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Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) is increasing rapidly. The younger age, significantly improved prognosis, and relative morbidity of the standard-of-care cisplatin and radiotherapy in this population have led to the popularization of the concept of treatment de-escalation. The recent results of the first 3 randomized de-escalation trials, however, have shown a clear detriment in survival when cisplatin is omitted or substituted. In view of these results, the Head and Neck Cancer International Group identified the need to issue guidance regarding future de-escalation studies for patients with HPV-positive head and neck cancer to avoid the possibility of patients being harmed. We review the current state of the literature regarding HPV de-escalation trials and present a framework and guidance on future and existing clinical trials for treatment de-escalation of HPV-positive OPC. De-escalation paradigms of HPV-positive OPC should be evaluated in phase II studies, and results should be awaited before proceeding to phase III studies. Implementation into clinical practice before high-level evidence is available should not be undertaken in this context. Finally, harm-minimization techniques should also be evaluated as an alternative to de-escalation of treatment in these patient groups.

TPS3154 Background: Programmed cell death ligand 1 (PD-L1) is a cell-surface protein involved in the programmed cell death protein 1 (PD-1)/PD-L1 immune checkpoint, which inhibits T-cell activation. Elevated PD-L1 expression is observed across a broad spectrum of solid tumor types. Expression of PD-L1 in tumors can signal through PD-1 on T cells to inhibit T-cell effector function. Blockade of the PD-1/PD-L1 signaling axis may restore antitumor immunity by reactivating T-cell effector function in the tumor microenvironment. SGN-PDL1V is a novel, investigational vedotin antibody–drug conjugate directed to PD-L1 with multiple proposed mechanisms of action including monomethyl auristatin E (MMAE)-directed cytotoxicity, bystander effect, and immunogenic cell death (ICD). Even in xenograft models with low, heterogeneous PD-L1 expression, SGN-PDL1V demonstrated antitumor activity via direct cytotoxicity and the bystander effect. Cytotoxicity mediated by SGN-PDL1V also led to immune activation due to MMAE-induced ICD (Kwan et al 2021). These preclinical findings provide a rationale for evaluating SGN-PDL1V in patients (pts) with advanced solid tumors. Methods: SGNPDL1V-001 (NCT05208762) is a phase 1, first-in-human, multicenter, open-label trial designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-PDL1V in pts with advanced solid tumors. This study includes 3 parts: dose escalation (Part A), dose and schedule optimization cohorts (Part B), and dose expansion in disease-specific cohorts and a biology cohort (Part C). Adult pts (≥18 years) with histologically/cytologically confirmed metastatic/unresectable solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, melanoma, or ovarian cancer, will be eligible. Pts must have ECOG PS 0–1 and have failed or are unable to tolerate standard therapies. Pts must have PD-L1 expression ≥1 by tumor proportion score or combined positive score based on historical testing. Prior treatment with an MMAE-containing agent or an anti–PD-L1 agent (within 6 months) is not permitted. Primary endpoints include adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative dose-level safety. Secondary endpoints include rate and duration of objective response, progression-free survival, overall survival, PK, and incidence of antidrug antibodies. Exploratory endpoints include pharmacodynamics (PD), PK/PD relationships, and patient-reported outcomes. Safety and antitumor activity endpoints will be assessed using descriptive statistics. Objective response rate will be analyzed by tumor type, dose levels, and schedules. Enrollment for Part A is ongoing at sites in North America and is planned in Europe. Clinical trial information: NCT05208762.

A MESSAGE FROM ASCO’S PRESIDENT I remember when ASCO first conceived of publishing an annual report on the most transformative research occurring in cancer care. Thirteen reports later, the progress we have chronicled is remarkable, and this year is no different. The research featured in ASCO's Clinical Cancer Advances 2018 report underscores the impressive gains in our understanding of cancer and in our ability to tailor treatments to tumors’ genetic makeup. The ASCO 2018 Advance of the Year, adoptive cell immunotherapy, allows clinicians to genetically reprogram patients’ own immune cells to find and attack cancer cells throughout the body. Chimeric antigen receptor (CAR) T-cell therapy—a type of adoptive cell immunotherapy—has led to remarkable results in young patients with acute lymphoblastic leukemia (ALL) and in adults with lymphoma and multiple myeloma. Researchers are also exploring this approach in other types of cancer. This advance would not be possible without robust federal investment in cancer research. The first clinical trial of CAR T-cell therapy in children with ALL was funded, in part, by grants from the National Cancer Institute (NCI), and researchers at the NCI Center for Cancer Research were the first to report on possible CAR T-cell therapy for multiple myeloma. These discoveries follow decades of prior research on immunology and cancer biology, much of which was supported by federal dollars. In fact, many advances that are highlighted in the 2018 Clinical Cancer Advances report were made possible thanks to our nation’s support for biomedical research. Funding from the US National Institutes of Health and the NCI helps researchers pursue critical patient care questions and addresses vital, unmet needs that private industry has little incentive to take on. Federally supported cancer research generates the biomedical innovations that fuel the development and availability of new and improved treatments for patients. We need sustained federal research investment to accelerate the discovery of the next generation of cancer treatments. Another major trend in this year’s report is progress in precision medicine approaches to treat cancer. Although precision medicine offers promise to people with cancer and their families, that promise is only as good as our ability to make these treatments available to all patients. My presidential theme, “Delivering Discoveries: Expanding the Reach of Precision Medicine,” focuses on tackling this formidable challenge so that new targeted therapies are accessible to anyone who faces a cancer diagnosis. By improving access to high-quality care, harnessing big data on patient outcomes from across the globe, and pursuing innovative clinical trials, I am optimistic that we will speed the delivery of these most promising treatments to more patients. Sincerely, Bruce E. Johnson, FASCO ASCO President, 2017 to 2018

Purpose The incidence of human papilloma virus (HPV)–positive oropharyngeal cancers has risen rapidly in recent decades among men in the United States. We investigated the US population–level effect of prophylactic HPV vaccination on the burden of oral HPV infection, the principal cause of HPV-positive oropharyngeal cancers. Methods We conducted a cross-sectional study of men and women 18 to 33 years of age (N = 2,627) within the National Health and Nutrition Examination Survey 2011 to 2014, a representative sample of the US population. Oral HPV infection with vaccine types 16, 18, 6, or 11 was compared by HPV vaccination status, as measured by self-reported receipt of at least one dose of the HPV vaccine. Analyses accounted for the complex sampling design and were adjusted for age, sex, and race. Statistical significance was assessed using a quasi-score test. Results Between 2011 and 2014, 18.3% of the US population 18 to 33 years of age reported receipt of at least one dose of the HPV vaccine before the age of 26 years (29.2% in women and 6.9% in men; P < .001). The prevalence of oral HPV16/18/6/11 infections was significantly reduced in vaccinated versus unvaccinated individuals (0.11% v 1.61%; Padj = .008), corresponding to an estimated 88.2% (95% CI, 5.7% to 98.5%) reduction in prevalence after model adjustment for age, sex, and race. Notably, the prevalence of oral HPV16/18/6/11 infections was significantly reduced in vaccinated versus unvaccinated men (0.0% v 2.13%; Padj = .007). Accounting for vaccine uptake, the population-level effect of HPV vaccination on the burden of oral HPV16/18/6/11 infections was 17.0% overall, 25.0% in women, and 6.9% in men. Conclusion HPV vaccination was associated with reduction in vaccine-type oral HPV prevalence among young US adults. However, because of low vaccine uptake, the population-level effect was modest overall and particularly low in men.

