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PURPOSE To provide evidence-based recommendations for practicing physicians and other health care providers on immunotherapy and biomarker testing for head and neck cancers. METHODS ASCO convened an Expert Panel of medical oncology, surgical oncology, radiation oncology, radiology, pathology, and patient advocacy experts to conduct a literature search, including systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2000 through 2022. Outcomes of interest included survival, overall response, and locoregional control. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 28 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS When possible, evidence-based recommendations were developed to address biomarker testing, first-line treatment regimens based on programmed death ligand-1 scores, immunotherapy in platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma, immunotherapy in nasopharyngeal carcinoma, and radiation therapy in combination with immunotherapy for treatment of local recurrence. Additional information is available at www.asco.org/head-neck-cancer-guidelines .

93 Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a debilitating side effect associated with many chemotherapeutic agents. It significantly impacts quality of life during treatment, causes lasting neuropathy, and may also shorten the treatment regimen, potentially impacting clinical benefit. The pathology of CIPN is still not completely understood, however, increasing evidence suggests sphingosine-1-phosphate (S1P) may be an important signaling molecule. Altered neuronal sphingolipid metabolism has been linked to neuropathic pain, evidenced by elevated plasma levels of S1P in patients receiving chemotherapy. Methods: BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P. BXQ-350 was investigated in an adult Phase 1 dose-escalation safety study in heavily pretreated all-comer cancer patients with advanced solid malignancies ( NCT02859857 ). The primary objective was to determine the safety profile and potential clinical activity of BXQ-350 as monotherapy. Samples were collected to explore potential biomarkers. Results: BXQ-350 was safe and well tolerated. Clinical signs of activity were observed in 13 patients (~17.8% of evaluable patients) experiencing a clinical benefit (PR, SD) up to cycle 6 and beyond including: 4 CRC, 1 pancreatic, and 1 GIST patient. Two patients are still on study six years after enrollment, including 1 CRC. Interestingly, a pancreatic cancer patient with chronic CIPN at time of enrollment spontaneously reported a significant improvement of her neuropathic symptoms shortly after receiving BXQ-350. Investigation of potential improvements in patients with chronic CIPN at time of enrollment revealed that 4 out of 10 patients experienced an improvement of their symptoms that seemed to be associated with a decrease in S1P systemic levels following BXQ-350 administration. BXQ-350 was subsequently investigated in a murine oxaliplatin-CIPN preclinical model with results showing a dose-dependent prevention/resolution of CIPN correlating with decreasing systemic S1P levels. Conclusions: Results of this Phase 1 study in heavily pretreated patients shows that BXQ-350 was well tolerated and seems to generate a clinical benefit via modulation of S1P. There were preliminary signs that BXQ-350 may alleviate symptoms of CIPN in relation to decreasing S1P concentration. Additional studies are underway to better understand this novel mechanism of action. Clinical trial information: 02859857 .

154 Background: Sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Many publications have demonstrated that ceramides are proapoptotic, synergize with cancer treatments, and mitigate chemoresistance. Findings also demonstrated that sphingosine-1-phosphate (S1P) is a key sphingolipid that promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies of colorectal cancer patients have shown high levels of ceramides being associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism continues to be a promising treatment approach. Methods: BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in an all-comer cancer patients with advanced solid malignancies ( NCT02859857 ) to determine its safety profile and potential clinical activity as monotherapy. Samples were collected to explore potential biomarkers. Results: 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 (PR, SD), with the majority experiencing a decrease in systemic S1P levels and an increase in C18 levels. 8 patients (~11% of evaluable patients) had PFS > 6 months, with 2 patients still on study six years after enrollment. Analysis of plasma samples also revealed an increase in anti-tumoral cytokines (IFNg, TNFa, IL-2) and a decrease in pro-tumoral ones (IL-6, 8, 10). Among patients with PFS > 6 months, there were 4 recurrent CRC patients (1PR, 3SD): 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 6 years. Conclusions: Results of this Phase 1 study in heavily pretreated patients show BXQ-350 was well tolerated and seem to generate a clinical benefit in CRC patients via modulation of S1P and ceramides. A phase 2 trial of BXQ-350 in combination with FOLFOX/Bevacizumab in newly diagnosed mCRC is on-going with plans to further investigate this novel mechanism of action. Clinical trial information: 02859857 .

