In this exploratory epigenome-wide association study (EWAS), we sought to investigate associations of pre-treatment blood-derived DNA methylation with survival and response outcomes among patients with recurrent/metastatic (R/M) head and neck squamous cell carcinomas (HNSCCs) who received immune checkpoint inhibitor (ICI) therapy. Patients with R/M HNSCC were recruited from the Dana-Farber Cancer Institute, Dartmouth Cancer Center, and Rhode Island Hospital. Peripheral blood was collected prior to the start of ICI, and DNA methylation was measured using the Illumina EPIC V1 and V2 BeadArrays. After strict quality control, the top 10% most variable CpG sites (n = 67,712) were included in an EWAS of methylation with overall survival (OS) and progression-free survival (PFS). Models were adjusted for key covariates, including the DNA methylation-derived immune cell-type proportions. Among the 116 patients enrolled, 64 (55.2%) died during follow-up, and 22 (19.0%) experienced cancer progression. Of the 30 patients (25.9%) who remained progression-free, 13 showed a complete response to the ICI therapy. We identified two CpG sites (cg04079758 and cg10654272) that were associated with improved PFS (false discovery rate [FDR] < 0.05). The CpG sites cg04079758 and cg10654272 are located in the South Shelf region on chromosome 19 and in an OpenSea region on chromosome 6, respectively. Additionally, one of the CpG sites, cg04079758, was located in Kallikrein 9 (KLK9), a gene involved in tissue remodeling and inflammation within the tumor microenvironment. No CpG site was statistically significantly associated with OS. Distinct blood DNA methylation signatures may be associated with ICI therapy-related outcomes in patients with R/M HNSCC.

6040 Background: In HPV-negative HNSCC, TGF-β overexpression creates fibrotic barriers within the tumor microenvironment that limit tumor penetration and drive resistance to anti-EGFR and anti-PD1 therapy. Ficerafusp alfa is the first and only bifunctional EGFR-directed antibody designed to trap TGF-β, enabling tumor penetration of immune cells and driving deep and durable responses for potential overall survival (OS) benefit. Methods: Two dose-expansion cohorts of an ongoing phase 1/1b study (NCT04429542) enrolled adults with 1L R/M HNSCC with PD-L1 CPS ≥1. Patients received ficerafusp alfa 750 or 1500 mg IV on D1, 8, and 15 plus pembrolizumab (pembro) 200 mg IV Q3W. Assessments included objective response rate (ORR), duration of response (DOR), and progression free survival (PFS) per RECIST v1.1; OS; safety; and pharmacodynamic (PD) and pharmacokinetic analyses. This is the first report of long-term efficacy follow-up across two cohorts of ficerafusp alfa. Results: As of December 16, 2025, 61 HPV-neg pts were treated in two cohorts (750 mg, n=31; 1500 mg, n=30); 58 pts were efficacy evaluable. Exposure increased in an approximately dose-proportional manner with manageable safety observed in both cohorts. A higher proportion of pts had exposure levels associated with meaningful efficacy with 1500 mg vs 750 mg dosing. Improved outcomes were observed in the 1500 mg vs 750 mg cohort, including deep responses (≥80% tumor shrinkage in 80% vs 47% of responders) and mPFS (9.9 mo vs 6.9 mo), along with increased markers of TGF-β inhibition and tumor penetration in paired biopsies, and increased pro-inflammatory cytokines in blood (Table). Conclusions: Deeper and more durable tumor responses were observed with ficerafusp alfa 1500 mg vs 750 mg. Exposure and PD markers of TGF-β inhibition demonstrated dose-related trends consistent with mechanism of action. Together, these data suggest that TGF-β inhibition with ficerafusp alfa facilitates T-cell infiltration, enhancing immunologic activity, contributing to deep and durable responses for patients with HPV-neg HNSCC. These findings support the rationale for FORTIFI-HN01, an ongoing phase 2/3 trial evaluating this combination in 1L PD-L1 pos, HPV-neg, R/M HNSCC (NCT06788990). Clinical trial information: NCT04429542 . Endpoint (efficacy set) Ficerafusp alfa750 mg + pembroN=30 Ficerafusp alfa1500 mg + pembroN=28 Confirmed ORR/complete response rate, n (%) 17 (57)/4 (13) 15 (54)/6 (21) Responders with ≥80% shrinkage, n (%) 8/17 (47) 12/15 (80) Median DOR, mo NR 21.7 Proportion of responses >12 mo, n (%) 9/17 (53) 9/15 (60) Median PFS, mo 6.9 9.9 Median OS, mo NR 21.3 Tumor TGF-β inhibition: mean change from baseline in pSMAD2, % −16.4 (n=5) −33.2 (n=7) Immune activation: mean change from baseline in blood TNF-α/IFN-γ, % 25.6/163, (n=24) 64.9/346 (n=20)

