Abstract Background: Metastatic uveal melanoma (mUM) has a very poor prognosis with a historical survival rate of <10% at 5 yrs. Tebentafusp, a first in class ImmTAC bispecific (gp100 x CD3), is approved for adult HLA-A*02:01+ patients with unresectable or mUM based on a phase 3 study demonstrating improved overall survival (OS) compared to investigator’s choice (IC) (HR 0.51; IMCgp100-202; NCT03070392). This benefit was maintained at the 3-yr follow-up (HR 0.68), with a 3-yr OS rate of 27% for tebentafusp and 18% for IC. Molecular response assessed by ctDNA reduction was a better indicator of OS benefit than traditional RECISTv1.1 measurements. Here we report updated analyses of OS after a minimum follow-up of 5 yrs. Methods: In this randomized, open-label, Phase 3 trial, first line HLA-A*02:01+ mUM patients were randomized 2:1 to receive tebentafusp or IC of single-agent pembrolizumab, ipilimumab or dacarbazine, stratified by lactate dehydrogenase. Primary endpoint was OS. ctDNA reduction was an exploratory endpoint. OS was estimated using Kaplan-Meier methods and treatment effects compared using Cox proportional hazards model. A Cox model, adjusted for baseline and time-varying covariates at progression, compared post-progression survival in tebentafusp patients with versus without treatment beyond radiographic progression (TBP). Results: 378 patients were randomized to tebentafusp (252) or IC (126; 82% pembrolizumab). With extended follow-up, the OS continued to favor tebentafusp, with a stratified hazard ratio of 0.67 (95% CI, 0.54-0.85). The 5-year OS rate for tebentafusp was 16% (95% CI, 11-21) vs 8% (95% CI, 4-14) for IC. The OS benefit was evident even in patients with known poor prognostic factors, including those with large tumors ≥ 10 cm. OS benefit was also seen in patients who did not have radiographic response including those with best response of progressive disease (PD) or those with a best change of tumor growth (>20%). Notably, in the tebentafusp arm, TBP was associated with better OS compared to no TBP, even after adjusting for covariates (HR 0.61; 95% CI, 0.44-0.83). In tebentafusp-treated patients, longer OS was associated with undetectable ctDNA at baseline or ctDNA reductions ≥50% by week 9. Among 21 ctDNA-evaluable patients who survived ≥ 5 years, 15 had undetectable baseline ctDNA and the remaining 6 had ctDNA clearance. Deep reductions in ctDNA were seen in patients regardless of baseline tumor burden and across all RECIST categories. Conclusions: Tebentafusp demonstrates durable, long-term OS benefit in first line HLA-A*02:01+ patients, which at 5 years is the longest OS follow-up in a randomized trial in mUM. OS benefit is evident in those with poor prognostic factors and remains independent of radiographic response, with ctDNA levels proving to be a better indicator of activity. This is the first report of long-term OS benefit in a solid tumor treated with an ImmTAC therapy. Citation Format: Paul Nathan, Sophie Piperno-Neumann, Jessica C. Hassel, Marcus O. Butler, Max Schlaak, Ryan J. Sullivan, Reinhard Dummer, John M. Kirkwood, Joseph J. Sacco, Alexander N. Shoushtari, Josep M. Piulats, April KS Salama, Marlana Orloff, Anthony M. Joshua, Sebastian Ochsenreither, Lauris Gastaud, Brendan Curti, Lev Demidov, Mohammed Milhem, Bartosz Chmielowski, Kari Kendra, Paolo Antonio Ascierto, Eric H. Bernicker, Richard D. Carvajal, Omid Hamid, Laura Collins, Sarah Lockwood, Jaymin M. Patel, Jean-Francois Baurain, Piotr Rutkowski. Five-year survival with tebentafusp in previously untreated metastatic uveal melanoma in a phase 3 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT029.