3074 Background: Therapeutic targeting of EGFR has demonstrated efficacy in common advanced malignancies such as colorectal cancer (CRC), squamous cell of the head and neck (SCCHN), and non-small cell lung cancer (NSCLC). TGFβ has pro-tumorigenic effects on migration, invasion and tumor-specific immunosuppression, which may enhance the oncogenic effects of activated EGFR. Inhibition of EGFR signaling can lead to TGFβ upregulation as a resistance mechanism. BCA101 is a bifunctional recombinant fusion protein consisting of a chimeric anti-EGFR antibody and an extracellular domain (ECD) of human TGFβRII which demonstrated anti-tumor activity in several preclinical models. Methods: Patients with EGFR-driven advanced solid cancers refractory to standard therapies received BCA101 at escalating doses from 64 mg to 1000 mg intravenously (IV) weekly across 6 dose levels using a 3+3 design to determine dose limiting toxicities (DLT, established within 21 days of initial dosing), maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary endpoints include detailed pharmacokinetic (PK), pharmacodynamic (PD) studies in serial tumor and/or blood samples and assessment of anti-tumor activity. Results: As of 2/11/2021, 21 patients received single agent BCA101 at 64 (n = 3), 240 (n = 7), 500 (n = 2), 750 (n = 3), 800 (n = 3) or 1000 (n = 3) mg IV weekly, including patients with CRC (n = 6), SCCHN (n = 5) uveal melanoma (n = 2), ovarian cancer (n = 2), glioblastoma multiforme (n = 2), conjunctival melanoma, chordoma, pancreatic cancer and anal squamous cell carcinoma (all n = 1). These patients had 1-7 prior lines of antineoplastic therapy (median 4), including 3 patients with prior EGFR inhibitor exposure. Adverse events (AE) related to BCA101 observed in > 1 patient included grade (G) 1-2 rash (n = 9), G 1-2 lipase elevation (n = 2). G3 vitreous hemorrhage at the 240 mg dose level has been the only DLT. The MTD has not been reached and the RD will be based on safety, exposure and pending PD data. Saturation of the clearance was observed at doses above 500mg. Dose proportional increase in Cmax and AUC were observed with doses of 750-1000mg. Best RECISTv1.1 response was stable disease (SD) in 3/10 evaluable patients, with 1 patient on drug ≥4 months. Conclusions: BCA101 is well tolerated at biologically active doses. BCA101 is now being tested in combination with the PD-1 antibody pembrolizumab in patients with SCCHN and anal carcinoma. Clinical trial information: NCT04429542.

TPS6087 Background: Head and neck squamous cell carcinoma (HNSCC) accounts for more than 830,000 new cancer cases each year worldwide. The prognosis for recurrent and/or metastatic (R/M) HNSCC patients remains poor with an estimated median overall survival (mOS) of 7-15 months in the first line setting and 5-8 months in the second line setting and beyond. Approximately 4-8% of HNSCC tumors are driven by gain-of-function mutations in the HRAS (m HRAS) proto-oncogene. Tipifarnib is a potent and selective farnesyltransferase inhibitor that disrupts HRAS function by blocking required protein membrane localization, and subsequent cellular growth and survival. Data from a prior phase 2 study (RUN-HN; NCT02383927) of tipifarnib in R/M m HRAS HNSCC patients in the second line plus setting demonstrated encouraging efficacy, with an objective response rate (ORR) of 55% and mOS of 15.4 months for patients with mHRAS variant allele frequency (VAF) ≥ 20%, providing support for pursuing a pivotal trial in this patient population. Methods: AIM-HN (NCT03719690) is a global, open-label single-arm pivotal study evaluating the efficacy and tolerability of tipifarnib in second line plus R/M m HRAS HNSCC patients. The primary objective is to determine the ORR in patients with a m HRAS VAF ≥ 20% (High VAF population), as assessed using RECIST v1.1 by Independent Review Facility. Key secondary objectives include the ORR for patients of all VAF levels, and the duration of responses for both VAF≥ 20% and all VAF levels. Key inclusion criteria include: histologically confirmed head and neck cancer of squamous histology not amenable to local therapy with curative intent; known tumor missense HRAS mutation (with VAF determined and available) detected by Next Generation Sequencing; ECOG performance status of 0-1; measurable disease by RECIST v1.1; and adequate organ function. Key exclusion criteria include: salivary gland, thyroid, (primary) cutaneous squamous or non-squamous histologies; intolerable Grade 2 or ≥ Grade 3 neuropathy or unstable neurological symptoms within 4 weeks of Cycle 1 Day 1; or active, uncontrolled infections requiring systemic therapy. Tipifarnib is administered at a dose of 600 mg, orally with a meal twice a day for 7 days in alternating weeks (Days 1-7 and 15-21) of 28-day cycles until discontinuation criteria are met. All patients are being followed for safety through the End of Treatment visit, roughly 30 days after treatment discontinuation or immediately before the administration of another anticancer treatment, whichever occurs first. Upon therapy discontinuation, all patients are being followed approximately every 12 weeks for survival status, and the use of subsequent therapy. The IDMB last reviewed data in October 2020 and recommended the trial continue as planned. AIM-HN is continuing to enroll patients globally. Ho et al, JCO, accepted. Clinical trial information: NCT03719690.

2613 Background: GEN-009 is an adjuvanted personalized cancer vaccine containing up to 20 neoantigens selected by ATLAS, an ex vivo bioassay screening autologous T cells for immune responses against both neoantigens as well as Inhibigens. Inhibigen-specific T cells suppress immunity and have been shown to accelerate tumor progression in mice and are avoided in GEN-009. In cohort A, all patients immunized in the adjuvant setting with GEN-009 monotherapy developed immune responses. Nearly all (99%) of selected peptides were immunogenic: ex vivo CD4+ and CD8+ fluorospot responses specific for 51% and 41% of immunized peptides, respectively. Seven of 8 patients continue without progression with a median follow up of 18 months. Methods: GEN-009 is being evaluated in patients (pts) with advanced cancer who received standard-of-care (SOC) PD-1 inhibitor as monotherapy or in combination therapy during vaccine manufacturing. Five vaccine doses were administered over 24 weeks in combination with a PD-1 CPI. Patients who progressed prior to vaccination received alternative salvage therapy followed by GEN-009 in combination. Peripheral T cell responses were measured by fluorospot assays in ex vivo and in vitro stimulation. Results: 15 pts received GEN-009 in combination with a PD-1 inhibitor; 1 patient received GEN-009 monotherapy. Median number of neoantigens per vaccine was 14 (5-18). GEN-009-related adverse events were limited to vaccine injection site reactions and mild myalgias or fatigue. Longitudinal evaluation of ex vivo T cell responses revealed that sequential vaccination with GEN-009 had an overall additive effect on the robustness of IFNγ secretion and responses were persistent for at least 6 months in some patients. Epitope spread was detected in CPI sensitive patients, but not in CPI refractory patients receiving salvage therapy. Three patients who responded to PD-1 inhibition followed by disease stabilization then demonstrated further reduction after GEN-009 vaccination that could represent vaccine effect. Eight of 9 CPI responsive patients are progression-free from 3 to 10 months after first vaccine dose. Four of 7 CPI refractory patients have experienced unexpected prolonged stable disease after vaccination of up to 8 months after vaccination. 2 of 2 patients with available samples lost all evidence of circulating tumor DNA including non-targeted neoantigens. Conclusions: Vaccination with GEN-009 in combination with anti-PD-1 CPI in patients with advanced solid tumors shows little additive toxicity. Preliminary data demonstrate induction of broad neoantigen-specific immune responses and epitope spreading in the presence of PD-1 CPI. Broad immunity against tumor specific targets and encouraging patient outcomes support further study. Clinical trial information: NCT03633110.

6006 Background: Patients with resected HNSCC, with high-risk (positive margins, extracapsular spread [ECE]) or intermediate-risk pathological features have an estimated 1-year DFS of 65% and 69%, respectively. Immune checkpoint blockade improved survival of patients with recurrent/metastatic HNSCC, and preclinical models indicate radiotherapy (RT) synergizes with anti-PD-1. Therefore, we administered the PD-1 inhibitor pembrolizumab (pembro) pre- and post-surgery with adjuvant RT +/- cisplatin in patients with resectable, locoregionally advanced (clinical T3/4 and/or ≥2 nodal metastases) HNSCC (NCT02641093). Methods: Eligible patients received pembro (200 mg I.V. x 1) 1-3 weeks before resection. Adjuvant pembro (q3 wks x 6 doses) was administered with RT (60-66Gy) with or without weekly cisplatin (40mg/m2 X 6) for patients with high-risk and intermediate-risk features, respectively. The primary endpoint was 1-year DFS estimated by Kaplan Meier curves. Safety was evaluated by CTCAE v5.0. Pathological response (PR) to neoadjuvant pembro was evaluated by comparing pre- and post-surgical tumor specimens for treatment effect (TE), defined as tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris. PR was classified as no (NPR, < 20%), partial (PPR, ≥20% and < 90%) and major (MPR, ≥90%). Tumor PD-L1 immunohistochemistry was performed with 22c3 antibody and reported as combined positive score (CPS). Results: Ninety-two patients were enrolled. Seventy-six patients received adjuvant pembro and were evaluable for DFS. Patient characteristics included: median age 58 (range 27 – 80) years; 32% female; 88% oral cavity, 8% larynx, and 3% human papillomavirus negative oropharynx; 86% clinical T3/4 and 65% ≥2N; 49 (53%) high-risk (positive margins, 45%; ECE, 78%); 64% (44/69 available) had PD-L1 CPS ≥1. At a median follow-up of 20 months, 1-year DFS was 67% (95%CI 0.52-0.85) in the high-risk group and 93% (95%CI 0.84-1) in the intermediate-risk group. Among 80 patients evaluable for PR, TE scoring resulted in 48 NPR, 26 PPR and 6 MPR. Patients with PPR/MPR had significantly improved 1-year DFS when compared with those with NPR (100% versus 68%, p = 0.01; HR = 0.23). PD-L1 CPS ≥ 1 was not independently associated with 1-year DFS, but was highly associated with MPR/PPR (p = 0.0007). PPR/MPR in PD-L1 CPS < 1, ≥1 and ≥20, were estimated as 20, 55 and 90%, respectively. Grade ≥ 3 adverse events occurred in 62% patients with most common including dysphagia (15%), neutropenia (15%), skin/wound infections (10%), and mucositis (9%). Conclusions: PR to neoadjuvant pembro is associated with PD-L1 CPS≥1 and high DFS in patients with resectable, local-regionally advanced, HNSCC. Clinical trial information: NCT02641093.