6058 Background: Ficerafusp alfa is the first and only bifunctional EGFR-directed antibody designed to trap TGF-β, enabling tumor penetration of immune cells and driving deep and durable responses. Depth of response has been shown to correlate with prolonged progression free survival (PFS) and overall survival (OS) in several solid tumors. However, such data are limited in R/M HPV-negative HNSCC. Here we performed exploratory analyses to evaluate whether depth of response achieved with ficerafusp alfa and pembrolizumab is associated with prolonged duration of response (DOR), PFS and OS. Methods: Three cohorts of a phase 1/1b study (NCT04429542) in 1L, R/M HNSCC, with PD-L1 CPS ≥1 evaluated ficerafusp alfa (750mg QW,1500 mg QW, or 2000 mg Q2W) IV combined with pembrolizumab IV. Objective response rate (ORR) per RECIST v1.1, DOR, PFS, and OS were assessed. In the pooled efficacy evaluable set from the three cohorts, we explored if the magnitude of tumor regression, comparing tumor regression ≥80% regression (defined as a deep response) vs. tumor regression 0 to <80%, is predictive of longer-term clinical outcomes (DOR, PFS, OS). Results: As of December 16, 2025, 85 patients with HPV-negative disease were efficacy evaluable across three cohorts (n=30, n=28, and n=27 at 750mg, 1500mg, and 2000mg doses of ficerafusp alfa, respectively). Among these, the confirmed ORRs were 57%, 54%, and 48%, respectively, including 47%, 80%, and 77% of responders achieving a deep response. In the pooled efficacy evaluable set the percentage of patients with a deep response was 36%, with tumor regression 0 to <80% was 46%, and no tumor regression was 18%. mDOR was longer for patients with a deep response compared to patients with tumor regression 0 to <80% (21.9 mo vs 8.2 mo, HR 0.27). mPFS was also longer in patients with a deep response compared to patients with tumor regression 0 to <80% (26.4 mo vs 6.5 mo, HR 0.19). mOS was not reached (NR) in patients with deep response and 14.9 mo in patients with tumor regression 0 to <80% (NR vs 14.9 mo, HR 0.17). Conclusions: Ficerafusp alfa plus pembrolizumab demonstrated deep responses across multiple dose levels. Deep responses were associated with improved long-term efficacy outcomes, including DOR, PFS, and OS. This suggests that depth of response may represent a clinically meaningful surrogate for understanding long-term efficacy outcomes in HPV-negative HNSCC. Clinical trial information: NCT04429542 . Tumor Regression0 to <80%N=39 Tumor Regression ≥ 80% (Deep Response)N=31 mDoR (mo) 8.2 21.9 HR [vs < 80% tumor regression] (95% CI) N/A 0.27 [0.10, 0.71] mPFS (mo) 6.5 26.4 HR [vs No DR] (95% CI) N/A 0.19 [0.09, 0.40] mOS (mo) 14.9 NR HR [vs No DR] (95% CI) N/A 0.17 [0.07, 0.41]

6038 Background: Concurrent blockade of LAG-3 may enhance efficacy of anti–PD-1 therapies. We present safety and clinical activity data from a Phase 1 study in patients (pts) with head and neck squamous cell carcinomas (HNSCC) treated with anti–LAG-3 (fianlimab) + anti–PD-1 (cemiplimab). Methods: Two expansion cohorts of adult pts with recurrent and/or metastatic HNSCC with no curative options who were anti–PD-1/PD-L1-naïve (cohort 11) or anti–PD-1/L1-experienced with most recent dose within 3 months (mos) prior to screening (cohort 12) were enrolled. All pts received fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks (wks) for up to 24 mos. Tumor measurements were performed every 6 wks for 24 wks, then every 9 wks. Results: 15 pts each in cohort 11 and 12 (total N=30; median age: 69 years) were enrolled and treated with fianlimab + cemiplimab as of 04 Oct 2023 data cutoff.For cohorts 11 and 12 respectively, 80% and 87% of pts were male, and 53% and 80% were White. All pts had prior cancer-related systemic therapy. 33% (5/15) and 87% (13/15) of pts in cohorts 11 and 12 had ≥2 lines of prior therapies, respectively. For cohorts 11 and 12, median treatment duration was 12 wks (mean: 41 wks) and 13 wks (mean: 24 wks), and median follow-up was 12 mos and 10 mos, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 47% of pts each in cohorts 11 and 12. Serious TEAEs occurred in 13% and 20% of pts in cohorts 11 and 12, respectively. Treatment-related TEAEs (TRAEs) were reported in 67% of pts in cohorts 11 and 53% of pts in cohort 12. The most common TRAEs (any grade) were hypothyroidism (33%) in cohort 11; and fatigue (20%) and pneumonitis (20%) in cohort 12. Grade ≥3 TRAEs occurred in 7% of pts in cohorts 11 and 13% of pts in cohorts 12. Treatment-related immune-related AEs were reported in 47% and 40% of pts in cohorts 11 and 12, respectively. Treatment was discontinued due to any TEAE in 2 pts in cohort 12. In cohort 12, there was one death due to grade 5 respiratory failure attributable to aspiration pneumonia. RECIST 1.1-based investigator-assessed objective response rate (ORR) was 33% (5 partial responses [PRs]) in cohort 11 and 7% (1 PR) in cohort 12. The disease control rate (DCR) was 47% and 67% in cohorts 11 and 12, respectively. Kaplan–Meier estimation of median progression-free survival was 2 mos (95% CI, 1–14) in cohort 11 and 4 mos (95% CI, 1–7) in cohort 12 pts. Duration of responses were 17, 10, 20, 22, and 20 mos in 5 responders in cohort 11; and 32 mos in 1 responder in cohort 12. Estimated event-free probability at 12 month was 33% (95% CI, 12–56) in cohort 11 and 16% (95% CI, 3–40) in cohort 12 pts. Conclusions: Fianlimab + cemiplimab in pts with HNSCC showed signs of clinical activity with durable responses among pts with anti–PD-1/PD-L1-naïve (cohort 11) and anti–PD-1/L1-experienced (cohort 12), with an acceptable safety profile which warrants further investigation. Clinical trial information: NCT03005782 .