Accurate prognostic markers are essential for guiding effective lung cancer treatment strategies. The level of 5-hydroxymethylcytosine (5hmC) in tissue is independently associated with overall survival (OS) in lung cancer patients. We explored the prognostic value of cell-free DNA (cfDNA) 5hmC through genome-wide analysis of 5hmC in plasma samples from 97 lung cancer patients. In both training and validation sets, we discovered a cfDNA 5hmC signature significantly associated with OS in lung cancer patients. We built a 5hmC prognostic model and calculated the weighted predictive scores (wp-score) for each sample. Low wp-scores were significantly associated with longer OS compared to high wp-scores in the training [median 22.9 versus 8.2 months; p = 1.30 × 10−10; hazard ratio (HR) 0.04; 95% confidence interval (CI), 0.00–0.16] and validation (median 18.8 versus 5.2 months; p = 0.00059; HR 0.22; 95% CI: 0.09–0.57) sets. The 5hmC signature independently predicted prognosis and outperformed age, sex, smoking, and TNM stage for predicting lung cancer outcomes. Our findings reveal critical genes and signaling pathways with aberrant 5hmC levels, enhancing our understanding of lung cancer pathophysiology. The study underscores the potential of cfDNA 5hmC as a superior prognostic tool for guiding more personalized therapeutic strategies for lung cancer patients.

There is incontrovertible and increasing evidence that the changing climate because of the production and burning of fossil fuels has impact on health care delivery and outcomes around the world.Recently, global publications and professional medical societies, including the American Medical Association, have called for action and declared climate change a public health crisis that threatens the health and well-being of all people. 1 The intent of this statement is to affirm ASCO's commitment to addressing the impact of climate change on cancer, with a focus on specific actions guided by our mission pillars of research, education, and quality toward improved cancer prevention, outcomes, and equitable cancer care across the globe.ASCO represents almost 50,000 global physicians and other health care professionals specialized in cancer treatment, diagnosis, and prevention.ASCO members are dedicated to conducting research that leads to improved patient outcomes and are committed to ensuring that evidence-based practices for the prevention, diagnosis, and treatment of cancer are equitably available to all patients.Therefore, ASCO supports efforts to reduce the uneven public health burden resulting from the changing climate and the burning of fossil fuels by advancing evidence-based policy and practice.In early 2022, ASCO joined the Medical Society Consortium on Climate and Health, an organization that convenes associations representing over 700,000 medical providers to amplify the message that climate change is having an impact on health and wellness and to pursue policies that achieve equitable solutions to promote better outcomes for all.Amid growing concern of the potential for climate change to exacerbate widening cancer care inequities, this statement builds upon previously endorsed relevant ASCO policies including those on cancer disparities and health equity, cancer prevention, rural health, telemedicine, and skin cancer.ASCO intends to support the cancer community as we examine how to reduce the burden and impact of climate change on our patients and our professional work. Overview of Climate Change and the Impact on Cancer CareThe earth is warming owing to the accumulation of greenhouse gases in the atmosphere, which are largely attributed to the burning of fossil fuels.The increase in greenhouse gases is associated with increasing levels of carbon dioxide, rising temperatures, rising sea levels, and increasing frequency, intensity, and duration of extreme weather events, such as heat waves, droughts, wildfires, floods, and hurricanes.While these events are disruptive to health care broadly, cancer care, which requires consistent and frequent access to health services, is particularly vulnerable to weather-related disruptions.Such disruptions can stem from damage to local infrastructure, patient ability to access clinical sites, or the availability of oncology professionals to provide care safely.In addition to limiting direct access to care, severe weather events distant from a point of care can lead to disruption in delivery of goods essential for care and thereby have a widespread impact.

e20563 Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1), and its ligand (PD-L1) are the mainstay of treatment for metastatic non-small cell lung cancer (NSCLC) in patients lacking targetable driver mutations. However, optimal predictive biomarkers are lacking. We used a plasma cell-free DNA (cfDNA) 5-hydroxymethylcytosine (5hmC) signature-based predictive model to assess treatment response and potentially select patients eligible for ICI monotherapy. Methods: 40 plasma samples were collected from adult patients with stage III or IV lung cancer at Houston Methodist Hospital between 2019 and 2022. These were divided into a training (n = 24) and validation (n = 16) set. By identifying genes associated with progression free survival (PFS), a 16-gene signature was used to develop a 5hmC predictive model. A weighted predictive score (wp-score) based on the model was calculated for each patient and grouped into low and high wp-scores. Results: Low wp-scores were associated with higher objective response rate(ORR) in both training and validation set and better correlated with response rates compared to PD-L1. In the training set, PFS was longer in low wp-scores compared to high wp-scores (median 12.3 versus 3.0 months; p = 3.5x10-6; hazard ratio (HR) 4.6x10-10). This was also seen in the validation set (median 7.6 versus 1.8 months p = .0012; HR 0.12). Contrarily, high ( > 1%) or low ( < 1%) PD-L1 was not associated with PFS (median 6.8 versus 6.0 months; p = .40; HR 0.70; 95% CI, 0.30–1.60) or overall survival (OS) (median 10.1 versus 12.0 months; p = .38; HR 0.56; 95% CI, 0.15–2.10). 15 out of the 40 total patients received ICI monotherapy. Among these, low wp-scores (n = 8) were significantly associated with longer PFS compared to high wp-scores (n = 7), (median 19.6 versus 2.8 months; p = .00073; HR: 0.059). OS although longer, was not significant among the two groups (median 38.1 versus 10.5 months; p = .12). Conclusions: Our study provides a proof of concept that cfDNA 5hmC signature can be used to predict response to ICI therapy and select patients appropriate for monotherapy. It is a more sensitive and specific biomarker to PD-L1. Larger studies are underway to further validate cfDNA 5hmC based-signature predictive model. [Table: see text]

