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AbstractObjectivesOropharyngeal squamous cell carcinoma (OPSCC) has been rising. This manuscript looks to explore racial disparities in the surgical management of OPSCC.MethodsA cancer database was queried for patients with OPSCC diagnosed from 2004 to 2017. Univariate and multivariable logistic regressions were used to evaluate associations between patient race/ethnicity, surgical treatment, and reasons for lack of surgery.Results37 306 (74.3%) patients did not undergo surgery, while 12 901 (25.7%) patients did. Non‐Hispanic black (NHB) patients were less likely to undergo surgery than other races (17.9% vs. 26.5%; p < 0.0001). In clinical discussions, the Asian, Native American, Hawaiian, Pacific Islander (ANAHPI), and unknown race group was more likely to directly refuse surgery when recommended (2.5% vs. 1.5%; p = 0.015).ConclusionRacial differences exist in treatment for OPSCC. NHB patients are less likely to actually undergo surgical management for OPSCC, while other patients are more likely to directly “refuse” surgery outright when offered.

The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation of this pathway is a common mechanism in various cancers. Here, we report that CDK2 is a novel regulator of the ERK pathway via USP37 deubiquitinase (DUB). Mechanistically, CDK2 phosphorylates USP37, which is required for USP37 DUB activity. Further, USP37 deubiquitinates and stabilizes ERK1/2, thereby enhancing cancer cell proliferation. Thus, CDK2 is able to promote cell proliferation by activating USP37 and, in turn, stabilizing ERK1/2. Importantly, combined CDK1/2 and EGFR inhibitors have a synergetic anticancer effect through the downregulation of ERK1/2 stability and activity. Indeed, our patient-derived xenograft (PDX) results suggest that targeting both ERK1/2 stability and activity kills cancer cells more efficiently even at lower doses of these two inhibitors, which may reduce their associated side effects and indicate a potential new combination strategy for cancer therapy.

Introduction: Prior AF screening trials demonstrated low yield, highlighting the need for more targeted approaches. An AI algorithm was developed to identify ECG signatures of AF risk during normal sinus rhythm, which has been validated in diverse external populations. Hypothesis: An AI-guided, targeted screening approach could improve the diagnosis of AF. Methods We conducted a pragmatic decentralized trial to prospectively recruit patients with stroke risk factors but no prior AF. The AI algorithm was applied to the ECGs performed in routine practice and divided patients into high- or low-risk groups. The primary endpoint was AF lasting ≥ 30 seconds on a subsequent 30-day continuous cardiac rhythm monitor. In a secondary analysis, trial participants were 1:1 propensity score-matched to real-world controls derived from the eligible but unenrolled population. Results A total of 1,003 patients from 40 U.S. states completed the study, with a mean age of 74 [SD 8.8] years. Over a mean of 22.3 days of continuous monitoring, AF was detected in 6 (1.6%) of low-risk patients and 48 (7.6%) of high-risk patients (OR 4.98 [2.11-11.75], p<0.001). Compared to usual care, AI-guided AF screening was associated with increased detection of AF (high-risk group: 4.2% vs. 11.1%, p<0.001; low-risk group: 0.9% vs. 2.4%, p=0.12) over a median follow-up of 10 months. Conclusions A prospective pragmatic study found that the AI a can risk-stratify a relatively uniform population (i.e., older adults at risk for stroke) to detect AF during short-term cardiac monitoring. Furthermore, when compared with usual care, AI-guided cardiac monitoring was associated with increased AF detection. As such, an AI-guided AF screening approach, leveraging existing EHR data and infrastructure, could be effective, patient-centered, and massively scalable, thereby reducing unnecessary health utilization and diagnosis-related anxiety (Clinicaltrials.gov: NCT04208971).

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.

