This open-label, single-arm, non-randomized, multicenter phase II trial using neoadjuvant nivolumab and lirilumab before and after salvage surgical resection is, to our knowledge, the first study to evaluate immune checkpoint blockade as a therapeutic strategy for locoregionally recurrent, surgically salvageable head and neck cancer. Our findings of substantial rates of pathologic response (43%), excellent safety and tolerability, and overall encouraging survival outcomes in heavily pre-treated patients with locoregionally recurrent SCCHN highlights the promising activity of immune checkpoint blockade in this setting regardless of PD-L1 statusparticularly when considering the limitations of reirradiation. This approach warrants further investigation as a therapeutic strategy for recurrent, resectable SCCHN.Research.

Background Glioblastoma patients are treated with radiation therapy, chemotherapy, and corticosteroids, which can cause myelosuppression. To understand the relative prognostic utility of blood-based biomarkers in GBM and its implications for clinical trial design, we examined the incidence, predictors, and prognostic value of lymphopenia, neutrophil-to-lymphocyte ratio (NLR) and platelet count during chemoradiation (CRT) and recurrence. Methods This cohort study included 764 newly diagnosed glioblastoma patients treated from 2005-2019 with blood counts prior to surgery, within 6 weeks of CRT and at first recurrence available for automatic extraction from the medical record. Logistic regression was used to evaluate exposures and Kaplan-Meier was used to evaluate outcomes. Results Among the cohort, median age was 60.3 years; 87% had Karnofsky performance status (KPS) ≥ 70, 37.5% had gross total resection, and 90% received temozolomide (TMZ). During CRT, 37.8% (248/656) patients developed grade 3 or higher lymphopenia. On multivariable analysis (MVA), high NLR during CRT remained an independent predictor for inferior survival (AHR=1.57, 95%CI=1.14-2.15) and shorter progression-free survival (PFS) (AHR= 1.42, 95%CI= 1.05-1.90). Steroid use was associated with lymphopenia (OR=2.66,1.20-6.00) and high NLR (OR=3.54,2.08-6.11). Female sex was associated with lymphopenia (OR=2.33,1.03-5.33). At first recurrence, 28% patients exhibited grade 3 or higher lymphopenia. High NLR at recurrence was associated with worse subsequent survival on MVA (AHR=1.69, 95%CI= 1.25-2.27). Conclusions High NLR is associated with worse outcomes in newly diagnosed and recurrent glioblastoma. Appropriate eligibility criteria and accounting and reporting of blood-based biomarkers are important in the design and interpretation of newly diagnosed and recurrent glioblastoma trials.

2590 Background: Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus (HPV) types 6 & 11. RRP proliferates in the squamous epithelium lining the respiratory tract impacting breathing, swallowing, and voice and carries a 3-5% risk of malignant transformation. Given the multi-focality of the disease and tolerized host immune response against HPV, in part through upregulation of the PD1:PDL1 axis, the safety and efficacy of systemic pembrolizumab (pembro) as a novel treatment for this benign tumor patient (pt) population was evaluated in a phase II clinical trial. Methods: RRP pts > 12 years of age were treated with pembro 200mg every 3 weeks. Primary endpoints were best overall response (ORR) (measured by endoscopic lesional burden) and safety. Greater than 5 pts with disease response out of 21 (assuming > 1 of first n = 11 with disease in response) provided 86% power to distinguish between a 15% and a 38% ORR (one-sided 8% binomial test). HPV-specific CD8+ T cell frequency and functional states and biomarkers of response and immune resistance are being evaluated in serial tissue and liquid biopsies (up to 8 biopsies/patient over the 24 months of treatment). Results: The Simon two-stage, stage 1 criteria was met. A total of 21 patients were enrolled and all are now off treatment. Median age (range) was 45 (19-68), 57% (12/21) were male and 67% (14/21) were white. 48% (10/21) had Juvenile-onset (Jo)-RRP, 57% (12/21) had pulmonary RRP involvement, and 19% (4/21) had SCC derived from their RRP. 62% (13/21) completed 24 months of treatment. Reasons for discontinuation included disease progression (14%, 3/21), treatment related adverse event (TRAEs) (14%, 3/21), and study withdrawal (10%, 2/21). A partial response (≥25% reduction in endoscopic tumor burden score) was observed in 57% (12/21) (95% CI: 34%-78.2%) of pts (7 of 10 with Jo-RRP and 5 of 11 with Adult-onset (Ao)-RRP disease responded). Stable disease was observed in 33% (7/21). No complete responses were observed. Fatigue was the most frequent TRAEs; Grade 3 TRAEs included uveitis and hypophysitis, both of which were reversible upon pembro discontinuation and steroid use. At a median follow-up: 25.6 (6.2-38.1 months), the mean number of surgical interventions was reduced by 7 surgeries/year (p = 0.004) in pts treated on the trial for > 12 months, and, upon treatment completion, durable clinical benefit was observed with no additional treatment needed for the duration of the clinical trial follow-up for some pts. Conclusions: Pembro reduces the need for routine surgical interventions based on the durable response rates being achieved. Further study of pembro +/- other agents is warranted to achieve and sustain complete responses in this population. Clinical trial information: NCT02632344.

