T cells have important functions in development and disease processes through T cell receptor (TCR)-dependent activities. Many tools were developed to predict the binding between TCRs and antigens. However, one of the uncertainties is whether such tools can decipher how small changes in the TCRs or antigenic peptides contribute to binding. We develop a deep learning model, pMTnet-omni, which not only predicts the binding vs. non-binding of TCRs towards pMHCs, but also distinguishes the stronger vs. weaker binding of TCRs similar in sequence. We leverage this capability to interpret the biological rules that govern TCR-antigen pairing. This also enables pMTnet-omni to accurately predict variant TCRs with desired stronger or weaker binding to the antigen, in conjunction with a Lab-in-the-Loop (LiL) mechanism. We show that pMTnet-omni can also predict binding of TCRs towards similar pMHCs. Overall, we provide a flexible toolkit for research and translational applications involving antigens and TCRs.

Supplemental Figure 4. Cytokine changes (post-selinexor, pre-docetaxel) significantly associated with clinical outcomes.

Supplemental Figure 5. Sample radiographic responses (n=3, all TP53 wild type).

The capability to profile the landscape of antigen-binding affinities of a vast number of antibodies (B cell receptors, BCRs) will provide a powerful tool to reveal biological insights. However, experimental approaches for detecting antibody–antigen interactions are costly and time-consuming and can only achieve low-to-mid throughput. In this work, we developed Cmai (contrastive modeling for antigen–antibody interactions) to address the prediction of binding between antibodies and antigens that can be scaled to high-throughput sequencing data. We devised a biomarker based on the output from Cmai to map the antigen-binding affinities of BCR repertoires. We found that the abundance of tumor antigen-targeting antibodies is predictive of immune-checkpoint inhibitor (ICI) treatment response. We also found that, during immune-related adverse events (irAEs) caused by ICI, humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. We used Cmai to construct a BCR-based irAE risk score, which predicted the timing of the occurrence of irAEs. Song et al. developed a computational tool to profile binding pairs between tumor-derived antigens and antibodies from high-throughput B cell receptor sequencing data, predicting response to immune-checkpoint inhibitor therapy and risk of adverse events.

BACKGROUND:While male breast cancer incidence is rare, veteran status is found to be associated with increased risk, for incidence, a higher prevalence of male breast cancer patients was observed among male veteran prostate cancer survivors. This study leveraged the existing large-scale Veterans Affairs (VA) Prostate Cancer Data Core and examined factors associated with increased risk of male breast cancer incidence in veterans with prior prostate cancer diagnoses. METHODS:A retrospective cohort study of 1.3 million male veterans treated for prostate cancer at VA hospitals was conducted using the VA Prostate Cancer Data Core. Of these, 11,327 (0.86%) were newly diagnosed with male breast cancer on average 5.4 years post prostate cancer diagnosis. RESULTS:Multivariate Cox and competing risk model results found that younger onset age of prostate cancer (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.97-0.98), metastasized prostate cancer (HR 2.03, 95% CI 1.90-2.17), being Non-Hispanic (N-H) Black (HR 1.10, 95% CI: 1.05-1.15), radiation (HR 1.06, 95% CI: 1.02-1.11) and androgen deprivation therapy (ADT; HR 1.24, 95% CI 1.17-1.32) were associated with significantly increased risk of male breast cancer diagnosis. Prolonged use of cardiovascular disease (CVD) medications, furosemide (HR 1.51, 95% CI 1.39-1.63), spironolactone (HR 1.36; 95% CI 1.15-1.61), and digoxin (HR 1.50, 95% CI: 1.29-1.72), significantly increased risk for male breast cancer incidence. CONCLUSIONS:Younger age onset of prostate cancer, metastasized prostate cancer, prolonged use of CVD medications, radiation, and ADT cancer treatment were factors significantly associated with increased risk of being diagnosed with male breast cancer among male veteran prostate cancer survivors. The study findings may shed insights in cardio-oncology specific risk factors for male breast cancer among prostate cancer survivors.

Supplemental Figure 1. Next generation sequencing results (n=16 cases).