9553 Background: RP1 is an enhanced potency oncolytic version of HSV1 that expresses human GM-CSF and the fusogenic protein GALV-GP R-. IGNYTE is a multicohort phase 1/2 study that evaluates the safety and efficacy of RP1 in combination with nivo (NCT03767348) in a range of tumor types. Preliminary data demonstrated a durable anti-tumor activity and tolerability for RP1+nivo. Here, we present updated results from the initial and melanoma (mel) and anti-PD1 naïve non-melanoma skin cancer (NMSC) cohorts with RP1+nivo. Methods: RP1 is administered via intratumoral injection Q2W, up to 10 mL/visit, first alone at a dose of 106 PFU/mL and then starting with the 2nd dose at 107 PFU/mL in combination with nivo (240 mg IV Q2W for 4 months (mos) then 480 mg IV Q4W up to 2 yrs) for up to 8 doses, with the option to re-initiate RP-1. Eligible patients (pts) must have at least one measurable & injectable tumor of ≥ 1 cm, ECOG 0-1, and no prior oncolytic therapy. For mel, both anti-PD1 naïve and failed pts were eligible, for NMSC pts who were anti-PD1 naïve. Results: As of data extraction on January 31, 2022, 13/36 pts with mel (36.1%) and 19/31 pts with NMSC (61.3%) had a best response of PR or CR. For mel this was 5/8 (62.5%), 6/16 (37.5%), 0/6 and 2/6 (33.3%) for pts with anti-PD1 naïve cutaneous, anti-PD1/anti-PD1+anti-CTLA-4 failed cutaneous, uveal and mucosal mel respectively. For the anti-PD1 naïve NMSC this included 11/17 (64.7%), 1/4 (25%), 3/4 (75%) and 4/6 (66.6%) patients with CSCC, BCC, MCC and angiosarcoma respectively, including 8/17 (47.1%) being CR for CSCC. Current immature median DOR was 13.27 mos (current range 3.67-16.93 mos) for mel, and 7.32 mos (current range 1.88-23.11mos) for anti-PD1 naïve NMSC. Any grade TEAE ( > 25%) in all cohorts combined were fatigue, nausea, pyrexia, chills, diarrhoea, pruritus, and influenza-like illness. TEAE ≥grade 3 ( > 5%) were disease progression and fatigue. No deaths related to RP1 was observed, with one death related to nivo (myocarditis). Biomarker data from paired biopsies indicated robust T cell infiltration and an increase in tumor inflammation gene signature post-treatment. Clinical responses observed were independent of baseline tumor PD-L1 expression status. Conclusions: RP1 in combination with nivo provides a durable anti-tumor activity in pts with skin cancers, including anti-PD1 failed and anti-PD1/anti-CTLA-4 failed mel. The combination continued to be generally well tolerated with no new safety signals identified. Based on this data, enrollment into both a registration-directed cohort of pts who have anti-PD1 failed cutaneous mel (n = 125) and a cohort of pts with anti-PD1 failed NMSC (n = 30) is ongoing. Up-to-date data from this ongoing trial will be reported at the conference. A randomized Ph2 trial of RP1+cemiplimab vs. cemiplimab alone in anti-PD1 naïve NMSC is also underway (NCT04050436). Clinical trial information: NCT03767348.

e15045 Background: Chemical Induced Peripheral Neuropathy (CIPN) is a debilitating and serious side-effect associated with many chemotherapeutic treatments. Often, CIPN is a dose-limiting toxicity, and its effects can be long-lasting in some patients. The pathology of CIPN is thought to involve not only cytotoxicity of neuronal cells, but also inflammation and immune responses. Hence, it is not surprising that the sphingolipid sphingosine-1-phosphate (S1P) is thought to be a key contributor to CIPN. Methods: BXQ-350, a nanovesicle comprised of recombinantly expressed Saposin C and dioleoylphosphatidylserine, has broad anticancer activity. It modulates sphingolipid metabolism and signaling, lowers S1P and increases pro-apoptotic ceramides, and induces an anti-tumoral immune response. BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 )*. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetics, efficacy profile and to elucidate potential biomarkers. Results: Interestingly, several patients with established CIPN spontaneously reported improvement of their neuropathy-related symptoms following BXQ-350 administration. Plasma samples from those patients revealed changes in circulating levels of sphingolipids and cytokines, including reduction of circulating levels of S1P and of IL-6, IL-8, cytokines, following BXQ-350 dosing. These properties of BXQ-350 were subsequently investigated in a murine oxaliplatin-CIPN preclinical model; results showed a dose-dependent prevention/resolution of CIPN, which also correlated with decreasing systemic S1P levels. Additional plasma based CIPN specific biomarkers were investigated, and preclinical results suggest that BXQ-350 may also favorably inhibit specific immune cells that favor CPIN. Conclusions: These preclinical and clinical observations related to CIPN, coupled with the fact that BXQ-350 acts synergistically with many chemotherapies and radiation, warrant further its investigation into preventing or improving CIPN related symptoms in cancer patients. Clinical trial information: 02859857.