Tissue biomarkers for immune checkpoint inhibitor (ICI) response are limited by tumor sample heterogeneity and availability. This study identifies clinically actionable pretreatment blood biomarkers that are associated with ICI treatment response and survival in recurrent/metastatic head and neck squamous cell carcinoma. A prospective multi-center study enrolled 100 patients before standard-of-care immunotherapy. Blood immune profiles, measured by methylation cytometry, were assessed alongside tumor mutational burden (TMB) and PD-L1 combined proportion score (CPS). TMB and PD-L1 CPS were available for 56 and 91 patients, respectively. High neutrophils, monocytes, and neutrophil-to-lymphocyte ratio were associated with worse survival, while high CD4T cells, especially naïve CD4T cells, and lymphocyte-to-monocyte ratio were associated with better survival. Significant interactions between TMB and peripheral immune profiles for both progression-free and overall survival were found. Clinically relevant pretreatment peripheral immune biomarkers were identified, demonstrating the potential of DNA-based immune profiling to predict ICI response before treatment.

e20081 Background: Standard NA immune checkpoint blockade for patients with resectable NSCLC targets PD1 only and must be combined with platinum-based chemotherapy. In a randomized phase 2 NA study, ipi + nivo demonstrated greater immune-mediated efficacy compared to nivo alone with major pathologic response (MPR) 50% vs. 24%, Cascone T, et al. Nat Med. 2021;27(3):504-14). Preclinical and clinical studies have demonstrated that low doses of radiation enhance immune response by multiple mechanisms (dsDNA breaks, induction of STING, transcription of pro-inflammatory proteins, increased expression of neoantigens while sparing effector T cells). An approach incorporating low dose radiation as an immune stimulant potentially may improve immune-mediated efficacy and shorten the duration of NA treatment compared to approaches that use combined cytotoxic chemotherapy. Methods: This single-arm trial tested NA ipi (1 mg/kg d1) + nivo (3mg/kg d1, 15, 29) plus low-dose SBRT delivered as 2 fractions (4Gy x 2) to the gross primary tumor and nodal disease immediately following day 1 infusion and completed by day 3 in patients with medically operable stage IB-III NSCLC Patients went on to surgical resection between days 49 -63. The primary efficacy outcome measure was pathologic response (including MPR, and complete PR (CPR)). Secondary outcome measures included safety, and exploratory biomarkers of immune response in pre- and post-operative blood and tissue. A two-stage design was employed to stop the study for lack of efficacy if fewer than 3 of the first 9 evaluable patients achieved MPR or experienced undue toxicity. Results: Patients were treated on study: 4 men, 5 women, aged 40-71, stage IB (2), IIB (5), IIIA (1), IIIB (1); adenocarcinoma 7 (all EGFR,ALK -), squamous 2; ECOG PS 0-1 (9); all were former smokers. There were no dose limiting toxicities. Study-related toxicities were ≤ grade 2 including rash (2) and abdominal pain (1). There were no study-related surgical complications. One patient (IIIA, T1N2) experienced clinical and radiologic progression during study treatment and was confirmed to have pleural metastases at surgery. Of 7 patients resected to date, there was 1 CPR, 0 further MPR and 1 patient with surgery pending. All resected patients had some treatment effect, 3 were down staged and these elected not to receive adjuvant cytotoxic chemotherapy. The only patient to progress in 8 months med f/u was the patient progressing during NA therapy. Conclusions: Low-dose radiation with concurrent NA ipi + nivo was safe and well tolerated in this small cohort but did not improve MPR compared to historical phase 2 data of ipi + nivo alone. Standard and exploratory biomarkers of immune response will be presented to determine if patient selection played a role in these results. Clinical trial information: NCT04933903 .

e20085 Background: Definitive chemoradiation (CRT) followed by consolidative immunotherapy with durvalumab (IO) demonstrated survival benefit and is now standard of care for Stage III Non-small Cell Lung Cancer (NSCLC). However, local-regional control (LRC) remains a concern with intrathoracic progression representing the most common site of failure. Adding stereotactic body radiotherapy (SBRT) boost may enhance the immunogenicity and antigenicity of tumor cells by regulating cell surface receptors and augmenting T-lymphocyte infiltration into tumor. SBRT boost also allows escalated dose to the primary tumor while minimizing dose to critical structures. Methods: Patients with Stage III NSCLC planned for definitive concurrent CRT with 1 year of consolidative IO were prospectively enrolled on a single institutional pilot trial. IO started 6-8 weeks after completion of CRT. SBRT was delivered between cycle 1 and 2 of IO to the residual, primary tumor (20 Gy in 2 fractions for peripheral, 19.5 Gy in 3 fractions for central tumors). Residual tumors needed to be < 120 cc. Lymph nodes were not boosted. Primary endpoints were grade (gr) ≥3 toxicities (CTCAE V4.03) and progression free survival (PFS). Secondary endpoints were Overall Survival (OS), LRC, and distant metastasis (DM). A sample size of 25 patients was proposed to determine safety and efficacy. Results: Accrual was slower than anticipated, and the study closed with 11 patients enrolled over 54 months. Slow accrual was due to a low rate of eligibility based on post CRT clinical status and SBRT target limitations. 1 patient withdrew consent before receiving treatment leaving 10 evaluable patients. Median age was 73 years and median CRT dose was 60 Gy (range 60-66 Gy). 6/10 of patient were adenocarcinoma. 5/10 pts had central tumor location. Median follow-up for evaluable patients is 2.2 years. OS was 90%, 70%, and 70% at 1-year, 2-years, and 3 years, respectively. PFS was 90%, 47%, and 47% at 1 year, 2 years, and 3 years, respectively. LRC was 100%, 83%, and 63% at 1 year, 2 years, and 3 years, respectively. Rates of DM were 0%, 12%, and 34% at 1 year, 2 years, and 3 years, respectively. 1 patient developed gr 3 pneumonitis requiring discontinuation of IO. 1 additional patient developed gr 2 pneumonitis requiring a brief pause in IO therapy and resumed IO without any further complications. One patient developed gr 5 myocarditis 29 days after the first dose of IO and 18 days after SBRT, on investigation deemed to be myocarditis secondary to IO. There was no other gr 3 toxicity attributable to IO or SBRT. Conclusions: The addition of SBRT to consolidative IO in stage III NSCLC patients treated with CRT was feasible. The single gr 5 toxicity was attributed to IO. SBRT boost demonstrated encouraging efficacy and manageable toxicity and merits further study. Our data adds to the growing evidence of harnessing tumor immunogenicity in enhancing IO responses. Clinical trial information: NCT03589547 .