Purpose Human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPV-associated OPSCC for reduced radiation dose as a means of sparing late sequelae. Methods Patients with HPV16 and/or p16-positive, stage III-IV OPSCC received three cycles of IC with cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensity-modulated radiation therapy (IMRT) 54 Gy with weekly cetuximab; those with less than cCR to IC at the primary site or nodes received 69.3 Gy and cetuximab to those regions. The primary end point was 2-year progression-free survival. Results Of the 90 patients enrolled, 80 were evaluable. Their median age was 57 years (range, 35 to 73 years), with the majority having stage T1-3N0-N2b OPSCC and a history of ≤ 10 pack-years of cigarette smoking. Three cycles of IC were delivered to 77 of the 80 patients. Fifty-six patients (70%) achieved a primary-site cCR to IC and 51 patients continued to cetuximab with IMRT 54 Gy. After median follow-up of 35.4 months, 2-year progression-free survival and overall survival rates were 80% and 94%, respectively, for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with < T4, < N2c, and ≤ 10 pack-year smoking history who were treated with ≤ 54 Gy of radiation (n = 27). At 12 months, significantly fewer patients treated with a radiation dose ≤ 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). Conclusion For IC responders, reduced-dose IMRT with concurrent cetuximab is worthy of further study in favorable-risk patients with HPV-associated OPSCC. Radiation dose reduction resulted in significantly improved swallowing and nutritional status.

Human papillomavirus (HPV) is now established as the principal cause of an increase in incidence of a subset of head and neck squamous cell cancers (HNCs) in numerous geographic regions around the world. Further study of the epidemiology of HPV-positive HNC will be critical to the development and implementation of public health interventions to reverse these global incidence trends. Here, recent data are reviewed to provide insight into several topics, including incidence trends and projections for HPV-positive HNC; the worldwide HPV-attributable fraction; sex disparities in cancer risk; the epidemiology of oral HPV infection; the latency period between infection and cancer; the potential impact of prophylactic HPV vaccination; and prospects for secondary prevention through screening for oral HPV infection or seroreactivity to viral antigens. The identification of a single necessary cause for any cancer provides a rare and perhaps extraordinary opportunity for cancer prevention.

3107 Background: Tumor-specific neoantigens provide personalized targets for immunotherapy. Vaccines against epitopes predicted by in silico approaches very rarely induce CD4+ and CD8+ ex vivo T cell responses regardless of formulation. ATLAS selects neoantigens for vaccine inclusion using ex vivo screening of all patient-specific mutations to identify pre-existing CD4+ or CD8+ T cell responses and to exclude Inhibigens, which are inhibitory peptides that suppress immunity and accelerate tumor progression. The Inhibigen burden correlates with patient outcomes in observational studies and rapid tumor progression in mouse models. Methods: GEN-009-101 is a phase 1/2a study testing safety, immunogenicity and clinical activity in immune responsive tumors. After next-generation tumor sequencing and ATLAS testing of autologous leukocytes, up to 20 stimulatory synthetic long peptides adjuvanted with poly-ICLC comprise each personalized vaccine. Eight vaccinated patients have been followed for sustained immunological responses and clinical outcomes. Results: The 40 doses given across patients have induced only mild local discomfort and no DLT. Vaccination has generated immune responses against 99% of administered peptides, with both CD8+ and CD4+ responses in ex vivo fluorospot assays. To date, no patients have developed recurrent disease. Broad immunity develops as early as Day 29 and is sustained for over 12 months. Immune response against individual peptides is correlated with peptide concentration (OR = 1.26, p≤0.0001) but not with other classifiers such as GRAVY index (Grand Average of Hydropathy), tumor type, injection site or sex. The Inhibigen burden prior to treatment again correlates with disease progression. Conclusions: GEN-009 identifies tumor specific immune targets from the individual patient’s tumor mutagens. Initial clinical data show that ATLAS antigen selection may be critical to the induction of broad, rapid and sustained immunity against tumor specific neoantigens. Clinical vaccination with PD-1 blockade is in process. Clinical trial information: NCT03633110 . [Table: see text]

6563 Background: To determine the negative predictive value (NPV) of 12-14 week post-treatment PET/CT for 2-year progression-free survival (PFS) and 2-year locoregional control (LRC) in NRG-HN002, which is a two-arm phase II trial for patients with low-risk, non-smoking associated p16-positive LA-OPC randomized in a 1:1 ratio to reduced-dose IMRT with or without cisplatin. Methods: PET/CT scans were reviewed both centrally and locally by participating institutions. Tumor response evaluations for primary site, right neck, and left neck were carried out using a 5-point ordinal scale (‘Hopkins Criteria’). Overall scores were then assigned as ‘Negative,’ Positive,’ or ‘Indeterminate.’ Patients who had a ‘Negative’ score for all three evaluation sites were given an overall score of ‘Negative.’ The endpoints were NPV for LRC and PFS at 2 years testing NPV ≤ 90% vs > 90% (1-sided alpha 0.10 and 76% power). Results: There were 316 patients enrolled, of whom 306 were randomized and eligible. Of these, 131 (42.8%) patients consented to a post-therapy PET/CT, and 117 (89.3%) patients were eligible for PET/CT analysis. The median time from end of treatment to PET/CT scan was 94 days (range 52-139). The rates of 2-yr PFS and LRC in the analysis subgroup were 91.3% and 93.8%, respectively. Based on central review, post-treatment scans were negative for residual tumor for 115 patients (98.3%) and positive for 2 patients (1.7%). The NPV for 2-year LRC was 94.5% (90% lower confidence bound [LCB] 90.6%; p = 0.07). NPV for 2-year PFS was 92.0% (90% LCB 87.7%; p = 0.30). Similar NPV results were obtained based on analysis of local reviews. Conclusion: Within the context of deintensification with reduced-dose radiation, the NPV of a 12-14 week post-therapy PET/CT for 2-year LRC is statistically > 90%, similar to that reported for patients receiving standard chemoradiation. However, in this study, there was not enough evidence to conclude that the NPV of a 12-14 week post-therapy PET/CT for 2-year PFS is > 90%. Grant acknowledgement: This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA180803 (IROC), UG1CA189867 (NRG Oncology NCORP) from the National Cancer Institute (NCI). This project is funded, in part, under a Grant with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. Clinical trial information: NCT02254278 .