TPS9597 Background: RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity. Clinical data in combination with nivolumab has demonstrated a high rate of deep and durable response in patients with advanced skin cancer. Solid organ transplantation (SOT) is an important lifesaving procedure for patients with a wide range of end-organ diseases, but requires patients (pts) to undergo lifelong immunosuppression to prevent allograft rejection, and skin cancers (SCs) – including cutaneous squamous cell carcinoma (CSCC) – are common post-transplant malignancies. SC in SOT pts is generally managed with surgical resection, radiation therapy, and chemotherapy or targeted therapy. The use of immune checkpoint inhibitors in SOT recipients has improved outcomes but is associated with a high risk of allograft rejection. Thus, there is a high unmet need for a safe and effective treatment that also protects pts from allograft rejection. The objective of this study is to assess the safety and efficacy of single-agent RP1 in SOT patients with SCs, with a focus on CSCC. Methods: This study will enroll up to 65 evaluable SOT pts with locally advanced or metastatic SCs. The study has two parts. In Part A, pts will receive an initial dose of 1 x 106 plaque-forming units (PFU) of RP1. Two weeks later they will receive 1 x 107 PFU of RP1 and continue every two weeks until pre-specified study endpoints are met. In Part B, after determining the safety and tolerability in the initial cohort with kidney and liver transplants, the study may also enroll heart and lung transplant recipients. RP1 will be administered by intra-tumoral injection, utilizing image guidance as clinically appropriate. Key inclusion criteria are pts with confirmed recurrent, locally advanced or metastatic CSCC and up to 10 pts with non-CSCC SC, stable allograft function and ECOG performance status of ≤1. Pts with prior systemic anti-cancer treatment are allowed. Key exclusion criteria are prior treatment with an oncolytic therapy, active herpetic infections or prior complications of HSV-1 infection and a history of organ graft rejection within 12 months. The primary objective of the trial is to assess efficacy determined by objective response rate and safety of single agent RP1. Additional secondary endpoints include duration of response, complete response rate, disease control rate, progression-free survival and overall survival. Clinical trial information: NCT04349436.

e15007 Background: BXQ-350 was investigated in a Phase 1 dose-escalation safety study of all-comer cancer patients with advanced solid malignancies, including high grade gliomas ( NCT02859857 ) (safety/efficacy results reported in a separate abstract). The primary objective of this single agent study was to describe the safety profile and to determine the maximum tolerated dose. Multiple secondary parameters were included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and elucidation of potential biomarkers. BXQ-350 is a nanovesicle of recombinantly expressed Saposin C (SapC) and dioleoylphosphatidylserine. In nature, SapC is a protein encoded by the Psap gene, and serves as an allosteric activator of several enzymes involved in sphingolipid/ceramide metabolism, enzymes which are being investigated as novel therapeutic targets in cancers. Indeed, sphingolipids are a class of bioactive signaling molecules implicated in multiple cellular processes and molecular pathways. Amongst these sphingolipids, Sphingosine-1-Phosphate (S1P) induces cancer cell survival and proliferation, activates multiple oncogenic pathways, and promotes a pro-tumoral microenvironment. SapC has broad anticancer activity, lowering S1P and increasing ceramides, also inducing an anti-tumoral immune response. Methods: Lipodomic analysis (sphingolipids) and cytokines were analyzed in plasma samples of a subset of patients enrolled in this study. Results: Analysis of plasma biomarker samples, collected throughout the period patients were on study, reveals notable changes of circulating sphingolipids and cytokines. A subset of patients exhibited clinical benefits following BXQ-350 administration (see other presentation for details; ̃17% of the evaluable patients remained on study up to Cycle 6; and 8 patients (̃11%) with PFS> 6 months). Concomitant circulating changes in S1P and other ceramides may be indicative of treatment effect. Also, concurrent changes in circulating levels of pro/antitumoral cytokines were noted. Conclusions: While these results are exploratory and preliminary in nature, these initial results warrant further investigation. These observations will be further explored in specific cancer and non-cancer indications. Clinical trial information: 02859857.