Introduction A hypoxic tumor microenvironment inhibits the normal functioning of immune cells. Studies have hypothesized that anticoagulants that can penetrate and bind to factor Xa in the tumor microenvironment, can enhance T-cell function and augment immunotherapy activity. This study compared objective response rate and progression-free survival of lung cancer patients on concomitant immunotherapy treated with direct-acting oral anticoagulants versus enoxaparin.Methods This single-center retrospective study included 73 adults with stage-IV lung cancer who received at least two cycles of immunotherapy and one month of anticoagulant therapy with direct-acting oral anticoagulants (Arm A) versus enoxaparin (Arm B) between June 1, 2016, to September 30, 2022. Primary endpoint was objective response rate, and secondary endpoints were rates of complete response, progression-free survival, incidence of thrombotic events, and major bleeding.Results Objective response rate at 6 months was 24.5% versus 25% while progression-free survival at 6 months was 54.7% versus 45% in Arm A versus Arm B, respectively. Complete response rates at 6 months were 7.5% in Arm A versus 0% in Arm B. One patient in Arm A and two in Arm B had a recurrent deep vein thrombosis. Nine patients in Arm A and two in Arm B were diagnosed with new deep vein thrombosis. One patient in Arm B was diagnosed with new pulmonary embolism. Two major bleeding events occurred in Arm B.Conclusions Our study suggests a trend toward improved progression-free survival at 6 months with no new safety concerns in lung cancer patients on concurrent immunotherapy and direct-acting oral anticoagulants.

Immune checkpoint inhibitors (ICIs) drastically improve therapeutic outcomes for lung cancer, but accurately predicting individual patient responses to ICIs remains a challenge. We performed the genome-wide profiling of 5-hydroxymethylcytosine (5hmC) in 85 plasma cell-free DNA (cfDNA) samples from lung cancer patients and developed a 5hmC signature that was significantly associated with progression-free survival (PFS). We built a 5hmC predictive model to quantify the 5hmC level and validated the model in the validation, test, and control sets. Low weighted predictive scores (wp-scores) were significantly associated with a longer PFS compared to high wp-scores in the validation [median 7.6 versus 1.8 months; p = 0.0012; hazard ratio (HR) 0.12; 95% confidence interval (CI), 0.03–0.54] and test (median 14.9 versus 3.3 months; p = 0.00074; HR 0.10; 95% CI, 0.02–0.50) sets. Objective response rates in patients with a low or high wp-score were 75.0% (95% CI, 42.8–94.5%) versus 0.0% (95% CI, 0.0–60.2%) in the validation set (p = 0.019) and 80.0% (95% CI, 44.4–97.5%) versus 0.0% (95% CI, 0.0–36.9%) in the test set (p = 0.0011). The wp-scores were also significantly associated with PFS in patients receiving single-agent ICI treatment (p < 0.05). In addition, the 5hmC predictive signature demonstrated superior predictive capability to tumor programmed death-ligand 1 and specificity to ICI treatment response prediction. Moreover, we identified novel 5hmC-associated genes and signaling pathways integral to ICI treatment response in lung cancer. This study provides proof-of-concept evidence that the cfDNA 5hmC signature is a robust biomarker for predicting ICI treatment response in lung cancer.

