mOS) and OS rates were estimated using the Kaplan–Meier method. OS hazard ratios (HRs) and 95% CIs were calculated using Cox modeling, with imAEs as a time-varying covariate and stratified by etiology (HBV/HCV/others), ECOG (0/1), and macro-vascular invasion (yes/no) for pts with vs without imAEs of any grade. Pts with >1 imAE were counted once. Results: In total, 388 pts (STRIDE) and 388 pts (D) were included in the analysis. Any grade imAEs, Grade 3 or 4 imAEs, and imAEs leading to discontinuation occurred in 139 (35.8%), 49 (12.6%), and 22 (5.7%) pts, respectively for STRIDE and 64 (16.5%), 25 (6.4%), and 10 (2.6%) pts, respectively for D. imAEs requiring high-dose steroids (≥40 mg prednisone or equivalent daily) occurred in 78 (20.1%) pts for STRIDE and 37 (9.5%) pts for D. An improvement in OS was seen with STRIDE in pts with imAEs vs pts without (HR, 0.73; 95% CI, 0.56–0.95). OS rates at 6, 12, and 24 months (mo) were higher for STRIDE in pts with imAEs vs pts without. The association between imAEs and OS was less clear for D and may be limited by small pt number. In a landmark analysis of pts with vs without imAEs within 6 mo of STRIDE (n=307) or D (n=287), OS HRs (95% CIs) were 0.65 (0.47–0.90) and 1.39 (0.95–2.04), respectively. Conclusions: In HIMALAYA, imAEs with STRIDE or D were manageable and generally low grade. In this exploratory analysis, the occurrence of imAEs was associated with improved OS for STRIDE, generally consistent with findings for other ICIs. Clinical trial information: NCT03298451 . [Table: see text]

7006 Background: Older adult patients (pts) with Philadelphia-chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) have poor survival with chemotherapy. The α-CD22 Ab-drug conjugate inotuzumab ozogamicin (InO) and α-CD19/CD3 T-cell engager blinatumomab (blina) were each superior to chemotherapy in Phase III studies in relapsed/refractory B-ALL. Because InO induces high CR rates and blina can induce durable remissions in low burden disease, we conducted a Phase II trial of induction InO then blina for older adults with newly-diagnosed (ND), Ph-, B-ALL. Methods: Eligible were pts ≥60 years old with ND, Ph-, CD22+ (≥20% of blasts) B-ALL without plan for allogeneic HCT (alloHCT). Pts with CNS leukemia or liver disease were excluded. Induction IA was InO 0.8 mg/m 2 day (d) 1, 0.5 mg/m 2 d8, d15 IV on a 21d cycle. Pts with adequate cytoreduction (marrow blasts by ≥50% or cellularity ≤20%) after IA went to IB if in CR/CRi (InO 0.5 mg/m 2 d1, d8, d15 IV; 28d cycle) or IC if no CR/CRi (InO 0.8 mg/m 2 on d1 and 0.5 mg/m 2 on d8 and d15 IV; 28d cycle). Those without cytoreduction to IA started course II blina. Pts without events in IA/B/C received course II blina CIV (9 mcg/d x 7d then 28 mcg/d x 21d; 14d break; 28 mcg/d x28d). Pts with CR/CRi to InO received 2 more 28d cycles of blina, others received 3 more. CNS prophylaxis was methotrexate 15 mg intrathecal x 8. The primary endpoint was 1-yr event-free survival (EFS) with a lower limit of a 90% CI for 1-yr EFS >10% defined as success. EFS was the time from therapy start to failure to achieve CR/CRh/CRi by end Course II, progression, relapse, or death, whichever occurred first. Results: Thirty-three eligible pts were treated (1 ineligible, 2 nd malignancy). The median age was 71 years (range 60-84). Median WBC count was 3,200/mcl (range 6-38,000). Median CD22 expression was 92% (range 21-100%). Eight pts had therapy-related ALL. The cumulative CR rates through Course IA/B/C and Course II were 85% and 97%, respectively (Table). With median follow up of 22 mo, the 1-yr EFS was 75% (95% CI 61-92%). The 2-sided 90% CI was 63-89% for 1-yr EFS with lower bound above 10% indicating regimen success. Twelve pts had events: 9 relapses, 2 deaths in remission (1 after alloHCT), and 1 death without remission from respiratory failure with sinusoidal occlusion syndrome of liver. The 1-yr OS was 84% (95% CI 72-98%). Nine pts have died, 6 after relapse. Conclusions: InO induction then blina consolidation is highly active for ND, Ph-, CD22+ B-ALL. The regimen is an option for older adults and a comparator regimen for future studies. Support: U10CA180821, U10CA180882, U10CA180820 https://acknowledgments.alliancefound.org . Clinical trial information: NCT03739814 . N=33 I A/B/C II Composite CR* 28 ( 85%) 32 ( 97%) CR 15 (45%) 19 (58%) CRh 11 (33%) 12 (36%) CRi 2 (6%) 1 (3%) Refractory 3 (9%) † - 1-yr EFS 75% (95% CI 61-92%) 1-yr OS 84% (95% CI 72-92%) *CR+CRh+CRi † 1 completed IA only

Background: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation. We aimed to investigate how ERK5 reprograms myeloid cells to the proinflammatory senescent phenotype, subsequently leading to atherosclerosis. Methods: A ERK5 S496A (dephosphorylation mimic) knock in (KI) mouse model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9), and atherosclerosis was characterized by hypercholesterolemia induction. The plaque phenotyping in homozygous ERK5 S496A KI and wild type (WT) mice was studied using imaging mass cytometry. Bone marrow–derived macrophages were isolated from hypercholesterolemic mice and characterized using RNA sequencing and functional in vitro approaches, including senescence, mitochondria reactive oxygen species, and inflammation assays, as well as by metabolic extracellular flux analysis. Results: We show that atherosclerosis was inhibited in ERK5 S496A KI mice. Furthermore, ERK5 S496 phosphorylation mediates both senescence-associated secretory phenotype and senescence-associated stemness by upregulating AHR (aryl hydrocarbon receptor) in plaque and bone marrow–derived macrophages isolated from hypercholesterolemic mice. We also discovered that ERK5 S496 phosphorylation could induce NRF2 (NFE2-related factor 2) SUMOylation at a novel K518 site to inhibit NRF2 transcriptional activity without altering ERK5 catalytic activity and mediates oxidized LDL (low-density lipoprotein)–induced senescence-associated secretory phenotype. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) also inhibited ERK5 S496 phosphorylation, suggesting the involvement of ERK5 S496 phosphorylation in the anti-inflammatory effects of these ERK5 kinase inhibitors. Conclusions: We discovered a novel mechanism by which the macrophage ERK5-NRF2 axis develops a unique senescence-associated secretory phenotype/stemness phenotype by upregulating AHR to engender atherogenesis. The finding of senescence-associated stemness phenotype provides a molecular explanation to resolve the paradox of senescence in proliferative plaque by permitting myeloid cells to escape the senescence-induced cell cycle arrest during atherosclerosis formation.

Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.