Purpose: Patients with Kirsten rat sarcoma viral oncogene (KRAS)-mutant non-small cell lung cancer (NSCLC) have limited therapeutic options. Based on the activity of nuclear export inhibition in preclinical models, we evaluated this strategy in previously treated, advanced KRAS-mutant NSCLC.Patients and Methods: The primary outcomes of this multicenter phase I/II dose-escalation trial of selinexor plus docetaxel were safety and tolerability. Selinexor was started 1 week before docetaxel to permit monotherapy pharmacodynamic assessment.Results: Among 40 enrolled patients, the median age was 66 years, 55% were female, and 85% were White. The MTD was selinexor 60 mg orally weekly plus docetaxel 75 mg/m2 every 3 weeks. The most common adverse events were nausea (73%, 8% grade >= 3), fatigue (70%, 5% grade >= 3), neutropenia (65%, 60% grade >= 3), and diarrhea (58%, 10% grade >= 3). Of 32 efficacy-evaluable patients, 7 (22%) had partial responses and 18 (56%) had stable disease. Outcomes were not associated with KRAS mutation type but were significantly better in cases with wild-type TP53 (42%), including response and disease control rates (27% and 80% vs. 9% and 27%, respectively; P = 0.03) and progression-free survival (median 7.4 vs. 1.8 months; HR, 0.2; 95% confidence interval, 0.07-0.67; P = 0.003). After selinexor initiation and prior to docetaxel administration, serum lactate dehydrogenase levels increased an average of 51 U/L in TP53-altered cases and decreased an average of 48 U/L in TP53 wild-type cases (P = 0.06).Conclusions: Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS-mutant NSCLC. The regimen has promising efficacy in TP53 wild-type cases, in which selinexor monotherapy may also have activity.

Supplemental Table 2. Treatment-emergent adverse events occurring in at least 10% of the overall cohort according to dose level of selinexor.

Background:In non-small cell lung cancer (NSCLC), programmed death-ligand 1 (PD-L1) expression has moderate ability to predict immune checkpoint inhibitor (ICI) benefit. In clinical practice, PD-L1, a cell surface protein, cannot be characterized in currently available blood-based tests such as circulating tumor DNA assays. To understand the biologic effects of PD-L1 more fully and evaluate whether blood-based tests could provide insight into its expression, we determined the association between PD-L1 expression and systemic immune parameters. Methods:We collected pre- and post-treatment (6-week) peripheral blood samples in patients with NSCLC treated with ICI. Using multiplex panels and cytometry by time of flight (CyTOF), we analyzed specimens for baseline and post-treatment changes in cytokines, autoantibodies, and immune cell populations. We determined the association between case characteristics, immune parameters, and tumor PD-L1 expression (categorized as <1%, 1-49%, and ≥50%) using Chi-square, one-way analysis of variance (ANOVA), and Kruskal-Wallis tests, accounting for multiple comparisons. Results:A total of 119 patients were included in the analysis, of whom 41 (34%) had PD-L1 expression <1%; 44 (37%), 1-49%; and 34 (29%), ≥50%. PD-L1 expression was not associated with any demographic, tumor, or treatment characteristics. Among 39 cytokines evaluated, baseline levels of macrophage migration inhibitory factor (MIF) were significantly greater in high PD-L1 positive cases. Among 124 autoantibodies included in the analysis, three (anti-aggrecan, -proteoglycan, and -nucleosome) demonstrated significantly greater post-ICI treatment increases in cases with higher PD-L1 expression. In PD-L1 positive cases, baseline abundance of natural killer T (NKT) cells (P=0.001) and activated monocytes (P=0.04) were significantly lower, while post-treatment increases in mature natural killer (NK) cells were significantly greater (P=0.006). Conclusions:NSCLC PD-L1 expression is associated with few systemic immune parameters, suggesting that effects on anti-tumor immunity may occur predominantly in the tumor microenvironment and that blood-based assays are unlikely to provide meaningful surrogates of this biomarker.