Supplementary Table from A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer

9043 Background: Older individuals with advanced/metastatic NSCLC have inferior outcomes compared to younger patients. Aside from baseline comorbidities and treatment-limiting toxicities, identifying factors that impact overall survival (OS) in this population is needed. The aim of this study is to assess characteristics impacting outcomes in patients ≥80 years with NSCLC using the NCDB. Methods: Adults ≥80 years with NSCLC, stage III/IV disease, diagnosed between 2015-2018, and available demographic data were included. Age, sex, race, insurance status, hospital subtype, Charelson-Deyvo comorbidity (CDCC) index, cancer stage (III/IV), geographic region in the United States (US), and histologic NSCLC subtypes were compared. Kaplan-Meier methodology assessed differences in median OS, and differences were compared using hazard ratios (HR) with 95% confidence intervals (CI). Pearson Chi-Squared test assessed the significance of covariates, and a p value < 0.05 was considered statistically significant. Results: There were 42,356 patients included. Median age was 83 (80-90) years, 20,422 were (48.2%) female, 35,653 (84.2%) were white, 37,738 (89.1%) had medicare coverage, 11,055 (26.1%) received treatment at an academic hospital, and 14,383 (33.9%) received care in the southern United States. Treatment at an academic hospital (HR: 0.91 [95% CI: 0.87, 0.95], p < 0.001), females (HR: 0.82 [95% CI 0.81, 0.84], p < 0.001), Medicaid (HR: 0.77 [95% CI: 0.65, 0.93], p = 0.005) vs no insurance, and adenocarcinoma (HR: 0.79 [95% CI: 0.74, 0.84], p < 0.001) or squamous cell carcinoma (HR: 0.84 [95% CI: 0.80, 0.90, p < 0.001] had better outcomes. Patients in the Northeastern (HR: 0.90 [95% CI: 0.87, 0.93], p < 0.001), Southern (HR: 0.92 [95% CI: 0.89, 0.94], p < 0.001), and Western (HR: 0.89 [95% CI: 0.88, 0.93], p < 0.001) US had better OS compared to the Midwest. Compared to whites, patients who were black (HR: 0.92 [95% CI: 0.88, 0.85], p < 0.001), Asian (HR: 0.77 [95% CI: 0.72, 0.82], p < 0.001), Hispanic (HR: 0.83 [95% CI: 0.78, 0.88], p < 0.001), or other (HR: 0.88 [95% CI: 0.79, 0.97) had better outcomes. Per year increase in age (HR 1.009 [95% CI: 1.006, 1.013], p < 0.001), patients with CDCC score of 1 (HR: 1.16 [95% CI: 1.14, 1.19], p < 0.001), 2 (HR: 1.22 [95% CI: 1.18, 1.27], p < 0.001), and ≥3 (HR: 1.33 [95% CI: 1.284, 1.380], p < 0.001) vs 0, and stage IV NSCLC (HR: 1.83 [95% CI: 1.79, 1.88], p = 0.000) had poorer survival. Conclusions: White race, males, uninsured status, receipt of treatment in the Midwest, community hospital treatment, large cell histology, advancing age, stage IV disease, and increasing CDCC score all had poorer outcomes in adults ≥80 years with advanced NSCLC. These factors should be taken into consideration when discussing the diagnosis, management, and expectations of the disease course with patients in the geriatric age group.

BackgroundImmune checkpoint-induced pneumonitis (ICIP) is one of the most fatal adverse events caused by immune checkpoint inhibitors (ICI) and accounts for 35% of anti-PD-[L]1-related deaths. Risk factors including thoracic radiation and use of EGFR tyrosine kinase inhibitors have been identified as contributors to ICIP development. However, there has been very limited information on obstructive pulmonary disease as a risk factor.ObjectiveThe purpose of this study is to evaluate the incidence and management of ICIP in a cohort of patients with pre-existing obstructive pulmonary disease.MethodsThis retrospective, descriptive study, includes data from 139 patients between January 1, 2017 and August 31, 2022. Patients included were adult patients 18 years or older, received at least 2 cycles of an immune checkpoint inhibitor, and had a history of an obstructive pulmonary disorder prior to administration. Patients were excluded if they had literature-established risk factors for pneumonitis.ResultsThe incidence of ICIP was 7.19% (10 out of 139 patients). From a management perspective, 90% of patients had immunotherapy held, 40% received oral steroids, and 70% received intravenous steroids at the time of ICIP identification. After receiving treatment for the initial episode of ICIP, 6 patients restarted immunotherapy and 3 (50%) subsequently experienced a recurrent episode. One patient experienced grade 4 ICIP event and subsequently died from respiratory failure attributed to ICIP.ConclusionThese findings indicate that a pre-existing history of an obstructive pulmonary disorder may be a risk factor for the development of ICIP and subsequent recurrence of ICIP when rechallenged.