e15059 Background: Bexion recently completed an all-comer Phase 1 clinical study of BXQ-350 in patients with advanced solid tumors including high grade gliomas to evaluate the safety profile and to determine the maximum tolerated- or biologically effective dose. BXQ-350 is a nanovesicle comprised of recombinantly expressed Saposin C (SapC) and dioleoylphosphatidylserine. SapC, a human protein encoded by the Psap gene, is an allosteric activator of several enzymes involved sphingolipid metabolism. Sphingolipids are bioactive signaling molecules implicated in multiple cellular processes including apoptosis and immune stimulation/inhibition. In nonclinical studies, BXQ-350 evidences broad anticancer activity, selectively inducing apoptosis of cancer cells by modulating sphingolipids (ceramides/S1P), and BXQ-350 acts synergistically with multiple classes of anticancer agents and treatments. Methods: In the trial (NTC02859857), performed at four US sites, BXQ-350 was administered intravenously for a minimum of 6 cycles over 28 weeks at escalating doses from 0.7 mg/kg up to 2.4 mg/kg. Multiple secondary parameters were included to characterize its pharmacokinetics, efficacy profile and identify potential biomarkers. Results: Results indicate that: i) BXQ-350 was safe and well-tolerated as no DLT was observed and an MTD was not reached; ii) treatment related adverse events leading to discontinuation were typical for this patient population and disease related; iii)* biomarker analyses suggest positive modulation of sphingolipid metabolism and stimulation of the immune system; iv)* surprisingly, some patients noted improvement of existing peripheral neuropathies. RANO or RECIST ver 1.1 criteria were used to evaluate tumor response: 13 patients reached Cycle 6 restaging (17% ORR); 8 patients (11.0% of evaluable patients) demonstrated progression free survival over more than 6 months; and 2 patients (a GBM and CRC patient) are still on study after 5 years. * subject of separate abstracts. Conclusions: In conclusion, BXQ-350 is a first-in-human and first-in-class novel biologic whose Phase 1 results suggest that it may have clinical utility either as a monotherapy or when combined with other targeted agents. Clinical trial information: 028559857.

e18086 Background: BRAF (BRAF mut) is the most common mutation in PTC (45% prevalence). It is associated with a higher clinical stage, tumor recurrence, absence of tumor avidity, and treatment failure. Methods: BRAF WT or BRAF mut (n = 538) PTC tumors tested with NextGen Sequencing on DNA (592 genes or WES) and RNA (WTS) by Caris Life Sciences (Phoenix, AZ) were analyzed. PD-L1 expression was tested by IHC (22c3 antibody, ≥1 combined positive score (CPS) being positive). Real world overall survival (rwOS) was obtained from insurance claims data, calculated from treatment start to last contact. Time-on-treatment (TOT) is calculated from start to end of treatment. Kaplan-Meier estimates were used for comparison. Statistical significance was determined using Fisher’s-Exact/Mann Whitney/X2 test with Benjamini-Hochberg correction. Differential gene expression was analyzed using the Limma R package (q < 0.001, logFC > 1.5, -log10 FDR > 20). Gene Set Enrichment Analysis (GSEA) was used with a p < 0.01 cutoff. Results: BRAF mut were found in PTC (69%, 369/538) but not in the follicular subtype (0/117). No gender difference was seen in BRAF mut PTC (F: 53%, 297/538). BRAF mut were more prevalent in metastases compared to primary/local tumors (42% vs. 30%) and BRAF mut was highest in metastatic lymph nodes (55%, 130/235). TERT promoter was the most common mutation in both BRAF mut and WT groups but higher in BRAF mut (64% vs 40%, q < 0.0001), while NRAS (0.2% vs 23%, q < 0001), HRAS (0% vs 8.8%, q < 0001), KRAS (0.4% vs 5.4%, q < 0001), and EIF1AX (0% vs 6.6%, q = 0.0005) mutations were more prevalent in BRAF WT PTC. PD-L1 expression was higher in the BRAF mut patients compared to WT (37% vs 22%, q < 0.01). BRAF mut PTCs were associated with higher immune cell infiltrate including M1 macrophages, and Treg cells, but lower M2 macrophages, NK cells, CD4+ T cells, and myeloid dendritic cells (all q < 0.01). GSEA analysis revealed enrichment in IL6, JAK, and STAT3 signaling, inflammatory response, apoptosis, and interferon gamma response (all NES = 1.5 - 1.8, p < 0.01) gene sets. DCSTAMP was the most differentially expressed gene in BRAF mut tumors relative to WT (logFC = 4.4). When comparing BRAF mut with WT, no significant difference in rwOS was seen (NR vs 50 mo, HR 0.73, P> 0.2). In BRAF mut patients, treatment with multikinase inhibitors (n = 32) was associated with longer rwOS compared to BRAF inhibitor treatment (n = 37) (61 mo vs 27 mo, HR 0.364, P< 0.05). Despite small patient number, data suggests BRAF mut patients may benefit from immunotherapy (n = 4) when compared to BRAF inhibitors (n = 31) (TOT, HR = 0.35, p = 0.07). Conclusions: Our data highlights new genomic signatures that indicate potential new, while also validating current targets for BRAF mut PTC: higher PD-L1 expression, immune infiltrate, and inflammatory gene signature. Clinical trials are needed to assess the best sequencing of therapies used in this group, particularly TKIs vs BRAF inhibitors and the role of immunotherapy.

