1534 Background: While the official purpose of ClinicalTrials.gov is to satisfy regulatory requirements from the U.S. Food and Drug Administration meant to safeguard human subjects, the database also serves as the most comprehensive record of ongoing clinical trials for patient and provider use. Previous studies have focused on compliance with results reporting and completeness of information within restricted subsets of the database. Taking the perspective of a potential participant or their provider, the purpose of this study was to assess the accessibility of ClinicalTrials.gov contact information across actively recruiting oncology and non-oncology studies. Methods: This study included all actively recruiting interventional studies listed in the ClinicalTrials.gov database as of June 11, 2025. We assessed the completeness of location and contact information by multiple factors including oncology versus non-oncology study, sponsor type, trial phase, study start date, and date of last posted update. Within oncology studies, we further analyzed information availability by disease subsite. Results: We identified 47,703 actively recruiting interventional trials, among which 12,400 (26.0%) pertained to oncology. Within these oncology studies, 3178 (25.6%) had an industry sponsor, 9729 (78.5%) had a study phase listed (among which 59.4% were Phase 2 studies), and 4311 (34.8%) involved an FDA-regulated drug. Across both oncology and non-oncology studies, 2678 (5.6%) were missing any central contact information. While all trials had at least one study location listed, 3492 (7.3%) did not include a location-specific contact name and 9994 (21.0%) had neither a location-specific contact phone nor email address (24.1% for oncology, 19.8% for non-oncology). Within oncology trials, 50.9% of studies with an industry sponsor lacked any location-specific contact phone or email, compared to 11.3% for NIH sponsors and 14.9% for other (including academic) sponsors. Completeness of location-specific contact information was similar across trial phases. By oncology disease subsite, thoracic trials (29.8%) or those including multiple disease subsites (33.8%) most often lacked location-specific contact phone and email, whereas head and neck (15.4%) and neuro-oncology (16.3%) trials were least likely to do so. Conclusions: Location remains a primary means by which many potential trial participants filter clinical trial opportunities. Missing location-specific contact information, particularly among trials with industry sponsors, is an area of potential improvement that could be addressed by increased attention or more stringent registration requirements. While emerging strategies to improve clinical trial accessibility include artificial intelligence-powered platforms, these are only as good as the primary data on which they are built.

TPS6134 Background: Head and neck squamous cell carcinoma (HNSCC) has high recurrence rates despite standard perioperative treatments such as surgery with adjuvant radiotherapy and/or chemotherapy, with about 35% of patients relapsing. Neoadjuvant immune checkpoint therapy has shown promise: in the Phase III KEYNOTE-689 trial, adding perioperative pembrolizumab to standard care significantly improved median event-free survival (51.8 vs 30.4 months), leading to FDA approval in June 2025. However, only 9.4% of patients achieved a major pathologic response, a key predictor of reduced relapse and a surrogate for long-term benefit in other cancers. This low response rate underscores the need for more effective strategies to expand and deepen durable immune-mediated tumor responses in HNSCC. Our strategy is to develop a combination immunotherapy/gene therapy targeting the immunosuppressive myeloid populations such as tumor-associated macrophages (TAMs) and neutrophils (TANs), which are increasingly recognized as key mediators of immune evasion and poor outcomes. VLPONC-01 is a novel, non-replicating, viral particle-based therapy to target TAMs and TANs. VLPONC-01 efficiently delivers self-amplifying RNA (saRNA) encoding an engineered human Interleukin 12 (IL-12) gene into cells in the tumor microenvironment (TME), leveraging the natural tropism of Venezuelan equine encephalitis virus (VEEV). Within transfected cells, the RNA amplifies itself and directs the cell to produce and secrete IL-12 protein. The released IL-12 is expected to concentrate in the TME, where it activates immune cells and enhances their ability to attack cancer cells. Methods: This is a first-in-human, phase 1, open-label trial evaluating the safety and early efficacy of intratumoral administration of VLPONC-01 in patients with HNSCC, focusing on its ability to reduce tumor burden and lessen surgical morbidity. Furthermore, it will characterize IL-12-driven alterations in the tumor microenvironment and determine the synergistic potential of combining this approach with anti-PD-1 immunotherapy. The study includes two cohorts: Cohort A tests weekly intratumoral injection in recurrent and/or metastatic tumor patients to assess safety and determine dose levels, while Cohort C randomizes patients with resectable tumors into three groups to receive low-dose VLPONC-01 plus pembrolizumab, high-dose VLPONC-01 plus pembrolizumab, or pembrolizumab alone, prior to surgery. Outcomes include dose-limiting toxicities, surgical delays, systemic cytokine responses, and tumor response assessed by imaging and pathology. Clinical trial information: NCT06736379 .