6500 Background: ECOG-ACRIN 3311 examines reduced postoperative therapy in patients with “intermediate risk” p16+ oropharynx cancer (OPC) undergoing primary transoral surgical management. We report the primary endpoint of 2-year progression free survival (PFS) for patients randomized to 50Gy vs 60Gy without chemotherapy. Methods: Between December 2013 and July 2017, 82 credentialed surgeons performed transoral resection (TOS) for 519 OPC patients (cT1-2 stage III/IV AJCC7 without matted neck nodes); post-operative management was determined by pathologically assessed risk. Among 353 eligible and treated patients, Arm A enrolled 10% (N=37) for clear margins, 0-1 nodes, no extranodal extension (ENE)), Arms B (50Gy, N=102) or C (60Gy, N=104) randomized 58%, for clear/close margins, 2-4 + nodes, or ENE ≤1mm, while Arm D (N=110, 60-66Gy plus weekly cisplatin, 40 mg/m2, positive margin with any T stage, >4 + nodes, or >1mm ENE) enrolled 31%. Arm D assignment was based on >1mm ENE (76%), > 4 nodes (27%), and/or positive margins (11%). Intermediate-risk patients were stratified by smoking history (>10 pk-yr). Of the 80 pts (15%) deemed ineligible, 28 had scans/labs not done per protocol, however treatment arm distribution for all patients mirrored that for the 353 pts eligible and treated. Results: Median follow-up was 31.8 months. 2 yr PFS for Arms A, B and C were 93.9% (90% CI=87.3%, 100%), 95.0% (90% CI=91.4%, 98.6%) and 95.9% (90% CI=92.6%, 99.3%) respectively, while Arm D was 90.5% (90% CI=85.9%, 95.3%). The regimen of TOS + low-dose radiation is considered worthy of further study, since the primary endpoint of the upper bound of the 90% CI (in the intermediate risk group) exceeding 85% was met. Of 17 progression events, 7 were locoregional. There were 10 distant recurrences: Arm A=1, Arm B=2, Arm C=4, Arm D=3. Grade III/IV treatment-related AE rates were 15%/2% during surgery, 13%/2% for Arm B and 25%/0% for Arm C. There were 2 treatment-related deaths (one surgical and one Arm D). Conclusions: Transoral resection of p16+ OPC is safe and results in good oncologic outcome, presenting a promising deintensification approach. For patients with low-risk disease, 2-yr PFS is favorable without post-operative therapy. For those with uninvolved surgical margins

Purpose We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost (AFX-C) versus standard fractionation (SFX) in locally advanced head and neck carcinoma (LA-HNC). Patients and Methods Patients had stage III to IV carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks (SFX) or 72 Gy in 42 fractions over 6 weeks (AFX-C). Cisplatin doses were 100 mg/m2 once every 3 weeks for two (AFX-C) or three (SFX) cycles. Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria. Overall survival (OS) and progression-free survival (PFS) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test. Locoregional failure (LRF) and distant metastasis (DM) rates were estimated by using the cumulative incidence method and Gray's test. Results In all, 721 of 743 patients were analyzable (361, SFX; 360, AFX-C). At a median follow-up of 7.9 years (range, 0.3 to 10.1 years) for 355 surviving patients, no differences were observed in OS (hazard ratio [HR], 0.96; 95% CI, 0.79 to 1.18; P = .37; 8-year survival, 48% v 48%), PFS (HR, 1.02; 95% CI, 0.84 to 1.24; P = .52; 8-year estimate, 42% v 41%), LRF (HR, 1.08; 95% CI, 0.84 to 1.38; P = .78; 8-year estimate, 37% v 39%), or DM (HR, 0.83; 95% CI, 0.56 to 1.24; P = .16; 8-year estimate, 15% v 13%). For oropharyngeal cancer, p16-positive patients had better OS than p16-negative patients (HR, 0.30; 95% CI, 0.21 to 0.42; P < .001; 8-year survival, 70.9% v 30.2%). There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status. Conclusion When combined with cisplatin, AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC. Long-term high survival rates in p16-positive patients with oropharyngeal cancer support the ongoing efforts to explore deintensification.

Purpose Combining cisplatin or cetuximab with radiation improves overall survival (OS) of patients with stage III or IV head and neck carcinoma (HNC). Cetuximab plus platinum regimens also increase OS in metastatic HNC. The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival (PFS). Patients and Methods Eligible patients with stage III or IV HNC were randomly assigned to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Acute and late reactions were scored using Common Terminology Criteria for Adverse Events (version 3). Outcomes were correlated with patient and tumor features and markers. Results Of 891 analyzed patients, 630 were alive at analysis (median follow-up, 3.8 years). Cetuximab plus cisplatin-radiation, versus cisplatin-radiation alone, resulted in more frequent interruptions in radiation therapy (26.9% v 15.1%, respectively); similar cisplatin delivery (mean, 185.7 mg/m2 v 191.1 mg/m2, respectively); and more grade 3 to 4 radiation mucositis (43.2% v 33.3%, respectively), rash, fatigue, anorexia, and hypokalemia, but not more late toxicity. No differences were found between arms A and B in 30-day mortality (1.8% v 2.0%, respectively; P = .81), 3-year PFS (61.2% v 58.9%, respectively; P = .76), 3-year OS (72.9% v 75.8%, respectively; P = .32), locoregional failure (19.9% v 25.9%, respectively; P = .97), or distant metastasis (13.0% v 9.7%, respectively; P = .08). Patients with p16-positive oropharyngeal carcinoma (OPC), compared with patients with p16-negative OPC, had better 3-year probability of PFS (72.8% v 49.2%, respectively; P < .001) and OS (85.6% v 60.1%, respectively; P < .001), but tumor epidermal growth factor receptor (EGFR) expression did not distinguish outcome. Conclusion Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely. PFS and OS were higher in patients with p16-positive OPC, but outcomes did not differ by EGFR expression.

6073 Background: Nivo, which inhibits the programmed death-1 (PD-1) receptor, improved survival for pts with platinum-refractory recurrent/metastatic HNSCC. A clinical trial evaluated the safety of adding nivo to 4 standard intensity modulated (chemo) radiotherapy (RT) regimens (see table) for pts with newly diagnosed IR/HR HNSCC. Primary endpoint was safety and feasibility. Methods: Eligibility included IR (p16+ oropharynx [op], T1-2N2b-N3/T3-4N0-3, >10 pack-years [pys], or T4N0-N3/T1-3N3, ≤10 pys) & HR HNSCC (oral cavity, larynx, hypopharynx, p16- op, T1-2N2a-N3/T3-4N0-3). 10 pts/arm (8 evaluable; 0-2/8 DLTs acceptable). Nivo (dose & schedule varied per arm) started 2 wks pre-RT & continued 3 months post-RT. Feasibility of adjuvant nivo months 3-12 post-RT defined as ≥4 of 8 pts/arm received 7 doses. Arm 4 limited to age ≥70, Zubrod performance status (PS) 2, CrCl 10 pys, 62% p16+ op, 72% T3-4, 85% N2-3. Grade ≥3 nivo-related AEs: adrenal insufficiency, diarrhea-3, anemia, fatigue-2, mucositis-3, nausea, vomiting, lipase increase-6, amylase increase-2, lymphocyte/neutrophil/WBC decrease-4, hyponatremia-3, anorexia, maculo-papular rash. SAE in 4/10, 4/9, 5/10 & 4/10. DLTs, adjuvant chemo feasibility, median follow-up (mo), progression or death events per arm shown in table. Conclusions: Nivo concomitant with all (chemo)RT regimens was safe for patients with newly diagnosed IR/HR HNSCC but adjuvant nivo was infeasible after high-dose cisplatin or in cisplatin-ineligible patients ( NCT02764593 ). Preliminary data on progression/death is provided. Acknowledgements: Support for this study was provided by Bristol-Myers Squibb Company. Clinical trial information: NCT02764593. [Table: see text]

6008 Background: Anti-PD-1/PD-L1 are active in metastatic oropharynx squamous cell carcinoma (OPC). Durvalumab (durva) and tremelimumab (tremi) target respectively PD-L1 and CTLA-4, which in combination may be synergistic. Here we report the safety and interim results of durva vs. durva+tremi prior to surgery in a window of opportunity trial in OPC. Methods: Pts were randomized 1:1 to durva 1500 mg or durva 1500 mg + tremi 75 mg IV Q4W x 2 cycles. The primary objective was to quantify pre- and post-treatment differences in CD8+ tumor infiltrating lymphocytes for the two arms. Secondary objectives included safety, toxicity, ORR by RECIST, fraction of patients undergoing surgery at 8 wks, and percentage viable tumor cells in the surgical specimen. Serial pre- and post-treatment blood and tumor specimens were collected for ongoing correlative analyses. Results: 28 pts enrolled: median age 64y, 27 (96%) male, 19 (68%) newly diagnosed, most (63%) at stage IVA (AJCC 7th Ed), 9 (32%) had locoregional recurrence, 24 (86%) p16 positive, and 22 (79%) had ≤ 10 PPY smoking history. Median follow-up was 7.6 months. The most common AEs were fatigue (36%), leukopenia/lymphopenia (25%), transaminitis (25%), and rash (21%). Grade 3 AEs occurred in 4 (14%) pts: 2 elevated lipase, 1 diarrhea, and 1 hepatitis, all were manageable. There were no grade >3 AEs. ORR was 43%: 50% had SD (including 29% tumor shrinkage in 1 pt). Treatment effect in the surgical specimen was observed in 19 (79%) of 24 evaluable pts; 2 pts had major pathologic response (≤ 10% viable tumor) at the primary site. Efficacy was equivalent in both arms. The 2 pts with PD and 1 pt with SD were switched to chemotherapy after durva +/- tremi before resection; interestingly, each achieved a pCR in the primary. Most pts (57%) didn’t receive radiotherapy after surgery. There was a statistically significant association between ORR and treatment effect (p=0.014). The median percentage of viable tumor in the primary was 37.5% in pts with PR, and 82.5% in SD (p=0.003). Conclusions: Durva +/- tremi prior to surgery was well tolerated in OPC pts. Activity is encouraging with treatment effect seen in 79% of pts. The primary endpoint and complete efficacy data will be presented. Clinical trial information: NCT03144778.

