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 .

BACKGROUND:Patients with HPV+ oropharyngeal cancer (OPC) have worse outcomes with longer smoking history (≥ 10 pack-years). This has been confirmed in trials of primary radiotherapy but not surgery, suggesting differential smoking impact by treatment received. We assessed smoking-related outcomes at a single institution. METHODS:Kaplan-Meier and Cox proportional hazards regression compared < 10 versus ≥ 10 pack-years by treatment received for progression-free survival (PFS) and overall survival (OS). RESULTS:Smoking was associated with worse PFS in both primary (chemo)radiation (HR = 1.73 [1.12-2.69], p = 0.01) and primary surgery cohorts (HR = 1.77 [1.02-3.07], p = 0.04). In surgery patients, this association was attenuated after adjusting for socioeconomic indicators (HR = 1.69 [0.97-2.93], p = 0.06). On recursive partitioning analysis, ≥ 25 pack-years was associated with worse PFS and OS overall and among radiotherapy patients. CONCLUSIONS:Smoking impacts outcomes in HPV + OPC regardless of treatment modality. Treatment-specific differences in prior randomized studies may reflect underlying differences in patient characteristics. ≥ 25 pack-years was associated with worse outcomes.

To develop effective nanostructured immunotherapeutics, identifying structural parameters that maximize immune response is essential. Spherical nucleic acids (SNAs) provide a modular platform for coordinated antigen-adjuvant delivery, where subtle structural differences can markedly influence potency. Herein, three SNAs were designed with HLA-A2-restricted HPV16 E711-19 peptide and CpG adjuvant, nearly identical in composition but differing in antigen presentation. All enhanced dendritic cell activation and CD8+ T cell cytotoxicity in primary human cells compared to peptide-CpG admixture; however, one variant, N-HSNA, elicited the strongest response, inducing ~8-fold higher interferon-γ secretion and ~2.5-fold greater cytotoxicity. In tumor-bearing AAD mice, N-HSNA reduced tumor burden by ~3.5-fold, prolonged survival, and expanded CD8+ T cells. Transcriptomic profiling revealed up-regulation of activation genes and suppression of exhaustion markers. In patient-derived HPV+ head and neck cancer spheroids, N-HSNA enhanced cytotoxicity ~2.5-fold, establishing antigen placement and orientation as key parameters for translational cancer immunotherapy.

Abstract Purpose: We evaluated the pan-PI3K inhibitor buparlisib with weekly cisplatin and radiotherapy among patients with locally advanced (LA) squamous cell cancer of the head and neck (SCCHN) and tobacco history. Patients and Methods: Patients with stage III/IV LA-SCCHN (AJCC7), ≥10 pack-year tobacco use treated with curative intent were enrolled. Patients received buparlisib during a 2-week run-in phase and during standard 70Gy of radiotherapy plus weekly cisplatin. An exploratory analysis of genomic sequencing was performed on biopsy specimens Results: Twenty-three patients were enrolled (n=17 at the MTD (buparlisib 40 mg daily, CDDP 30mg/m2/week)). Ninety-one percent (21/23) had stage IV disease. HPV was detected in 15 of 18 cases with oral/oropharyngeal disease. 5 patients suffered recurrences of whom 3 had activating mutations along the PI3K pathway. In 5 patients whose disease responded during the 2 week run-in phase with buparlisib alone, 3 of 4 with sequencing data showed loss-of-function mutations in either Tumor Necrosis Factor Receptor Associated Factor 3 (TRAF3), and/or Cylindromatosis Lysine Deubiquinatinase (CYLD). Preclinical studies with mutations in TRAF3 or CYLD via CRISPR/Cas9 knockout in HPV+SCCHN cells demonstrate that loss of TRAF3 or CYLD may sensitize SCCHN cell lines to PI3K through mechanisms other than blocking NFκb pathway. Conclusions: Buparlisib with CRT was feasible and active, though escalation to the standard weekly cisplatin dose of 40 mg/m2 was not possible. Our data suggests that TRAF3/CYLD mutant SCCHN may be susceptible to PI3K inhibition whereas PI3K pathway activation appeared to be associated with poor outcomes in this limited dataset.