BACKGROUND:Neoadjuvant PD-1/PD-L1 blockade yields robust efficacy in advanced cutaneous squamous cell carcinoma (cSCC), yet many patients fail to achieve a complete or major pathologic response. The reasons why some patients experience response but others do not are unclear. METHODS:We profiled cSCC specimens before, after 1 dose, and after 3-4 doses of PD-1/PD-L1 blockade to uncover resistance mechanisms and predict therapeutic response. In total, 27 patients across three cohorts, including two phase II trials, were studied. We created 1.7 mm tissue-core microarrays and performed single-cell spatial transcriptomics, including spatial clustering, gene-set enrichment, and spatial correlation analyses. RESULTS:After profiling all samples, six distinct spatial niches emerged, each differentially enriched in responders versus non-responders. A high antigen presentation niche, B/plasma cell enriched niche, and inflammatory keratinocyte niche were more frequent in responders, whereas proliferative keratinocyte, low antigen presentation myeloid, and fibroblast-rich epithelial-mesenchymal transition niches prevailed in non-responders. Notably, spatial niche profiling on pretreatment samples outperformed PD-L1 status in predicting pathologic response. Each niche displayed unique gene coexpression modules, suggesting niche-specific resistance mechanisms. Individual tumor analyses revealed varied immune evasion strategies, including defective interferon-induced antigen presentation, immunosuppressive myeloid environments, and epithelial-mesenchymal transition. CONCLUSIONS:Our single-cell spatial transcriptomic approach identifies six spatial niches that predict immunotherapy response better than PD-L1 status using only 1.7 mm tissue cores and may inform the development of biomarkers. Our results further underscore the heterogeneity of resistance mechanisms among cSCC patients, highlighting the need for tailored therapeutic strategies.

6006 Background: Single agent pembrolizumab in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC) has limited activity. The immunosuppressive tumor microenvironment (TME) includes regulatory T cells (Treg)s and myeloid-derived suppressor cells (MDSC)s, which may contribute to the low responses to anti-PD-1 therapy. Preclinical studies demonstrate that anti-PD-1 antibodies induce Treg activation through the AKT pathway. AKT blockade selectively inhibits the proliferation of human Tregs compared to conventional T cells. Furthermore, inhibiting the AKT pathway limits MDSC infiltration and differentiation while boosting effector T cell function within tumors. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. This phase II trial compares the efficacy of combination ipatasertib plus pembrolizumab (I+P) versus pembrolizumab (P) monotherapy in R/M HNSCC. Methods: This is a prospective, two-arm, phase II, multicenter trial for 1 st line treatment of R/M HNSCC. Patients were randomized 1:1 to either Arm 1 - P 200mg on day 1 with I 400mg daily on days 1-14 of 21-day cycles, or Arm 2 – P monotherapy. PD-L1 CPS score ≥1 was required. The primary objective is to compare the PFS between the two arms. Secondary objectives included safety and ORR per RECIST 1.1. Results: As of 1/21/2026, 52 patients were randomized, with 27 enrolled in the I+P arm. The median age was 67 and 77% were male. The primary tumor sites were 46% oral cavity, 38% oropharynx, and 15% larynx. Among pts with oropharynx primary, 75% were p16 positive. PD-L1 CPS score was ≥20 in 60%. In the I+P arm the most common G1-3 treatment-related adverse events (TRAEs) occurring in ≥10% were diarrhea (70.4%), fatigue (44.4%), Nausea (40.7%), AST increase (18.5%), ALT increase (14.8%), and maculopapular rash (14.8%). Only 1 pt had grade 3 diarrhea. In P arm the most common G3 TRAEs were maculopapular rash (29.2%), AST increase (16.7%), and diarrhea (12.5%). There were no G4 or G5 TRAEs. Four patients required dose reduction of ipatasertib, primarily for diarrhea. Ten pts in the I+P arm and 6 pts in P arm required dose interruptions. One patient in each arm discontinued due to adverse events. At the data cutoff 4 pts remain on treatment in I+P arm and 2 remain on P arm. The ORR in I+P arm and P arm was 41% and 17% respectively. The CR rate was 15% in I+P arm and 4.2% in P arm. The DCR (CR+PR+SD) was 70% in I+P arm and 42% in P arm. With a median follow up of 7.0 months, the PFS in I+P arm is 8.1 months (95% CI: 4 – NA) and in P arm is 6.2 months (95% CI 1.9 – 13.5). Conclusions: I+P demonstrated an acceptable safety profile and shows promising clinical activity in R/M HNSCC. Clinical trial information: NCT05172258 .