Chaturvedi, Anil K Anderson, William F Lortet-Tieulent, Joannie Curado, Maria Paula Ferlay, Jacques Franceschi, Silvia Rosenberg, Philip S Bray, Freddie Gillison, Maura L eng Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't 2013/11/20 06:00 J Clin Oncol. 2013 Dec 20;31(36):4550-9. doi: 10.1200/JCO.2013.50.3870. Epub 2013 Nov 18.; International audience; PURPOSE: Human papillomavirus (HPV) has been identified as the cause of the increasing oropharyngeal cancer (OPC) incidence in some countries. To investigate whether this represents a global phenomenon, we evaluated incidence trends for OPCs and oral cavity cancers (OCCs) in 23 countries across four continents. METHODS: We used data from the Cancer Incidence in Five Continents database Volumes VI to IX (years 1983 to 2002). Using age-period-cohort modeling, incidence trends for OPCs were compared with those of OCCs and lung cancers to delineate the potential role of HPV vis-a-vis smoking on incidence trends. Analyses were country specific and sex specific. RESULTS: OPC incidence significantly increased during 1983 to 2002 predominantly in economically developed countries. Among men, OPC incidence significantly increased in the United States, Australia, Canada, Japan, and Slovakia, despite nonsignificant or significantly decreasing incidence of OCCs. In contrast, among women, in all countries with increasing OPC incidence (Denmark, Estonia, France, the Netherlands, Poland, Slovakia, Switzerland, and United Kingdom), there was a concomitant increase in incidence of OCCs. Although increasing OPC incidence among men was accompanied by decreasing lung cancer incidence, increasing incidence among women was generally accompanied by increasing lung cancer incidence. The magnitude of increase in OPC incidence among men was significantly higher at younger ages (< 60 years) than older ages in the United States, Australia, Canada, Slovakia, Denmark, and United Kingdom. CONCLUSION: OPC incidence significantly increased during 1983 to 2002 predominantly in developed countries and at younger ages. These results underscore a potential role for HPV infection on increasing OPC incidence, particularly among men.

6017Background: 2Despite aggressive adjuvant treatment, locally advanced HNSCC patients undergoing primary surgical resection with high risk [HR] features (extracapsular extension of lymph nodes (L...

6028Background: Nivo is the only immunotherapy to significantly improve overall survival (OS) in pts with platinum (plt)–refractory R/M SCCHN. In the randomized, open-label, phase 3 CheckMate 141 t...

6010Background: Nivolumab, which inhibits the programmed death-1 (PD-1) receptor, improved survival for patients (pts) with platinum-refractory recurrent/metastatic HNSCC compared with standard the...

TPS118 Background: Oropharyngeal squamous cell carcinoma (OPSCC) is classified by HPV status. Patients with HPV negative OPSCC have worse prognosis when compared to HPV positive. The epidemic of HPV associated OPSCC emphasizes the need to improve outcomes and reduce treatment related toxicities in this patient population. Taken together, there is an unmet need for novel treatment approaches to improve survival and/or quality of life in patients with OPSCC. Checkpoint inhibitors, particularly anti-PD-1/PD-L1, have shown encouraging activity in metastatic head and neck SCC. Targeting both PD-1 and CTLA-4 pathways may have additive or synergistic activity. Durvalumab and tremelimumab are immune checkpoint inhibitors that target, respectively, PD-L1 and CTLA-4. The optimal integration of novel therapeutics into clinical practice requires a thorough understanding of the molecular effects of treatment that is best evaluated by longitudinal tumor sampling. Minimally invasive transoral robotic surgery (TORS) provides opportunities to leverage standard-of-care surgery to interrogate the tumor microenvironment after neoadjuvant treatment. Methods: This is a randomized, window of opportunity trial evaluating durvalumab single agent or combined with tremelimumab in OPSCC patients amenable to curative intent surgery. The primary objective is to quantify differences in CD8+ TILs between pre- and post-treatment surgical specimens in patients treated with durvalumab vs. durvalumab plus tremelimumab. Secondary objectives include assessing the safety and toxicity of durvalumab plus or minus tremelimumab in the preoperative setting; objective response rate by RECIST at 8 weeks; percentage of patients undergoing surgery at 8 weeks; percentage of viable tumor cells in the surgical specimen; and patient-reported outcomes. Pre- and post- treatment tumor and blood based immune biomarkers will be evaluated and correlated with HPV status, outcomes, and toxicity. Eligible patients must be ≥ 18 years old, have surgically resectable stage II-IVA newly diagnosed OPSCC or loco-regional recurrence from an OPSCC primary ≥ 6 months after completion of curative intent treatment, and have a performance status ECOG 0-1. Enrollment is ongoing. Clinical trial information: NCT03144778.

Purpose To investigate the impact of human papillomavirus (HPV) on the epidemiology of oral squamous cell carcinomas (OSCCs) in the United States, we assessed differences in patient characteristics, incidence, and survival between potentially HPV-related and HPV-unrelated OSCC sites. Patients and Methods Data from nine Surveillance, Epidemiology, and End Results program registries (1973 to 2004) were used to classify OSCCs by anatomic site as potentially HPV-related (n = 17,625) or HPV-unrelated (n = 28,144). Joinpoint regression and age-period-cohort models were used to assess incidence trends. Life-table analyses were used to compare 2-year overall survival for HPV-related and HPV-unrelated OSCCs. Results HPV-related OSCCs were diagnosed at younger ages than HPV-unrelated OSCCs (mean ages at diagnosis, 61.0 and 63.8 years, respectively; P < .001). Incidence increased significantly for HPV-related OSCC from 1973 to 2004 (annual percentage change [APC] = 0.80; P < .001), particularly among white men and at younger ages. By contrast, incidence for HPV-unrelated OSCC was stable through 1982 (APC = 0.82; P = .186) and declined significantly during 1983 to 2004 (APC = −1.85; P < .001). When treated with radiation, improvements in 2-year survival across calendar periods were more pronounced for HPV-related OSCCs (absolute increase in survival from 1973 through 1982 to 1993 through 2004 for localized, regional, and distant stages = 9.9%, 23.1%, and 18.6%, respectively) than HPV-unrelated OSCCs (5.6%, 3.1%, and 9.9%, respectively). During 1993 to 2004, for all stages treated with radiation, patients with HPV-related OSCCs had significantly higher survival rates than those with HPV-unrelated OSCCs. Conclusion The proportion of OSCCs that are potentially HPV-related increased in the United States from 1973 to 2004, perhaps as a result of changing sexual behaviors. Recent improvements in survival with radiotherapy may be due in part to a shift in the etiology of OSCCs.