3068 Background: The VA National Precision Oncology Program (NPOP), launched in 2016 as part of the White House’s Cancer Moonshot Initiative, aimed to revolutionize cancer care through precision medicine for Veterans. Oncologists at the VANTXHCS utilized molecular testing to identify potentially actionable mutations to tailor treatment strategies more accurately. This study aims to evaluate the impact of the identification and impact of potentially actionable mutations with treatment decisions and overall survival. Methods: We conducted a retrospective chart review of Veterans with molecular oncology testing (MOT) at VANTXHCS from August 2019 to May 2024 to assess cancer type, prevalence of potentially actionable mutations, treatment decisions, targeted therapy utilization, and overall survival (OS). Potential actionable mutations were determined based on AMP/ASCO/CAP Variant Categorization mapped to the OncoKB FDA-Recognized Human Genetic Variant Database at the time of review. Results: 570 Veterans, almost exclusively male (N = 523, 92%) with solid tumors had MOT during the study period. Lung (N = 211, 37%), GI (N = 105, 21%), prostate (N = 49, 9%), pancreatobiliary (N = 46, 8%), head and neck cancers (N = 35, 6%) and GU (N = 30, 5%) were most common with a median overall survival (OS) of 15.93 months. Potential actionable mutations were present in 107 (18.7%) tumors, however only 41 (38%) of the mutations were associated with an FDA approved targeted therapy at the time of testing. Six Veterans (5.6%) received targeted therapy. Reasons for not receiving targeted therapy included secondary mutations ( i.e ., KRAS), ECOG performance status, hospice or community care and death. Veterans with potentially actionable mutations had significantly worse. Conclusions: In the VANTXHCS Veteran population males with lung cancer represents the main tumor type with molecular oncology testing. We observe actionable mutations in nearly 20% of patients tested, with only a minor subset receiving targeted therapy. Our data showed that patients with a potentially actionable mutation have worse overall survival than those that do not. However, treatment with a targeted therapy can significantly improve survival. In conclusion, these findings underscore the need for further research to identify barriers to increase appropriate use of targeted therapies in a timely fashion to improve patient outcomes and advance precision oncology practices.

Supplemental Table 1. Representativeness of study participants.

PURPOSE:We investigated the efficacy and toxicity of thoracic radiation therapy (RT) plus concurrent and consolidation carboplatin with either solvent-based paclitaxel (sb-paclitaxel) or solvent-free nanoparticle albumin-bound paclitaxel (nab-paclitaxel). METHODS AND MATERIALS:This multicenter phase 1/2 randomized trial included patients with inoperable stage IIIA/B nonsmall cell lung cancer (AJCC 7) and an Eastern Cooperative Oncology Group performance status of 0-1. In phase 1, 6 patients received weekly nab-paclitaxel (50 mg/m²) and carboplatin (AUC 2) with concurrent thoracic RT (60 Gy in 30 fractions), followed by nab-paclitaxel (100 mg/m²) on days 1, 8, and 15 and carboplatin (AUC 6) on day 1 for two 21-day cycles. In phase 2, 92 patients were randomly assigned to weekly sb-paclitaxel (50 mg/m²) or nab-paclitaxel (40 mg/m²) with concurrent RT, followed by consolidation therapy with sb-paclitaxel or nab-paclitaxel and carboplatin for 2 cycles. RESULTS:Two phase 1 patients had dose-limiting toxicities, setting the phase 2 nab-paclitaxel dose at 40 mg/m². For the phase 2 cohort, 2-year overall survival was 67% for sb-paclitaxel and 56% for nab-paclitaxel (P = .10), with progression-free survival of 44% and 27%, respectively (P = .14). Fewer patients completed consolidation with nab-paclitaxel (26%) versus sb-paclitaxel (58%) (P = .005). Grade 3 and higher adverse events were more frequent with nab-paclitaxel (56%) than with sb-paclitaxel (30%) (P = .029). CONCLUSIONS:Nab-paclitaxel was associated with higher toxicity and numerically lower efficacy than sb-paclitaxel when used with thoracic radiation in locally advanced nonsmall cell lung cancer.

Supplemental Figure 6. Post-treatment serum LDH changes.

Supplemental Figure 3. Baseline cytokines significantly associated with clinical outcomes.

Supplemental Methods 1. Next-generation sequencing.

