Materials/Methods: 223 patients (from 44 institutions) with locally- advanced oral cavity or oropharynx cancer planned to be treated with definitive or post-op intensity-modulated (IM)RT (60-72 Gy [50 Gy to  2 oral sites]) plus cisplatin (weekly or q3wk) were randomized to receive 30 mg (nZ73) or 90 mg (nZ76) of GC4419, or placebo (nZ74) over 60-minutes IV, prior to each IMRT fraction. The primary endpoint was duration of SOM tested for each active dose level vs placebo (ITT population, 2-sided alpha 0.05). The secondary endpoints included SOM incidence and severity (i.e., specific incidence of WHO Grade 4 OM), safety, and Kaplan-Meier estimates of OS, PFS, LRC, and DMFS. Pairwise comparisons of Kaplan-Meier estimates (each active arm separately vs placebo) were made. Results: Baseline patient and tumor characteristics (86% male; 77% oropharyngeal; 87% Stage IV [AJCC 7 th ed]; 72% tumor HPV +; 29% never-smokers; median [range] pack yrs prior smokers 25 [0.1-140], cur- rent smokers 37.5 [3-100]), and treatment delivery (62% weekly cisplatin) were balanced. Efficacy and Safety results were previously reported (JCO 2019, PMID: 31618127) showing GC4419 90mg, compared with placebo, produced a significant, clinically meaningful reduction of SOM duration, incidence and severity, with acceptable safety. At a median follow-up for the entire cohort of 25.5 months (range: 0.2 to 31.9 months), Kaplan-Meier estimates of 1-year and 2-year OS, PFS, LRC and DMFS were statistically identical (Table 1). Conclusion: GC4419 does not compromise tumor control outcomes when used concurrently with curative-intent cisplatin and radiotherapy for head and neck squamous cell carcinoma. A Phase 3 trial ("ROMAN,” NCT 03689712) is enrolling. Author Disclosure: C.M. Anderson: Employee; University of Iowa Hos- pitals & Clinics, University of Iowa College of Nursing. Travel Expenses; Elekta. Enrolling patients on industry-sponsored clinical trial, discussing research related to trial drug with the company; Galera Therapeutics,Inc. Involved in lobbying congress, representing regional CRNA interests at the national A. C.M. Lee: None. D. Saunders: Research Grant; Health Sci- ences North. Honoraria; Amgen, Pfizer. Consultant; Dermtreat. Travel Expenses; Galera Therapeutics/Alira Health. A.E. Curtis: Travel Ex- penses; Galera Therapeutics. N.E. Dunlap: Honoraria; Osler Institute. Speaker’s Bureau; AstraZeneca. Advisory Board; Galera Therapeutics. C. Nangia: None. A. Lee: None. S.M. Gordon: Research Grant; Vigilant Biosciences. P. Kovoor: Stock; Gridalis, Saans Health; Saans Health, Baylor Plano. V. Bar-Ad: None. A.V. Peddada: None. K.T. Colvett: None. D.M. Blakaj: None. M. Bonomi: None. F. Worden: Research Grant; Lilly, Galera Therapeutics, Pfizer, Genetech. Consultant; Fusion. J. Holmlund: Independent Contractor; Galera Therapeutics. Consultant; Baxalta, Prometheus Labs. Stock Options; Galera Therapeutics. ad-hoc reviewer; Aspire IRB. J. Brill: Employee; Incyte, Array Bio- pharmaceuticals. Stock Options; Galera Therapeutics, Incyte, Array. M. Downs: Consultant; Statistics Collaborative, Inc. Travel Expenses; The Medicines Company, Seattle Genetics. S.T. Sonis: Partner; Primary Endpoint Solutions. Stock; Inform Genomics. Partnership; Immunity Health. volunteer advisor; Immunity Health. research leadership; Primary Endpoint Solutions, Biomodels. J. Buatti: Review chapters Up to Date; Up to Date. RESEARCH FEATURE LBA 3 HNSCC-associated CASP8 mutations promote resistance to apoptosis and mediate induction of immunosuppressive cytokines Z. Cui, H. Tal, J. Grandis, and D.E. Johnson; UCSF, San Francisco, CA Purpose/Objective(s): The CASP8 gene, encoding caspase-8 protease, is mutated in 10% of