PURPOSE:A first-in-human phase I study was conducted in patients with nasopharyngeal carcinoma to assess the safety and tolerability of VK-2019, a small-molecule selective inhibitor of Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1). PATIENTS AND METHODS:Pharmacokinetic and pharmacodynamic studies were performed, including the measurement of EBV DNA plasma levels. Twenty-three patients received VK-2019 orally once daily at doses ranging from 60 to 1,800 mg using an accelerated titration design, with cohort expansion at 1,800 mg. EBV genome copy number and spatial transcriptomic analyses were conducted on biopsies collected from three patients at baseline and after treatment. RESULTS:VK-2019 was well tolerated. One patient achieved a partial response. Pharmacokinetic results demonstrated good systemic exposure, with high intersubject variability. Decreases in EBV DNA plasma levels were observed in some patients. VK-2019 reduced EBV genome copy number and viral gene expression in patient tumor samples and induced changes in immune cell markers. CONCLUSIONS:VK-2019 at dosages up to 1,800 mg daily demonstrated an acceptable safety profile, achieved micromolar plasma concentrations, and showed on-target biological activity in tumors from patients with advanced EBV-positive nasopharyngeal carcinoma.

6092 Background: Squamous cell carcinoma metastatic to the head and neck arising from an unknown primary tumor (hnSCCUP) is a common presentation for HPV-associated oropharyngeal carcinoma. Previously, with traditional approaches, rates of primary site identification for hnSCCUP were low. Using diagnostic transoral robotic surgery (TORS), primary tumors are now routinely found. In this report, we evaluate the histopathology and oncologic outcomes of these tumors. Methods: A retrospective review was conducted on 100 patients referred to Stanford University for hnSCCUP evaluation between October 2013 and April 2022. A final cohort of 80 patients who remained classified as hnSCCUP after comprehensive multidisciplinary review was analyzed. Surgical excision followed a standardized protocol targeting oropharyngeal subsites, and specimens were meticulously analyzed by three H&N pathologists. Results: The primary site was identified in 66 of 80 patients (83%), with a mean tumor size of 6 mm (range: 2–20 mm). Among the identified tumors, 97% were staged as T1, and 71% measured ≤1 cm, confirming their predominantly microscopic nature. The most common tumor locations were the palatine tonsil (26%), lateral tongue base (24%), glossopharyngeal sulcus (21%), and midline tongue base (18%). Histologically, most tumors exhibited a pushing pattern embedded within lymphoid stroma, while 29% demonstrated a pagetoid growth pattern, spreading in a ribbon-like distribution along the superficial lymphoepithelium. Following diagnostic TORS, 23 patients (29%) underwent further surgery, including 10 with surgery alone and 13 with adjuvant therapy. Radiation alone was administered to 15 patients (19%), while 42 patients (53%) underwent chemoradiation. At a median follow-up of 38 months (range: 12–101 months), 77 patients (97%) were alive with no locoregional tumor recurrence. Two patients (2.5%) developed distant metastases, with one death, and one patient (1.2%) experienced persistent regional disease after chemoradiation. Functional swallowing outcomes declined temporarily across all treatment groups. At six months, patients who underwent surgery alone had the least decline in Functional Oral Intake Scale (FOIS) scores, while those receiving chemoradiation experienced the greatest impact. By one year, all patients showed significant recovery, with no long-term feeding tube dependence. Conclusions: With a systematic surgical technique for p16+ oropharyngeal carcinoma, diagnostic TORS has revealed a unique pattern of small-volume, often microscopic primary tumors often initially mistaken as hnSCCUP. In many cases, it seems the unknown primary represents a T1-microscopic tumor measuring < 1 cm in maximum diameter with a prominent pattern of submucosal spread.