6012 Background: Recurrent or metastatic (r/m) head and neck squamous cell carcinoma (HNSCC) is treated in the first-line with an immunotherapy-based approach, including in combination with platinum-based chemotherapy or as monotherapy, or platinum-based combination plus targeted therapy. Still, most pts experience disease progression, and the efficacy of subsequent line treatment options is limited. Tisotumab vedotin (TV) is an investigational antibody-drug conjugate directed to tissue factor. TV at 1.7 mg/kg IV Q2W has demonstrated encouraging antitumor activity in 2L-4L r/m HNSCC from the innovaTV 207 (NCT03485209) study. Here, we present data from the full cohort, Part C. Methods: innovaTV 207 is an open-label, global, phase 2, multicohort, multicenter study evaluating TV monotherapy or in combination for advanced solid tumors. In Part C, pts with r/m HNSCC received TV monotherapy (1.7 mg/kg IV Q2W). All pts were required to have received a platinum-based regimen, either in the r/m setting, or have persistent disease following platinum-based chemoradiation and a checkpoint inhibitor (CPI), if eligible. Primary endpoint was confirmed objective response rate (cORR) per investigator. Secondary endpoints included duration of response (DOR), time-to-response (TTR), and safety. Results: As of 6 Sept 2023, 40 pts with HNSCC were treated. 39 (97.5%) pts received prior platinum-based therapy. In the r/m setting, 25 (62.5%) pts received ≤2 prior lines of systemic therapy (median: 2; range: 1-3), 40 (100%) pts received prior CPI, 23 (57.5%) pts received prior taxane, and 27 (67.5%) pts received prior cetuximab. The most common subsites at diagnosis were oropharynx (n=16, of which 12 were p16 positive), larynx (n=10), and oral cavity (n=9). In the full cohort, cORR was 32.5% (95% CI, 18.6-49.1), with 1 complete response and 12 partial responses. Median DOR was 5.6 mo (95% CI, 3.0-NR) and median TTR was 1.4 mo. Among pts with ≤2 prior lines (n=25), cORR was 40.0% (95% CI, 21.1-61.3). In this subgroup, DOR is not yet mature (range: 1.2+ to 7.9+ mo), and among the 10 responders, 6 pts remain in response; median TTR was 1.5 mo. In the full cohort, 85.0% of pts had at least 1 treatment-related adverse event (TRAE). Grade ≥3 TRAEs occurred in 25.0% of pts, of which the most common were peripheral neuropathy events (12.5%). Adverse events of special interest were prespecified for ocular, peripheral neuropathy, and bleeding events, and occurred in 21 (52.5%), 19 (47.5%), and 15 (37.5%) pts, respectively. Updated efficacy and safety data are planned. Conclusions: TV demonstrated encouraging antitumor activity in a heavily pretreated r/m HNSCC population with a manageable safety profile consistent with previous TV monotherapy data. The study is ongoing; TV represents a promising treatment option for pts with r/m HNSCC who have progressed after prior platinum-based therapy and immunotherapy. Clinical trial information: NCT03485209 .