IntroductionThe aim of this study is to evaluate treatment patterns, survival outcomes, and factors influencing systemic treatment decisions in adults 80 years and older with NSCLC.MethodsThis was a retrospective National Cancer Database study evaluating outcomes in adults aged 80 years and older with advanced NSCLC. Patients were analyzed on the basis of systemic therapy, including none, chemotherapy or immunotherapy (IO) alone, and chemotherapy plus IO (chemotherapy + IO). Median overall survival (OS) was compared using Kaplan-Meier methodology. Hazard ratio with 95% confidence interval (CI) was used to assess differences in outcomes, and OR with 95% CI was used to assess factors contributing to systemic therapy provision.ResultsPatients 80 years and older (OR = 1.135 [95% CI: 1.127–1.142], p = 0.000), females (OR = 1.129 [95% CI: 1.085–1.175], p < 0.001), blacks (OR = 1.272 [95% CI: 1.179–1.372], p < 0.001), non-Hispanic whites (OR = 1.210 [95% CI: 1.075–1.362], p = 0.002), and those with increasing Charlson-Deyo Comorbidity Index score (p < 0.001) were less likely to receive systemic therapy. Median OS for no therapy, IO alone, chemotherapy alone, and chemotherapy plus IO was 2.63 (95% CI: 2.57–2.69), 10.68 (95% CI: 9.96–11.39), 12.35 (95% CI: 11.98–12.72), and 14.03 (95% CI: 13.87–14.88) months, respectively. In chemotherapy alone, mean OS was 1.12 months (95% CI: 0.55–1.70) (p < 0.001) longer with multiagent versus single agent. There was no difference between IO plus single agent versus IO plus multiagent chemotherapy (0.67 mo [95% CI −1.18 to 2.54], p = 1.00).ConclusionsAge, comorbidities, patient race, and sex affected systemic therapy provision. Multiagent chemotherapy and chemotherapy plus IO significantly improved survival; with the latter, survival was similar with IO plus single or multiagent chemotherapy.

This article presents a case of a 62-year-old Vietnamese woman with a history of Lynch syndrome (LS), who developed lung adenocarcinoma with EGFR L858R mutation. LS is an autosomal dominant cancer predisposition syndrome caused by a pathogenic germline variant in DNA mismatch repair genes, often leading to microsatellite instability. While LS is primarily associated with gastrointestinal, endometrial, ovarian, and urologic tract cancers, lung cancer accounts for less than 1% of LS-related cancers, with only six cases of LS-related lung cancer previously reported in the literature. The patient underwent multiple lines of treatment for her lung adenocarcinoma, including tyrosine kinase inhibitors, stereotactic body radiation therapy, pemetrexed and pembrolizumab, amivantamab, and fam-trastuzumab deruxtecan, but all resulted in only a partial response followed by a progressive disease. This case highlights the complex interplay of genetic cancer predisposition syndromes and the development of spontaneous driver mutations in the disease course and the subsequent management of tumors arising in these patients.

e21507 Background: Metastatic uveal melanoma carries a poor prognosis, especially for patients who are not eligible for Tebentafusp. Unlike cutaneous melanoma, checkpoint inhibitors have limited effect on uveal melanoma. The observation of Abscopal effect has inspired this study of adding radiotherapy to boost the efficacy of immunotherapy. Methods: We performed a retrospective study in Houston Methodist Hospital to evaluate the efficacy of combining immunotherapy with radiotherapy including either SBRT or Y-90 treatment. Clinical outcomes were determined by assessing best overall response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), progression-free survival(PFS) and overall survival. Results: A total of 8 patients were included for this study, among which one patient had previously progressed on immunotherapy. The median follow-up period was 19 months. The best overall response rate (ORR) and disease control rate (DCR) were 25% and 75% in patients received dual-modality combination treatment (including one complete response and one partial response). The PFS and overall survival in dual-modality combination treatment group were 5.4 months (95% CI, 1.1 to 14.9 months) and 18.7 month (95% CI, 11.1 to 23.9 months), respectively. Fifty percent of patients experienced grade 3-4 treatment-related adverse events. Conclusions: The combination of radiotherapy and immunotherapy is active in metastatic uveal melanoma with sustained response in selected patients. A randomized prospective trial may be required to confirm the benefits of dual-modality combination treatment.[Table: see text]

