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ABSTRACT Background As head and neck cancer survival rates improve, there is growing demand for quality survivorship care and tools to predict patient adherence; this study aims to evaluate an advanced practice provider ( APP )‐led survivorship clinic and assess these key metrics. Methods We performed a retrospective review of 213 head and neck cancer patients treated with curative radiation therapy between 2016 and 2023, to assess follow‐up adherence in an advanced practice provider–led survivorship clinic. Results With a median follow‐up of 2.4 years, follow‐up care metrics identified high completion percentages (> 90%) for lung cancer screening, smoking cessation, thyroid screening, dental evaluation, xerostomia, dysphagia, and dysgeusia. The HOUsing ‐based SocioEconomic Status ( HOUSES ) index at diagnosis showed a significant adherence difference (median percentile, 78% vs. 55%, adherent vs. nonadherent; p = 0.03). Conclusions High adherence rates with guideline‐defined care metrics are achievable in an advanced practice provider‐led head and neck cancer survivorship clinic. The HOUSES index may assist in predicting nonadherence; however, further studies are needed.

e18064 Background: Cell-free circulating tumor DNA (ctDNA)-based test has emerged as a promising tool in informing treatment modification in solid tumors. The clinical applications of ctDNA in head and neck squamous cell carcinoma (HNSCC) has been explored and here we report the clinical utilities of ctDNA in disease monitoring in HNSCC. Methods: HNSCC patients treated at our institution with available ctDNA test (Signatera) results between 2022 and 2024 were identified. Clinical information including disease site, stage and imaging results were collected and analyzed. Results: A total of 59 patients were identified. 21 (36%) patients had P16 + oropharyngeal cancer, 16 (27%) had oral cavity cancer, 9 (15%) patients had laryngeal cancer, 7 (12%) had P16-oropharyngeal cancer, 6 (10%) had perinasal sinus, hypopharyngeal or nasopharyngeal cancers. At the time of ctDNA test, 22 (36%) patients completed curative-intent treatment and had no radiographic evidence of disease (NED), 16 (26%) patients were treatment-naïve and had local/regional (LR) disease only, and 22 (36%) patients completed definitive treatment and developed radiographic evidence of LR recurrence or distant (D) metastatic disease. ctDNA was detectable in less than half (44%) of the treatment-naïve patients and the detection rate was even lower (14%) in the subgroup of p16+ oropharyngeal cancer. However, among patients with LR recurrent and distant metastatic disease, majority (77%) had positive ctDNA. ctDNA was undetectable in most of the patients (80%) who completed definitive treatment and were NED radiographically. Among the 3 patients who had detectable ctDNA, 2 were subsequently found to have recurrent disease on images and 1 is still on surveillance (table). Conclusions: Positive ctDNA was detected in most of the HNSCC with LR recurrent or distant metastatic disease, supporting its potential role in treatment response monitoring in this group of patients. Detectable ctDNA preceded radiographic evidence of recurrent disease in a small number of patients, suggesting the possibility of minimal residual disease detection using ctDNA in a subgroup of patients. Treatment history S/P definitive treatment Treatment naive S/P definitive treatment Radiographic evidence of disease (patient number) No (21) Yes (16; LR only) Yes (21; LR only: 10, distant: 11) ctDNA negative 18 9 4 ctDNA positive 3 (recurrence confirmed on subsequent imaging in 2 patients) 7 17

e18031 Background: HPV+ OPSCC has better outcomes than HPV negative OPSCC but more distant metastatic potential. ICM in HPV+ OPSCC are rare. Data regarding risk factors, clinical presentation and outcomes after ICM diagnosis is limited. This study describes clinical characteristics and outcomes of patients (pts) with HPV+ OPSCC who develop ICM. Methods: Retrospective analysis of pts with HPV+ OPSCC and ICM between 2010 - 2024. Demographic, clinicopathologic, and survival data was collected. Skull base recurrences were excluded. Univariate and multivariate analyses used Cox proportional hazard models; continuous variables binarized by receiver operator curves. Survival assessed via Kaplan-Meier method; reported as median (95% CI). Calculations use BlueSky (v10.3.1). Results: Among 1,999 pts with HPV+ OPSCC, 16 (0.8%) had ICM. Pt characteristics and treatment are summarized in Table 1. Primary tumor sites were base of tongue (56%), tonsil (38%), and unknown (13%). Most pts (n=8, 50%) presented with stage IV disease (6 extracranial metastasis (ECM), 1 ICM only, 1 both). Frontal and parietal lobes were the most frequent ICM sites. Neurological symptoms were present in 10 (62%) pts; ICM was incidentally found in 6 (38%) pts. Median overall survival (mOS) from initial diagnosis was 34 months (21 – not reached) and median time from diagnosis to ICM was 24 months (range 1-112). mOS following ICM detection was 10.9 months (4 -18). On multivariate analysis, only surgical resection (hazard ratio [HR] 0.03, p<0.01) and radiotherapy (HR 0.01, p<0.02) were independently associated with post-ICM survival. With median follow up of 100 months, 14 pts (88%) had died; 2 (12%) were alive. Conclusions: ICM from HPV+ OPSCC are rare but devastating with a mOS <1 year from detection. Most pts were symptomatic, had de novo metastatic disease, and had other sites of metastases. Surgical resection and radiation were associated with improved OS. Multicenter efforts to investigate predictors, multiomic sequencing and identification of pt subsets who may benefit from ICM screening are warranted. Baseline characteristics of Pts with ICM in HPV+ OPSCC. Variable Summary statistics (n=16) Median age (range) 58 (34-71) Male 14 (88%) Smoking history 10 (60%) Clinical stage at diagnosis Stage I: 4 (25%) Stage II: 2 (12.5%) Stage III: 2 (12.5%) Stage IV: 8 (50%) Symptoms at ICM diagnosis Incidental: 6 (38%)Neurological: 10 (62%) Seizure (n=3) Motor/Sensory symptoms (n=3) Altered mental status (n=2) Cognitive symptoms (n=1) Dizziness (n=1) ICM site Frontal lobe: 7 (44%) Parietal lobe: 7 (44%) Occipital lobe: 4 (25%) Temporal lobe: 2 (13%) Cerebellum: 2 (13%) Concurrent ECM Bone: 11 (69%) Lung: 9 (56%) Lymph node: 6 (38%) Liver: 5 (31%) Kidney: 1 (6%) Cranial nerve: 1 (6%) Treatment after ICM Radiotherapy: 15 (94%) Chemotherapy: 10 (63%) Immunotherapy: 9 (56%) Surgery: 8 (50%)

8545 Background: Brain metastases (BM) correlate with poor prognosis, occurring in 10% of non-small cell lung cancer (NSCLC) patients (pts) at diagnosis and up to 40% over the disease course. Immunotherapy (IO) with or without chemotherapy has become the new standard of care for stage IV NSCLC. However, the survival benefit of IO in pts with BM remains unclear as most studies are limited to small sample sizes or highly selected pts with asymptomatic or treated BMs. This study represents the largest real-world data analysis evaluating the survival benefits of IO in stage IV NSCLC pts with BM. Methods: Demographics, clinical features, and survival were analyzed in stage IV NSCLC pts with BM from the National Cancer Database (NCDB) from 2014-2020. A multivariate Cox proportional hazards modeling assessed factors impacting mortality. Results: Of 204,249 pts with stage IV NSCLC, 30% had BM. The mean age was 68 years, with 54% male. Most pts were White (82%), followed by Black (12%) and Asian (3.1%). Government insurance covered 70% of pts, and 26% had private insurance. Adenocarcinoma was the predominant histology (62%), followed by squamous cell carcinoma (SCC) (20%). Liver and bone metastases were observed in 19% and 42% of pts, respectively. Among pts with BM, 18% received immunotherapy, 53% received chemotherapy, 66% received whole-brain radiation, and 18% received limited-brain radiation. Multivariate Cox analysis showed that pts receiving IO had a 46% lower mortality risk compared to not receiving IO (HR: 0.54, 95% CI: 0.51–0.56, p < 0.001), demonstrating the independent benefit of IO in pts with BM, regardless of brain radiation or chemotherapy. Females had a lower mortality risk than males (HR: 0.88, 95% CI: 0.85–0.91, p < 0.001). Asian (HR: 0.71, 95% CI: 0.64–0.79), Hispanic (HR: 0.76, 95% CI: 0.65–0.89), and Black pts (HR: 0.88, 95% CI: 0.84–0.93) had improved survival as compared to White. Pts with private insurance have lower mortality risk (HR: 0.94, 95% CI: 0.90–0.98), compared to lack of insurance (HR: 1.19, 95% CI: 1.08–1.31). SCC was linked to worse survival (HR: 1.28, 95% CI: 1.22–1.35). Conclusions: IO significantly improves survival in pts with NSCLC with BM, regardless of brain radiation therapy or chemotherapy. However, survival disparities based on histology, insurance status, and demographic factors persist, highlighting the need for more equitable treatment strategies.