Background: NOTCH1 is the second most frequently mutated gene in HNSCC with mutations present in 10-15% of tumors. NOTCH mutations can have an oncogenic or a tumor suppressor effect and activates and overexpresses downstream genes such as HEY1, HES1, MYC and CCND1, representing a specific NOTCH signature (NOTCHsig). Better understanding of the NOTCH pathway could be of clinical importance, with prognostic and therapeutic implications for HNSCC. Methods: HNSCC (N = 1576) patient tumors underwent DNA (592-gene or whole exome; N = 1576) and RNA (whole transcriptome; N = 799) sequencing at Caris Life Sciences (Phoenix, AZ). PD-L1+ expression was tested by IHC (22c3). NOTCHsig-High samples were defined as > 2-fold median expression of HEY1, HES1, MYC, or CCND1, while NOTCHsig-Low samples had < 2-fold median expression of each gene. Overall survival (OS) was calculated from insurance claim-based data using Kaplan-Meier estimate. Statistical significance was determined using Chi-square/Mann-Whitney U tests. Results: NOTCH1 mutations were identified in 16.4% (N = 258) of HNSCC patients, with increased prevalence in patients ≥60 years (19 vs 11% < 60 years, p < 0.001), primary tumors (19 vs 11% in metastases, p < 0.001), and p16- patients (23 vs 11% p16+, p < 0.001). Further stratification by PDL1 expression showed lower NOTCH1 mutations rates (12%) in PDL1- samples, while PDL1+ samples with low (Combined Positive Score, CPS 1-20) and high (CPS > 20) expression had similar rates (21 and 25%, respectively). Overall, NOTCH1 mutations were associated with worse OS (1.2 HR, 95% CI 1.0-1.4, p = 0.03), and while no difference was observed in p16+ and p16- subgroups, p16- patients harboring NOTCH1 mutations were more frequently co-mutated with FAT1 (43 vs 19% in NOTCH1 WT, p < 0.01), PIK3CA (17 vs 9%, p < 0.05), and other rare variants. Among NOTCH1-WT patients, NOTCHsig-High was more common in p16- patients (56 vs 45% p16+, p < 0.01), metastases (59 vs 51% in primary, p < 0.05), and PDL1- patients (67 vs 53% PDL1+ low vs 47% PDL1+ high, p < 0.05). Overall, NOTCHsig-High was associated with worse OS (1.2 HR, 95% CI 1.0-1.4, p = 0.03), with no difference in OS observed in p16- subgroups, while p16+ NOTCHsig-High was associated with worse OS (1.6 HR, 95% CI 1.1-2.2, p < 0.01). Among the NOTCHsig genes, high expression of MYC was the strongest predictor of worse OS (1.8 HR 95% CI 1.2-2.7, p < 0.01). Conclusions: NOTCH1 mutations and high expression of NOTCH-regulated genes in NOTCH1-WT patients were associated with p16- status and poor clinical outcomes. These data support a wider involvement of NOTCH signaling in HNSCC, highlighting its prognostic value and potential targetability in both p16- and p16+ patients. Further evaluation is warranted to determine whether NOTCH signaling influences treatment response and investigate its potential use in biomarker-driver clinical trials. Citation Format: Iole Ribizzi-Akhtar, Andrew Elliott, Erica Golemis, Trisha Michel Wise-Draper, Farah Rukshana Abdulla, Wafik S. El-Deiry, Ariel E. Birnbaum. Analysis of the NOTCH pathway in HNSCC: A target with a wide prognostic and therapeutic potential [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-024.

Introduction: TV, a tissue factor (TF)-directed antibody-drug conjugate, is approved under accelerated approval in the US at a dose of 2.0 mg/kg IV administered every 3 weeks (Q3W) for adult patients (pts) with recurrent or metastatic (r/m) cervical cancer who have progressed on or after chemotherapy. TV is also being evaluated in several advanced solid tumors known to express TF, including SCCHN; antitumor activity has been observed at the approved dose level. Previous reports show that modifying the dosing schedule to optimize key PK parameters such as AUC, Cmax, and Ctrough can lead to further improvement in clinical efficacy. A population PK model based on 399 pts across clinical trials suggests that when TV is administered at 1.7 mg/kg IV on Days 1 and 15 of a 28-day cycle (Q2W), pts are predicted to achieve 24% higher AUC, a higher Ctrough level, and a lower Cmax, compared with the approved cervical cancer regimen (2.0 mg/kg Q3W). Here, we report the first analysis of TV 1.7mg/kg Q2W for r/m SCCHN that has progressed after prior platinum combination with or without immunotherapy. Methods: innovaTV 207 (NCT03485209) is an open label phase 2 multi-center study evaluating TV monotherapy or in combination for advanced tumors, including pts with r/m SCCHN. In Part C of the study, eligible pts could have received up to 3 lines of systemic therapy for r/m disease and must have received prior therapy with a platinum-based regimen and a checkpoint inhibitor (CPI), if eligible. TV was administered at 1.7 mg/kg IV Q2W. The primary endpoint was objective response rate (ORR), and secondary endpoints included safety and tolerability. Results: At data cutoff (28Nov2022), 15 pts with SCCHN were treated. The median number of prior lines for r/m disease was 2. All pts received prior platinum therapy and majority (93%) received a CPI. 67% of pts received cetuximab and 53% received taxanes, for r/m SCCHN. Confirmed ORR was 40% (95% CI: 16.3, 67.7), with 1 complete response and 5 partial responses. The safety profile was generally consistent with that observed across TV monotherapy clinical studies. 13 pts experienced a treatment-related adverse event (TRAE), most commonly asthenia (n=7), peripheral sensory neuropathy (PSN) (n=7), and vomiting (n=5). 4 pts experienced Grade ≥3 TRAEs. 2 pts discontinued treatment due to an AE (PSN and dry eye, n=1 each). 11 pts received 3 or more cycles of treatment (1 cycle = 28 days). Conclusions: For pts with r/m SCCHN who have progressed after prior platinum combination and immunotherapy, TV may be a promising treatment option. Preliminary data suggest encouraging antitumor activity at a higher exposure with Q2W administration while maintaining an acceptable safety profile. The innovaTV 207 study is still enrolling and different dosing regimens are currently being evaluated across advanced solid tumors. Citation Format: Beatriz Cirauqui, Sebastien Salas, William William, Ariel E. Birnbaum, Kristi Schmidt, Xuesong Guan, Ibrahima Soumaoro, Leonardo Nicacio, Fortunato Ciardiello. Tisotumab vedotin (TV) in squamous cell carcinoma of head and neck (SCCHN): interim analysis from innovaTV 207 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT164.