Ad/PNP (Gedeptin®) is a non-replicating adenoviral vector expressing E. coli purine nucleoside phosphorylase (PNP) for intratumoral injection (IT) followed by IV administration of fludarabine (Flu) (Parker, Sorscher. Curr Pharm Design. 2017). The resulting metabolite, fluoroadenine (F-Ade), inhibits RNA and protein synthesis, irrespective of mitotic state. This provides an anticancer modality directed at the quiescent cancer cell compartment and tumor microenvironment (TME). F-Ade has activity against human-tumor xenografts when as few as 2.5-10% of cells express PNP. Initial evaluation of single cycle Gedeptin in patients with head & neck cancer (H&N Ca) and melanoma demonstrated safety and efficacy with a response rate of 66.7% in the two highest dose cohorts (Rosenthal, et al. Ann Oncol. 2015). No subject experienced DLT and none discontinued study therapy. There was no evidence for increased treatment-related adverse events or serious adverse events (SAEs) across dose cohorts. The most frequent treatment-emergent adverse events were associated with IT injection, primarily injection site pain. A follow-on trial with repeated cycles of Gedeptin in 8 patients with advanced H&N Ca (6 with squamous cell Ca, 1 with nasopharyngeal Ca, 1 with lymphoepithelial Ca) has now been completed. With each 28-day cycle, subjects received 3 IT injections of 2.0 X 1011 viral particles of Gedeptin over 2 days followed by 3 daily infusions of Flu 25 mg/m2. Patients were heavily pretreated with median time from diagnosis of 46.7 months, four prior lines of systemic therapy (range 2-5), and prior surgery and/or radiotherapy. Patients completed one to five cycles of therapy. Stable disease was observed in three patients (37.5%), and progressive disease in two (25%). Responses were non-evaluable among three patients (37.5%). Median PFS and OS were each 7.0 months. Lower efficacy was thought due to more refractory disease, lower total Gedeptin dose and/or poor transduction efficiency. Toxicity was acceptable with a low rate of treatment-related AEs. Four deaths were reported due to disease progression. Five patients (62.5%) experienced SAEs: dysphagia, vomiting, fever, pneumonia, dehydration, and tumor hemorrhage. These were considered not treatment related, except vomiting (possibly related). Correlative endpoints describe successful tumor transduction, PNP transgene expression, and potential biomarkers corresponding to tumor regression. Enrollment was challenging in these heavily pretreated patients. In preclinical studies, Gedeptin/Flu strongly sensitizes tumors to immune checkpoint inhibition (ICI), presumably by destroying tumor tissue locally and exposing neoantigens, enhancing immune response, and promoting activity of ICI. Accordingly, an upcoming Phase II trial will evaluate Gedeptin/Flu/pembrolizumab as neoadjuvant therapy in patients with primarily relapsed squamous cell H&N squamous cell cancer. A. Dimitrios Colevas, Eric J. Sorscher, William B. Parker, Luis Fernando Ramirez, Jeong S. Hong, Regina Rab, Nicole C. Schmitt, Madison M. Stallings, Kelly T. McKee, Eben Rosenthal, Erica Raiden, Nabil F. Saba, J. Marc Pipas, Joseph M. Curry. Viral-vectored, gene-directed prodrug therapy (Gedeptin) in needle-accessible solid tumors [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 CT165.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.

BACKGROUND:Advance care planning and serious illness conversations can help clinicians understand patients' values and preferences. Data are limited on how to increase the number of these conversations and what their effects are on care patterns. We hypothesized that using a machine learning survival model to select patients for serious illness conversations, along with trained care coaches to conduct the conversations, would increase uptake in patients with cancer at high risk of short-term mortality. METHODS:We conducted a cluster-randomized, stepped-wedge study on the physician level. Oncologists entered the intervention condition in a random order over 6 months. Adult patients with metastatic cancer were included. Patients with a less than 2-year computer-predicted survival and no prognosis documentation were classified as high priority for serious illness conversations. In the intervention condition, clinicians received automated weekly emails highlighting high-priority patients and were asked to document prognoses for them. Care coaches contacted these patients to conduct the remainder of the conversation. The primary endpoint was the proportion of visits with prognosis documentation within 14 days. RESULTS:We included 6372 visits with 1825 patients in the primary analysis. The proportion of visits with prognosis documentation within 14 days was higher in the intervention condition than in the control condition: 2.9% vs 1.1% (adjusted odds ratio = 4.3, P < .001). The proportion of visits with advance care planning documentation was also higher in the intervention condition: 7.7% vs 1.8% (adjusted odds ratio = 14.2, P < .001). For high-priority visits, the advance care planning documentation rate in intervention visits was 24.2% and in control visits was 4.0%. CONCLUSION:The intervention increased documented conversations, with contributions by both clinicians and care coaches.