6106 Background: Treatment options for pts with R/M SGC are limited. Responses to chemotherapy (CT) are low with high toxicity and responses to immune checkpoint inhibition (ICI) are <10%. Pemetrexed (PTX) is safe and tolerable with responses reported in pts with R/M SGC. 1 Given enhanced responses with PTX and pembrolizumab (PMB) for lung cancer, we hypothesized that PTX and PMB will have activity for SGC. Herein we present the efficacy results in pts with non-adenoid cystic carcinoma (ACC). Methods: MC200708 is a single arm phase II study of PTX and PMB in pts with R/M SGC (NCT04895735). Pts were treated in 2 cohorts: ACC (cohort A) and non-ACC (cohort B). Key eligibility criteria: ≥18 years, ECOG 0-1, measurable disease. Prior ICI and/or PTX was allowed. Key exclusion criteria: serious comorbidities, autoimmune disease, and brain metastases. Simon’s 2-stage design was used for each cohort. Primary endpoint was overall response rate (ORR). Secondary endpoints: progression free survival (PFS), overall survival (OS), and toxicity. All pts received PTX 500 mg/m2 IV + PMB 200 mg IV q3 weeks until progression or treatment intolerance. Imaging was q3 cycles. Results: 25 pts were enrolled Aug 2021-Feb 2024; 1 cancelled prior to treatment. Of 24 eligible and treated pts, median age was 59.5 years (46-77), 66.7% male, performance status 0 (62.5%) or 1 (37.5%). Histologies were salivary duct carcinoma (SDC, 11), acinic cell carcinoma (8), mucoepidermoid carcinoma (MEC, 3), myoepithelial carcinoma (1), and carcinoma NOS (1). 7 pts had no prior therapies (29.2%). The remaining pts had 1 (33.3%), 2 (29.2%), or ≥ 3 lines of therapy (8.3%). 83.3% of pts had no prior ICI. Median cycles of treatment was 8 (2-34), and duration of response was 12.5 months (4.1-20.6). 9 of 24 pts had a confirmed partial response (PR) for ORR of 37.5% (CI: 18.8-59.4). PRs were seen in 7 pts with SDC (7 of 11, 63.6% PR), 1 with MEC, and 1 with acinic cell. Stable disease (SD) was seen in 5 (20.8%), progressive disease in 8 (33.3%), and 2 didn’t have post-baseline imaging, but were considered non-responders per protocol. Clinical benefit rate was 58.3% (CI: 36.6-77.9). With median follow-up of 12.0 months (2-34.7), median OS is 20.7 months (CI: 17.3-not reached) and median PFS is 6.2 months (CI: 2.1-17.3). 1-year OS and PFS rate is 76.3% (95% CI: 59.9-97.2) and 36.1% (CI: 21.01-62.2), respectively. Common toxicities were grade 1 fatigue and nausea. 6 pts (25.0%) had ≥1 grade 3-4 toxicity possibly related to treatment, mostly hematologic. The 4 pts with grade 3-4 non-heme toxicity had grade 3 fatigue, rash, and heart failure, and 1 grade 4 hypokalemia. Correlative studies investigating biomarkers of response are underway. Conclusions: PTX and PMB has activity in pts with R/M SGC, with promising responses in pts with SDC and median response duration of 1 year. 1 Viscuse et al. Head Neck 2019;41(6):E99-103. Clinical trial information: NCT04895735 .