Background:Despite high response rates to epidermal growth factor receptor (EGFR) inhibitors, patients with advanced EGFR mutant non-small cell lung cancer (NSCLC) generally experience disease progression within 2 years. We evaluated whether consolidative radiation therapy (RT) to residual sites of disease at the time of expected best response to EGFR inhibition prolongs disease control. Methods:This multicentre, single-arm phase 2 trial was conducted at two sites in the USA. Eligible patients (aged ≥18 years) had advanced EGFR mutant (exon 19 or 21) NSCLC not restricted by number, site, or size of metastases; ECOG 0-2; and no prior treatment with EGFR or immune checkpoint inhibitors. Patients with stable or responding disease after 8 weeks of osimertinib 80 mg orally daily received radiation therapy (RT) to persisting lesions, followed by continued osimertinib until progression or intolerance. The primary endpoint was progression-free survival (PFS) in all participants who received at least one dose of osimertinib, assessed radiographically every 8 weeks. Secondary endpoints were toxicity, duration on osimertinib, and overall survival (OS). This trial is registered with Clinicaltrials.gov, NCT03667820. Findings:Between Oct 15, 2018, and July 1, 2021, 42 patients (32 female, 10 male) were enrolled and initiated osimertinib, of whom 32 (76%) received consolidative RT, primarily stereotactic RT. The most common reasons RT was not administered were insufficient residual disease (10%) and inadequate response (5%). At a median follow-up of 35.7 months, median PFS was 32.3 months (95% CI, 21.9-51.7), median OS was 45 months (95% CI, 39.3-56.4), and median duration of osimertinib was 32.4 months. Osimertinib-related toxicities, including skin, nail, and gastrointestinal events, occurred at expected rates and were almost always grade 1-2. Two patients (5%) developed pneumonitis, including one grade 4 event. Interpretation:These findings show osimertinib plus consolidative RT was well tolerated and demonstrates promising efficacy in patients with advanced EGFR mutant NSCLC. Because this approach may be less complex and less toxic than multi-agent targeted therapy regimens for this population, the results of ongoing randomised trials testing similar strategies are awaited. Funding:AstraZeneca and the Biostatistics Shared Resource, UT Southwestern Harold C. Simmons Comprehensive Cancer Center.

Supplemental Figure 2. Transcriptional signatures identified through RNA sequencing.

We report the case of corneal transplant rejection in a 77-year-old male receiving durvalumab as consolidative therapy for stage IIIB non-small cell lung cancer (NSCLC). Following successful chemoradiation and initiation of durvalumab, the patient underwent a right corneal transplant for corneal dystrophy. Six months after an initially stable post-transplant course, he developed progressive visual decline culminating in graft failure 1 year later despite treatment with prednisone eye drops. This case adds to the limited evidence implicating immune checkpoint inhibitors (ICIs) in corneal graft rejection, emphasizing the need for multidisciplinary evaluation and close monitoring of corneal transplant recipients undergoing ICI therapy.

BackgroundA useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI.MethodsUsing two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women).ResultsInitial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE.ConclusionsIn contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.

9116 Background: Although osimertinib has become standard first-line (1L) therapy for patients (pts) with EGFRm mNSCLC, a subset treated with earlier-generation EGFR-targeted TKIs and chemotherapy have had long-term survival. We sought to characterize clinical features of long-term survival in pts with EGFRm mNSCLC treated prior to the osimertinib era. Methods: Data were abstracted from electronic medical records at 12 cancer centers participating in the Academic Thoracic Oncology Medical Investigator’s Consortium (ATOMIC). We included patients with mNSCLC with sensitizing mutations in EGFR who started 1L systemic therapy before 2015. Survival distributions and predictors were assessed using Kaplan-Meier estimates and a multivariable Cox proportional hazards model including time-dependent brain metastasis (met) development, age, 1L therapy (targeted vs. chemotherapy), sex, race, and smoking status. Multivariable logistic regression was used to evaluate baseline predictors associated with 5+ year survival vs. not for those with known survival status at 5 years after start of 1L. Results: We identified 304 patients (69% female, 56% White, 29% Asian, mean age 61.2). First-line targeted therapy was given in 70% of patients. With a median follow-up of 81.5 months, median overall survival was 63.5 months (95% CI 59.4-71.9). 135 (44%) pts survived 5+ years; among those with baseline next-generation sequencing (NGS), presence of a baseline pathogenic ERBB2 variant was higher in 5+ year survivors (4/51 [8%], 2x amplification, y772_A775dup, S310F) v others (1/65 [2%], amplification). Among 161 pts with baseline brain imaging, both baseline and on-treatment development of brain mets were associated with worse survival (HR 1.29, 95% CI 1.21-1.37; HR 1.59, 95% CI 1.47-1.72; both P < 0.001). Excluding 22 patients lost to follow-up before 5 years, a history of smoking (OR 2.99, 95% CI 1.35-6.90, P = 0.008) and baseline brain metastases (OR 3.57, 95% CI 1.64-8.13, P = 0.002) were associated with death before 5 years. Conclusions: Long-term survivors with EGFRm mNSCLC treated before the osimertinib era were more likely to be nonsmokers and have no baseline brain metastases. This highlights a subset of EGFRm patients who had excellent outcomes with older treatment strategies and may not benefit as much from intensification approaches. Additional baseline mutational data will be presented at the conference.