BACKGROUND:Immune checkpoint inhibitors (ICIs) are associated with cardiotoxicities such as myocarditis. However, data on the implementation and outcomes of cardiac biomarker screening remain limited. OBJECTIVES:The aim of this study was to examine the impact of cardiac troponin I (cTnI) surveillance integrated with symptom-based triaging in patients receiving immunotherapy. METHODS:A single-center retrospective cohort study was conducted among adults who underwent routine serial cTnI monitoring during immunotherapy between January 2019 and October 2021. For patients with elevated cTnI, clinical presentation, management, and outcomes were analyzed. Major adverse cardiac events included arrhythmia, myocarditis, heart failure, acute coronary syndrome, stroke, and pericardial effusion. Patients were followed for 24 months from their first ICI dose. RESULTS:Among 428 patients (mean age 67.1 ± 13.9 years, 60.3% men), 42 (9.8%) had elevated cTnI detected through monitoring. Compared with symptomatic patients, asymptomatic patients more often underwent outpatient evaluation (88.0% vs 17.6%; P < 0.001) and continued immunotherapy (68.0% vs 35.3%; P < 0.001), whereas symptomatic patients more often underwent myocarditis-specific diagnostics such as cardiac magnetic resonance imaging (58.8% vs 8.0%; P = 0.001) and received immunosuppression (47.1% vs 8.0%; P = 0.008). The cumulative incidence of major adverse cardiac events at 1.5 years following cTnI elevation was 19.0% (95% CI: 7.0%-31.1%) and was significantly higher in symptomatic vs asymptomatic patients (subdistribution HR: 18.9; 95% CI: 2.2-162.5; P = 0.008). Symptomatic patients had a significantly higher risk for all-cause mortality at 2-year follow-up (HR: 3.24; 95% CI: 1.06-9.94; P = 0.04). In total, 6 patients were diagnosed with myocarditis, with no cardiac-related deaths. CONCLUSIONS:cTnI surveillance integrated with symptom-based triaging can facilitate early intervention and treatment of cardiotoxicities such as myocarditis.

There is increasing interest in use of neoadjuvant immunotherapy (NAT) in advanced cutaneous squamous cell carcinoma (cSCC) to reduce surgical morbidity and forego adjuvant therapy, while potentially improving survival outcomes. To assess the cost to Medicare of NAT compared with up-front surgery. This cohort study was a post hoc analysis of a phase 2 clinical trial evaluating the feasibility of neoadjuvant atezolizumab. The study was conducted from June 2021 to December 2023 at a tertiary-level academic institution among 20 patients with advanced stage II-IV cSCC. Up to 3 doses of neoadjuvant atezolizumab, followed by surgical resection with or without adjuvant radiation therapy. Direct medical costs in US dollars of care received on trial were compared with baseline treatment plans of up-front surgery developed a priori from a Medicare payer perspective. Of 20 patients with advanced cSCC enrolled (median [range] age, 71.5 [53-88] years; 17 male [85.0%]), most individuals had stage III (12 patients [60.0%]) or IV (5 patients [25.0%]) disease. The median (range) follow-up was 14.2 (3.5-28.7) months. Compared with $26 602.67 for up-front surgery, NAT was associated with mean overall costs of $51 561.02, or a 93.8% increase, equivalent to $24 958.36 (95% CI, $22 057.95 to $24 692.43) per patient, which was primarily associated with the drug acquisition costs of atezolizumab ($30 603.96). NAT was associated with mean cost reductions from $12 707.07 to $10 543.71 (17.0%) in surgery and $11 711.97 to $7157.32 (38.9%) in radiation across all patients compared with up-front surgery. Adjuvant radiation therapy was obviated in 5 of 17 patients not previously irradiated (29.4%), reducing costs of radiation. Mean (SD) surgical complexity was reduced from 63.81 (30.55) to 44.71 (32.49) work relative value units (wRVUs; difference, 19.10 wRVU; 95% CI, 5.00 to 33.20 wRVU). NAT was associated with 5 fewer free flaps, 4 fewer neck dissections, 5 more organ-preserving resections, and 3 conversions from inpatient to outpatient surgery. This study found that treatment with 3 doses of NAT was associated with an overall cost increase compared with up-front surgery, driven by drug acquisition costs, and cost reductions from less extensive surgical resections and obviated adjuvant radiation. Predictive markers for response to NAT could optimize patient selection and improve cost-effectiveness. ClinicalTrials.gov Identifier: NCT04710498.

BACKGROUND:Nasopharyngeal carcinoma (NPC) mortality varies based on multiple risk factors. While NPC mortality is higher in Asia, little is known about Asian subgroups in the United States (US). METHODS:Using the 2005-2020 National Vital Statistics System, we examined NPC mortality by age, race (non-Hispanic black, Hispanic white (HW), non-Hispanic white (NHW), Chinese, Filipino, Asian Indian, Japanese, Korean, Vietnamese), sex, and nativity (Untied States or foreign-born). RESULTS:Upon disaggregation, Chinese (1.96 [CI: 1.78-2.16]), Filipino (0.68 [0.68-1.11]), and Vietnamese Americans (0.68 [0.52-1.10]) had the top age-adjusted mortality rates (AAMR per 100 000 person-years). Foreign-born Chinese, Vietnamese, Filipinos, Asian Indians, and NHW had higher AAMRs compared to US-born persons. All male groups had higher AAMR compared to females. Stratifying for race, nativity, and sex, foreign-born Chinese males (4.09 [3.79-4.40]) had the highest AAMR. CONCLUSION:These findings demonstrate the importance of disaggregating NPC mortality data by Asian subgroups, providing valuable insights for targeted public health interventions in the United States.