Human papillomavirus (HPV) is now recognized to play a role in the pathogenesis of a subset of head and neck squamous cell carcinomas (HNSCCs), particularly those that arise from the lingual and palatine tonsils within the oropharynx. High-risk HPV16 is identified in the overwhelming majority of HPV-positive tumors, which have molecular-genetic alterations indicative of viral oncogene function. Measures of HPV exposure, including sexual behaviors, seropositivity to HPV16, and oral, high-risk HPV infection, are associated with increased risk for oropharyngeal cancer. HPV infection may be altering the demographics of HNSCC patients, as these patients tend to be younger, nonsmokers, and nondrinkers. There is sufficient evidence to conclude that a diagnosis of HPV-positive HNSCC has significant prognostic implications; these patients have at least half the risk of death from HNSCC when compared with the HPV-negative patient. The HPV etiology of these tumors may have future clinical implications for the diagnosis, therapy, screening, and prevention of HNSCC. J Clin Oncol 24:2606-2611. © 2006 by American Society of Clinical Oncology

Purpose People with HIV infection in the United States frequently smoke tobacco. We sought to characterize lung cancer incidence among HIV-infected individuals, examine whether cancer risk was related to HIV-induced immunosuppression, and assess whether the high prevalence of smoking explained elevated risk. Methods We conducted a retrospective cohort study at an HIV specialty clinic in Baltimore, MD (1989-2003). Incident lung cancers were identified using hospital records. We used negative binomial regression to compare incidence across subgroups defined by demographics, use of highly active antiretroviral therapy (HAART), and HIV markers. Standardized incidence ratios (SIRs) compared incidence with an urban reference population (Detroit, MI). We adjusted SIRs for the effect of smoking, using smoking prevalences estimated from part of the cohort and the general population. 95% CIs and P values were two sided. Results Thirty-three lung cancers were observed among 5,238 HIV-infected patients (incidence: 170 per 100,000 person-years). Incidence increased with age (P < .0001), but did not differ by sex, race, or CD4 count. Incidence tended to increase with calendar year (P = .09) and HAART use (P = .10), and was inversely related to HIV viral load (P = .03), but these associations were attenuated with age adjustment. The SIR was 4.7 (95% CI, 3.2 to 6.5) versus the general population. Twenty-eight lung cancer patients (85%) and 69% of the cohort were smokers. After smoking adjustment, risk remained elevated (SIR, 2.5; 95% CI, 1.6 to 3.5). Conclusion Lung cancer risk was substantially elevated in HIV-infected individuals. Incidence was unrelated to HIV-induced immunosuppression. Notably, incidence remained high after adjustment for smoking, suggesting the involvement of additional factors.

6050 Background: Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, demonstrated longer median overall survival (7.5 vs 5.1 months) and improved response (13.3% vs 5.8%) versus investigator choice chemotherapy (ICC) in patients with recurrent SCCHN after platinum failure in CheckMate 141 (NCT02105636), a randomized, open-label Phase 3 trial. We screened peripheral blood lymphocytes (PBL) to identify biomarkers which may predict response to nivolumab. Methods: Paired baseline (day 1) and on treatment (day 43) PBL samples (n = 36; 24 nivolumab; 12 ICC) were analyzed using multicolor flow cytometry and a non-competing anti-PD-1 antibody. Results were correlated with clinical outcome: responders (complete/partial response) and non-responders (stable or progressive disease). Results: Levels of CD8+ T cells at baseline and on treatment were higher in nivolumab responders compared to non-responders (23% vs 13%; P< 0.05). Interestingly, PD-1+ CD8+ and PD-1+ CTLA-4+ CD8+ effector T cells (likely exhausted T cells) decreased about 2-fold following nivolumab in both responders and non-responders ( P< 0.05), whereas, the decrease in CTLA-4+ CD8+ effector T cells following nivolumab was significant in responders only (8% vs 5%; P< 0.05). Levels of PD-1+ TIM-3+ CD8+ effector cells decreased following nivolumab in non-responders only (11% vs 7%; P< 0.05), a similar non-significant reduction was observed in responders. Levels of PD-1+ Tregs were lower in responders than non-responders at baseline (19% vs 33%; P< 0.01), and following nivolumab (12% vs 20%; P< 0.001). As in T-effector cell populations, PD-1+ Tregs decreased about 1.6-fold after nivolumab in both responders and non-responders ( P< 0.01). Interestingly, baseline Ki67+ Treg levels were lower in non-responders (28% vs 17%; P< 0.05). Conclusions: Response to nivolumab may be associated with higher levels of CD8+ T cells and CTLA-4+ CD8+ effector T cells, and lower PD-1+ CD8+ effector T cells and PD-1+ Tregs at baseline. Targeting both PD-1 and CTLA-4 axes is warranted in SCCHN to overcome suppressive signals in CD8+ effector T cells and in Treg cells expressing both checkpoint receptors. Clinical trial information: NCT02105636.

6019 Background: In CheckMate 141, a randomized, phase 3 trial, nivo demonstrated superior overall survival (OS) and better tolerability in patients (pts) with PR R/M SCCHN compared with IC. Pts with SCCHN progressing within 6 mos of platinum in the primary treatment setting have dismal prognosis. We report outcomes in pts who were PR in the primary or adjuvant setting, and updated results in the overall population. Methods: Pts (N = 361) with PR R/M SCCHN were randomized 2:1 to nivo 3 mg/kg every 2 weeks or weekly IC (methotrexate, docetaxel, or cetuximab). Primary endpoint was OS estimated by Kaplan-Meier method. Cox proportional hazards models were used to estimate hazard ratios (HRs) and confidence intervals (CIs). Additional endpoints include objective response rate (ORR) and safety. Outcomes were analyzed overall and post hoc in pts who were PR in the primary/adjuvant setting and received nivo/IC as 1L R/M therapy. Results: Characteristics of the 78 (21.6%) pts who received nivo (n = 52) or IC (n = 26) in the 1L R/M setting were similar to the overall population.Nivo significantly improved OS vs IC among 1L R/M pts (median [95% CI]: 7.7 mo [3.1, 13.8] vs 3.3 mo [2.1, 6.4]; HR [95% CI] = 0.56 [0.33, 0.95]); 12-mo OS rate: 39.2% vs 15.4%. ORR was 19.2% for nivo vs 11.5% for IC in this subgroup. At 11.4-mo minimum follow-up, updated efficacy and safety in the overall population were similar to the primary analysis. Median OS (95% CI) was 7.7 mo (5.7, 8.8) for nivo vs 5.1 mo (4.0, 6.2) for IC; HR (95% CI) = 0.71 (0.55, 0.90); P = 0.0048. For nivo vs IC, the 18-mo OS rate was 21.5% vs 8.3% and ORR was 13.3% vs 5.8%. Nivo doubled the median duration of response vs IC (9.7 vs 4.0 mo). Grade 3–4 treatment-related adverse event rates for nivo vs IC were 15.3% vs 36.0% overall and 27.5% vs 32.0% for 1L R/M pts; there were no new deaths due to study drug toxicity. Conclusions: Nivo significantly improved OS and increased ORR vs IC in a 1L R/M subgroup, supporting its use as 1L therapy for pts with PR R/M SCCHN. Nivo continued to show a significant survival benefit and better tolerability vs IC in pts with PR R/M SCCHN. Clinical trial information: NCT02105636.

6020 Background: In CheckMate 141, nivo resulted in significantly prolonged overall survival (OS), favorable safety, and stable quality of life vs IC in patients (pts) with platinum-refractory (PR) R/M SCCHN. Cetuximab, a formal trial stratification factor, permits exploratory subgroup assessment. Outcomes by prior cetuximab use are described. Methods: CheckMate 141 was a randomized, open-label, phase 3 trial (NCT02105636) in which pts (N = 361) with PR R/M SCCHN were randomized 2:1 and stratified by prior cetuximab use to nivo 3 mg/kg every 2 weeks or IC of methotrexate, docetaxel, or cetuximab. The primary endpoint was OS; additional endpoints were progression-free survival (PFS), objective response rate (ORR), and safety. A multivariate analysis will explore influence of additional factors. Results: Nivo improved OS vs IC regardless of prior cetuximab, and improvement was greater in pts without prior cetuximab (Table). Median OS was longer for nivo vs IC in pts with PD-L1 expression ≥ 1% regardless of prior cetuximab, and in pts with PD-L1 expression < 1% without prior cetuximab. Among pts with PD-L1 expression ≥ 1%, ORR was higher with nivo vs IC with/without prior cetuximab. PFS was similar regardless of prior cetuximab. Grade 3–4 treatment-related adverse event rates for nivo vs IC were 11.7% vs 40.9% with prior cetuximab and 15.4% vs 26.7% without prior cetuximab. Conclusions: OS and ORR improved with nivo vs IC regardless of prior cetuximab use, and the magnitude of benefit was greater in pts without prior cetuximab exposure. These results support the use of nivo for R/M SCCHN regardless of prior cetuximab use. Clinical trial information: NCT02105636. [Table: see text]