e16610 Background: Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 1-2 per million per year. The optimal treatment remains unclear as does the benefit of chemotherapy (chemo) in patients (pts) with resectable ACC. Methods: The SEER database (2000–2021) was used to identify ACC pts > 18 years. Variables of interest included age, race, household income, rural-urban classification, stage, chemo, radiation therapy (RT), and surgery. Statistical analyses were conducted using ANOVA, Kruskal-Wallis, and Kaplan-Meier methods to compare survival outcomes according to variables of interest. Results: Of the 2,598 pts identified, 1,564 (60%) were female. The majority of pts (85%) were white, followed by black (9%). Most pts (87%) resided in metropolitan areas. Pts with localized, regional, or distant metastatic disease comprised 25%, 17% and 36% of the group, respectively. 40% of pts underwent radical or total surgical removal of the primary site disease while 9%, 2%, and 1% underwent partial surgical removal, excision, or debulking surgery, respectively, and 30% did not undergo surgery. 34% of pts received chemo and 8% received RT. The median overall survival (mOS) for the entire cohort was 15 months (m) (95% CI: 14–17 m). No significant differences in OS were observed among pts of different races or household incomes. Distant metastatic disease was significantly associated with worse mortality when compared with regional or localized diseases (mOS: 5 m vs. 20 m vs 60.6 m, respectively, p < 0.001). Surgical intervention of any kind was associated with longer survival when compared to those who did not undergo surgery (18 m vs. 3 m, HR 0.33, p < 0.0001). Among the 971 pts with distant metastatic disease, pts who received chemo had a superior mOS compared to those who did not receive chemo or with unknown chemo status (8 m vs. 2 m, p < 0.0001). This OS advantage remained significant even after excluding pts who underwent surgery (5 m vs. 2 m, p < 0.0001). While chemo was also associated with longer mOS (29 m vs. 27 m, p < 0.0001) in localized disease, this survival advantage was not present in pts with localized disease managed with surgery (27 m vs. 27 m, p = 0.061). Although chemo was associated with numerically longer mOS in pts with regional disease, the difference was not significant. Conclusions: ACC with distant metastatic disease carries a poor prognosis yet demonstrates superior survival in pts who receive chemo. Surgery is associated with better survival outcomes, but there is no additive benefit from chemo in those with localized disease managed with surgical resection.