303 Background: Six months of a GnRH agonist with SRT is a standard of care for patients with unfavorable features and a detectable PSA post-RP. FORMULA-509 was designed to evaluate whether adding six months of AAP and Apa to this regimen could improve outcomes. Methods: FORMULA-509 (NCT03141671) is an investigator-initiated, multi-center, open-label, randomized trial. Patients had PSA≥0.1 post-RP and one or more unfavorable features (Gleason 8-10, PSA>0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time <10 months, negative margins, persistent PSA, gross local/regional disease, or Decipher High Risk). All patients received SRT plus 6 months of GnRH agonist and randomization was to concurrent bicalutamide 50 mg or AAP 1000mg/5mg + Apa 240mg QD. Radiation to pelvic nodes was required for pN1 and optional for pN0. The primary endpoint was PSA progression-free survival (PFS) and secondary endpoint was metastasis-free survival (MFS) determined by conventional imaging. The study was powered to detect a HR of 0.50 for PFS and a HR of 0.30 for MFS, each with 80% power and one-sided type I error of 0.05. Stratification was by PSA at study entry (>0.5 vs.≤0.5) and pN0 vs pN1. Analyses within these subgroups were pre-planned. Results: 345 participants (332 evaluable) from 9 sites were randomized from 11/24/2017 to 3/25/2020 (172 bicalutamide, 173 AAP/Apa). Median follow-up was 34 (6-53) months; 29% were pN1 and 31% had PSA >0.5 ng/mL. The HR for PFS was 0.71 (90% CI 0.49-1.03), stratified one-sided log-rank p=0.06 (3-year PFS was 68.5% bicalutamide vs 74.9% AAP/Apa). The HR for MFS was 0.57 (90% CI 0.33-1.01), stratified one-sided log rank p=0.05 (3-year MFS was 87.2% bicalutamide vs 90.6% AAP/Apa). In a pre-planned analysis by stratification factors, AAP/Apa was significantly superior for patients with PSA >0.5 for PFS [HR 0.50, (90% CI 0.30-0.86), p=0.03 (2-sided); 3-year PFS 46.8% bicalutamide vs. 67.2% AAP/Apa] and for MFS [HR 0.32 (90% CI 0.15-0.72), p=0.01 (2-sided); 3-year MFS 66.1% bicalutamide vs. 84.3% AAP/Apa.] No statistically significant benefit was detected in pre-planned analyses of stratification subgroups defined by PSA≤0.5, pN0, or pN1. Adverse events were consistent with the known safety profiles of the agents being studied, with more rash and hypertension in the AAP/Apa arm. Conclusions: Although this primary analysis did not meet the pre-specified threshold for statistical significance, it does strongly suggest that the addition of AAP/Apa to SRT+6 months of ADT may improve PFS and MFS, particularly in the subgroup of patients with PSA>0.5 where a pre-planned subgroup analysis by stratification factors observed a statistically significant benefit for both PFS and MFS. Clinical trial information: NCT03141671 .

Background Glioblastomas comprise heterogeneous cell populations with dynamic, bidirectional plasticity between treatment-resistant stem-like and treatment-sensitive differentiated states, with treatment influencing this process. However, current treatment protocols do not account for this plasticity. Previously, we generated a mathematical model based on preclinical experiments to describe this process and optimize a radiation therapy fractionation schedule that substantially increased survival relative to standard fractionation in a murine glioblastoma model. Methods We developed statistical models to predict the survival benefit of interventions to glioblastoma patients based on the corresponding survival benefit in the mouse model used in our preclinical study. We applied our mathematical model of glioblastoma radiation response to optimize a radiation therapy fractionation schedule for patients undergoing re-irradiation for glioblastoma and developed a first-in-human trial (NCT03557372) to assess the feasibility and safety of administering our schedule. Results Our statistical modeling predicted that the hazard ratio, when comparing our novel radiation schedule with a standard schedule, would be 0.74. Our mathematical modeling suggested that a practical, near optimal schedule for re-irradiation of recurrent glioblastoma patients was 3.96 Gy x 7 (1 fraction/day) followed by 1.0 Gy x 9 (3 fractions/day). Our optimized schedule was successfully administered to 14/14 (100%) patients. Conclusions A novel radiation therapy schedule based on mathematical modeling of cell-state plasticity is feasible and safe to administer to glioblastoma patients.