9042 Background: Treatment of advanced/metastatic NSCLC in older patients is hindered by performance status, comorbidities, and treatment toxicities. Moreover, whether multiagent chemotherapy in combination with immune checkpoint inhibitor (ICI) therapy outweighs a conservative approach is controversial. This study aims to assess treatment patterns and outcomes in patients ≥80 years with NSCLC through data provided by the national cancer database (NCDB). Methods: Adults ≥80 years with stage III/IV NSCLC, available treatment data, and diagnosis between 2015-2018 were included. Patients were stratified by therapy including none, ICI alone, chemotherapy alone, and chemotherapy+ICI; radiation and surgical management was also assessed. Median overall survival (OS) was evaluated by Kaplan-Meier survival methods, and differences were assessed by hazard ratios (HR) and 95% confidence intervals (CI). The mean difference in OS was compared between systemic therapy arms. Pearson Chi-Squared tests assessed the significance of treatment differences, with a p-value of < 0.05 considered statistically significant. Results: There were 42,356 patients included; 29,698 (70.1%) had stage IV disease and 26,314 (62.1%) had adenocarcinoma. A total of 3,248 (7.7%) received ICI, 11,505 (27.2%) received chemotherapy, 2,393 (5.6%) received chemotherapy+ICI, and 25,210 (59.5%) received no therapy. Median OS for no therapy, ICI, chemotherapy, and chemotherapy+ICI was 2.63 (95% CI: 2.57, 2.69), 10.68 (95% CI: 9.96, 11.39), 12.35 (95% CI: 11.98, 12.72), and 14.03 (95% CI: 13.87, 14.88) months, respectively. Compared to no therapy, ICI alone (HR: 0.377 [95% CI: 0.361, 0.393], p = 0.000), chemotherapy alone (HR: 0.439 [95% CI: 0.426, 0.452], p = 0.000), and chemotherapy+ICI (HR: 0.345 [95% CI 0.328, 0.363], p = 0.000) improved OS. Compared to ICI, chemotherapy and chemotherapy+ICI had a longer mean OS difference of 2.48 (95% CI 1.82, 3.13) (p < 0.001) and 1.9 (95% CI 1.01, 2.78 (p < 0.001) months, respectively. In chemotherapy alone, the median OS was 1.12 months (95% CI: 0.55, 1.70) (p < 0.001) longer with multiagent vs single agent. There was no difference between chemotherapy vs chemotherapy+ICI (0.57 months [95% CI: 0.16, 1.31], p = 0.234), or for ICI+single agent vs ICI+multiagent (0.67 months [95% CI -1.18, 2.54], p = 1.00). Treatment with radiation (HR: 0.664 [95% CI: 0.649, 0.679], p < 0.001), primary-sit(HR: 0.495 [95% CI: 0.465, 0.527], p < 0.001) and non-primary surgery (HR: 0.867 [95% CI: 0.811, 0.927], p < 0.001), and receipt of ICI vs no ICI (HR: 0.912 [95% CI 0.873, 0.954], p < 0.001) improved OS. Conclusions: Patients ≥80 years with NSCLC derived most benefit from multiagent chemotherapy or chemotherapy+ICI, with no OS difference between ICI+single or ICI+multiagent therapy. ICI alone and no therapy had inferior OS. Future trials to corroborate this finding would benefit the elderly population.