Patients with newly diagnosed or relapsed/refractory (R/R) anaplastic thyroid cancer (ATC) and R/R poorly differentiated thyroid cancer (PDTC) have limited treatment options and an overall poor prognosis. ICAM-1, a cell surface glycoprotein also known as CD54 overexpressed in a variety of cancers including thyroid cancers, is known to play a key role in tumorigenesis. AIC100 is a 3rd generation ICAM-1 directed CAR T-cell product engineered with affinity-tuned technology to selectively bind and kill tumor cells to improve safety. Another unique feature for AIC100 is co-expression of somatostatin receptor 2 to allow CAR T-cell monitoring with DOTATATE PET scan. We present here updated results from phase 1 dose-escalation clinical trial NCT04420754. The multicenter study was designed to explore 3 dose levels (DLs) of AIC100 at 1x 107, 1 x 108, and 5 x 108, respectively. An additional DL4 (7.5 x 108) was explored since no dose-limiting toxicities (DLTs) were observed previously. Key eligibility included adult patients (≥18 years) with newly diagnosed or R/R ATC or R/R PDTC, who had measurable disease, and with ECOG status 0-2. AIC100 was infused intravenously 48 hours after completing lymphodepletion (Fludarabine/Cyclophosphamide x 3 days). Primary objectives included safety assessment/DLTs within 30 days of AIC100 infusion and to determine the recommended phase 2 dose (RP2D). As of 12-Dec-2024, 24 patients were enrolled and 15 (8 ATC; 7 PDTC) with a median age of 59 (range, 47-69) years were infused with AIC100 at 4 DLs. Patients were predominantly male (N = 11), with a median of 2 (range, 1-4) prior lines of systemic therapies. No DLTs were observed in the originally planned DLs 1-3. Two patients in the exploratory DL4 developed grade 3 pneumonitis. 10 (66.7%) patients developed grade 1/2 CRS. No ICANS or other SAEs related to AIC100 occurred at DLs 1-3. 11 patients were evaluable for efficacy in DLs 1-3 at day 42 after infusion; responses were assessed per study site. No responses were observed in DL1. For evaluable patients in DL 2 and 3 (n = 9), the objective response rate (ORR) and disease control rate (DCR, defined as ORR + stable disease (SD)) were 22% and 56%, respectively. For ATC patients at DL2-DL3 (N=4), the ORR was 50% [1 each with partial response (PR) and complete response (CR) in DL 2 and 3, respectively]. In PDTC at DL2-DL3 (N=5), DCR was 60%. AIC100 expansion was observed in all patients. Additional transaltional data will be presented at the meeting. Based on safety and efficacy, 5 x 108 (DL3) was declared as RP2D. AIC100, a first-in-human ICAM-1 directed CAR T-cell therapy, demonstrated an acceptable safety profile in patients with relapsed/refractory ATC and PDTCs. The observed durable responses in DL2 and DL3 are encouraging and provide a proof of concept for potential role of AIC100 in aggressive thyroid cancer patients and other advanced cancers. DL3 is determined as the RP2D. Cohort expansion at RP2D will be initiated in Q2 2025 in 2 indications; ATC and PDTC. Samer A. Srour, Jochen H. Lorch, Mark E. Zafereo, Victoria M. Villaflor, Yan Xing, Sonal Gupta, Mimi I-Nan Hu, Ramona Dadu, Adam Lin, Yang Lu, Melissa Cushing, Scott Avecilla, Theresa Scognamiglio, Moonsoo Jin, Janusz Puc, Tripti Gaur Gaur, Stacey Ukrainskyj, Sebastian A. Mayer, Koen Van Besien, Maria E. Cabanallas. ICAM-1 directed chimeric antigen receptor (CAR) T cells (AIC100) in patients with advanced thyroid cancers: Clinical and translational data from the phase 1 dose escalation study [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 CT206.

Programmed cell death protein 1 (PD-1) inhibitors have revolutionized the treatment of many cancers, seven of which are approved by the US Food and Drug Administration (FDA). No head-to-head phase 3 randomized controlled trials (RCTs) comparing PD-1 inhibitors have been conducted so it remains unknown whether clinically meaningful differences exist between them. Preclinical studies that have directly compared PD-1 inhibitors support a differentiating profile associated with toripalimab compared to pembrolizumab and nivolumab with regard to their PD-1 binding sites, binding orientations, and impact on T cell function. Findings of similar or greater benefit among patients with low/no PD-L1 expression versus high/intermediate PD-L1 expression with toripalimab plus chemotherapy were also observed in advanced nasopharyngeal carcinoma and non-small cell lung cancer for both overall survival and progression-free survival. However, determination of clinically-meaningful differences between PD-1 inhibitors requires sufficiently powered head-to-head RCTs.