TPS6100 Background: Tisotumab vedotin (TV; TIVDAK) is a tissue factor (TF)-directed antibody-drug conjugate that has been granted accelerated approval in the US for treatment of adults with recurrent/metastatic (r/m) cervical cancer with disease progression on or after chemotherapy. TV remains investigational in other tumor types including squamous cell carcinoma of the head and neck (HNSCC) and squamous non-small cell lung cancer (sqNSCLC). This abstract presents the addition of Part D to innovaTV 207 (NCT03485209), a global, open label, multicenter phase 2 trial investigating the safety, tolerability, and activity of TV in solid tumors. Untreated patients (pts) with r/m HNSCC or sqNSCLC enrolled in Part D will receive either TV in combination with pembrolizumab (pembro) or TV + pembro and a platinum agent. Based on encouraging preliminary safety and efficacy results with 2.0 mg/kg TV once every 3 weeks (Q3W) in combination with pembro or carboplatin (carbo) in innovaTV 205 cervical cancer study cohorts, TV is being evaluated at 2.0 mg/kg Q3W in combination with pembro or pembro + carbo (or cisplatin). Methods: Up to 140 treatment-naive pts with r/m HNSCC or sqNSCLC will be enrolled in Part D of innovaTV 207. First, the All-Comers cohorts for HNSCC and sqNSCLC will each enroll up to 30 pts, regardless of PD-L1 expression, for Q3W dosing with 2.0 mg/kg TV in combination with 200 mg pembro and AUC 5 carbo. After enrollment in the HNSCC All-Comers Cohort is complete, up to 20 pts with HNSCC will be enrolled into a Cisplatin Safety Cohort for dosing with 2.0 mg/kg TV in combination with 200 mg pembro and 100 mg/m2 cisplatin. Completion of enrollment in the All-Comers Cohort for each tumor type will also be followed by enrollment of up to 30 pts with HNSCC (CPS ≥1) and 30 pts with sqNSCLC (TPS ≥1%) into PD-L1 Selected cohorts for dosing with TV in combination with 200 mg pembro. Response will be assessed every 6 weeks for the first 6 months, every 12 weeks for the next 6 months, and then every 6 months after that. Pts with HNSCC must have had no previous systemic therapy for metastatic disease (exception is systemic therapy given as part of multimodal treatment for locally advanced disease completed > 6 months prior). Pts with NSCLC must have histologically or cytologically documented squamous cell NSCLC and must not have had any previous systemic therapy for metastatic disease or radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of study drug. The primary endpoint is investigator-determined confirmed ORR per RECIST v1.1. Secondary endpoints include confirmed and unconfirmed ORR per RECIST v1.1, disease control rate, duration of response, time to response, PFS, OS, safety and tolerability, pharmacokinetics, and immunogenicity. The trial opened in June 2018 and was amended to add Part D in November 2021. Part D enrollment will begin in early 2022; updates will be provided at the meeting. Clinical trial information: NCT03485209.

Background Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone. Methods In this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] <1%), head and neck squamous cell carcinoma (HNSCC; CPI-naïve), urothelial cancer (post-CPI), and melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria in Solid Tumors version 1.1 after 6 weeks and every 9 weeks thereafter. Safety and pharmacokinetic data were provided for all enrolled patients; efficacy data focused on HNSCC and NSCLC cohorts. Results Overall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC. Conclusions Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC. Trial registration number NCT02475213 .

Survivorship care in cancer patients involves 4 essential components: surveillance (detect recurrence of cancer), prevention of cancer (smoking cessation and encouraging age appropriate malignancy work-up), management of cancer and treatment-related side effects; and coordination of care between oncology teams and primary care provider. National and international oncology groups have endorsed Survivorship care plans (SCP) with or without a dedicated survivorship care visit (SCV) as an important aspect of quality cancer care.

e21174 Background: Mutations (mt) in the KRAS gene are common oncogenic drivers in advanced NSCLC. The KRAS mt subtypes and certain co-mutations (co-mt) have prognostic and predictive implications. New drugs promise to uniquely target KRAS G12C, raising interest in studying the unique clinical and molecular characteristics of this subtype. Methods: We retrospectively identified 56 KRAS mt advanced NSCLC patients (pts) that underwent Next-Generation Sequencing (NGS) from 06/2015 to 12/2020. We used a commercial NGS panel that tested for > 300 genomic alterations, including substitutions, insertions, deletions and copy number alterations. For statistical analysis, we divided the patients into G12C and non-G12C groups. Results: In our cohort of 56 KRAS mt pts, median age was 67 (range: 58-74) with a predominance of females (63%) and heavy smokers (89%). KRAS G12C was the most common subtype 38%; G12V 14%, G12D 11%, G12S 11%, G13D 7% and others < 5% each. G12C, G12D and G13D groups had a higher proportion of PD-L1+ tumors (84%, 100%, and 100% respectively, p = 0.02) compared to other KRAS subtypes. Pts in G12C group were on average older (median age 71 vs 61, p = 0.02) than non-G12C. Most frequent co-mt in G12C were TP53 (33%), STK11 (29%), TET2 (19%), RB1 (14%), CDKN2A/B (14%) , MCL1 (14%) and ASXL1 (14%) ; for non-G12C, they were TP53 (54%), CDKN2A/B (37%), STK11 (34%) and RBM10 (17%). CDKN2A/B co-mt (37% vs 14%, p = 0.08) was significantly more frequent in non-G12C group and TET2 in G12C (19% vs 0%, p = 0.016). Non-G12C group more frequently had high TMB (17% vs 0%, p = 0.07) compared to G12C. No difference in survival was seen between G12C and non-G12C groups. We observed no difference in PFS (p = 0.31) or OS (p = 0.64) between smokers and no/light-smokers with KRAS mt. Co-mt with KEAP1 and SMARCA4 were significantly associated with survival in KRAS mt. Compared to KRAS+/KEAP1wt, KRAS +/ KEAP1+ pts had poor PFS (median 1.1 vs 7.5 m, p < 0.0001) and OS (1.1 vs. 27.8 m, p < 0.0001) measured from start of initial therapy. KRAS+/SMARCA4+ had worse PFS (1.0 vs 6.9 m, p < 0.0001) and OS (1.4 vs. 27.8, p = 0.0001) compared to KRAS+/SMARCA4wt. KRAS mt pts with STK11/KEAP1 that were treated with immunotherapy-based regimens had shorter PFS (1.1 vs 7.6 m, p = 0.001) and OS (1.4 vs 90.9 m, p = 0.0007) compared to those treated with chemotherapy alone. Conclusions: Our data shows that pts with KRAS co-mt with STK11/KEAP1 had worse PFS and OS with the addition of immunotherapy compared to chemotherapy alone, highlighting the potential implications of these co-mt patterns on treatment outcomes. The types of co-mts are similar between KRAS G12C and non-G12C, with the exception of CDKN2A/B (less likely) and TET2 (more likely). Larger data sets are warranted to confirm our observations and determine if these co-mts may create a predictive model for individualized therapy for KRAS mt pts, potentially independent of current predictive markers.