6003 Background: The incidence of HPV-positive oropharyngeal cancers has risen in recent decades among US men. The potential impact of HPV vaccines on oral HPV infections has yet to be evaluated in efficacy-trials or surveillance studies. Methods: To evaluate the impact of prophylactic HPV vaccination on oral HPV infections in the US population, we conducted a cross-sectional study among men and women aged 18-33 years (n = 2,627) in the National Health and Nutrition Examination Survey, 2011-2014. We examined the effect of self-reported receipt of ≥1 vaccine dose on oral HPV infection (vaccine-types 16/18/6/11) prevalence among vaccinated vs. unvaccinated individuals. Additional outcomes included percent reduction in infection-prevalence among vaccinated individuals and population-level effectiveness of vaccination. Analyses accounted for the complex sampling design. Comparisons between vaccinated and unvaccinated individuals were conducted using binary logistic regression, with adjustment for age, gender, and race. Statistical significance was assessed using a quasi-score test. Results: During 2011-2014, 18.3% of the US population aged 18-33 years reported receipt of ≥1 HPV vaccine-dose prior to age 26 (29.2% in women and 6.9% in men; P< 0.001). The prevalence (population-weighted) of oral HPV16/18/6/11 infections was significantly reduced in vaccinated vs. unvaccinated individuals (0.11% vs. 1.61%; P= 0.008), corresponding to an estimated 88.2% (95%CI = 5.7%-98.5%) reduction in prevalence. Notably, oral HPV16/18/6/11 prevalence was significantly reduced in vaccinated vs. unvaccinated men (0.0% vs. 2.13%; P= 0.007). In contrast, prevalence for 33 non-vaccine HPV types was similar (3.98% vs. 4.74%; P= 0.24). Accounting for HPV vaccine-uptake, the population-level effectiveness of HPV vaccination on the burden of oral HPV16/18/6/11 infections was 17.0% overall, 25.0% in women and 6.9% in men. Conclusions: HPV vaccination substantially reduced vaccine-type oral HPV infection prevalence among young adults (ages 18-33 years) in the US population during 2011-2014. However, due to low vaccine uptake, population-level effectiveness was modest overall and particularly low in men.

TPS6097 Background: Nivolumab (Nivo), a monoclonal antibody to the programmed death-1 (PD-1) immune checkpoint receptor, improved overall survival (OS) for patients (pts) with platinum-refractory, recurrent/metastatic HNSCC compared with standard therapy. A placebo controlled phase IIR trial was designed to investigate the hypothesis that Nivo added to platinum-based CRT will improve progression free survival (PFS) for pts with newly diagnosed IR/HR HNSCC. Methods: Eligibility includes IR HNSCC (p16+, oropharynx T1-2N2b-N3/T3-4N0-3, > 10 pack-years (pys) or T4N0-N3, T1-3N3 ≤ 10 pys) and HR HNSCC (oral cavity, larynx, hypopharynx, or p16(-) oropharynx, stage T1-2N2a-N3 or T3-4N0-3). After safety evaluation in 8 evaluable pts, 176 pts will be randomized (1:1) to cisplatin (40 mg/m2/week X 7) with radiation (IMRT, 70 Gy in 7 weeks) +/- Nivo/placebo (240 mgs q14 days X 5, then 480 mgs q28 X3). Primary endpoint is PFS. Secondary endpoints include OS, acute and chronic toxicity, quality of life and biomarkers (tumor PD-L1 expression; E6/7 seroreactivity and frequency of functional circulating and intraumoral T cells). Parallel with Phase IIR are sequential safety evaluations (see Table) in platinum eligible and ineligible ( > 70 years; ≥3 grade neuropathy; ≥2 hearing loss; or CrCl < 60 ml/min) cohorts (N = 10-20) of Nivo +/- Liri (anti-KIR) or Ipi (anti-CTLA4) concomitant with RT alone, cisplatin-RT or cetuximab-RT platforms followed by 3 months of adjuvant immunotherapy. The primary endpoint is safety and feasibility. With 8 evaluable pts, the probability of treatment assessed as toxic is > 78% when the true toxicity rate is > 45% and treatment assessed tolerable is > 80% if the true toxicity rate is < 20%. Clinical trial information: NCT02764593. [Table: see text]

5 Background: Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, demonstrated longer median overall survival (7.5 vs. 5.1 months) and improved response (13.3% vs. 5.8%) versus investigator choice chemotherapy (ICC) in patients with recurrent SCCHN after platinum failure in CheckMate 141 (NCT02105636), a randomized, open-label Phase 3 trial. We screened peripheral blood lymphocytes (PBL) to identify biomarkers which may predict response to nivolumab. Methods: Paired baseline (day 1) and on treatment (day 43) PBL samples (n=36; 24 nivolumab; 12 ICC) were analyzed using multicolor flow cytometry and a non-competing anti-PD-1 antibody. Results were correlated with clinical outcome: responders (complete/partial response) and non-responders (stable or progressive disease). Results: Levels of CD8+ T cells at baseline and on treatment were higher in nivolumab responders compared to non-responders (23% vs. 13%; p

Oropharyngeal squamous cell carcinomas are etiologically heterogeneous, with one subset attributable primarily to human papillomavirus (HPV) infection and another to alcohol and tobacco use. These subsets are clinically and molecularly distinct, and these distinctions extend to patient prognosis. 1 In this issue of the Journal of Clinical Oncology, Licitra et al 2 report that patients with HPV DNA–positive oropharyngeal cancers have an approximately 60% reduction in 5-year mortality when compared with patients with HPV-negative tumors, who have a considerably worse prognosis. These data corroborate several previous single-institutional, retrospective analyses that reported similarly improved disease

6054Background: ECOG-ACRIN (E3311) examines the role of transoral head and neck surgery in treatment deintensification for stage III/IV p16+ oropharyngeal cancer (OPC). Patients with lateralized, r...

TPS6101Background: Current therapies for pts with R/M SCCHN achieve poor survival, so more effective and better tolerated treatments are needed. Tumors can evade immune detection by exploiting inhi...

6024Background: Therapeutic de-intensification for OPC underscores the need for accurate patient-specific assessment of risk. Current risk stratification is based on HPV tumor status, tobacco use, ...

6009Background: Patients (pts) with R/M SCCHN have poor prognosis, and median OS for pts with platinum-refractory disease is ≤6 mo. We investigated if nivo, a fully human IgG4 anti-PD-1 mAb improve...

6005 Background: Human papillomavirus-positive oropharyngeal carcinoma (HPV-OPC) has a favorable prognosis; however, 10-25% of HPV-OPC cases recur. Oral HPV DNA detection is associated with HPV-OPC...

6021 Background: The prevalence, severity, and functional implications of high-dose radiation for locally advanced head and neck cancer (HNC) are substantial. E1308 allowed dose reduction of IMRT (54Gy) in HPV+ patients if a complete clinical response were obtained to induction chemotherapy (IC). The VHNSS V2 instrument was used to quantify symptom burden following treatment. Methods: The VHNSS V2 is a 50-item survey, scored 0 (none) to 10 (severe) arranged into symptom clusters. The tool was utilized pre-treatment, and at 6 and 12 months to pts with resectable stage III/IVa,b HPV+ oropharyngeal HNC who received IC q3 weeks x 3 with paclitaxel 90mg/m2 days (D) 1,8, 15, cisplatin 75mg/m2 D1, and standard weekly cetuximab (C). IC response determined IMRT dose independently at primary site and involved nodes: C-IMRT 54Gy/27 if cCR and 69.3Gy/33 if < cCR. Only pts who completed ≥ 50% of the items in a given symptom cluster were considered evaluable for that cluster Results: 80 pts were enrolled (3 did not rec...

e17036 Background: In preclinical HNSCC models, combined EGFR and Src inhibition with radiation has additive and possibly synergistic effects. We conducted a 3+3 standard Ph1 trial to determine the...

LBA6006 Background: HPV+ patients (pts) in E2399 obtained a 2-yr 95% survival and 86% PFS after IC and 70Gy chemoradiation. We hypothesized reduced-dose IMRT (54Gy, 23% reduction) in HPV+ OPSCC pts could maintain high LR control and 85% 2-yr PFS in pts with cCR to IC. Methods: Pts with resectable stage III/IVa,b HPV+ OPSCC received IC q3 weeks x 3 with paclitaxel 90mg/m2 days (D) 1,8,15, cisplatin 75mg/m2 D1, and standard cetuximab (Cetux) weekly schedule. IC response determined IMRT dose independently at primary and involved nodes: IMRT 54Gy/27 if cCR vs. 69.3Gy/33 if

TPS6103 Background: There is rapid accumulation of data pointing to a potential role of sorafenib in the setting of recurrent/metastatic SCCHN. The combination of sorafenib to a cisplatin-docetaxel...