TPS9594 Background: Tebentafusp is a bispecific (gp100 x CD3) ImmTAC that can redirect T cells to target gp100+ melanoma cells. In a Phase (Ph) 3 trial, tebentafusp demonstrated an overall survival (OS) benefit (HR 0.51) compared to investigator's choice (IC) in first line HLA-A*02:01+ patients with metastatic uveal melanoma (mUM). Gp100, which has limited expression in normal cells, is overexpressed in melanoma, including skin melanoma, supporting the investigation of tebentafusp in non-uveal melanoma. In a first-in-human trial, tebentafusp monotherapy demonstrated a promising 1-year OS (~74%) in anti-PD(L)1 naïve HLA-A*02:01+ patients with metastatic cutaneous melanoma (mCM). In a subsequent Ph1 trial, tebentafusp combined with anti-PDL1, with or without anti-CTLA4, demonstrated a 1-year OS of 75% in patients with mCM who progressed on prior anti-PD(L)1 therapy, which compares favorably with recent benchmarks (1-year OS 38%-57%) in similar patient populations. 1-3 The promising activity of tebentafusp as monotherapy and in combination with anti-PD(L)1 agents in advanced melanoma (AM) provides the rationale to conduct a Ph2/3 trial of tebentafusp (TEBE-AM; NCT05549297) in patients who have progressed on standard of care therapies. In mUM trials, RECIST response underestimated the OS benefit of tebentafusp, whereas a strong association was shown between OS and early reduction in ctDNA levels relative to baseline. 4 As an early measure of changes in tumor burden, ctDNA reduction is included as an innovative dual primary endpoint with OS for the Ph2 part of this study. Methods: TEBE-AM is a multicenter, open-label, seamless Ph2/3 study in HLA-A*02:01+ patients with non-uveal AM who have progressed on prior anti-PD(L)1, received prior ipilimumab, and a prior BRAF/MEK inhibitor regimen if actionable BRAF mutation is present. Patients are randomly assigned (1:1:1) to receive tebentafusp monotherapy, tebentafusp combined with pembrolizumab, or IC. In the IC arm, patients may enroll in clinical trials of investigational agents, receive local standard of care, or receive best supportive care, while being followed for key endpoints. Randomization into the Ph3 portion will commence immediately following completion of accrual into the Ph2 portion. Efficacy from the Ph2 portion may inform changes to the Ph3 design. Primary endpoints are ctDNA reduction relative to baseline and OS in Ph2 and OS in Ph3. Ph2 enrollment opened in Jan 2023 in the US and is expected to open in other countries mid-2023. Clinical trial registration: NCT05549297. 1. Zimmer L, et al. Eur J Cancer 75:47–55, 2017. 2. Silva IPD, et al. J Clin Oncol 38:10005–10005, 2020. 3. Arance AM, et al. J Clin Oncol 39:S9504, 2021. 4. Carvajal RD, et al. Nat Med 28:2364-2373, 2022. Clinical trial information: NCT05549297 .

For people at elevated risk for lung cancer, lung cancer screening (LCS) reduces lung cancer mortality. People with non-nicotine substance use disorders (SUDs) have elevated rates of smoking compared with the general population, highlighting them as a priority population for LCS consideration. Although research has shown LCS is underutilized, there is little literature to inform whether organizations that serve individuals with SUDs have existing clinical protocols surrounding LCS. In the current study, we examine the LCS eligibility and referral practices among these organizations. We conducted a statewide needs assessment survey in 2021 to discern how tobacco use was being addressed at Texas organizations that provide treatment or services to individuals with SUDs. Respondents were asked to report on their center’s LCS eligibility and referral practices. The analytic sample consists of 125 respondents who represented 23 federally qualified health centers, 29 global local mental health authorities (LMHAs), 12 substance use treatment programs in LMHAs, and 61 standalone substance use treatment centers. Very few respondents indicated that healthcare providers at their center made referrals to LCS for patients (8.8%); a few respondents indicated that their healthcare providers assessed patients’ eligibility for LCS but did not make referrals (3.2%). Intervention and implementation efforts are needed in these and other SUD healthcare settings to bolster organizational capacity and ensure that patients are being navigated to lung cancer screening at multiple touch points across the care continuum.

