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PURPOSE To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.

TPS9592 Background: CSCC is the second most common skin cancer with an estimated incidence of 1 million cases per year in the US. While the surgical cure rate for CSCC is > 95%, some pts have high risk of recurrence as assessed by immune status, primary disease stage, extent of nodal involvement, presence of extracapsular extension (ECE), and prior treatment. Postoperative RT is recommended for these pts but relapse with locoregional recurrence or distant metastases may still occur. C-POST is evaluating the efficacy of cemiplimab as adjuvant therapy for pts with high-risk CSCC. Here, we provide summary of the most recent study protocol amendment. Methods: C-POST is a randomized, placebo-controlled, double-blind, multicenter Phase 3 study to evaluate cemiplimab as adjuvant treatment for pts with high-risk CSCC, based on surgical and clinicopathologic findings, who completed surgery and postoperative RT (minimum total dose 50Gy, within 10 weeks before randomization) (NCT03969004). Pts with at least one of the following high-risk features are eligible: (1) nodal disease with (a) ECE and at least one node ≥20 mm or (b) at least three lymph nodes positive on surgical pathology report, regardless of ECE; (2) in-transit metastases; (3) T4 lesion; (4) perineural invasion; and (5) recurrent CSCC with at least one other risk factor. Pts with CSCC involvement in at least three lymph nodes (feature 1b) were added to the eligibility criteria, as this group was found to be at similar risk of CSCC recurrence as the initially planned study population. Protocol amendment now allows patients with chronic lymphocytic leukemia (CLL) who are not on active treatment to be enrolled. The study has two parts. In Part 1 (blinded), pts are randomly assigned 1:1 to receive cemiplimab 350 mg or placebo intravenously every 3 weeks for 12 weeks, followed by cemiplimab 700 mg or placebo every 6 weeks for 36 weeks. In optional Part 2 (unblinded), pts in the placebo arm who experience disease recurrence and pts in the cemiplimab arm who experience disease recurrence ≥3 months after completion of 48-week treatment in Part 1 are eligible to receive open-label cemiplimab for up to 96 weeks. The trial is expected to enrol 412 pts from about 100 sites in North and South America, Europe, and Asia-Pacific regions. Key primary objective is to compare disease-free survival; secondary objectives include evaluating overall survival, freedom from locoregional relapse, and distant relapse with adjuvant cemiplimab versus placebo in patients with high-risk CSCC. This study is once again open for enrolment following interruptions owing to the COVID-19 pandemic. Clinical trial information: NCT03969004.

Purpose The College of American Pathologists produced an evidence-based guideline on testing, application, interpretation, and reporting of human papillomavirus (HPV) and surrogate marker tests in head and neck carcinomas that was determined to be relevant to the American Society of Clinical Oncology (ASCO) membership. Methods The College of American Pathologists HPV Testing in Head and Neck Carcinomas guideline was reviewed by ASCO content experts for clinical accuracy and by methodologists for developmental rigor. On favorable review, an ASCO Expert Panel was convened to review the guideline contents and recommendations. Results The ASCO Expert Panel determined that the recommendations from the HPV Testing in Head and Neck Carcinomas guideline, published in 2018, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the guideline and added minor qualifying statements. Recommendations It is recommended that HPV tumor status should be determined for newly diagnosed oropharyngeal squamous cell carcinomas. HPV tumor status testing may be performed by surrogate marker p16 immunohistochemistry either on the primary tumor or from cervical nodal metastases only if an oropharyngeal primary tumor is present. The threshold for positivity is at least 70% nuclear and cytoplasmic expression with at least moderate to strong intensity. Additional confirmatory testing may be done at the discretion of the pathologist and/or treating clinician. Pathologists should not routinely determine HPV tumor status in nonsquamous carcinomas of the oropharynx or non–oropharyngeal squamous cell carcinomas of the head and neck. When there is uncertainty of histologic type or whether a poorly differentiated oropharyngeal tumor is nonsquamous, HPV tumor status testing may be warranted and at the discretion of the pathologist and/or treating clinician. Additional information is available at: www.asco.org/head-neck-cancer-guidelines .

LBA3 Background: Cervical cancer is a common cause of cancer-related death among women worldwide. Standard treatment for locally advanced disease is chemoradiation. However, a significant percentage of women still relapse and die from the development of distant metastatic disease. OUTBACK was designed to determine the effects of giving adjuvant chemotherapy after chemoradiation on survival. Methods: OUTBACK is an international randomized phase III trial of the Gynecologic Cancer InterGroup (GCIG). Participating groups (countries) included ANZGOG (Australia and New Zealand), NRG (USA, Saudi Arabia, Canada, China), and Singapore. Eligible women had locally advanced cervical cancer (FIGO 2008 stage IB1 and node positive, IB2, II, IIIB or IVA) that was suitable for primary treatment with chemo-radiation with curative intent. Women were randomly assigned to either standard cisplatin-based chemo-radiation (control) or standard cisplatin-based chemo-radiation followed by adjuvant chemotherapy (ACT) with 4 cycles of carboplatin and paclitaxel, after stratification for nodal status, participating site, FIGO stage, age, and planned extended-field radiotherapy. The primary end point was overall survival (OS) at 5 years. Secondary endpoints included progression-free survival (PFS); adverse events (AE); and patterns of disease recurrence. The target sample size of 900 provided 80% power with 95% confidence to detect an improvement in OS at 5 years from 72% (control) to 80% (ACT), with some over-accrual to account for non-compliance with ACT and loss to follow-up. Results: 919 of 926 women recruited from April 2011 to June 2017 were eligible and included in the primary analysis: 463 assigned ACT, 456 control. ACT was started in 361 (78%) women assigned to receive it. Median follow-up was 60 months (IQR 45-65). OS at 5 years was similar in those assigned ACT versus control (72% vs 71%, difference

6036 Background: T-VEC, a genetically modified herpes simplex virus-1, is the first FDA- and EMA-approved oncolytic viral immunotherapy designed to enhance systemic antitumor immune responses. R/M HNSCC is a disease with considerable clinical complexity and poor prognosis. Pembro is a PD-1-specific humanized monoclonal antibody currently approved as first-line Tx for this disease, but there is an unmet need among many patients (pts). To meet this gap, the safety and preliminary efficacy of T-VEC plus pembro in pts with R/M HNSCC was evaluated in a phase 1b study (Harrington et al. Clin Cancer Res. 2020). Here, we present results of the final analysis of this study (NCT02626000). Methods: Eligible pts (≥18 yrs) had ECOG-PS of 0 or 1; histologically confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx unsuitable for curative surgical resection or radiotherapy; platinum-refractory and with injectable tumors. Pts with known active CNS metastases and any systemic or local therapy 28 days before enrollment were excluded. T-VEC was injected intralesionally up to 8.0 mL of 106 PFU/mL according to lesion sizes on day 1; after 3 weeks, subsequent doses of ≤8.0 mL of 108 PFU/mL were given Q3W. Pembro was given intravenously at 200 mg Q3W. Pts were followed-up for 36 mos after the last patient was enrolled in the study. Key endpoints (irRECIST per investigator assessment) were objective response rate (ORR), best overall response (BOR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 36 pts (80.6% male) were enrolled and treated: 28 (77.8%) had confirmed PD-L1-positive tumor (CPS ≥1), 5 (13.9%) were HPV-positive, 13 (36.1%) had metastatic disease, and 19 (52.8%) had prior lines of therapy in the R/M setting. At the final analysis, 7 pts (19.4%) completed the study, and 29 (80.6%) discontinued the study due to death. Safety profile was consistent with that at 1-yr analysis (Harrington et al. Clin Cancer Res. 2020). Confirmed ORR was seen in 16.7% (95% CI, 6.4–32.8). No patient had a complete response as their BOR, 6 (16.7%) had a partial response, 8 (22.2%) had stable disease, 6 (16.7%) had progressive disease, 6 (16.7%) were unevaluable, and 10 (27.8%) died before the first response assessment. The DCR was 38.9% (95% CI, 23.1–56.5). The median DOR was 45.9 mos (95% CI, 8.5–NE). The median PFS was 3.0 mos (95% CI, 2.0–5.8), and the median OS was 5.8 mos (95% CI, 2.9–11.4). Conclusions: The safety results at 3 yrs for T-VEC plus pembro in pts with R/M HNSCC were consistent with those of the 1-yr analysis. Although the response rate was consistent with that observed with pembro alone in historical HNSCC studies, the extended DOR in responding patients warrants further investigation. Clinical trial information: NCT02626000.