6105 Background: Immunoprofiling and preclinical studies with patient derived organotypic tumor spheroids supported therapeutic targeting of programmed death (PD)-1 and cytotoxic T lymphocyte antigen (CTLA)-4 pathways in thyroid tumors. We previously presented initial results of a phase 2 clinical trial evaluating dual immune checkpoint inhibition with nivolumab (N) and ipilimumab (I) in advanced incurable thyroid carcinoma (TC) (ASCO 2020, PMID: 39446365) with data cutoff at 24 months (mo) follow up. Methods: This nonrandomized phase 2 clinical trial evaluated N (3 mg/kg every 2 weeks) + I (1 mg/kg every 6 weeks) in the primary patient population of RAIR DTC, with exploratory cohorts in ATC and MTC. Primary endpoints were objective response rate (ORR), with secondary endpoints of safety, progression-free survival (PFS), and overall survival (OS). Here, we present long term results (data cutoff 12/27/24), with median follow up of 75.3 mo for the overall population. Results: 49 patients (32 RAIR DTC, 10 ATC, and 7 MTC) were evaluable, 51% female, with median age of 65 years (range 30-88). Median duration of follow up (by cohorts) for this analysis was 74.9 mo (range 12.7 - 82.1) for RAIR DTC, 67.6 mo (29.9 - 84.4) for ATC and 81.1 mo (75 - 82.1) for MTC. ORR was 9.4% (in RAIR DTC), 30% (ATC), and 0% (MTC), all partial responses. Previously unreported, median duration of response (DoR) was 30 mo (range: 18.1 – 69.7) for RAIR DTC, and 23.2 mo (9.1 - 73.1) for ATC. Updated median PFS was 4.9 mo (95% CI 2.1, 17.0) for RAIR DTC, 4.3 mo (0.5, NA) for ATC, and 2.1 mo (0.9, 4.0) for MTC. 5-year PFS rates were 14.6% (95% CI 4.3%, 30.9%) for RAIR DTC, and 26.7% (4.8%, 56.3%) for ATC. Updated median OS was 44.6 mo (95% CI 24.6, NA) for RAIR DTC, 13.8 mo (1.2, NA) for ATC, and 46.1 mo (12.2, NA) for MTC. 5-year OS rates were 39.0% (95% CI 22.2%, 55.4%) for RAIR DTC, 30.0% (7.1%, 57.8%) for ATC, and 42.9% (9.8%, 73.4%) for MTC. Conclusions: Exceptionally durable responses were observed in the exploratory cohort of ATC (median DoR: 23.2 mo). To the best of our knowledge, this is the longest follow up reported for patients with aggressive thyroid carcinoma treated with immunotherapy. 5-year OS rate of 30% in incurable ATC is congruent with one prior report of 25.7% at another large volume cancer center (PMID: 3597734), but compares favorably with the historical rates reported for ATC in the SEER database (8% for all stages and 4% for distant metastatic disease). Biomarker studies are currently underway to identify exceptional responders and long-term survivors. Clinical trial information: NCT03246958 . RAIR DTC(N=32) ATC(N=10) Median PFS (95% CI), mo 4.9 (2.1, 17.0) 4.3 (0.5, NA) 5 year PFS (95% CI) 14.6% (4.3%, 30.9%) 26.7% (4.8%, 56.3%) Median OS (95% CI), mo 44.6 (24.6, NA) 13.8 (1.2, NA) 5 year OS (95% CI) 39.0% (22.2%, 55.4%) 30.0% (7.1%, 57.8%)

We report the case of a female patient in her 60s diagnosed with a Grade 2 cutaneous neuroendocrine tumour. The patient was referred after dermatological resection of a mass on her right frontal scalp. Pathologic examination at an outside centre initially misclassified the tumour as hidradenocarcinoma. Physical examination revealed a 3.5 cm ulcerative plaque at the scalp vertex. MRI revealed a prominent right pre-auricular lymph node and a 3.5 cm heterogeneous scalp mass suspicious for residual tumour. Both areas were fluorodeoxyglucose avid on positron emission tomography. On surgical re-resection of the tumour and nodal basins, pathologic examination yielded the diagnosis of cutaneous neuroendocrine tumour metastatic to intra-parotid lymph nodes. The patient completed a course of radiotherapy but, at seventeen months, was found to have recurrent local and metastatic pulmonary disease. The patient subsequently underwent surgical resection of the residual tumour as well as radiotherapy and palliative chemotherapy. The patient continues to be closely followed.