9029 Background: Molecular biomarkers such as EML4-ALK fusion variant 3 (V3) and TP53 mutation are associated with poor prognosis in patients (pts) with anaplastic lymphoma kinase fusion positive ( ALK+) non–small cell lung cancer (NSCLC). We evaluated the effect of EML4-ALK fusion variants and TP53 mutation status on time to treatment discontinuation (TTD) of first-line (1L) treatment with a next-generation ALK tyrosine kinase inhibitor (TKI) in pts with ALK+ NSCLC in the real-world setting. Methods: Pts with advanced/metastatic NSCLC who were ALK+ in circulating tumor DNA by Guardant360 (G360) liquid biopsy test from Jan 1, 2018, to Dec 31, 2021, and received 1L monotherapy with a next-generation ALK TKI (alectinib, brigatinib, ceritinib, lorlatinib) were identified in the Guardant INFORM clinical-genomics database. Median TTD of 1L ALK TKI treatment was determined by Kaplan-Meier (KM) methods. The impact of EML4-ALK fusion variant and TP53 mutation status on TTD was evaluated. Results: Database search identified 495 pts with advanced/metastatic NSCLC who had ALK fusion by G360; of these, 214 pts received 1L treatment with a next-generation ALK TKI; 164 had G360 testing before treatment (alectinib, n=147; brigatinib, n=7; ceritinib, n=2; lorlatinib, n=8). Among these 164 pts, median age was 58.6 y, 53% were female, and 29% had baseline brain metastases. Median follow-up from start of 1L treatment was 14.8 mo. Median TTD was 19.6 mo (95% CI: 13.6–not reached [NR]). TP53 mutations were detected in 66 pts (40%). Median (95% CI) TTD in pts with TP53 mutation vs WT was 17.1 (9.5–28.5) vs 21.9 mo (14.3–NR; log-rank P=0.1712). Of 130 pts with EML4-ALK fusion variant type detected, 63 (48%) had V1, 54 (42%) V3, 8 (6%) V2, 4 (3%) V5, and 1 (1%) V8. In pts with EML4-ALK fusion V1 vs V3, median (95% CI) TTD was 19.0 (13.6–NR) vs 21.8 mo (8.7–NR; HR: 0.73; log-rank P=0.3039), with the KM plot showing numerically longer TTD in pts with V1 vs V3 during the first 18 mo and lines crossing at the tail end. Of 117 pts with both an EML4-ALK fusion variant (V1/V3) and TP53 data, 21 (18%) had both V3 and a TP53 mutation. Pts with co-occurring EML4-ALK V3 and TP53 mutation had the shortest TTD (median TTD 8.7 [3.9–NR; HR: 2.59; P=0.0219]; Table). Conclusions: Among pts with NSCLC and ALK fusion, co-occurrence of EML4-ALK V3 and TP53 mutation is common and associated with poor prognosis and high risk of early discontinuation of 1L treatment with a next-generation ALK TKI, most likely due to disease progression. Additional novel or combination therapies are warranted for this subpopulation. [Table: see text]

7569 Background: B-cell lymphoma 2 inhibitors (BCL-2i) are well tolerated and effective in treating B-cell lymphoproliferative disorders such as CLL. Investigational agent lisaftoclax is a novel, oral, highly selective and potent BCL-2i. Preclinical data show a strong synergistic effect of lisaftoclax plus ibrutinib in an ibrutinib-insensitive PDXWM1 model. Methods: This global, open-label, multicenter study evaluates the safety and efficacy of lisaftoclax alone and combined with ibrutinib or rituximab in pts with WM. Pts were enrolled in 3 arms: Arm A (lisaftoclax), BTKi-resistant/intolerant pts; Arm B (lisaftoclax plus ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax plus rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high TLS risk. Primary objectives were pharmacokinetics (PK), safety, and efficacy assessments; responses were assessed per IWWM criteria. Results: As of January 25, 2023, 46 pts were enrolled (Arm A [n = 14]; up to 1,000 mg; Arm B [n = 24]; up to 1,200 mg; Arm C [n = 8]; up to 800 mg). Baseline characteristics are shown in the table. Median (range) treatment duration was 6 (1-18; Arm A), 14 (1-27; B), and 8 (2-26; C) months. Overall response rates (ORRs) were: Arm A, 25% (median time to response [MTTR], 4.3 months); Arm B, 90.9% (MTTR, 1.9); Arm C, 37.5% (MTTR, 4.4). No significant difference was observed between pts with and without CXCR4-mut. At 1,200 mg, 1 DLT (grade 3 clinical TLS), due to pre-existing renal impairment, was reported. At 1,000 mg, 1 grade 3 laboratory TLS occurred in Arm B because of dehydration and active symptomatic therapies; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (13%), leukocytopenia (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmias were not observed. Only 1 pt required dose reduction (due to neutropenia). MTD has not been reached. A total of 14 pts discontinued study treatment because of disease progression (n = 5) and AE (n = 1). Lisaftoclax plus ibrutinib showed a PK exposure comparable to ibrutinib alone, indicating no potential DDI. Conclusions: Lisaftoclax alone or combined with ibrutinib/rituximab demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. Internal study identifier: APG2575WU101. *SA and ML are co-first authors. Clinical trial information: NCT04260217 . [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]