PURPOSE To evaluate the feasibility of administering three doses of neoadjuvant atezolizumab before curative surgical resection in patients with advanced cutaneous squamous cell carcinoma (cSCC). PATIENTS AND METHODS This single-arm phase II trial included patients with cSCC of the head and neck with stage III or IV disease, or stage II lesions for which standard therapy would incur an unacceptable morbidity. Patients received up to three doses of atezolizumab at a fixed dose of 1,200 mg every 21 days before undergoing surgical resection. The primary end point was the percentage of patients able to complete three doses of therapy and be eligible for surgical resection without discontinuation due to toxicity or progression. Secondary end points included unconfirmed RECIST 1.1 response rate, pathological response rate (major and complete pathological response), and safety and tolerability of atezolizumab. RESULTS Twenty patients were enrolled and treated. Sixteen (80%) of 20 patients completed three doses of atezolizumab, and all patients were eligible for surgical resection. A pathological complete response was seen in seven (35%; 95% CI, 15.4 to 59.2) patients, and a major pathological response (<10% viable tumor) was seen in four (20%; 95% CI, 5.7 to 43.7) patients. RECIST responses were seen in eight (40%; 95% CI, 19.1 to 64.0) patients, and one (5%) patient progressed. Grade 3 or higher adverse events were seen in one (5%) patient who developed pneumonitis after the first dose of atezolizumab. CONCLUSION Neoadjuvant atezolizumab is feasible and well tolerated in patients with advanced cSCC and results in a high rate of major and complete pathological responses.

BACKGROUND:Epstein-Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) is an autologous adoptive T-cell immunotherapy generated from the blood of individuals and manufactured without genetic modification. In a previous phase II trial of locally recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) patients, first-line gemcitabine and carboplatin (GC) and EBV-CTL combination demonstrated objective antitumor EBV-CTL activity and a favorable safety profile. The present study explored whether this combined first-line chemo-immunotherapy strategy would produce superior clinical efficacy and better quality of life compared with conventional chemotherapy treatment. PATIENTS AND METHODS:This multicenter, randomized, phase III trial evaluated the efficacy and safety of GC followed by EBV-CTL versus GC alone as first-line treatment of R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the USA were included. Subjects were randomized to first-line GC (four cycles) and EBV-CTL (six cycles) or GC (six cycles) in a 1 : 1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety. CLINICALTRIALS:gov identifier: NCT02578641. RESULTS:A total of 330 subjects with NPC were enrolled. Most subjects in both treatment arms received four or more cycles of chemotherapy and most subjects in the GC + EBV-CTL group received two or more infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC + EBV-CTL subjects. The median OS was 25.0 months in the GC + EBV-CTL group and 24.9 months in the GC group (hazard ratio = 1.19; 95% confidence interval 0.91-1.56; P = 0.194). Only one subject experienced a grade 2 serious adverse event related to EBV-CTL. CONCLUSIONS:GC + EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS versus chemotherapy. This is the largest adoptive T-cell therapy trial reported in solid tumors to date.