the head and neck squamous cell carcinoma (HNSCC) tumors analyzed by The Cancer Genome Atlas (TCGA). To determine the potential impact of HNSCC-associated caspase-8 mutations on anti-tumor immunity and the development of HNSCC, we investigated the functional capacity of caspase-8 mutants to mediate death ligand induction of apoptosis and cytokine production. Materials/Methods: In this study, the endogenous CASP8 gene in HeLa cells was knocked out using CRISPR-Cas9 technology. The HeLa- CASP8 KO cells were then engineered for doxycycline-inducible expression of WT or 21 HNSCC-associated caspase-8 mutants (MT). The engineered cells were then stimulated with death ligands TRAIL, and analyzed for induction of apoptosis using MTT assays or annexin V staining. Induction of immunosuppressive cytokines was assessed by qPCR and ELISA assays. Those were further evaluated in the engineered HNSCC cell line PE/CA-PJ49-CASP8 KO cells. Results: HeLa-CASP8 KO cells engineered to express WT caspase-8 un- derwent rapid apoptosis following TRAIL treatment. By contrast, 16 of the 21 caspase-8 MTs expressing cells failed to undergo apoptotic cell death. Interestingly, 5 mutations (L7V, G11E, G11R, S99F, Y178del) occurring in the death effector domains (DEDs) domains of caspase-8, retain partial abilities to mediate TRAIL-induced apoptosis. TRAIL treatment of parental HeLa cells, but not HeLa-CASP8 KO cells, led to upregulation of the immunosuppressive cytokines IL-6, IL-8, and CXCL1. Exogenous expres- sion of WT caspase-8 in the KO cells restored TRAIL induction of the cy- tokines. Further, exogenous expression of caspase-8 proteins with mutations in the catalytic domain (R248, TT272-3del, D303G, D303V, D308G, S375*, R435*, R465*), also restored TRAIL induction of the immunosuppressive cytokines. Among these, caspase-8 D303G, restored HeLa and PE/CA-PJ49 CASP8 KO cells with prominent TRAIL induction of cytokines at both mRNA and protein levels. Moreover, cells expression MT proteins capable of TRAIL induction of the cytokines, were characterized by increased phospho-p65 following TRAIL treatment, suggesting a role for NF-kB in mediating cytokine induction by the MT proteins. Conclusion: Our findings demonstrate that HNSCC-associated caspase-8 mu- tations have lost the capacity, or exhibit reduced capacity, to mediate TRAIL- induced apoptosis. Hence, HNSCC cells harboring these mutations are likely more resistant to killing by immune cells which utilize death receptor-mediated apoptosis to kill target cells. Notably, MTs in the catalytic domains of caspase-8 protein retained the capacity to mediate TRAIL induction of immunosuppressive cytokines. These mutations are likely to enhance the immunosuppressive tumor microenvironment, further contributing to HNSCC development. Author Disclosure: Z. Cui: None. H. Tal: None. J. Grandis: None. D.E. Johnson: None. LATE-BREAKING POSTERS LBA 4 Mobile Patient-Facing Application for Tracking Patient- Reported Outcomes in Head-and-Neck Cancer Survivors: a Pilot Usability and Feasibility Study S. Teckie, 1 , 2 J. Solomon, 3 K. Kadapa, 3 K. Sanchez, 3 D. Frank, 3 D. Kamdar, 3 L. Pereira, 3 D. Kraus, 1,4 L. Potters, 2 and M. Diefenbach 5 ; 1 Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 2 Northwell Health, Lake Success, NY, 3 Northwell Health, New Hyde Park, NY, 4 Northwell Health, New York City, NY, 5 Northwell Health, Manhasset, NY Abstract LBA 2 Table Placebo (n[74) 30mg (n[73) 90mg (n[76) p-value 1-year OS 93% 91% 88% NS PFS 82% 86% 80% NS LRC 95% 95% 91% NS DMFS 92% 92% 95% NS 2-year NS OS 87% 85% 86% NS PFS 77% 76% 77% NS LRC 91% 89% 91% NS DMFS 90% 89% 91% NS International Journal of Radiation Oncology  Biology  Physics 1222