6012 Background: The excellent prognosis of patients with low risk HPV associated oropharyngeal squamous cell carcinoma has led to concerns about overtreatment and excessive toxicity with radiotherapy and cisplatin, leading to interest in de-intensification trials. We investigated whether cetuximab, an EGFR targeting antibody, when combined with radiotherapy would result in a decrease in symptom burden and toxicity with similar efficacy when compared to weekly cisplatin. Methods: TROG 12.01, a randomised, multicentre trial involving 15 sites in Australia and New Zealand enrolled patients with HPV associated oropharyngeal squamous cell carcinoma, AJCC 7th edition Stage III (excluding T1-2N1) or stage IV (excluding T4 and/or N3 and/or N2b-c if smoking history >10 pack years and/or distant metastases). Patients were randomised (1:1) to receive radiotherapy (70Gy in 35 fractions) with either weekly cisplatin, 7 doses of 40mg/m2 or cetuximab, loading dose of 400mg/m2 followed by 7 weekly doses of 250 mg/m2. The primary outcome was symptom severity assessed by the MD Anderson Symptom Inventory Head and Neck Symptom Severity Scale from baseline to 13 weeks post completion of radiotherapy using the area under the time-severity curve (AUC). Sample size was 170 evaluable patients to provide at least 90% power to detect an effect size of 0.5, using a 2-sided test at 0.05 level of significance. Trial was registered on ClinicalTrials.gov: NCT01855451. Results: Between 17th June 2013 and 7th June 2018, 189 patients were enrolled and 182 were evaluable, with 92 on cisplatin arm and 90 on cetuximab included in the main analysis. The median follow-up was 4.1 years (0.4 - 5.3). Analyses were performed in all eligible randomised patients that commenced treatment (modified intention-to-treat population). There was no difference in the primary endpoint of symptom severity; difference in AUC cetuximab – cisplatin was 0.05 (95%CI: -0.19, 0.30), p= 0.66. The T-score (mean number of > grade 3 acute adverse events) was 4.35 (SD 2.48) in the cisplatin arm and 3.82 (SD 1.8) in the cetuximab arm, p= 0.108. The 3 -year failure-free survival rates were 93% (95% CI: 86-97%) in the cisplatin arm and 80% (95% CI: 70-87%) in the cetuximab arm (hazard ratio = 3.0 (95% CI: 1.2-7.7); p=0.015. The increase in failures in the cetuximab arm was evenly split between distant and locoregional failures. Conclusions: For patients with low risk HPV associated oropharyngeal cancer, radiotherapy and cetuximab had inferior failure-free survival without improvement in symptom burden or toxicity compared to radiotherapy and weekly cisplatin. Radiotherapy and cisplatin remains the standard of care. Clinical trial information: NCT01855451.

e18644 Background: Polymorphisms in the DPYD gene, which encodes for dihydropyrimidine dehydrogenase (DPD), may impair DPD metabolism of fluoropyrimidines (FP) and cause life-threatening toxicities. The European Medicines Agency (EMA) recommend testing for DPD activity before FP therapy, but the Australian Therapeutic Goods Administration and the US Food and Drug Administration do not currently recommend this. At our hospital, pre-emptive DPYD gene screening was established in response to 7 cases of severe FP-toxicity and significant challenges for timely access to the life-saving antidote, uridine triacetate (UT), in the preceding 3 years. This study assessed the feasibility of a pharmacist-led DPYD gene testing service in an Australian cancer centre. Methods: Patients planned for FP therapy, without previous FP exposure, were referred to the Clinical Pharmacogenetics (CPGx) pharmacist for consenting, before a blood or buccal swab sample was taken. An external genomics company screened for the five Clinical Pharmacogenetics Implementation Consortium (CPIC) recommended gene variants (c.1905+1G > A, c.1679T > G, c.2846A > T, c.1236G > A and c.557A > G). Dose recommendations based on CPIC guidelines and phenotype were made to the treating clinician. Patients were followed-up for toxicity (graded according to CTCAE v5.0) at 3-5 days post first FP exposure and pre-cycle 2. Results: Between 16 December 2019 and 11 December 2020, 311 patients were planned for FP therapy. Genetic testing did not occur for 13 patients, in the first two months of program implementation mostly due to unfamiliarity with procedures. Of the 298 genotyped patients (median age 59.5 years, 52.7% female, 67.8% Upper and Lower Gastrointestinal, 18.1% Breast), 274 (91.9%) were seen by the CPGx pharmacist within 1 day of referral. Median time from samples being taken to result availability was 6 days. 286 patient (96.0%) results were reported and acted upon prior to the planned cycle 1 FP commencement date. Overall, 1 patient (0.3%, 95%CI 0.1-1.9) was identified as a poor metaboliser and avoided FP therapy. Ten patients (3.4%, 95%CI 1.8-6.0) were identified as intermediate metabolisers, of which 2 patients did not receive chemotherapy due to changes in goals of care, 1 patient received only one cycle at 100% of the full dose but passed away due to disease progression, 1 patient required UT administration after cycle 2 despite 50% dose reductions for both cycles and 6 patients received an initial 50% dose reduction, where for subsequent cycles, 3 continued at this dose level, 2 had dose increases and 1 had a further dose reduction. 17 patients experienced at least one grade 3/4 toxicity pre-cycle 2; all had normal metaboliser phenotypes. Conclusions: A pharmacist-led DPYD gene testing service is feasible, with acceptable test result turnaround times and phenotype identification rates similar to that reported by the EMA.

109 Background: Trials in human papilloma virus associated oropharyngeal squamous cell carcinoma (HPVOPSCC), substituting cetuximab (CETUX) for cisplatin (CIS) with radiotherapy (RT), resulted in decreased efficacy without improved toxicity or symptom burden. We reported that high intratumoral immune cell (ITIC) CD103 expression (> 30%), a marker of tissue-resident memory T cells, is associated with better prognosis in unselected patients with HPVOPSCC treated with CIS/RT. In this study our aim was to determine whether low risk HPVOPSCC patients treated with CETUX/RT with high CD103 have a superior prognosis. Methods: TROG 12.01 and De-ESCALaTE are randomised multicentre trials that compared 70Gy RT/CETUX with 70Gy RT/CIS (weekly in TROG 12.01, 3-weekly in De-ESCALaTE) in patients with HPVOPSCC, low risk by Ang criteria: AJCC 7th Stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history > 10 pack years and/or distant metastases). In TROG 12.01 T4 and/or N3 patients were also excluded. Eligible patients required tumor samples available for immune cell quantification on immunohistochemistry. Data from the two trials were pooled, with analyses performed in eligible randomised patients who commenced treatment. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/ RT comparing CD103 ITIC > 30% (high) vs. < 30% (low). High/low CD103 were compared using Cox model adjusting for age, stage and trial. Results: Samples for CD103 testing were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. ITIC CD103 expression was high in 26% of patients. The median follow-up was 3.2 years. The 3 -year failure-free survival rates in patients treated with CETUX/RT were 92% (95% CI: 78-97%) in high CD103 and 74% (95% CI: 64-82%) in low CD103, adjusted HR 0.25 (95% CI: 0.14-0.44); p < 0.001. The 3 -year overall survival (OS) in patients treated with CETUX/RT were 100% in high CD103 and 86% (95% CI: 76-92%) in low CD103, p < 0.001. Superior FFS in the high CD103 group was independent of stage. In patients treated with CIS/RT there was no significant difference in FFS (3-year 86% in high CD103 and 90% in low CD103; p = 0.55) or in OS (3-year 100% in high CD103 and 95% in low CD103; p = 0.14). The increase in failures in the low CD103 patients treated with CETUX/RT was evenly split between distant and locoregional failures. Conclusions: ITIC CD103 separates CETUX/RT treated low risk HPVOPSCC into excellent and poor prognosis subgroups. In a low risk population CIS/RT achieves excellent outcomes in both high and low ITIC CD103 groups. The high ITIC CD103 population is a rational target for future de-intensification trials.

Merkel cell carcinoma (MCC) is a rare and highly aggressive neuroendocrine malignancy with a propensity for recurrence and a poor prognosis. Incidence of MCC is on the rise and is known to increase with advanced age, immunosuppression, and UV exposure. Merkel cell polyomavirus is implicated in the pathogenesis of virus-positive MCC and accounts for 80% of MCCs in the northern hemisphere and 25% in southern latitudes. In contrast, tumorigenesis of virus-negative MCC is linked to UV-induced DNA damage. Interplay between ubiquitous Merkel cell polyomavirus skin infections that commonly occur in healthy skin and other established risk factors, such as immunosuppression and UV exposure, remains poorly understood. Surgery and radiotherapy achieves excellent locoregional control; however, invariably, a significant proportion of patients develop disseminated disease that is incurable. Chemotherapy offers a high response rate for metastatic disease, but responses are short-lived and the impact on survival is not established. Recent advances in our understanding of the genetic landscape and immunobiology of MCC has led to investigation of novel treatments, including immune checkpoint inhibitors, which are likely to rapidly transform the way we manage these patients. We review epidemiologic, clinical, and histopathologic features of MCC; describe recent insights in MCC biology; and discuss novel therapeutic approaches.

6517 Background: INDUCE-1 (NCT02723955) is a first-in-human study investigating GSK609, an IgG4 ICOS agonist non-T-cell depleting antibody, as monotherapy and combination therapy with anti-cancer agents that includes PE. A range of GSK609 dose levels (≥0.1–1 mg/kg) having biological and clinical activity were identified and evaluated in the expansion phase with GSK609 0.3 mg/kg selected as the dose for further investigation. Results from the HNSCC expansion cohorts (ECs) showed GSK609 has single agent activity in pts with relapsed/refractory disease, and early clinical activity in combination with PE in pts with anti-PD-1/L1 treatment-naïve disease (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). Updated results from the GSK609/PE HNSCC EC are presented. Methods: Eligible pts for the HNSCC EC had anti-PD-1/L1 treatment-naïve disease, ≤5 prior lines of therapy, measurable disease, and no active autoimmune disease. Pts received GSK609 0.3 mg/kg + PE 200 mg every 3 weeks (wks) until disease progression or unacceptable toxicity, up to 2 years (yrs)/35 cycles. Disease assessments were performed every 9 wks through wk 54 then every 12 wks thereafter. Pts were followed for survival and subsequent anti-cancer therapy. Results: As of 11 October 2019, 34 pts were enrolled and evaluable for efficacy analyses. The median age of this population was 61.5 yrs (range: 37–77); 85% were male; 53% received ≥1 prior line of therapy in the metastatic setting. ORR was 26% (95% CI: 12.9, 44.4; n = 9 with 4 complete and 5 partial responses); disease control rate was 68% (95% CI: 49.5, 82.6; n = 23). Among pts with PD-L1 IHC status by 22C3 pharmDx assay (n = 24; 71%), the majority of pts with a response or stable disease (SD) had PD-L1 CPS status < 20 (11 of 15 pts including 1 SD pt with CPS < 1). Median PFS was 5.6 months (95% CI: 3.9, 6,2). Median OS was not reached at time of analysis (95% CI: 8.2, NR); 6-month OS rate was 84% (95% CI: 66, 93). Treatment-related adverse events were reported in 66% of pts; the majority of events were Grades 1 or 2 with < 10% of pts experiencing ≥ Grade 3 events. Conclusions: This updated analysis with a more mature dataset shows promising clinical activity that supports further randomized investigation of GSK609 in combination with PE with an OS endpoint in HNSCC. Clinical trial information: NCT02723955 .

6530 Background: In the phase 3 KEYNOTE-048 trial ( NCT02358031 ) in R/M HNSCC (N = 882), 1L P vs E showed superior OS in PD-L1 CPS ≥20 and CPS ≥1 populations, noninferior OS in the total population, no PFS benefit, and favorable safety; 1L P+C vs E showed superior OS in CPS ≥20, CPS ≥1, and total populations, no PFS benefit, and comparable safety. Results of P or P+C vs E in incurable recurrent only, metastatic only, and R/M subgroups are shown. The metastatic only and R/M subgroups were combined and classified as metastatic. Methods: Patients with incurable recurrent (local and/or regional node recurrent disease) or metastatic HNSCC were randomly assigned 1:1:1 to P, P+C, or E. OS and PFS were estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs were based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate stratified by ECOG performance status, HPV status, and PD-L1 status. Data cutoff: Feb 25, 2019. Results: In the incurable recurrent only subgroup (n = 252), median OS was 11.5 vs 12.1 mo (P vs E) and 13.0 vs 11.1 mo (P+C vs E). In the metastatic subgroup (n = 620), median OS was 11.4 vs 9.7 mo (P vs E) and 13.0 vs 10.1 mo (P+C vs E). Median follow-up, OS, and PFS are shown in Table. Treatment-related adverse events (TRAE) in the incurable recurrent only subgroup: 49.4% (P), 94.7% (P+C), and 97.8% (E); grade 3-5 TRAEs rates: 16.0%, 78.7%, and 73.3%, respectively. TRAE rates in the metastatic subgroup: 61.6% (P), 96.4% (P+C), and 96.4% (E); grade 3-5 TRAEs rates: 17.6%, 69.5%, and 67.0%, respectively. Conclusions: P and P+C vs E were efficacious in the metastatic subgroup; in the relatively smaller subgroup of patients with incurable recurrent only HNSCC, the effect was less pronounced. Consistent with the total study population and regardless of disease state, the safety profile was favorable with P vs E and comparable with P+C vs E. These data further support use of 1L P or P+C in patients with R/M HNSCC. Clinical trial information: NCT02358031 . [Table: see text]

10018 Background: Cemiplimab monotherapy achieves clinically meaningful activity in pts with advanced CSCC (metastatic [mCSCC] or locally advanced [laCSCC] not amenable to curative surgery or curative radiation) and has a safety profile consistent with other anti–PD-1 agents. Based on initial data (median follow-up of 9.4 months in the pivotal study, NCT02760498), cemiplimab (cemiplimab-rwlc in the US) was approved for the treatment of pts with advanced CSCC. Historical data shows median overall survival (OS) of approximately 15 months with conventional chemotherapy or EGFR inhibitors (ASCO 2019, e21033). We present ~1-year additional follow-up from the largest prospective data set in advanced CSCC. Methods: Pts received cemiplimab 3 mg/kg Q2W (Group [Gp] 1; mCSCC; Gp 2, laCSCC) or cemiplimab 350 mg Q3W (Gp 3, mCSCC). The primary endpoint was objective response rate (ORR; complete response + partial response) per independent central review (ICR). Data presented here are per investigator review (INV); ICR data will be available at the meeting. Results: 193 pts were enrolled (Gp 1, n = 59; Gp 2, n = 78; Gp 3, n = 56). 128 pts had received no prior anti-cancer systemic therapy, 65 pts were previously treated. As of Oct 11, 2019 (data cut-off), median duration of follow-up was 15.7 months (range: 0.6–36.1) among all pts; 18.5 months (range: 1.1–36.1) for Gp 1, 15.5 months (range: 0.8–35.0) for Gp 2, and 17.3 months (range: 0.6–26.3) for Gp 3. ORR per INV was 54.4% (95% CI: 47.1–61.6) for all pts; 50.8% (95% CI: 37.5–64.1) for Gp 1, 56.4% (95% CI: 44.7–67.6) for Gp 2, and 55.4% (95% CI: 41.5–68.7) for Gp 3. ORR per INV was 57.8% (95% CI: 48.8–66.5) among treatment-naïve pts and 47.7% (95% CI: 35.1–60.5) among previously treated pts. Median duration of response (DOR) has not been reached (observed DOR range: 1.8–34.2 months). In responding pts, estimated proportion of pts with ongoing response at 24 months was 76.0% (95% CI: 64.1–84.4). Median OS has not been reached. Estimated OS at 24 months was 73.3% (95% CI: 66.1–79.2). The most common treatment-emergent adverse events (TEAEs) by any grade were fatigue (34.7%), diarrhea (27.5%), and nausea (23.8%). The most common grade ≥3 TEAEs were hypertension (4.7%) and anemia and cellulitis (each 4.1%). Conclusions: For pts with advanced CSCC, cemiplimab achieves ORRs, DOR and survival superior to what has been reported with other agents. Clinical trial information: NCT02760498.

TPS6591 Background: Pembrolizumab as part of first-line treatment for patients (pts) with R/M HNSCC has improved survival. However, in order to further improve outcomes in this population investigation of rational combinations targeting different mechanisms that cancers exploit to evade the immune system is required. ICOS, a member of the CD28/B7 immunoglobulin receptor superfamily, provides a co-stimulatory signal augmenting T-cell proliferation, cytokine production, cytotoxic function and survival. GSK609 is a humanized IgG4 antibody selected for its potent agonist activity and non-depleting properties. The rationale for targeting ICOS with GSK609 plus PD-1 blockade with PE is supported by preclinical and clinical evidence (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). INDUCE-3 trial (NCT04128696) will explore if the addition of GSK609 to PE improves outcomes of pts with R/M HNSCC. Methods: INDUCE-3 uses a 2-in-1 adaptive design that has the option to seamlessly expand from an initial Phase 2 to a Phase 3 study. Pts (n = 600) will be stratified by PD-L1 status and HPV status (oropharynx only) then randomly assigned in a 1:1 ratio to receive GSK609 plus PE or PL plus PE, every 3 weeks until progression, unacceptable toxicity, or up to 35 cycles. GSK609 plus PE will be assessed for superiority versus PL plus PE in overall survival (OS) and progression-free survival (PFS) per RECISTv1.1 as dual primary endpoints; secondary endpoints include PFS per immune-based RECIST; milestone OS; safety and tolerability; time to deterioration in patient-reported physical function and pain. Efficacy and patient-reported outcome endpoints will be assessed in the PD-L1 combined positive score (CPS) ≥1 and ≥20 populations. Key eligibility criteria are aged ≥18 years; locally incurable R/M HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; no prior systemic therapy in the R/M setting; PD-L1 CPS ≥1 by central testing; measurable disease per RECIST v1.1 and ECOG PS 0/1. Recruitment is ongoing in countries across the globe. Funding: Study is funded by GlaxoSmithKline and in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Clinical trial information: NCT04128696 .

TPS6589 Background: The PD-1 inhibitor pembrolizumab is currently approved as first-line monotherapy for patients with R/M HNSCC whose tumors express PD-L1 combined positive score (CPS) ≥1. In a phase 1b/2 trial (NCT02501096) of pembrolizumab plus lenvatinib (multikinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRa, RET, and KIT) in solid tumors, the combination demonstrated promising antitumor activity and a manageable safety profile in patients with HNSCC. LEAP-010 (NCT04199104) is a randomized, double-blind, placebo-controlled, phase 3 study that will evaluate the efficacy and safety of first-line pembrolizumab with or without lenvatinib in patients with PD-L1–positive R/M HNSCC. Methods: Key eligibility criteria include histologically confirmed R/M HNSCC incurable by local therapies, PD-L1–positive tumor (CPS ≥1) as determined by central laboratory, measurable disease as assessed by blinded independent central review (BICR) per RECIST v1.1, and ECOG performance status (PS) 0 or 1. Patients will be randomly assigned 1:1 to pembrolizumab plus lenvatinib or pembrolizumab plus placebo. Randomization will be stratified by PD-L1 status defined by tumor proportion score ( < 50% vs ≥50%), human papillomavirus status for oropharynx cancer (positive vs negative), and ECOG PS (0 or 1). Patients will receive intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles (~2 years) and oral lenvatinib 20 mg or placebo once daily; patients may continue to receive lenvatinib or placebo after pembrolizumab treatment is complete. Treatment will continue until BICR-verified disease progression or unacceptable toxicity. Pembrolizumab retreatment (second course) for 17 additional cycles will be allowed for eligible patients who stop pembrolizumab and subsequently experience BICR-verified disease progression. These patients could have stopped treatment with stable disease, partial response, or complete response or after 35 cycles of pembrolizumab for reasons other than disease progression or toxicity. Tumor imaging assessment will be performed at week 6, then every 6 weeks until 1 year, and thereafter every 9 weeks. Primary end points are objective response rate and progression-free survival, assessed by BICR per RECIST v1.1, and overall survival. Secondary end points are duration of response and safety and tolerability. Recruitment is ongoing; planned enrollment is ~500 patients. Clinical trial information: NCT04199104 .

TPS10084 Background: CSCC is the second most common skin cancer. While the surgical cure rate for CSCC is > 95%, a proportion of pts are considered to have high risk for recurrence as assessed by immune status, primary disease stage, extent of nodal involvement, presence of extracapsular extension, and prior treatment. Post-operative RT is recommended for pts with high-risk features, but relapse with locoregional recurrence or distant metastases may still occur. This study evaluates the efficacy of cemiplimab, a human anti‒PD-1 monoclonal antibody, as an adjuvant therapy for pts with CSCC with high-risk features, after surgery and RT. Methods: This randomized, placebo-controlled, double-blind, multicenter, Phase 3 study will evaluate cemiplimab as an adjuvant treatment for pts with high-risk CSCC, based on surgical and clinicopathologic findings, who have completed surgery and post-operative RT (NCT03969004). Immunocompromised pts were excluded. The trial will enrol 412 pts from about 100 sites in North America, Europe, and Asia-Pacific regions. Pts with at least one of the following high-risk features are eligible: a) nodal disease with extracapsular extension b) in-transit metastases c) T4 lesion d) perineural invasion, and e) recurrent CSCC with at least one other risk factor. In Part 1 (blinded), pts will be randomized 1:1 to receive cemiplimab 350 mg or placebo intravenously every 3 weeks (Q3W) for up to 48 weeks. In optional Part 2 (unblinded), pts in the placebo arm who experience disease recurrence or pts in the cemiplimab arm who experience disease recurrence ≥3 months after completion of 48-week treatment in Part 1 will be eligible to receive open-label cemiplimab 350 mg Q3W for up to 96 weeks. Key objectives are to compare disease-free survival (primary) as well as overall survival, freedom from locoregional relapse, and distant relapse (secondary) of adjuvant cemiplimab vs placebo in pts with high-risk CSCC. This study is currently open for enrollment. Clinical trial information: NCT03969004.

6505 Background: 1L P vs E improved OS in PD-L1 CPS ≥20 and CPS ≥1 populations, and led to noninferior OS in the total population, with favorable safety; 1L P+C vs E had superior OS in CPS ≥20, CPS ≥1, and total populations with comparable safety in the phase 3 KEYNOTE-048 study (NCT02358031) in patients with R/M HNSCC. Neither P vs E nor P+C vs E improved PFS in the PD-L1 CPS ≥20, CPS ≥1, or total populations. Here, we present the progression after the next line of therapy (PFS2) to assess the effect of 1L P or P+C and subsequent anticancer therapy on patient outcomes. Methods: Patients with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting were randomly assigned 1:1:1 to P, P+C, or E. PFS2 was defined as time from randomization to objective tumor progression on next-line therapy or death from any cause. PFS2 was estimated using the Kaplan-Meier method as an exploratory outcome confined to those receiving subsequent therapy after 1L P. HR and 95% CIs were based on a Cox regression model with Efron’s method of tie handling with treatment as a covariate (stratified by ECOG performance status [PS], HPV status, and PD-L1 for CPS ≥1 and total populations; by ECOG PS and HPV status for CPS ≥20 population). Data cutoff: Feb 25, 2019. Results: Of 882 (301 [P]; 281 [P+C]; 300 [E]) treated patients,422 (P: 148 [49.2%]; P+C: 115 [40.9%]; E: 159 [53.0%]) received subsequent anticancer therapy after 1L P, most commonly C (P: 135 [44.9%]; P+C: 88 [31.3%]; E: 102 [34.0%]); EGFR inhibitor (P: 59 [19.6%]; P+C: 37 [13.2%]; E: 19 [6.3%]); and immune checkpoint inhibitor (P: 6 [2.0%]; P+C: 12 [4.3%]; E: 50 [16.7%]); patients may have received more than one type of subsequent therapy. Median PFS2 is reported in Table. Conclusions: In patients with R/M HNSCC, longer median PFS2 was observed in the CPS ≥20 and CPS ≥1 populations for P vs E, and in the CPS ≥20, CPS ≥1, and total populations for P+C vs E. These data further support use of 1L P or P+C in patients with R/M HNSCC. Clinical trial information: NCT02358031 . [Table: see text]

10033 Background: Cemiplimab-rwlc (cemiplimab), a PD-1 Inhibitor, showed a robust clinical response in patients (pts) with metastatic (mCSCC) or locally advanced (laCSCC) CSCC not eligible for curative surgery/radiation. This post hoc exploratory analysis examined data from the EORTC cancer specific 30-item HRQL questionnaire (QLQ-C30) for pts participating in a cemiplimab phase 2 clinical trial (clinicaltrials.gov NCT02760498). Methods: Adults (N = 193) with invasive CSCC, ≥1 lesion and ECOG performance status ≤1 received IV cemiplimab 3mg/kg q2w (mCSCC n = 59; laCSCC n = 78) or 350mg q3w (mCSCC n = 56). At baseline (BL) and day 1 of each treatment cycle, pts were administered the QLQ-C30. Mixed effects repeated measures (MMRM) models were used to estimate mean change from BL to cycle 5 (C5) for domains/items of the QLQ-C30. For pts with data from BL to C5, the proportion who reported clinically meaningful improvement or worsening (≥10 points) or maintenance (those who did not have ≥10 point change) on each domain was determined for combined and individual treatment groups. Results: BL scores indicated moderate to high levels of functioning and low symptom burden. From BL to C5, a clinically meaningful improvement in pain score was observed (least squares [LS] mean [standard error] change -12.1 [2.1]; P< .0001); other domains/items remained stable or showed a trend towards improvement (LS mean changes < 10 points). By C5, the majority of pts experienced clinically meaningful improvement or remained stable across key domains (Table). Similar findings were observed on individual symptoms (85%-94% for dyspnea, nausea/vomiting, diarrhea, constipation, appetite loss) and in each treatment group. Conclusions: Cemiplimab-treated patients achieved a clinically meaningful reduction in pain and most pts either improved or maintained their HRQL, function with low symptom burden. Clinical trial information: NCT02760498. [Table: see text]

6544 Background: The KEYNOTE-048 study (Burtness, at al. Lancet 2019;394:1915–28) led to approval of PE in combination with 5-FU/plat for first-line (1L) treatment of head and neck squamous cell carcinoma (HNSCC). The Phase I INDUCE-1 study (NCT02723955) has shown that GSK609±PE has a manageable safety profile in patients (pts) with advanced solid tumors (Hansen, at al. Annals of Oncology 2018;29[suppl_8]:viii404) and that GSK609 combined with PE has anti-tumor activity in pts with anti-PD-1/L1-naïve HNSCC (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). To evaluate the safety of GSK609±PE in combination with 5-FU/plat, we initiated additional safety cohorts. Methods: Pts eligible for GSK609+5-FU/plat had a diagnosis of advanced selected solid tumors and ≤5 prior lines of systemic therapy. Pts eligible for GSK609+PE+5-FU/plat had a diagnosis of recurrent or metastatic 1L HNSCC deemed incurable by local therapies. 5-FU/plat was administered every 3 weeks (Q3W) for 4-6 cycles (Burtness, at al. Lancet 2019;394:1915–28); GSK609 24 or 80 mg ±PE 200 mg were administered Q3W for up to 2 years/35 cycles or until disease progression or unacceptable toxicity. Results: Twenty-nine pts were enrolled in the 5-FU/plat safety cohorts: 10 pts in the GSK609+5-FU/plat cohort and 19 pts in the GSK609+PE+5-FU/plat cohort. With GSK609+5-FU/plat, 9/10 (90%) pts experienced ≥ 1 adverse event (AE). Of 32 AEs of any grade, 9 were Grade ≥3 and 3 were serious AEs (SAEs). Two of the 3 SAEs were related to study treatment (oral mucositis and febrile pancytopenia). With GSK609+PE+5-FU/plat, 18/19 (94.7%) pts experienced ≥ 1 AE. Of 119 AEs of any grade, 24 were Grade ≥3 and 15 were SAEs. Of the 15 SAEs, 11 were related to study treatment (febrile neutropenia [n=4], colitis [n=2], diarrhea [n=1], vomiting [n=1], acute kidney injury [n=1], cardiac chest pain [n=1] and lung infection [n=1]). For all cohorts, no Grade 5 AEs were observed. For 10 pts evaluable for confirmed best overall response in all cohorts, 2 pts had partial response, 6 pts had stable disease and 2 pts were nonevaluable. No difference in GSK609 exposure was observed relative to GSK609 monotherapy. Conclusions: The safety profile of GSK609 in combination with 5-FU/plat±PE is manageable. Most AEs were Grades 1 or 2 and consistent with PE and chemotherapy toxicities. Continued follow-up to investigate long-term safety and efficacy of this combination is warranted. Clinical trial information: NCT02723955 .

6015 Background: Cemiplimab (REGN2810) produced substantial antitumor activity with durable responses in Phase 1 CSCC expansion cohorts and Phase 2 metastatic (m) CSCC cohort. We now present the primary analysis of the Phase 2 laCSCC cohort (NCT02760498; data cutoff date: Oct 10, 2018). Methods: Pts with laCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 78 pts were enrolled (59 M/ 19 F; median age: 74 years; ECOG PS: 0 in 38 pts, 1 in 40 pts; primary CSCC site: head/neck in 79.5%; prior systemic therapy: 15.4%; prior radiotherapy: 55.1%). Median duration of follow-up was 9.3 months (range: 0.8–27.9). ORR by central review was 43.6% (95% CI: 32.4–55.3; 10 CRs and 24 PRs); investigator-assessed (INV) ORR was 52.6% (95% CI: 40.9–64.0; 13 CRs and 28 PRs). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 24.2 months and was still ongoing. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.8% (95% CI: 51.1–73.5). Median observed time to response was 1.9 months (range: 1.8–8.8). Median progression-free and overall survival have not been reached. Tumor PD-L1 status is available for 48/78 pts, tumor mutational burden analysis (from targeted exome panel) is ongoing for ≥40/78 pts; response correlation analyses are planned. The most common treatment-emergent adverse events (AEs; all grades, Grade ≥3) were fatigue (42.3%, 1.3%), diarrhea and pruritus (both 26.9%, 0%), and nausea (21.8%, 0%). INV grade ≥3 immune-related AEs occurred in 10.3% of pts. One pt died due to an unknown cause that was assessed as treatment-related. Conclusions: Cemiplimab 3 mg/kg Q2W showed substantial antitumor activity, durable responses, and acceptable safety profile in pts with laCSCC. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.

9526 Background: Primary analysis (Oct 2017) of cemiplimab (REGN2810) in pts with mCSCC in a Phase 2 study demonstrated substantial antitumor activity, durable responses, and acceptable safety profile. We now report 12-month follow-up data from these pts (NCT02760498; data cutoff date: Sep 20, 2018). Methods: Pts with mCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 59 pts (median age: 71 years) were enrolled. Median duration of follow-up was 16.5 months (range: 1.1–26.6). ORR by central review was 49.2% (95% CI: 35.9–62.5; 10 CRs and 19 PRs [4 CRs and 25 PRs by investigator-assessment (INV)]). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 21.6 months and was still ongoing. Observed DOR exceeded 12 months in 22/29 pts (75.9%) with response. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.7% (95% CI: 49.1–75.0). Median observed time to response was 1.9 months (range: 1.7–9.1). Median progression-free survival was 18.4 months (95% CI: 7.3–not evaluable); median overall survival has not been reached. The most common treatment-emergent adverse events (all grades, Grade ≥3) were diarrhea (28.8%, 1.7%), fatigue (25.4%, 1.7%), and nausea (23.7%, 0%). By INV, grade ≥3 immune-related adverse events occurred in 13.6% of pts. Conclusions: This analysis demonstrates substantial antitumor activity and increasing DOR with cemiplimab 3 mg/kg Q2W in pts with mCSCC. There were no new safety signals. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.

6000 Background: KEYNOTE-048 is a phase 3 study of P or P + chemo (C) vs EXTREME (E) as 1L therapy for R/M HNSCC (NCT02358031). At the second interim analysis (IA2), P significantly improved OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 populations and had noninferior OS in the total population with favorable safety; P+C significantly improved OS in the total population with comparable safety. We present the protocol-specified final results. Methods: 882 pts with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W for 24 mo (n = 301), P for 24 mo + 6 cycles of C (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/d for 4 d Q3W) (n = 281), or E (cetuximab 400 mg/m2 loading/250 mg/m2 QW + 6 cycles of chemo) (n = 300). OS superiority was tested sequentially for P+C vs E in the CPS ≥20 population, then the CPS ≥1 population, and for P vs E in the total population (superiority thresholds: one-sided P = .0023, .0026, and .0059, respectively). Data cutoff was 25 Feb 2019 (~25 mo after last pt randomized). Results: P+C significantly improved OS vs E in the CPS ≥20 (HR 0.60, 95% CI 0.45-0.82, P = .0004; median 14.7 vs 11.0 mo) and CPS ≥1 (HR 0.65, 95% CI 0.53-0.80, P < .0001; median 13.6 vs 10.4 mo) populations. HR (95% CI) for PFS was 0.76 (0.58-1.01) for CPS ≥20 and 0.84 (0.69-1.02) for CPS ≥1. ORR (P+C vs E) was 42.9% vs 38.2% for CPS ≥20 and 36.4% vs 35.7% for CPS ≥1; median DOR was 7.1 vs 4.2 mo and 6.7 vs 4.3 mo, respectively. P did not significantly improve OS vs E in the total population (HR 0.83, 95% CI 0.70-0.99, P = .0199; median 11.5 vs 10.7 mo). HR (95% CI) for PFS was 1.29 (1.09-1.53). ORR (P vs E) was 16.9% vs 36.0%; median DOR was 22.6 vs 4.5 mo. All-cause gr 3-5 AE rates were 54.7% for P, 85.1% for P+C, and 83.3% for E. Conclusion: Overall, KEYNOTE-048 showed that compared with E, P+C had superior OS in the PD-L1 CPS ≥20, CPS ≥1, and total populations with comparable safety and P had superior OS in the CPS ≥20 and ≥1 populations, noninferior OS in the total population, and favorable safety. These results support pembrolizumab and pembrolizumab + platinum + 5-FU as new 1L standards of care for R/M HNSCC. Clinical trial information: NCT02358031.

A multidisciplinary team from the Peter MacCallum Cancer Centre in Melbourne, Australia, developed a performance data suite to support a service improvement project based on lean manufacturing principles in its 19-chair chemotherapy day unit (CDU) and cytosuite chemotherapy production facility. The aims of the project were to reduce patient wait time and improve equity of access to the CDU.A project team consisting of a pharmacist and CDU nurse supported the management team for 10 months in engaging staff and customers to identify waste in processes, analyze root causes, eliminate non-value-adding steps, reduce variation, and level workloads to improve quality and flow. Process mapping, staff and patient tracking and opinion surveys, medical record audits, and interrogation of electronic treatment records were undertaken.This project delivered a 38% reduction in median wait time on the day (from 32 to 20 minutes; P.01), 7-day reduction in time to commencement of treatment for patients receiving combined chemoradiotherapy regimens (from 25 to 18 days; P.01), and 22% reduction in wastage associated with expired drug and pharmacy rework (from 29% to 7%; P.01). Improvements in efficiency enabled the cytosuite to increase the percentage of product manufactured within 10 minutes of appointment times by 29% (from 47% to 76%; P.01).A lean improvement methodology provided a robust framework for improved understanding and management of complex system constraints within a CDU, resulting in improved access to treatment and reduced waiting times on the day.

The study reported by Wuthrick et al in the article that accompanies this editorial provides additional evidence that patients with advanced head and neck cancer (HNC) should be treated in highvolume HNC centers for optimal survival outcomes. This study was a retrospective subgroup analysis of the impact of treatment center expertise on the overall survival (OS) of patients with oropharyngeal cancer and known human papillomavirus and smoking status who were treated as part of the Radiation Therapy Oncology Group (RTOG) 0129 randomized trial. In this study, high patient accrual to previous RTOG trials was used as a surrogate for HNC expertise. There were a total of 471 patients: the majority (321 patients) were treated at one of 88 historically lowaccrual centers (HLACs), whereas 150 patients were treated at one of 13 historically high-accrual centers (HHACs). Looking back over a 15-year history of RTOG HNC trials, the authors defined HHACs as the top tertile of accrual centers, with an average of more than 42 patients accrued per center. Patients treated at HLACs had inferior outcomes, with 5-year locoregional failure rates of 36% compared with 21% for patients treated at HHACs, and 5-year OS rates of 51% compared with 69% for patients treated at HHACs. There was a 91% increased risk of death for patients treated at HLACs after adjusting for age, T and N classification, performance status, smoking, and human papillomavirus status. Sensitivity analysis showed the results to be consistent when the cutoff for high accrual was decreased from 42 patients (top 5% of centers) to 25 patients (top 10% of centers) or when accrual was treated as a continuous variable. The authors showed that unacceptable radiotherapy (RT) protocol noncompliance was higher in HLACs compared with HHACs (11% v 5%; P .04), but in multivariable analysis, the impact of this on OS was only approximately 20% of the total impact of accrual volume on OS. This discrepancy likely reflects the requirement for expertise across the gamut of diagnostic, therapeutic, and support services to ensure optimal patient outcomes. However, it is also likely that RT quality could have contributed more to the observed difference, given that the quality assurance (RT QA) analysis was limited to total dose, overall treatment time, and field borders. There was no review of the diagnostic imaging and accuracy of gross tumor volume delineation, and no assessment of radiation dosimetry to the gross tumor volume or planning target volumes. There were no significant differences between HLACs and HHACs with respect to acute or late grade 3 to 5 treatment toxicities, but specific data on treatment-related deaths would have been of interest. The overall message from this study is remarkably similar to that from the Trans Tasman Radiation Oncology Group (TROG) 02.02 substudy published in 2010 that investigated the impact of radiation protocol compliance and quality in a randomized trial evaluating the addition of the hypoxic cytotoxin tirapazamine to chemoradiotherapy. It was the first HNC trial to include comprehensive RT QA and was able to quantify the impact of major RT protocol violations on patient outcomes. RT was found to be protocol noncompliant in 208 of 820 patients (25%). A secondary review was conducted of 206 of the 208 noncompliant plans, with 97 of 206 (47%) predicted to have an adverse impact on outcome. Indeed, these patients, compared with patients with protocolcompliant plans, had double the 2-year locoregional failure rate (46% v 22%) and an absolute reduction in 2-year OS of 20% (50% v 70%). Importantly, the probability of receiving poor-quality RT was most highly correlated with the number of patients who were enrolled at centers. The centers with the lowest accrual numbers ( 5 patients) had a disproportionate number of RT protocol violations compared with centers with large accrual numbers ( 20 patients): 30% versus 5% (P .001). As Wuthrick et al have highlighted in their article, the effect of center experience and expertise may be much greater with intensity-modulated RT (IMRT), which was not used in the RTOG 0129 and TROG 02.02 studies but is now the standard of care. Although the conformality of IMRT provides many advantages, specifically, the reduced dose to normal tissues (salivary, mandible, and pharyngeal muscles), it can also increase the risk of a geographic miss. This may occur if there is inaccurate patient assessment and/or tumor voluming which is more likely to result in a geographic miss than with previous large-volume, treat-everything RT fields. Hence, the potential for even greater disparity in HNC outcomes in low-volume centers could be much higher in the current IMRT era. The other factor to note is that at least the RTOG HLACs were enrolling some patients in clinical trials. There is another layer of HNC work that is being performed around the world in community centers that rarely or never enroll their patients onto clinical trials and rarely publish their treatment outcomes. So these patients could quite possibly have worse outcomes than the patients in this study who were seen at HLACs. This lack of data from such HNC centers contributes to the difficulties in JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L

Purpose Universal screening for chronic hepatitis B virus (HBV) infection before chemotherapy has been recommended. We evaluated the cost-effectiveness of HBV screening before chemotherapy given for nonhematopoietic solid tumors (STs). Methods A decision-analytic model was used to compare the cost-effectiveness of universal screening conducted per professional guidelines versus no screening in hypothetical patient cohorts beginning adjuvant chemotherapy for early breast cancer or palliative chemotherapy for advanced non–small-cell lung cancer. Survival times were extrapolated using Markov models. Probabilities were derived from published studies and costs estimated from the perspective of the Australian health care system. One-way and probabilistic sensitivity analyses were performed, including with the application of an alternative HBV screening strategy. Results Using an incremental cost-effectiveness ratio threshold of $50,000 (Australian dollars) per life-year (LY) saved, universal HBV screening was not cost-effective for adjuvant patients ($88,224/LY, 13% probability of being cost-effective), palliative patients ($1,344,251/LY, 0%), or pooled (all) patients ($149,857/LY, 1%). Sensitivity analyses found that screening approached cost-effectiveness among adjuvant patients with the highest reported rates of undiagnosed chronic HBV (65%, $59,445/LY) or HBV reactivation with chemotherapy (41%, $56,537/LY). Cost- effectiveness was also significantly influenced by HBV population prevalence. An alternative screening strategy using hepatitis B surface antigen testing only produced the most economically favorable results, with $30,126/LY (80% probability) for adjuvant patients and $51,201/LY (43%) for the pooled cohort. Conclusion Universal HBV screening conducted per current guidelines is not cost-effective in patients with STs. Screening may be economically favorable in selected patient subpopulations and/or with simplification of the screening strategy.

Universal screening for chronic hepatitis B virus (HBV) before chemotherapy has been recommended by the Centers for Disease Control. We sought to determine the prac- tice of Australian oncologists with regard to HBV screening in patients with solid tumors (STs) and their clinical experience of HBV reactivation (HBVR). Methods: A survey was sent to all consultant members of the Medical Oncology Group of Australia. One hundred eighty-eight responses (63% response rate) were received. We also reviewed the incidence of HBV in patients with STs screened at the Peter MacCallum Cancer Centre (Melbourne, Australia). Results: Fifty-three percent of medical oncologists screen for HBV, but only 19% screen all patients. The most common rea- sons given for performing screening were anecdotal experience of HBVR (46%) and perceived sufficient evidence for screening of some patient subgroups (42%). Sixty-five percent of those who screened did so only in subgroups, usually selecting patients on the basis of ethnicity (82%). Oncologists who did not screen most commonly cited inadequate evidence for a benefit of screening (72%). Twenty-two percent of oncologists had wit- nessed one or more HBVR events, representing one event per 45 years of respondents' practice. HBVR events reported (n 54) consisted of asymptomatic liver test abnormalities only (44%), symptomatic hepatitis (28%), decompensated liver failure (19%), and death (7%). In 206 patients with STs screened for HBV, 1.0% (n 2) were HBV surface antigen positive, and 14.9% hepatitis B core antibody positive. Conclusion: The majority of Australian medical oncologists have not adopted universal HBV screening before chemothera- py. Further evidence of the benefit and cost effectiveness of universal screening in patients with STs will be required to alter practice.

Purpose Promising results in a randomized phase II trial with the hypoxic cytotoxin tirapazamine (TPZ) combined with cisplatin (CIS) and radiation led to this phase III trial. Patients and Methods Patients with previously untreated stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either CIS (100 mg/m2) on day 1 of weeks 1, 4, and 7 or CIS (75 mg/m2) plus TPZ (290 mg/m2/d) on day 1 of weeks 1, 4, and 7 and TPZ alone (160 mg/m2/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS). The primary end point was overall survival (OS). The planned sample size was 850, estimated to result in 334 deaths, which would provide 90% power to detect a difference in 2-year survival rates of 60% v 70% for CIS versus TPZ/CIS, respectively (hazard ratio = 0.69). Results Eight hundred sixty-one patients were accrued from 89 sites in 16 countries. In an intent-to-treat analysis, the 2-year OS rates were 65.7% for CIS and 66.2% for TPZ/CIS (TPZ/CIS – CIS: 95% CI, −5.9% to 6.9%). There were no significant differences in failure-free survival, time to locoregional failure, or quality of life as measured by Functional Assessment of Cancer Therapy–Head and Neck. Conclusions We found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves OS.

TPS6094Background: Preclinical data in murine cancer models show improved tumor growth control and survival when radiation therapy (RT) is combined with a PD-1 inhibitor. Pembrolizumab is effective...

TPS5600Background: Patients with recurrent and metastatic cervical carcinoma experience modest survival benefit with first-line platinum-based chemotherapy with or without bevacizumab. Those with p...

TPS6090Background: Although the EXTREME regimen is a Category 1 evidence-supported combination recommended by NCCN guidelines as first-line (1L) treatment for patients with R/M SCCHN, it is associa...

Purpose To determine the association between tumor hypoxia, treatment regimen, and locoregional failure (LRF) in patients with stage III or IV squamous cell carcinoma of the head and neck randomly assigned to radiotherapy (70 Gy in 35 fractions over 7 weeks) plus either tirapazamine and cisplatin in weeks 1, 4, and 7 and tirapazamine alone in weeks 2 and 3 (TPZ/CIS) or cisplatin and infusional fluorouracil during weeks 6 and 7 (chemoboost). Patients and Methods Forty-five patients were enrolled onto a hypoxic imaging substudy of a larger randomized trial. Pretreatment and midtreatment [18F]-fluoromisonidazole positron emission tomography scans (FMISO-PET) were performed 2 hours after tracer administration, with qualitative scoring of uptake in both primary tumors and nodes. Results Thirty-two patients (71%) had detectable hypoxia in either or both primary and nodal disease. In patients who received chemoboost, one of 10 patients without hypoxia had LRF compared with eight of 13 patients with hypoxia; the risk of LRF was significantly higher in hypoxic patients (exact log-rank, P = .038; hazard ratio [HR] = 7.1). By contrast, in patients who received the TPZ/CIS regimen, only one of 19 patients with hypoxic tumors had LRF; risk of LRF was significantly higher in chemoboost patients (P = .001; HR = 15). Similarly, looking at the primary site alone, in patients with hypoxic primaries, zero of eight patients treated with TPZ/CIS experienced failure locally compared with six of nine patients treated with chemoboost (P = .011; HR = 0). Conclusion Hypoxia on FMISO-PET imaging, in patients receiving a nontirapazamine-containing chemoradiotherapy regimen, is associated with a high risk of LRF. Our data provide the first clinical evidence to support the experimental observation that tirapazamine acts by specifically targeting hypoxic tumor cells.

In the article that accompanies this editorial, Janssens et al report the outcome results of a phase III trial of accelerated radiotherapy with carbogen and nicotinamide (ARCON) versus accelerated radiotherapy alone in the treatment of 345 patients with stages T2 to T4, any nodal stage, M0 laryngeal cancer. Despite the sound biologic rationale for accelerated radiotherapy plus carbogen and nicotinamide (ARCON) and the promising results from a large preceding nonrandomized study, no evidence of a therapeutic gain was seen in the definitive phase III trial. Specifically, no significant differences were observed in laryngeal preservation rates, disease-free survival, overall survival, treatment-related toxicity, or functional outcomes. The authors did note an improved regional nodal complete response rate in the ARCON arm as assessed clinically, but this did not translate into any improvement in disease-free survival after “salvage” neck dissection. Unfortunately, both the article and the protocol are unclear as to whether a neck dissection was stipulated for patients who failed to achieve a regional complete response by a certain time after treatment. If this was the case, the required neck dissection would normally be considered part of the definitive treatment package, and patients undergoing surgery would not be scored as having sustained a regional failure. In a translational research substudy involving 79 patients, the investigators estimated the hypoxic fraction of tumor cells in biopsies of the primary tumor by using pimonidazole staining. They reported that regional (but not local) control was significantly improved by treatment with ARCON in patients with more hypoxic primary tumors (defined as 2.6% pimonidazole staining) but not in patients with better oxygenated tumors. However, this conclusion is based on small numbers of neck failures and appears to take no account of the original neck node classification of these patients. It can therefore be considered no more than a hypothesisgenerating observation. Although these findings are consistent with the notion that any benefit from a hypoxia-targeting therapy will be restricted to the population with demonstrable hypoxia, an important caveat is that they did not actually assess hypoxia in the nodes. The hypoxia status of the primary and nodes has been reported to be discordant in studies that used hypoxic positron emission tomography (PET) imaging. ARCON is the latest in the growing list of interventions targeting hypoxia that have failed to realize their predicted potential in the treatment of unselected populations of patients with head and neck cancers. Strategies thathavepreviouslybeensubjectedtorandomizedclinical trials includehyperbaricoxygen, hypoxiccell radiosensitizers(misonidazole, etanidazole, and nimorazole), fast neutron therapy, concurrent chemotherapy with mitomycin C, and the hypoxic cell cytotoxin tirapazamine. Although a recent meta-analysis of trials of hypoxic modification did show a small but significant survival benefit, only nimorazole has entered clinical practice, and then only in Denmark, in combination with radiation without chemotherapy. It is an axiom of rational targeted therapy that the intervention can be successful only if the target is present and cure limiting. In the case of therapies targeting hypoxia, this requires not only that tumors harbor hypoxic clonogenic cells before treatment, but also that effective reoxygenation does not occur during treatment. Another important consideration as to whether hypoxia is cure limiting, at least for oropharyngeal tumors, is a tumor’s human papillomavirus (HPV) status. Recent data suggest that HPV-associated oropharyngeal cancers have a similarly high incidence of hypoxia compared with HPVnegative head and neck cancers but nonetheless retain their favorable prognosis. Furthermore, there are data from exploratory analyses of three randomized trials of hypoxia-targeting therapies that suggest that any benefit from these therapies may be restricted to patients with HPV-negative tumors. Several strategies have been used to detect tumor hypoxia before treatment, albeit with inconsistent correlations with outcome. These include oxygen electrode measurements, histochemical markers, plasma markers, functional imaging, and gene expression profiling. Use of such tests may enlarge the patient population potentially able to benefit from hypoxiatargeted therapy. Retrospective analyses of the Danish Head and Neck Cancer Study (DAHANCA) 5 trial have suggested that some of these tests may be predictive of benefit from nimorazole, and we have previously reported that patients with PETimageable hypoxia may benefit from tirapazamine. Nevertheless, such approaches have not been incorporated into phase III trials, at least in part because of the lack of a validated, reproducible test of tumor hypoxia that has been demonstrated to be suitable for use in multi-institutional clinical trials. The efficiency of reoxygenation during treatment is more difficult to measure and interpret. There are limited data from three small [18F]-misonidazole PET imaging studies about the persistence of hypoxia during treatment and correlation with outcome. It is noteworthy that in the Trans Tasman Radiation Oncology Group JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 15 MAY 2

PURPOSE: To determine the efficacy and safety of epirubicin, cisplatin, and infusional fluorouracil (5-FU) chemotherapy followed by radiation with concurrent cisplatin in patients with locally and/or regionally advanced nasopharyngeal cancer. PATIENTS AND METHODS: Thirty-five patients were treated with three cycles of induction chemotherapy with epirubicin 50 mg/m2 and cisplatin 75 mg/m2 combined with continuous-infusion 5-FU 200 mg/m2 daily for 9 weeks, followed by concurrent chemoradiation of 60 Gy in 2-Gy fractions with cisplatin 20 mg/m2 daily for 5 days in weeks 1 and 6. RESULTS: Median age was 43 years, 74% had World Health Organization type III histology, and 91% had stage IV disease (International Union Against Cancer, ed 4). All patients received three cycles of induction chemotherapy, and 97% completed chemoradiation. The estimated 4-year progression-free survival rate was 81% (95% CI, 59% to 93%), and the estimated 4-year overall survival rate was 90% (95% CI, 74% to 97%). Only two patients have had a locoregional relapse by the close-out date despite the use of only 60 Gy. Induction chemotherapy was well tolerated, with 11% grade 3 or 4 stomatitis, 26% grade 3 vomiting, and no episodes of febrile neutropenia. Acute toxicities of chemoradiation were as follows: 23% grade 3 or 4 vomiting, 6% febrile neutropenia, 31% grade 3 mucositis, and 23% grade 3 skin toxicity. The most prevalent grade 3 late effects were xerostomia and hearing loss. CONCLUSION: This regimen was well tolerated, can be delivered as planned, and has resulted in excellent locoregional disease control and survival in patients with locally advanced nasopharyngeal cancer.

TPS6090 Background: Approximately half of patients (pts) with HNSCC are diagnosed with locally advanced disease and treated with surgery or concomitant chemoradiotherapy (CRT) with cisplatin. Unfortunately, disease recurs in 40% to 60% of patients. The PD-l inhibitor pembro is approved for recurrent/metastatic HNSCC. CRT has immunomodulatory effects; preclinical data suggest that efficacy can be improved by adding pembro. The phase 3 KEYNOTE-412 trial (NCT03040999) will explore if CRT + pembro can improve outcomes of pts with LA-HNSCC. Methods: Adult pts with newly diagnosed, pathologically proven, treatment-naive LA-HNSCC will be enrolled. Study population will include p16-negative HNSCC (any T3-T4 or any N2a-N3 [AJCC 7th edition]) and p16-positive oropharyngeal cancer (any T4 or any N3). Other eligibility criteria: measurable disease per RECIST v1.1 by blinded independent central review (BICR), provision of tumor sample for biomarker analyses, ECOG PS 0 or 1, and eligible for definitive CRT but not considered for primary surgery. Pts will be randomly assigned 1:1 to receive either pembro 200 mg every 3 weeks (Q3W) plus CRT, which includes radiotherapy (RT; accelerated [70 Gy, six 2 Gy fractions/wk] or standard [70 Gy, five 2 Gy fractions/week] fractionation) plus cisplatin 100 mg/m2 Q3W for 3 cycles only, or placebo Q3W plus CRT. Pts will be stratified by RT regimen, tumor site/p16 status, and disease stage. Treatment will continue until centrally confirmed disease progression, unacceptable AEs, decision to withdraw by pt or investigator, or completion of 17 doses of pembro/placebo. Disease status will be evaluated by CT or MRI 12 weeks after end of CRT, every 4 months during the next 2 years, and then every 6 months during years 3-5. Pts will be evaluated for neck dissection at 12 weeks after CRT. AEs will be monitored and graded using CTCAE v4.0 throughout the trial and for 30 days (90 days for serious AEs) after end of treatment. Primary efficacy end point is event-free survival per RECIST v1.1 by BICR. Key secondary end points: overall survival, quality of life, and safety and tolerability of pembro. Approximately 780 pts will be enrolled. Clinical trial information: NCT03040999.

6008 Background: We report on the first multi-centre randomized phase III trial of post-operative radiotherapy (PORT) vs post-operative chemo-RT (CRT) in high-risk cutaneous squamous cell carcinoma of the head and neck (cSCCHN) (NCT00193895). Methods: The primary objective was to determine whether there was a freedom from loco-regional relapse (FLRR) difference between patients randomly assigned to 60-66Gy (6-6.5 weeks) with or without weekly carboplatin (AUC 2) following resection of gross disease. Patients were stratified to high-risk nodal (either extracapsular nodal extension, intra-parotid nodal disease of any size or number, cervical nodal disease with ≥2 nodes or largest node > 3cm) or high-risk primary (T3-T4 or in-transit metastases). Patients with both features were stratified to the high-risk nodal group. Secondary objectives included disease-free survival (DFS), overall survival (OS) and acute & late toxicity (CTCAE V3). Results: 321 patients were randomly assigned between 2005-2014, with 11 not commencing treatment protocol due to disease progression or withdrawal of consent. Of the 310 patients commencing treatment protocol (157 RT and 153 CRT), 230 (74%) had high-risk nodal, 70 (22%) high-risk primary and 10 (3%) both. Median follow up was 60 months, median RT dose was 60Gy and 85% randomised to CRT completed 6 cycles of carboplatin. The 2- & 5-year FLRR (95% CI) for the RT arm was 88% (83-93%)/83% (77-90%) and for CRT 89% (84-94%)/87% (81-93%) (HR 0.85; 95%CI [0.46-1.55]; p = 0.59). The 2- & 5 year DFS (95% CI) for the RT arm was 78% (72-85%)/67% (60-76%) and for CRT 83% (77-89%)/73% (66-81%) (HR 0.85; 95%CI [0.55-1.29]; p = 0.43). The 2- & 5 year OS (95% CI) for the RT arm was 88% (83-93%)/76% (69-84%) and for CRT 88% (83-94%)/79% (72-86%) (HR 0.95; 95%CI [0.58-1.57]; p = 0.84). 134 (43%) experienced Grade 3/4 skin toxicity; 49% RT, 37% CRT (p = 0.039). 12 (3.9%) experienced Grade 3/4 subcutaneous fibrosis; 2.5% RT, 5.2% CRT. Conclusions: While surgery and PORT provided excellent FLRR with acceptable toxicity, the addition of weekly carboplatin did not improve outcomes in high-risk cSCCHN. Clinical trial information: NCT00193895.

TPS3113 Background: Inducible T cell Co-Stimulator (ICOS), a member of the CD28/B7/CTLA-4 receptor superfamily expressed on T cells after engagement with cognate antigen and activation, provides a co-stimulatory signal augmenting T cell proliferation, survival and cytokine production. GSK3359609 is a humanized IgG4 antibody selected for its potent agonist activity against human ICOS. The unique mechanistic profile of an ICOS agonist antibody, such as GSK3359609, offers an opportunity to investigate the antitumor potential of targeting a T cell co-stimulator alone and in combination with other cancer immunotherapies such as pembrolizumab. Methods: INDUCE-1 is a first- in-human study evaluating safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of GSK3359609 administered as an intravenous (IV) infusion once every 3 weeks (Q3W) alone (Part 1) and in combination with 200 mg pembrolizumab (Q3W IV infusion) or other immunotherapy (Part 2) in approximately 304 adult patients. In dose escalation, eligible patients are required to have selected relapsed/refractory solid tumors. Primary objective is to determine safety, tolerability, and maximum tolerated or administered dose. Modified toxicity probability interval method will inform dose escalation decisions (minimum 3 patients per dose level [DL]). In expansion, cohorts may be defined by factors such as tumor histology, biomarker features, or prior treatment. More than one GSK3359609 DL may be evaluated in an expansion cohort by random assignment. Blood immunophenotyping is monitored in all patients; tumor biopsies (before and on-treatment) are optional in escalation and required in expansion to provide biomarker data that may inform on optimal dose selection as well as mechanistic understanding of GSK3359609. Efficacy measures are every 9 weeks and are according to immune-related RECIST. As of 7 Feb 2017, the first 3 monotherapy DL cohorts completed without dose limiting toxicities; DL 4 enrollment is ongoing. Study is funded by GlaxoSmithKline and is in collaboration with Merck & Co., Inc. Clinical trial information: NCT02723955.

PURPOSE: To determine the maximum-tolerated dose of tirapazamine when combined with cisplatin and radiation in patients with T3/4 and/or N2/3 squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: The starting schedule was conventionally fractionated radiotherapy (70 Gy in 7 weeks) with concomitant cisplatin 75 mg/m2 and tirapazamine 290 mg/m2 (before cisplatin) in weeks 1, 4, and 7 and tirapazamine alone 160 mg/m2 three times a week in weeks 2, 3, 5, and 6. Positron emission tomography scans for tumor hypoxia (18F misonidazole) were performed before and during radiotherapy. RESULTS: We treated 16 patients with predominantly oropharyngeal primary tumors, including 10 patients with T4 or N3 disease. Febrile neutropenia occurred toward the end of radiotherapy in three out of six patients treated on the initial dose level. Two of these patients also developed grade 4 acute radiation reactions. Another 10 patients were treated with the same doses, but the week 5 and week 6 tirapazamine doses were omitted. This resulted in less neutropenia and only one dose-limiting toxicity (DLT) (febrile neutropenia), and eight out of 10 patients completed treatment without any dose omissions. In these 10 patients, the acute radiation toxicities were not obviously enhanced compared with chemoradiotherapy regimens using concurrent platinum and fluorouracil. 18F misonidazole scans detected hypoxia in 14 of 15 patients at baseline, with only one patient having detectable hypoxia at the end of treatment. With a median follow-up of 2.7 years, the 3-year failure-free survival rate was 69% (SE, 12%), the 3-year local progression-free rate was 88% (SE, 8%), and the 3-year overall survival rate was 69% (SE, 12%). CONCLUSION: DLT was due unexpectedly to febrile neutropenia, which could be overcome by omitting tirapazamine in weeks 5 and 6. The combination of tirapazamine, cisplatin, and radiotherapy resulted in remarkably good and durable clinical responses in patients with very advanced head and neck cancers. It warrants further investigation.

PURPOSE To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Fifty-one patients with advanced measurable or assessable NSCLC and performance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mg/m2 over 3 hours with premedication. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57%), extrathoracic metastatic disease (65%), and measurable disease (75%). Twenty-two percent had previously untreated stage III disease. RESULTS The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organization (WHO) grade IV neutropenia in only 16% of patients. Grade III/IV myalgia/athralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred. CONCLUSION The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase II trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.

e23158Background: Tumor hypoxia is associated with resistance to chemotherapy and radiotherapy. Recurrent/metastatic squamous cell carcinomas of the head and neck & skin (SCCHN/SCCS) and non-small ...

TPS6105Background: R/M SCCHN/SCCS have a poor prognosis. Molecularly targeted EGFR therapies provide some clinical benefit but are limited by systemic on-target side effects such as rash and diarrh...

e17017 Background: There is considerable interest in de-intensification strategies for good prognosis HPVOPC. Weekly cisplatin concurrent with radiotherapy is believed to be associated with less to...

5524^ Background: BNC105P is a tubulin polymerization inhibitor and a vascular disrupting agent (VDA) selectively active against tumor endothelium. Pre-clinical data has demonstrated greater than a...

TPS5632 Background: Cervical cancer is a global health problem and the most common cause of cancer-related death among women in developing nations. