Cooper, Anna C.

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

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

TPS6111 Background: Treatment options for recurrent and/or metastatic (R/M) salivary gland cancer (SGC) are limited with response rates to standard cytotoxic chemotherapy (CT) low at 10-30%, and responses to single-agent immune checkpoint inhibition (ICI) <10%. Current therapeutic agents used to treat R/M SGC have an unfavorable toxicity profile including cytotoxic CTs such as cisplatin and doxorubicin and the targeted therapy lenvatinib. Treatments with general applicability and acceptable side effect profile are urgently needed. Pemetrexed (PTX) is a multi-targeted anti-folate CT with an excellent safety and toxicity profile with promising responses reported in a case series of patients (pts) with R/M SGC (Viscuse P and Price K. Marked responses to pemetrexed chemotherapy for metastatic adenocarcinoma of the parotid gland: case series. Head Neck 2019;41(6):E99-103.). As the combination of PTX and pembrolizumab (PMB) showed enhanced responses and survival in pts with lung cancer, we hypothesize that PTX and PMB will have efficacy in pts with R/M SGC and that the combination will have improved anti-cancer activity compared with historical controls. Correlative studies on archived tissues include methylthioadenosine phosphorylase loss, PDL1 expression, and thymidylate synthase expression as potential biomarkers of response. Methods: MC200708 is a single institution (3-site), open-label, single arm phase II study of PTX and PMB in patients with R/M SGC. Pts will be treated in two cohorts: one for pts with adenoid cystic carcinoma (ACC) and the other for pts with all other types of SGC (non-ACC cohort). Eligible pts must be ≥18 years old, have a pathologically confirmed SGC that is not amenable to curative-intent therapy, ECOG 0-2, adequate organ function, and at least 1 measurable lesion by RECIST 1.1. Any number of lines of prior therapy is allowed; prior treatment with checkpoint inhibitors and/or PTX is allowed. Key exclusion criteria: serious medical co-morbidity or autoimmune disease, prior grade 3-4 adverse event (AE) or grade 2-4 lung AE with ICI, and uncontrolled brain metastases. Simon’s two-stage design will be used for each cohort separately given the expected difference in responses in pts with ACC and non-ACC. Primary endpoint is overall response rate. Secondary endpoints are progression free and overall survival and toxicity. All patients will receive the same treatment of PTX 500 mg/m2 IV + PMB 200 mg IV every 3 weeks until disease progression or treatment intolerance. Response assessments will occur every 3 cycles. Enrollment began July 2021 and 16 of the planned 45 patients (ACC cohort 9 of 20 pts, non-ACC 7 of 25) have been accrued. Clinical trial information: NCT04895735.