6007 Background: p16 is an important tumor suppressor and cell cycle regulator that is commonly lost in HPV-negative (-) and upregulated in HPV-positive (+) OPSCC. While the role of p16 expression in OPSCC as a surrogate marker of HPV infection and its association with prognosis are well established, its significance has not been studied in non-OPSCC including oral cavity, hypopharynx and larynx, where HPV infection is rare. We hypothesize that p16 expression is a prognostic biomarker of favorable outcome (progression-free and overall survival) in non-OPSCC. Methods: p16 expression in non-OPSCC from RTOG 0129, 0234 and 0522 was determined by immunohistochemistry (p16 mouse monoclonal antibody, prediluted, MTM-CINtech, 9518) and considered positive if >70% of the tumor cells demonstrated diffuse staining. The high risk HPV status in non-OPSCC from RTOG 0129 and 0522 was determined by in situ hybridization using a cocktail probe including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 66. Hazard ratios from Cox models were expressed as positive/negative, stratified by trial, and adjusted for age, gender, T, and N stage. Results: p16 expression was positive in 14.1% (12/85), 24.2% (23/95) and 19.0% (27/142) of non-OPSCC from RTOG 0129, RTOG 0234, and RTOG 0522, respectively. HPV ISH was positive in 6.5% (6/93) and 6.9% (7/101) of non-OPSCC from RTOG 0129 and RTOG 0522, respectively. There was moderate agreement between p16 and HPV status (kappa=0.53). The hazard ratios for p16 expression are 0.63 (p=0.03) and 0.56 (p=0.01) for PFS and OS, respectively. In 0522, there was no interaction between p16 status and two treatment arms (RT+cisplatin+/-cetuximab). In comparison of OPSCC and non-OPSCC, patients with p16(+) OPSCC have better PFS and OS than patients with p16(+) non-OPSCC, but patients with p16(-) OPSCC and non-OPSCC have similar outcomes. Conclusions: Similar to results in patients with OPSCC, patients with p16(+) non-OPSCC have better outcomes than patients with p16(-); however, the differential appears smaller than has been observed in HPV(+) OPSCC. Further studies are warranted to delineate the role of p16 expression as a prognostic biomarker in non-OPSCC and OPSCC. Clinical trial information: NCT00265941, NCT00047008, NCT00084318.

CRA6031 Background: Incidence of human papillomavirus-positive oropharyngeal cancer (HPV-OPC) is increasing, and spouses of these patients have high anxiety about their own HPV-related cancer risk. Methods: Partner study of 149 HPV-OPC and 81 of their spouse/long-term partners. Data collection included a 30-second rinse and gargle (at diagnosis and again 1 year later for 103 cases and 46 partners), computer-assisted risk factor survey, tumor collection (cases), and visual oral examination (spouses). Oral rinse samples were tested for 36 types of HPV DNA using PGMY09/11 primers and line-blot amplification, and HPV16 copy-number using real-time PCR. Results: Cases were primarily male (89%), white non-Hispanic (92%), had performed oral sex (94%), and never-smokers (51%) with a median age of 56 years. Twelve-month survival was high among never- and ever-smoking HPV-OPC (100% vs 93%, p=0.18). The 81 spouses of HPV-OPC were primarily female (81%), white non-Hispanic (92%), never-smokers (54%), with a median age of 53 years. Spouses were significantly less likely than cases to have >10 lifetime oral sex partners (11% vs 39%, p

6005 Background: HPV is associated with 60-80% of OPSCC. E2399 results showed IC followed by (f/b) paclitaxel (P)/3D RT (70Gy) improved 2-yr progression-free (PFS) for HPV+ compared to HPV- OPSCC. We studied a regimen with 20% radiation dose reduction to 54Gy in HPV + OPSCC patients (pts) with a clinical complete response (CCR) to IC. Methods: Stage III/IVA,B resectable HPV+ OPSCC were included. Eligible pts received IC q3 week x 3 with P 90mg/m2 days (D) 1,8, 15, cisplatin (CDDP) 75mg/m2 D1, and cetuximab (C) 400 mg/m2 D1, cycle 1 f/b C 250 mg/m2 weekly. Primary tumor and involved nodal response to IC were determined independently. Pts recieved IMRT 54Gy/27 fxs with weekly C for CCR vs. 69.3Gy/33 fxs with weekly C if

5566 Background: Human papillomavirus (HPV) infection is now recognized as a risk factor of oropharyngeal squamous cell carcinoma (OPSCC) and approximately 60% of OPSCC are HPV positive (+). ECOG 2399 using induction chemotherapy (IC) followed by chemoradiation demonstrated significantly improved 2-yr progression-free survival (PFS; 85% vs. 50%, p=0.05) and overall survival (OS; 94% vs. 58%p=0.004). These results have generated interest in development of less toxic regimens for HPV(+) patients with lower dose radiation. Methods: Design: This is a phase II clinical trial .The primary objective is the estimation of the 2-year PFS in the reduced dose RT arm. Secondary objectives include toxicity, OS, objective response, quality of life (QOL) and correlative studies of biomarkers. Eligibility Criteria: Patients with Stage III or IV resectable HPV(+) OPSCC. HPV(+) disease is defined as p16 IHC strongly (+) on at least 70% of cells, and/or HPV-16 ISH (+).Treatment : Patients received IC with a combination of paclitaxel 90mg/m2 on days 1,8, and 15, cisplatin 75mg/m2 on day 1, and cetuximab loading dose of 400 mg/m2 on day 1, cycle 1 followed by cetuximab 250 mg/m2 weekly, thereafter. Each cycle was 21 days for a total of 3 cycles. After completion of IC, patients were assessed clinically with a complete head and neck exam and imaging studies. Those with clinical CR at primary site received radiation to 54Gy plus cetuximab. Patients with clinical PR or SD at primary site received standard dose RT with cetuximab. Correlative Studies: The expression of biomarkers on tumor and blood samples and QOL parameters will be correlated with the clinical outcomes. Results: Current enrollment: Target accrual was 83 patients. The study accrued 90 patients from March 17, 2010 to accrual on October 19, 2011. Baseline characteristics reveal; median age 57 years, 94% male, 95% white, 47% never smokers, 10% 10 pyr smoking, 84% not current smokers, 39% node (N) stage N2b and 29% N2c, 22% tumor (T) stage T1, 52% T2, 16% T3, and 10% T4. Conclusions: Enrollment has just completed with no data analysis available.

5530 Background: NCCN recommends HNC patients (pts) be treated by providers with experience in HNC management. Whether treatment by experienced providers (measured by no. of pts treated) is associated with HNC survival outcome is unknown. Methods: Analysis included 471 pts in RTOG 0129 with stage III-IVa HNC with known tumor HPV and smoking status randomized to cisplatin concurrent with standard or accelerated fractionation radiotherapy (RT). Participating centers were stratified into pt accrual tertiles (ATs) to 21 RTOG HNC trials from 1997-2002. As a surrogate for experience, we investigated the independent effect of AT on OS and progression-free survival (PFS) in multivariable cox proportional hazards models. Results: Median follow up was 4.8 yrs (range 1.1 - 6.5). In Kaplan-Meier analysis, OS and PFS for pts at centers in the two lower AT (low accruing centers [LAC]) were similar and compared to the upper AT (high accruing centers [HAC]). Median accrual in LAC vs HAC was 11 vs 82 pts. Pts treated at LAC and HAC had similar age, HPV status, pack-years, N stage, comorbidities and study arm assignment (SAA), but pts at LAC had better performance status (PS)(Zubrod 0; 62% vs 52%; p=0.04), fewer T4 tumors (27% vs. 35%; p=0.05) and were more likely uninsured (12% vs 4%; p=0.009). Compared to HAC, LAC pts had significantly worse OS, (5 yr 51.0% vs 69.1%; p = 0.002), and PFS (5 yr 42.7% vs 61.8%; p = 0.001) and more locoregional failure (5 yr 36.4% vs 20.8%; p

5529 Background: Recent increases in incidence and survival of oropharyngeal cancers in the United States (U.S.) have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. Methods: HPV status was determined for 271 oropharyngeal cancer cases (1984-2004) collected by population-based cancer registries of the National Cancer Institute’s Surveillance, Epidemiology, and End Results program in Hawaii, Iowa, and Los Angeles. Tumor HPV status was determined by PCR and genotyping (Inno-LiPA), HPV16 viral load, HPV16 mRNA expression, and HPV16 in situ hybridization. Trends in HPV prevalence across four calendar periods were estimated using logistic regression. Survival of HPV-positive and HPV-negative cases was compared by Kaplan-Meier and multivariate Cox regression analyses. Results: HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (p-trend

5512 Background: Tumor HPV status is a strong, independent predictor of OPSCC survival and increasingly used for therapeutic decision making. Methods for classification are variable and not standar...