Background While infections are a known cause of morbidity and mortality in those receiving chemotherapy, the burden of infections in the ICI era is seldom explored. This analysis aimed to assess incidence of infections and risk factors in patients who received pembrolizumab (P), nivolumab (N), nivolumab/ipilimumab (N/I), or atezolizumab (A)-based therapies for NSCLC. Methods Data was collected from 7 hospitals for patients who received P, N, N/I, or A for NSCLC from 1/2017–8/2021. Date of last follow up was 12/2022. Covariates compared among infected and non-infected cohorts included age, gender, race, comorbidities, ECOG, chronic infections, and anti-infective at ICI initiation. Outcomes included rate of infection, association of infection between different ICIs, number of cycles received, all-cause emergency department (ED), hospital, and intensive care unit (ICU) admissions, and median overall survival (OS) and progression free survival (PFS). OS/PFS were evaluated using the Kaplan-Meier model. P-value <0.05 was considered statistically significant. Results There were 340 patients included: 243 (71.5%), 53 (15.6%), 15 (4.4%), and 29 (2.5%) received P, N, N/I, and A, respectively. Infection was reported in 146 (42.94%) patients; 111 (45.7%), 23 (43.4%), 2 (13.3%), and 10 (34.5%) received P, N, N/I, and A, respectively. Patients with COPD (OR 1.94 [95% CI 1.19, 3.15], p=0.007) and anti-infectives at ICI initiation (OR 2.99 [95% CI 1.34, 6.66], p=0.007) had a higher risk of infection. Compared to non-infected, infected patients had more ED (48 (32.88%) vs 40 (20.62%) p=0.011), hospital, (115 (78.77%) vs 74 (38.14%) p<0.001), and ICU admissions (37 (25.34%) vs 7 (3.61%) p<0.001). Median OS for infected vs non-infected was 11.87 (95% CI 7.97–17.3) vs 17.6 (95% CI 13.67–21.1) (p=0.286) months and PFS was 6.5 (95% CI 5.1–9.1) vs 7.1 (95% CI 6.2–8.9) (p=0.859) months, respectively. At last follow up, 100 (69.49%) infected and 116 (59.79%) non-infected died; 18 (18%) vs 4 (3.45%) deaths from infection, 13 (13.0%) vs 5 (4.31%) deaths from multiorgan failure, and 63 (63.0%) vs 100 (86.21%) deaths from primary disease (p<0.001), and 6 (6.0%) and 7 (6.03%) dying from other causes. Conclusions While infections appear to be frequent in patients receiving ICI for NSCLC, a smaller proportion are in the setting of non-P ICI regimens. Patients with COPD or who received anti-infectives at ICI initiation had a higher risk of infection. Infections contributed to higher all-cause hospitalization rate and mortality rate, but did not significantly impact survival. Studies to minimize infectious risk to improve patient morbidity and mortality are needed.

Novel predictive markers facilitate effective lung cancer treatment. Immune checkpoint inhibitors (ICIs) can drastically improve outcomes for lung cancer patients. However, currently no markers can accurately predict which patients will benefit from ICI therapies. We performed a genome-wide analysis of 5-hydroxymethylcytosine (5hmC) in 71 plasma cell-free DNA (cfDNA) samples from lung cancer patients. Using machine learning approaches, we developed a 5hmC signature for ICI treatment prediction in lung cancer in a training set and validated it in a validation set. We calculated a weighted-predictive score (wp-score) based on the model developed from the signature for each sample. The low wp-score was significantly associated with longer progression-free survival [P =.0015; 7.5 versus 2.5 months; hazard ratio (HR) 0.18; 95% confidence interval (CI), 0.058 - 0.57] and overall survival (P =.037; 14.9 versus 8.2 months; HR 0.21; 95% CI, 0.042 - 1.0) and higher objective response rate (81.8% versus 11.1%) compared to the high wp-score in the validation set. This signature was superior to programmed cell death 1 ligand for ICI treatment prediction and was specific to predict ICI treatment response in lung cancer patients. Moreover, we identified novel 5hmC-associated genes and signaling pathways important for lung cancer ICI treatment response. In summary, the plasma cfDNA 5hmC signature is an accurate predictor for ICI treatment response in lung cancer. Analysis of cfDNA 5hmC is a novel minimally invasive approach to guide treatment selection for lung cancer patients. Novel predictive markers facilitate effective lung cancer treatment. Immune checkpoint inhibitors (ICIs) can drastically improve outcomes for lung cancer patients. However, currently no markers can accurately predict which patients will benefit from ICI therapies. We performed a genome-wide analysis of 5-hydroxymethylcytosine (5hmC) in 71 plasma cell-free DNA (cfDNA) samples from lung cancer patients. Using machine learning approaches, we developed a 5hmC signature for ICI treatment prediction in lung cancer in a training set and validated it in a validation set. We calculated a weighted-predictive score (wp-score) based on the model developed from the signature for each sample. The low wp-score was significantly associated with longer progression-free survival [P =.0015; 7.5 versus 2.5 months; hazard ratio (HR) 0.18; 95% confidence interval (CI), 0.058 - 0.57] and overall survival (P =.037; 14.9 versus 8.2 months; HR 0.21; 95% CI, 0.042 - 1.0) and higher objective response rate (81.8% versus 11.1%) compared to the high wp-score in the validation set. This signature was superior to programmed cell death 1 ligand for ICI treatment prediction and was specific to predict ICI treatment response in lung cancer patients. Moreover, we identified novel 5hmC-associated genes and signaling pathways important for lung cancer ICI treatment response. In summary, the plasma cfDNA 5hmC signature is an accurate predictor for ICI treatment response in lung cancer. Analysis of cfDNA 5hmC is a novel minimally invasive approach to guide treatment selection for lung cancer patients.