1572 Background: Rn-222 is a radioactive gas found in rocks and soil. It emits alpha particles that cause dsDNA breaks and increase potential for carcinogenesis. Rn is the 2nd leading cause of LC in the US after smoking. EPA estimates >15,000 deaths/yr (9% of LC deaths) from Rn. We hypothesize that the impact of Rn exposure may be reflected in LC gene mutation (mut) profiles. Methods: Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in FFPE specimens from 159 LC patients (pts) from the Lifespan Cancer Institute in Rhode Island (2014- 2019), followed by validation in a larger cohort of 5,532 pts using Caris platform. Based on EPA Rn maps, we identified counties with high indoor Rn levels (>4 pci/L; HR), and compared gene mut patterns with those from low Rn zones (<4 pci/L; LR). Based on pt’s zip code of residence, we categorized them to HR and LR. In the validation cohort, p values adjusted for multiple comparison (q) of < .05 were considered significant. Results: In the pilot cohort, 35 pts (22%) were in HR and 124 (78%) in LR zones. Adenocarcinoma histology was most frequent (73%) and smoking prevalence was high (75%) in both groups. Most prevalent alterations were TP53, KRAS and CDKN2A muts. In the HR, we noted more frequent recurrent muts in 2 DNA repair genes (DDR): ATM (11 vs 1%, p= .00086) and CHEK2 (6 vs 0%, p= .047) when compared to LR group. When classified into major pathways implicated in lung carcinogenesis, higher frequency of mutations were seen in DDR in HR zones vs. LR (29 vs 13%, p= .038). In the validation cohort, 1,433 (26%) pts were in HR and 4099 (74%) in LR zones. Among the DDR genes, ATM muts in HR group tended to be more frequent (4.7 vs 3.4% in LR, p= .03) as well as PALB2 (0.9 vs 0.4%, p= .02) while no difference seen in CHEK2. Other genes with significantly higher prevalence in HR were TP53, SMARCA4 and NFE2L2 (q< .05); while KMT2D, KEAP1, CDKN2A, MET, NF2, DNMT3A, CCND1 and FAS show a trend (p< .05). EGFR muts were significantly more frequent in LR zones (8.4 vs 14.6%, q= .001). Similar to the pilot cohort, DDR pathway alterations trend to be higher in HR zones (14 vs 12%, p= .05). Using a high TMB cut-off >10, tumors from HR zones had significantly higher TMB when compared to LR zones (56 vs 48%, q= .0005). Conclusions: To our knowledge, this is the first attempt to elucidate the pathobiology of Rn induced LC using gene mut analyses. Our observations suggest that LC associated with higher Rn exposure may have disabled DNA repair pathways and higher TMB. Assuming uniform tobacco smoke exposure, higher Rn was not associated with EGFR mut.

•Describe four major sequelae of head and neck cancer treatment, including dysphagia, dysphonia, disfiguration, and pain.•Explore the palliative care needs of patients with treated head and neck cancer, including the psychological burdens of being cured of cancer, while continuing to have significant residual sequelae.•Develop and implement actionable strategies for head and neck cancer patients that integrate palliative care approaches into the oncology practice during treatment and in survivorship. Depending on age, stage and HPV status, patients with locally advanced head and neck cancer have a high chance of cure, something that can be elusive in other advanced cancers. To achieve cure, patients undergo intense treatment regimens, including a long course of radiation, cytotoxic chemotherapy, and sometimes disfiguring surgery. Treatments are often accompanied by significant physical, emotional, and spiritual pain and other forms of suffering. While the promise of cure is alluring, the physical and psychological impacts of treatment can devastate patients. Patients may be left with visible facial scars, a changed or absent voice, a tracheostomy, and a gastrostomy tube, pieces of hardware that are often initially introduced as temporary supports but often become life-long necessities. During and after completion of treatment, a multidisciplinary team including otolaryngology, oncology, radiation-oncology, speech therapy, nutrition, psychology, and palliative medicine can help support the individual needs of patients as they grapple with and navigate the process of regaining a sense of self, even if cured. Patients often describe how eating, talking, and kissing, usually regular activities and simple pleasures in a normal life, are vastly different and complicated in their post-treatment lives. While most patients express joy for cure and deep gratitude for their lives, the adjustment to the new normal may lead to dissonant emotions and possibly regrets regarding treatment choices. Patients often lament the burden of a challenging and complex recovery that persists long after cure. In this concurrent session, our interdisciplinary panel will review sequelae of head and neck cancer treatment and discuss treatment options for the major complications and persistent distressing symptoms. We will explore the physical and emotional challenges faced by head and neck cancer patients. In addition, we will discuss the integration of an interdisciplinary team approach into the usual care and current model of survivorship.