6048 Background: Recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) represents a marked unmet need. ROR2 is a cell-surface transmembrane receptor protein tyrosine kinase highly expressed in several tumor types including HNSCC. Ozuriftamab vedotin is a conditionally binding ROR2 antibody-drug conjugate designed to reduce off-tumor toxicity and improve pharmacokinetics by conditionally binding to ROR2 under low-pH conditions (pH<6.7) of the tumor microenvironment, thus sparing normal tissue. This novel mechanism avoids tissue-mediated drug disposition and improves pharmacokinetics. The recommended Phase 2 dose of 1.8 mg/kg was determined from the Phase 1 trial (NCT03504488). Methods: This multi-center, open-label, single-arm Phase 2 trial evaluated ozuriftamab vedotin in patients (pts) with R/M SCCHN previously treated with anti-PD-1 agents. Patients with SCCHN were enrolled and received 1.8 mg/kg of ozuriftamab vedotin given in 2 schedules: once every two weeks (Q2W) or days 1 and 8 of a 21-day cycle (2Q3W). Tumor assessments were conducted by CT or MRI every 6 weeks from Cycle 1 Day 1 until week 12, then every 8 weeks up to 1 year. Evaluable pts included those with at least one post-treatment scan. ROR2 expression was characterized by immunohistochemistry. Additional assessments included pharmacokinetic, pharmacodynamic, immunogenicity, and biomarker evaluations to characterize efficacy and safety. Results: As of May 31, 2024, 31 pts received ozuriftamab vedotin either Q2W (n=12) or 2Q3W (n=19) for a median of 84 days. Pts had a median of 3 prior lines of therapy, and all had experienced failure of anti–PD-1 therapy. Among 28 evaluable pts (evaluable as defined as having complete 1 post dose tumor assessment) for best overall response, there were 10 responders (36%; 1 confirmed complete response, and 5 confirmed/4 unconfirmed partial responses, and 14 stable disease. A disease control rate of 86% was observed. Median duration of response for all confirmed responders has not been reached (>3.6 months; 95% CI, 0.4–NE). Most adverse events (AEs) were grade 1-2, with fatigue (59%), anemia (34%), and nausea (34%) being the most frequent. Six pts (19%) experienced grade 3 treatment-related AEs (TRAEs). Two pts experienced a grade 4 TRAE (1 pt with hyponatremia in 2Q3W cohort, and 1 pt with neuropathy in Q2W cohort). No grade 5 TRAEs were observed. Conclusions: Pts treated with ozuriftamab vedotin achieved a high rate of disease control with acceptable tolerability. Shows promising efficacy, including in pts refractory to anti-PD1 and warrants further evaluation in SCCHN. Clinical trial information: NCT03504488 .

6112 Background: Patients with relapsed/refractory poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have limited treatment options and an overall poor prognosis. Several studies highlighted the role of ICAM-1, a cell surface glycoprotein that is expressed in a variety of cancers including thyroid cancers, in tumorigenesis. AIC100 is a 3 rd generation anti ICAM-1 CAR T-cell product engineered with an affinity-tuned technology to selectively bind and kill tumor cells to improve safety, and co-expresses somatostatin receptor 2 (SSTR2) to allow CAR T-cell activity tracking by DOTATATE PET scan. We present here the results from the phase 1 dose-escalation clinical trial NCT04420754. Methods: This is a phase 1 multicenter study designed to explore 3 dose levels (DLs) of AIC100 at 1x 10 7 , 1 x 10 8 , and 5 x 10 8 , respectively. Key eligibility included adult patients (≥18 years) with ICAM-1 positive relapsed/refractory PDTC or advanced ATC who had measurable disease, and with ECOG performance status 0-2. AIC100 was infused intravenously at least 48 hours after completing lymphodepletion (Fludarabine/Cyclophosphamide x 3 days). Primary objectives included safety assessment/dose-limiting toxicities (DLTs) in the first 30 days after AIC100 infusion and to determine the recommended phase 2 dose (RP2D). Results: As of Feb 02, 2024, 15 patients were enrolled and 10 (5 ATC; 5 PDTC) were infused with AIC100 in 3 DLs. The treated patients had a median age of 55 (range, 47-69) years, were predominantly males (N=8), and with a median of 2 (range, 1-4) prior lines of therapies. Autologous AIC100 was successfully manufactured for all patients. No DLTs were observed across all DLs, and the maximum tolerated dose was not reached. Six (60%) patients developed grade 1/2 CRS. No ICANS or other serious adverse events related to AIC100 occurred. Nine patients (3 in each DL) were evaluable for efficacy analysis at day 42 after infusion; responses were assessed per study site investigators and not centrally. For all patients, the objective response rate (ORR) was 22% [1 ATC with partial response (PR) at DL2 and 1 PDTC with complete metabolic response (CR) at DL3] and the disease control rate (DCR, defined as ORR + stable disease) was 56%. For evaluable patients in DLs 2 and 3 (n=6), the ORR and DCR were 33% and 67%, respectively. Peripheral blood CAR T-cell expansion by PCR was observed in all patients. DOTATATE PET activity correlated with CAR T-cell activity and tumor responses. Conclusions: This first-in-human ICAM-1 targeted CAR T-cell study demonstrated an excellent safety profile and promising antitumor activity for AIC100 in patients with PDTC and ATC. These favorable outcomes, including a PR in DL2 and a CR in DL3, provide a proof-of-concept and support further exploration of AIC100 to optimize the RP2D and to expand for other ICAM-1-positive neoplasms. Clinical trial information: NCT04420754 .

ImportanceAggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition.ObjectiveTo evaluate the efficacy of anti–programmed cell death 1 nivolumab and anti–cytotoxic lymphocyte–associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma.Design, Setting, and ParticipantsThis phase 2 nonrandomized clinical trial enrolled patients with RAIR DTC in a single center from October 2017 to May 2019, with exploratory cohorts in MTC and ATC. The data were analyzed between June 2021 and September 2023.InterventionIntravenous nivolumab, 3 mg/kg, every 2 weeks and ipilimumab, 1 mg/kg, every 6 weeks until disease progression, intolerable adverse events, or a maximum duration of 2 years.Main Outcomes and MeasuresThe primary end point of the study was objective response rate (ORR) in RAIR DTC, which was scored according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1. Key secondary end points included safety, progression-free survival, overall survival, and biomarker analyses.ResultsA total of 51 patients were registered, and 49 patients were evaluable for analysis. The median (range) age was 65 years (30-88 years), and 25 participants (51%) were female. ORR in the DTC cohort was 9.4% (3/32 [95% CI, 2.8%-28.5%]), with all partial responses in either oncocytic carcinoma (2/6 [33.0%]) or poorly differentiated thyroid carcinoma (1/5 [20.0%]). Clinical benefit rates were 62.5% (20/32) in the overall DTC cohort, including 83.3% (5/6) in oncocytic carcinoma and 40% (2/5) in poorly differentiated thyroid carcinoma. ORR in the exploratory ATC cohort was 30.0% (3/10 [95% CI, 6.7%-65.2%]), with a clinical benefit rates of 50.0% (5/10). No responses were observed in the exploratory MTC cohort. The safety profile was similar to prior reports with dual immune checkpoint inhibition (pruritus, rash, diarrhea, fatigue, and elevation of lipase and liver enzymes). The presence of NRAS tumor genetic sequence variations, but not BRAF V600E, was associated with worse outcomes.Conclusions and RelevanceThis phase 2 nonrandomized clinical trial reported clinical activity of dual immune checkpoint inhibition in aggressive thyroid cancer. The study did not meet its end point in the primary population of RAIR DTC and does not support further investigation in non–biomarker-selected DTC. However, the signal observed in ATC may merit further evaluation.Trial RegistrationClinicalTrials.gov Identifier: NCT03246958