e20141 Background: TET are rare and challenging entities in clinical practice. Prospective trials in thymoma and thymic carcinoma (TC) are scarce. Limited number of small trials investigated the role of ICI in TET, and showed some clinical efficacy, but also with immune related adverse events (irAE). Guidelines list ICI as a treatment option in the 2 nd line, although no FDA approval was granted. Aside from the small trials, there is limited real world data about the efficacy and toxicity of ICI in TET. Methods: We performed a retrospective chart review of the medical records of all patients (pts) with TET who were treated with ICI between 3/25/2011 and 11/30/2024 at 5 Mayo Clinic sites. We collected data about baseline characteristics, diagnosis, irAE, and outcomes. Kaplan-Meier method was used to calculate median progression free survival (mPFS), and hazard ratio (HR) with Cox proportional hazards regression. Results: 30 pts were included, 28 diagnosed with TC, and 2 with malignant thymoma. 70% of pts were male. Median age at time of diagnosis was 61 years (range: 15 to 82), and median ECOG at the time of diagnosis was 0. 29 pts received Pembrolizumab, and one received Durvalumab. Prior to ICI, 86.67% of patients received chemotherapy. 70% of pts discontinued ICI use, 60% due to progression, and 10% due to irAE. Overall response rate (ORR) was 23.33%, with 3.33% complete response, and 20% partial response. Disease control rate (DCR) was 63.33%. The mPFS was 10.13 months. At the time of analysis 60% of pts were still alive. 40% of patients had irAE. While the two patients with thymoma experienced irAE, only 33.33% of those with TC had these events. 26.67% of pts had thyroiditis. Pancreatitis, pneumonitis, dermatitis, and encephalitis each occurred in 3.33% of pts. The median time to irAE onset was 75 days. 25% of irAE were grade 1, 66.67% grade 2, 0% grade 3, and 8.33% grade 4, represented by the case of encephalitis. Resolution of irAE occurred in 33.33% of cases. When stratified according to the occurrence of irAE, the mPFS was the same in both groups, with or without irAE, being 10.13 months, HR=0.99 (95% CI 0.39 – 2.54). Conclusions: In this real-world cohort of pts with TET, efficacy of ICI matched what has been previously reported, with similar ORR and DCR, but with longer mPFS. However, irAE incidence was higher, but with less grade 3/4 events. Differently than what has been suggested in other diseases, irAE occurrence did not correlate with better outcomes. These results validate the role of ICI in the treatment of TET, especially TC. Nonetheless, improving patient selection, and developing other therapeutic strategies, including combinations of ICI and other drugs, for these malignancies remain essential. Importantly, the high incidence of irAE indicates that future investigations must also focus on safety of interventions and supportive care in TET.

Abstract Background: Leukocyte immunoglobulin-like receptor B2 (LILRB2) suppresses immune cell activation, particularly within myeloid cells in the tumor microenvironment (TME), while the PD-1/PD-L1 axis serves as a key immune checkpoint that inhibits T-cell function. SPX-303 is a novel bispecific antibody designed to simultaneously block LILRB2 and PD-L1, thereby revitalizing antitumor immune responses. Here, we present initial findings from the ongoing first-in-human Phase 1 trial of SPX-303 in patients with advanced solid tumors, including safety, pharmacokinetics (PK), and receptor occupancy (RO). Methods: This is an open-label, multicenter Phase 1 study for patients with advanced solid malignancies with 3+3 dose-escalation design, followed by an expansion cohort at the recommended Phase 2 dose (RP2D). SPX-303 is administered intravenously every three weeks and safety is assessed through CTCAE v5.0 criteria. Primary Objectives of this study are to determine the safety, tolerability, and RP2D of SPX-303. Secondary endpoints include antitumor activity as well as characterization of the PK and PD of SPX-303. This study is currently open and enrolling in escalation cohorts. Citation Format: Justin Moser, Hao Xie, Yujie Zhao, Yousef Zakharia, Dongdong Li, Brandon William, Dinh-Duc Nguyen, Jack Hovey, Tiffany Li, Robert Cai, Jichun Ma, Jingdong Qin, Martin Siekierzycki, Anthony Haight, Hua Jin, Weiwei Mao, Kevin Bin Li, Gui-Dong Zhu. A first-in-human phase 1 study on the safety, PK, receptor occupancy, and pharmacodynamic markers of SPX-303, a first-in-class LILRB2×PD-L1 bispecific antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT116.

Lung cancer remains the leading cause of cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, with nearly half of all patients diagnosed at an advanced stage. Immune checkpoint inhibitors (ICIs) harness the host immune system to combat malignant cells. ICIs, which target programmed death-ligand 1 (PD-L1), programmed cell death 1 (PD-1), and cytotoxic T-cell lymphocyte-4 (CTLA-4), have transformed the treatment landscape for advanced NSCLC. While a subset of patients experiences a long-term durable response, most patients will develop disease progression. New drugs targeting novel pathways are being tested in clinical trials to improve the efficacy of immunotherapy and overcome resistance patterns. This review aims to summarize the currently available ICIs for advanced NSCLC and describe emerging immunotherapies with recently published data from phase I/II clinical trials.