TPS6105 Background: Despite improvement in outcomes with checkpoint (PD-1) inhibitors in some patients (pts) with recurrent and metastatic head and neck squamous cell carcinoma (RM HNSCC), overall survival (OS) remains poor, necessitating novel therapy combinations. Fanconi Anemia (FA) and FA-related DNA repair pathways alterations have been associated with cumulative tumor mutational burden (TMB) due to genomic instability. High TMB is associated with improved response to PD-1 inhibitors. DNA pathway repair mutations have been reported in 17% of sporadic HNSCC. Ataxia-Telangiesctasia Mutated (ATM) loss has been reported in 60% of human HNSCC biopsies and FA-related defects were reported in 15-21% of human HNSCC biopsies and cell lines. Poly (ADP-ribose) polymerase (PARP) inhibition has already demonstrated efficacy as a single agent in multiple cancers which harbor a DNA repair defect. Preclinical data also showed PARP inhibitor (PARPi) upregulates PD-L1 expression in cancer lines and animal models via inactivation of glycogen synthase kinase 3 (GSK3β). Importantly, blockade of PD-1 re-sensitized PARPi treated cells to induce T-cell mediated cytotoxicity. Combination of PARPi and anti-PD-1 therapy significantly increased therapeutic efficacy in vivo compared to single agent. Therefore, we hypothesized that the combination of a PARPi (niraparib) and PD-1 blockade (dostarlimab) in our ongoing phase II study would enhance overall response (OR) and survival in R/M HNSCC pts (NCT04313504). Methods: Eligible pts must have a confirmed histopathology of non-cutaneous RM HNSCC not amenable to local therapy, progressive disease (PD) after at least one line of platinum-based chemotherapy and/or immunotherapy, age>18, ECOG

e14105 Background: We conducted a retrospective study to analyze the overall survival (OS) and progression free survival (PFS) among patients with bone metastases (BMs) from Non Small Cell Lung Carcinoma (NSCLC), Melanoma, Head and Neck Squamous Cell Carcinoma (HNSCC) and others (including genitourinary carcinoma) treated with immunotherapy (Nivolumab, Pembrolizumab, Ipilimumab or a combination). Methods: We retrospectively evaluated patients with BMs treated at our institute from 2012-2017 who received either immunotherapy alone or in combination with other therapies for BMs including: medical therapy (zoledronic acid or denosumab), radiation or surgery. Univariate analysis was utilized to analyze OS and PFS. Results: A total of 58 patients were identified, median age at diagnosis of BMs was 61 years (range 29 – 94). 39 patients were male (67.2%) and 47(81%) patients had good performance status (KPS 70-100) at the time of immunotherapy initiation. The median time to diagnosis of BMs was 11.4 months. 20 patients had a single BM, 16 had 2-4 BMs and 22 had ≥5 BMs. Axial-only BMs were seen in 27 patients, appendicular-only in 8 and both in 23 patients. 40 patients were symptomatic and 28 patients had skeletal events (pathological fractures, spinal cord compression or hypercalcemia). 51 patients had other metastatic sites at the time of initiation of immunotherapy. 25 patients received nivolumab, 20 patients received pembrolizumab and 4 patients received combination immunotherapy. 41 patients received additional treatments for BMs. The median OS from the start of immunotherapy was 5.15 months and median PFS was 3 months. On univariate analysis male sex (p = 0.03) and combination immunotherapy (p = 0.06) were associated with better OS. Patients who received additional treatments for BMs (p = 0.04) and combination immunotherapy (p = 0.02) had better PFS. Conclusions: Combination immunotherapy and use of additional treatment modalities for BMs is associated with better survival. Further analysis is required to validate these results. [Table: see text]