TPS6117 Background: Single agent pembrolizumab in relapsed / metastatic head and neck squamous cell carcinoma (R/M HNSCC) has an estimated ORR of 19% and median OS of 13.6 months. There are several factors which may influence which patients respond to antibodies targeting the PD-1 axis. Regulatory T cells (Tregs) play a significant role in an immunosuppressive tumor microenvironment. Anti-PD-1 antibodies induce Treg activation in part through AKT pathway activation, which may contribute to low response rates to checkpoint inhibitor therapy. AKT blockade selectively inhibits the proliferation of human Tregs. Additionally, inhibition of the PI3K-AKT-mTOR pathway limits myeloid-derived suppressor cells (MDSC) infiltration and differentiation, and boosts CD8+ T cell memory and effector function. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. This phase 2 trial is designed to compare progression-free survival (PFS) in first line R/M, HNSCC patients treated with the combination ipatasertib and pembrolizumab versus pembrolizumab monotherapy treatment. Methods: In this open-label randomized phase 2 multicenter trial, patients with R/M HNSCC are treated with pembrolizumab 200mg on day 1 +/- ipatasertib 400mg QD days 1-14 of 21-day cycles. Patients must have PD-L1 CPS score ³ 1, have measurable disease per RECIST 1.1, and consent to on-treatment biopsy. Patients will be excluded if they have received prior systemic therapy for R/M HNSCC, cannot swallow a pill, or require insulin for diabetes. The primary objective is to compare the PFS between the two arms. We will estimate the relative hazard ratio associated with ipatasertib plus pembrolizumab compared to pembrolizumab alone using the Cox Model where randomized treatment assignment is the only variable in the model. Secondary objectives include ORR, safety and tolerability of the combination, and changes in tumor immune cell infiltration, AKT signaling, and changes in peripheral blood immune cells. Ultimately, a total of 48 patients will be enrolled, with 24 patients in each cohort. To date, a total of 22 patients have been enrolled from 15 sites. Accrual is ongoing (NCT05172258). Clinical trial information: NCT05172258 .

Purpose:Immune checkpoint inhibitors (ICI) used as cancer therapy have been associated with a range of cardiac immune-related adverse events (irAEs), including fulminant myocarditis with a high case fatality rate. Early detection through cardiotoxicity screening by biomarker monitoring can lead to prompt intervention and improved patient outcomes. In this study, we investigate the association between cardiotoxicity screening with routine serial troponin I monitoring in asymptomatic patients receiving ICI, cardiovascular adverse event (CV AE) detection, and overall survival (OS). Methods:We instituted a standardized troponin I screening protocol at baseline and with each ICI dose (every 2-4 weeks) in all patients receiving ICI at our center starting Jan 2019. We subsequently collected data in 825 patients receiving ICI at our institution from January 2018 to October 2021. Of these patients, 428 underwent cardiotoxicity screening with serial troponin I monitoring during ICI administration (Jan 2019-Oct 2021) and 397 patients were unmonitored (Jan 2018-Dec 2018). We followed patients for nine months following their first dose of ICI and compared outcomes of CV AEs and OS between monitored and unmonitored patients. Additionally, we investigated rates of CV AEs, all-cause mortality, and oncologic time-to-treatment failure (TTF) between patients with an elevated troponin I value during the monitoring period versus patients without elevated troponin I. Results:We found a lower rate of severe (grades 4-5) CV AEs, resulting in critical illness or death, in patients who underwent troponin monitoring (0.5%) compared to patients who did not undergo monitoring (1.8%), (HR 0.17, 95% CI 0.02-0.79, p = 0.04). There was no difference in overall CV AEs (grades 3-5) or OS between monitored and unmonitored patients. In the entire cohort, patients with at least one elevated troponin I during the follow up period, during routine monitoring or unmonitored, had a higher risk of overall CV AEs (HR 10.96, 95% CI 4.65-25.85, p<0.001) as well as overall mortality (HR 2.67, 95% CI 1.69 - 4.10, p<0.001) compared to those without elevated troponin. Oncologic time-to-treatment failure (TTF) was not significantly different in a sub-cohort of monitored vs. unmonitored patients. Conclusions:Patients undergoing cardiotoxicity screening with troponin I monitoring during ICI therapy had a lower rate of severe (grade 4-5) CV AEs compared patients who were not screened. Troponin I elevation in screened and unscreened patients was significantly associated with increased CV AEs as well as increased mortality. Troponin I monitoring did not impact oncologic time-to-treatment-failure in a sub-cohort analysis of patients treated with ICI. These results provide preliminary evidence for clinical utility of cardiotoxicity screening with troponin I monitoring in patients receiving ICI therapy.