Purpose/Objective This study aimed to evaluate a novel methodology to identify subjects that could derive benefit from Buparlisib treatment in metastatic SCCHN patients. The analysis was focused on image analysis of H&E images to select features associated with improved clinical benefit from paclitaxel+buparlisib. Material/Methods BERIL-1 (NCT01852292) was a multicenter, randomized, double-blind, placebo-controlled phase II study evaluating treatment with either buparlisib + paclitaxel or placebo + paclitaxel in adult patients with histologically or cytologically confirmed recurrent or metastatic SCCHN. H&E stained whole slide images (WSI) were scanned at 40x and a model was developed to identify features of the tumor and the tumor immune microenvironment through digital pathology. We then evaluated spatial histological biomarkers from 145 subjects (73 in treatment & 72 in placebo arms) associated with improvement in efficacy endpoints of Progression Free Survival (PFS) and Overall Survival (OS) within and between the treatment and control arms. Results A deep learning model was developed that can accurately identify and classify tumor, necrotic and stromal areas as well as fibroblast, endothelial and immune cells (plasma, lymphocyte, granulocyte), from H&E images. The accuracy of this model was developed against the ground truth of human pathology analysis of the same images. This analysis demonstrated that a >10% infiltration of TILs (p=0.00058, HR=0.195) as well the heterogeneity of cells in the TME (p=0.015, HR=0.53) are both associated with a survival advantage in patients receiving the combination treatment when compared to placebo. Moreover, we discovered that the proximity of granulocytes to tumor cells (p=0.00006, HR=0.32) is associated with improved survival in patients treated with buparlisib + paclitaxel combination therapy. Conclusion This analysis highlights a novel approach, utilizing the common and cost-effective biomarker of H&E to identify metastatic SCCHN subjects that could derive therapeutic benefit from the combination of Buparlisib + paclitaxel. Further analysis will be conducted to determine if this method provides a better prediction of clinical benefit than regular pathology evaluation. This approach also highlights interesting and novel biological observations that underscore the mechanisms of this therapeutic combination that could lead to studies evaluating novel therapeutic combinations. The results of this analysis can be expanded to the ongoing Phase III BURAN study to further optimize and validate this method of identifying subjects for therapeutic intervention; providing a fast and cost effective method for clinicians to understand which subject would benefit from treatment with Buparlisib.

Thyroid carcinomas are the most common endocrine malignancy and commonly have alterations in the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/AKT signaling pathways in well-differentiated tumors. Alternative molecular alterations driving thyroid carcinomas have been identified rarely in the literature and are more likely to occur in poorly differentiated or anaplastic cases. In this study, uncommon genetic alterations such as MLH1, MSH2, NSD3::NUTM1, RET::SPECC1L, and G3BP2::FGFR2 were identified in patients with papillary thyroid carcinoma, poorly differentiated thyroid carcinoma, and differentiated high-grade thyroid carcinoma. Most of these tumors demonstrated an aggressive biological behavior. Atypical driver mutations in thyroid carcinomas can occur in patients with cancer predisposition syndromes as demonstrated by an NTRK1::TPM3 fusion in a patient with Li Fraumeni syndrome. In these settings of more aggressive disease, molecular testing targeting actionable fusions and mutations is important. As demonstrated in our case cohort, 100% of cases diagnosed as high-grade follicular-derived thyroid carcinoma had a mutation or fusion that is associated with worse prognosis, has a germline syndrome association requiring further work up, or an actionable mutation. This high yield seen in this cohort for molecular testing in patients with high-grade follicular-derived thyroid carcinoma suggests more routine molecular testing in this population would be a beneficial clinical practice.

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 .