BACKGROUND:The purpose of this nonrandomized, open-label, phase I study (NCT01285037) was to evaluate the safety and tolerability of merestinib, an oral antiproliferative and antiangiogenic kinase inhibitor, and to determine a recommended phase II dose and schedule for patients with advanced cancer.MATERIALS AND METHODS:This was a multicenter, nonrandomized, open-label, phase I study of oral merestinib consisting of six parts: dose escalation (part A), followed by a four-cohort dose-confirmation study (part B) and subsequently a four-part dose expansion and combination safety testing of merestinib with standard doses of cetuximab (part C), cisplatin (part D), gemcitabine and cisplatin (part E), and ramucirumab (part F) in patients with specific types of advanced cancers. Safety, tolerability, antitumor activity, and pharmacokinetics were evaluated in all cohorts.RESULTS:The dose escalation, confirmation, and expansion results support the dosing of merestinib at 120 mg once daily, based on acceptable exposure and safety at this dose. One complete response was observed in a patient with cholangiocarcinoma, and three patients with cholangiocarcinoma achieved a partial response. Overall, 60 (32%) of the 186 patients enrolled in the study had a best response of stable disease.CONCLUSION:This study demonstrates that merestinib has a tolerable safety profile and potential anticancer activity and warrants further clinical investigation.IMPLICATIONS FOR PRACTICE:Merestinib treatment in patients with advanced cancer demonstrated an acceptable safety profile and potential antitumor activity, supporting its future development in specific disease populations as a monotherapy and/or in combination with other therapies.

120 Background: Buprenorphine, a partial agonist at the mu opiate receptor, is an effective pain medication and use has increased for patients with cancer pain, especially those with concurrent opiate use disorder (OUD). Substance use disorder is common in head and neck cancer patients since alcohol and tobacco are predisposing factors. Definitive chemoradiation (chemoRT) for head and neck cancer is a difficult treatment with a high burden of symptoms, including mucositis pain, dysphagia and odynophagia. Patients undergoing concurrent chemoRT routinely require systemic opiates to manage pain and tolerate treatment. This is a review of our institution’s experience using buprenorphine and methadone for pain management in patients with OUD during chemoRT for head and neck cancer. Methods: We reviewed all cases seen in the Lifespan Cancer Institute head and neck cancer multidisciplinary clinic between July 2018 and June 2019. Approximately 40% of patients had a history of opiate use disorder and one-fifth of those were on medication-assisted treatment with buprenorphine or methadone. The charts of patients with OUD were reviewed with respect to history of buprenorphine or methadone use, pain scores during chemoRT, effectiveness of pain medications during chemoRT, and change of pain medication during treatment. Results: 5 patients on buprenorphine and 4 patients on methadone underwent treatment with chemoRT for head and neck cancer. Despite effectiveness for pain with other cancer patients, we did not find that buprenorphine was an effective opiate for patients undergoing chemoRT for head and neck cancer. All patients on buprenorphine had to be rotated off to another opiate (generally methadone) to achieve adequate pain relief. Median time to pain medication change was 3 weeks (range: prior to starting to week 5/7). The patients on methadone generally were able to tolerate treatment with minor adjustments to their methadone. Conclusions: The ceiling effect of buprenorphine that makes it effective for OUD is a barrier to managing the severe pain from chemoRT for head and neck cancer, while methadone is effective for both pain control and maintenance of sobriety during a taxing treatment.

e21211 Background: Radium-223 dichloride (Ra-223) is a targeted- alpha particle emitting therapy directed at bone metastases with high-linear energy transfer at a short-range. This study investigated the safety and efficacy of Ra-223 given after front-line chemotherapy in patients with non-small cell lung cancer (NSCLC) metastatic to bone. Methods: In this prospective phase II study, patients received up to 6 injections of Ra-223 (55 kBq/kg IV) q 4 weeks as maintenance therapy if they had not progressed after front-line chemotherapy. The primary end point was the proportion of patients who experienced their first symptomatic skeletal-related event (SSE) during study treatment. The control was a historic experimental arm consisting of 257 patients (majority having NSCLC) who received zoledronic acid 4mg q 3 weeks in which approximately 40% of patients experienced a SSE. Secondary endpoints included toxicity, time to SSE, PFS and OS. Results: Five of the planned 36 patients were enrolled (study closed due to slow accrual). Median number of cycles received was 3.8 (range 2-6). One patient developed a SSE (pathologic T7 fracture) after 219 days. The four remaining patients did not experience a SSE during follow-up. Treatment-related adverse events (TRAEs) were mostly grade 1/2. Two patients experienced grade 3 TRAEs; one diarrhea and one lymphopenia. No grade 4 TRAEs were seen. PFS at 6 months was 80.0% (95%CI, 20.4 to 96.9). PFS at 12 months was 40.0% (95%CI, 5.2 to 75.3). Median PFS was 10.3 months (95%CI, 4.0 to not reached). No patients expired over the planned one year of follow-up. Genomic testing and review of results are planned. Conclusions: Ra-223 has a highly favorable safety profile in patients with NSCLC who have received front-line chemotherapy. Though this study had few patients, the PFS and OS results suggest that Radium-223 might play a potential role in the treatment of NSCLC and warrants further investigation. Clinical trial information: NCT02283749.