6004 Background: Immuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein and 4 molecules of attenuated human interleukin-2 (IL-2), to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ HNSCC. Methods: CUE-101-01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ R/M HNSCC. Escalating doses of CUE-101 monotherapy (0.06 mg/kg to 8 mg/kg) were evaluated in R/M HNSCC refractory to ≥ 1 platinum or checkpoint inhibitor (CPI) based therapy, alone or combined with pembrolizumab (1 mg/kg to 4 mg/kg + 200 mg pembrolizumab) in the first line treatment of PD-L1+ R/M HNSCCs. Enrollment at the recommended phase 2 dose (RP2D) was expanded. Therapy was administered every 3 weeks (Q3W) until disease progression or intolerable toxicity. Safety, PK/PD, and antitumor activity were assessed. Results: Enrollment in both monotherapy and combination cohorts is now completed (N=80 patients, 49 in monotherapy and 31 CUE-101 plus pembrolizumab). Following dose escalation, 4 mg/kg Q3W of CUE-101 was selected for RP2D for both monotherapy and pembrolizumab combination cohorts. At data cut-off, adverse events (AEs) have been manageable and 92% grade ≤2. The most frequent grade 3 AEs reported include lymphocyte count decreased (7.6%), anemia (6.3%), decreased appetite (5.1%) and infusion-related reactions (5.1%). In combination with pembrolizumab no unanticipated significant safety concerns have emerged. Exposure-dependent PD effects of CUE-101 are consistent with IL-2 pharmacology and indicate preferential expansion of CUE-101 on E7-specific T cells. Among the 19 evaluable patients treated with the RP2D of CUE-101 plus pembrolizumab, an ORR of 47% (1 CR, 8 PRs), a Disease Control Rate (ORR + durable SDs) of 74%, and mPFS of 5.8 months [95% CI 2.56; NA] were observed. A median OS has not been reached. Of the 9 patients with confirmed objective responses, all achieved >99% reduction in HPV16 cfDNA in plasma during their treatment course. Among the 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) and mOS of 20.8 months [95% CI 11.0; NA] were observed. Conclusions: An ORR of 47% and a mPFS of 5.8 months were observed in R/M HNSCC patients treated with CUE-101 4 mg/kg + pembrolizumab as 1L therapy. A median OS of 20.8 was observed in patients treated with CUE-101 monotherapy as post-platinum/CPI therapy. CUE-101 continues to demonstrate safety, tolerability and meaningful clinical benefit in patients with HPV16+ R/M HNSCC. Clinical trial information: NCT03978689 .

Purpose/Objective(s)Novel combination therapies are needed to improve outcomes in RM-HNSCC. Magrolimab is a monoclonal antibody that blocks CD47, a “don't eat me” signal overexpressed on cancer cells. Magrolimab induces macrophage-mediated phagocytosis of tumor cells and may synergize with chemotherapy agents through enhancement of phagocytic signals. The phase 2 ELEVATE HNSCC multicenter, open-label study (NCT04854499) is evaluating magrolimab-containing regimens in patients (pts) with RM-HNSCC. Here, we report data from 2 safety run-ins (SRI1 and SRI2) designed to assess safety/tolerability and recommended phase 2 dose (RP2D) of magrolimab in combination with standard of care.Materials/MethodsPts in SRI1 with previously untreated RM-HNSCC received magrolimab+pembrolizumab+platinum+5-fluorouracil; pts in SRI2 with locally advanced or RM-HNSCC (1-2 lines of prior systemic therapy) received magrolimab+docetaxel. Magrolimab was first administered as a 1 mg/kg priming dose, followed by weekly 30 mg/kg doses for two 21-day cycles and then a maintenance dose of 60 mg/kg Q3W. Pembrolizumab and chemotherapy were given per standard of care. Primary endpoints of the SRI were incidence of adverse events (AEs) and dose-limiting toxicities (DLTs). Safety was assessed in pts who received ≥1 dose of study drug. The incidence of DLTs was assessed using pts who experienced a DLT during the DLT evaluation period or who completed ≥2 magrolimab and ≥1 combination agent doses. To select an RP2D, ≤2 of 6 DLT-evaluable pts could experience a DLT, or the magrolimab dose would be de-escalated and a new cohort would be assessed.ResultsAt least 6 pts from each SRI were DLT-evaluable. The safety analysis population was 6 pts in SRI1 and 7 pts in SRI2. No DLTs were reported. Treatment-emergent AEs (TEAEs) occurred in 6/6 (SRI1) and 7/7 (SRI2) pts. In SRI1, the most common (≥4 pts) TEAEs were fatigue (5/6), diarrhea, nausea, decreased platelet count, stomatitis, and decreased white blood cell count (4/6 each). In SRI2, the most common (≥4 pts) TEAEs were anemia (5/7) and fatigue (4/7). TEAEs leading to magrolimab discontinuation occurred in 1/6 pts in SRI1 (fatigue) and 1/7 pts in SRI2 (oral cavity fistula unrelated to study drug). In SRI1, no deaths were reported; in SRI2, 3 deaths were reported as unrelated to study treatment and occurred after the DLT evaluation period: oral cavity fistula, pneumonia, and disease progression (during long-term follow-up).ConclusionThe observed safety profile was as expected based on the known toxicity profiles of the individual agents. Magrolimab appears tolerable in these combinations. No DLTs or treatment-related deaths occurred. Magrolimab RP2D was declared at the initial dose level tested in both SRIs.