e18075 Background: There are no standard of care therapies in advanced incurable setting for BRAF wild type (WT) ATC, & after dabrafenib and trametinib (D+T) for BRAF V600E mutant ATC. We previously showed promising clinical activity of dual inhibition with N+I in exploratory cohort of 10 patients (pts) with advanced ATC in a single arm phase II clinical trial, with objective response rate (ORR) of 30% (NCT03246958, Lorch ASCO 2020). Here, we present efficacy and safety outcomes from a real-world cohort of pts with advanced ATC treated with N+I regimen. Methods: We conducted a retrospective cohort study of pts with advanced ATC (unresectable or with distant metastases, DM) who were seen at the Dana-Farber Cancer Institute (DFCI) thyroid cancer center from July 2021 to Jan 2024, received at least one dose of N+I with palliative intent & completed at least one response assessment (data cutoff, 1/31/24). Pts on the DFCI clinical trial were not included. Investigator-assessed ORR (for the first N+I based treatment regimen) and immune-related adverse events (irAEs, collected till cutoff regardless of ongoing treatment) were evaluated. Results: 19 pts with advanced ATC (5: unresectable disease, 14: DM) were included, BRAF WT 12/19 (63%). Median age was 70y (range, 34-81), 68% female. ECOG PS at start was 0-1 in 14/19 (74%), 2 in 4 (21%) & 3 in 1 (5%) pts. 5/19 (26%) pts received N+I concurrently with D+T; 4/5 (80%) in 2 nd line after either mixed response or progressive disease (PD) on D+T. Best overall response (BOR) in N+I+D+T group was partial response (PR, 1/5, 20%) & stable disease (SD, 4/5, 80%); ORR 20%. 14/19 (74%) pts received N+I, 12/14 (86%) as 1 st line palliative therapy. 5 pts in N+I group (all with DM) received local therapies concurrently (1: debulking thyroid surgery, 3: radiation therapy (RT) to thyroid, & 1: palliative RT to bone DM). BOR in N+I group were: complete response, CR (4/14, 28.6%); PR (3, 21.4%); SD (4, 28.6%); & PD (3, 21.4%); ORR 50%. Excluding 5 pts with concurrent local therapies, ORR was 33.3% (1/9 CR, 2/9 PR).PD-L1 TPS was available for 12/19 pts (4: N+I+D+T, 8: N+I) and ≥1 in all tumors (range, 1-100). In 8 pts in N+I group, ORR stratified by PD-L1 TPS: TPS <50 (range, 1-30): 0% (0/2: 1 SD, 1 PD), & TPS ≥50 (range, 80-100): 83.3% (5/6: 3 CR, 2 PR, 1 PD). Any grade irAEs were observed in 16/19 (84.2%) pts. ≥Grade 3 irAEs occurred in 11/19 (57.9%) pts, most frequent were colitis (5, 26.3%), dermatitis/pruritus (3, 15.8%), myocarditis (2, 10.5%), & adrenal insufficiency (2, 10.5%). There were no treatment-related deaths. Conclusions: In this largest real-world cohort study of pts with advanced ATC, N+I therapy showed high ORR of 50% (congruent with DFCI trial), albeit with high rates of iRAEs. High ORR was seen with PD-L1 TPS ≥50. Survival outcomes and genomic biomarkers, currently under investigation, will be presented at the meeting. N+I merit further investigation in an ATC focused clinical trial.

Importance Aggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition. Objective To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma. Design, Setting, and Participants This phase 2 nonrandomized clinical trial enrolled patients with RAIR DTC in a single center from October 2017 to May 2019, with exploratory cohorts in MTC and ATC. The data were analyzed between June 2021 and September 2023. Intervention Intravenous nivolumab, 3 mg/kg, every 2 weeks and ipilimumab, 1 mg/kg, every 6 weeks until disease progression, intolerable adverse events, or a maximum duration of 2 years. Main Outcomes and Measures The primary end point of the study was objective response rate (ORR) in RAIR DTC, which was scored according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1. Key secondary end points included safety, progression-free survival, overall survival, and biomarker analyses. Results A total of 51 patients were registered, and 49 patients were evaluable for analysis. The median (range) age was 65 years (30-88 years), and 25 participants (51%) were female. ORR in the DTC cohort was 9.4% (3/32 [95% CI, 2.8%-28.5%]), with all partial responses in either oncocytic carcinoma (2/6 [33.0%]) or poorly differentiated thyroid carcinoma (1/5 [20.0%]). Clinical benefit rates were 62.5% (20/32) in the overall DTC cohort, including 83.3% (5/6) in oncocytic carcinoma and 40% (2/5) in poorly differentiated thyroid carcinoma. ORR in the exploratory ATC cohort was 30.0% (3/10 [95% CI, 6.7%-65.2%]), with a clinical benefit rates of 50.0% (5/10). No responses were observed in the exploratory MTC cohort. The safety profile was similar to prior reports with dual immune checkpoint inhibition (pruritus, rash, diarrhea, fatigue, and elevation of lipase and liver enzymes). The presence of NRAS tumor genetic sequence variations, but not BRAF V600E, was associated with worse outcomes. Conclusions and Relevance This phase 2 nonrandomized clinical trial reported clinical activity of dual immune checkpoint inhibition in aggressive thyroid cancer. The study did not meet its end point in the primary population of RAIR DTC and does not support further investigation in non-biomarker-selected DTC. However, the signal observed in ATC may merit further evaluation.

6109 Background: Multi-kinase inhibitors show activity in both MTC & RAIR DTC. However, therapeutic options are limited after disease becomes refractory to one or two lines of standard of care therapies. We report here results of an investigator-initiated phase II clinical trial evaluating regorafenib in this population (NCT02657551). Methods: Patients with MTC (disease progression within 6-12 months, mo, prior to study registration) and RAIR DTC (progression within 12 mo) were enrolled regardless of prior lines of therapy. Regorafenib (each cycle 3 weeks ON/1 week OFF) was started at 80 mg daily, with planned escalation after 1 & 2 weeks to 120 mg daily & 160 mg daily, respectively, in absence of significant treatment-related adverse events (TRAEs). The highest tolerated dose was continued from cycle 2 onwards until progression. The primary endpoints were proportion progression-free at 10 months in MTC & overall response rate (ORR) by RECIST v1.1 in RAIR DTC. Simon two-stage design was utilized; MTC: <2 in 8 progression-free in first stage stops for futility, stage 2: enroll 13, >6/21 provides 81% power for proportion >20%; DTC: <3 in 9 in response in first stage stops for futility; stage 2: enroll 11, >7/20 provides 81% power for ORR >25%. Results: 17 patients (8 MTC, 9 DTC) were enrolled between April 2016 and October 2022. Among MTC, median (range) age was 54.7y (48.1, 62.8), 25% female. Among DTC, median age (range) was 62.8y (44.3, 75.8), 55.6% female. In MTC group, the proportion progression-free at 10 months was 12.5% (95% CI 0.3%, 52.7%) & did not meet the criteria to continue into 2 nd stage. ORR in MTC group was 12.5% (95% CI 0.3%, 52.7%). In DTC group, ORR was 11.1% (95% CI 0.3%, 48.2%), & did not meet the criteria to continue into 2 nd stage. No patients were receiving treatment at cutoff. Patients with MTC and DTC with objective responses (1 each) had received one (vandetanib) & no prior systemic therapy, respectively. The most common reason for discontinuation was disease progression in MTC (4, 50%) & DTC (5, 55.6%). Grade 3-4 TRAEs were observed in 8/17 (47.1%), most frequent were diarrhea, hypophosphatemia, & hypertension (each grade 3: 2, 11.7%). There were no treatment-related deaths. Median progression-free survival (PFS) in MTC & DTC were 5.3 (95% CI 3.6, 20.1) & 11.0 (95% CI 1.2, 24.0) mo, respectively. Median overall survival (OS) in MTC & DTC were 16.1 (95% CI 5.2, NA) and 20.1 (95% CI 1.6, NA) mo, respectively. Conclusions: Regorafenib clinical trial did not reach its primary endpoints in MTC and DTC. Analyses are planned to investigate impact of prior VEGFR inhibitor exposure, biomarkers and resistance mechanisms. Clinical trial information: NCT02657551 . [Table: see text]

BACKGROUND:There are limited therapeutic options for patients with recurrent/metastatic anaplastic thyroid carcinoma (ATC) and radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC) refractory to multikinase inhibitors. This multicenter trial evaluated sapanisertib, a next-generation oral kinase inhibitor of mTOR complexes 1/2, in ATC and RAIR DTC. METHODS:A safety run-in phase I was followed by nonrandomized phase II trial in ATC, with an exploratory cohort in RAIR DTC. The primary endpoint was the proportion of patients with ATC who were without disease progression at 4 months. Safety and survival outcomes were key secondary endpoints. RESULTS:Forty-six patients (20 ATC, 26 DTC) were enrolled including 40 (18 ATC, 22 DTC) who received recommended phase II dose of 5 mg daily. Eleven percent [2/18, 95% confidence interval (CI): 1.4-34.7%] of patients with ATC were progression-free at 4 months; 22.2% (4/18) had stable disease as best response. Enrollment in the ATC cohort stopped early with 18 patients out of the proposed 23 due to overall futility. One confirmed partial response (4.5%, 1/22) occurred in RAIR DTC, with stable disease in 63.6% (14/22) patients. Median progression-free survival was 1.6 (95% CI: 0.9-2.8) months and 7.8 (2.0-not reached) months in ATC and DTC, respectively. Grade 3 treatment-related adverse events occurred in 30% of patients who received the phase II dose, with the most common being anorexia, nausea, diarrhea, fatigue, skin rash, and hyperglycemia. Genomic alterations in the PI3K/AKT/mTOR pathway were not associated with response or progression-free survival. CONCLUSION:Sapanisertib monotherapy did not meet the primary endpoint of this trial (proportion progression-free at 4 months) in ATC and did not show clinically meaningful activity. Clinical trials with alternative therapeutic strategies are needed.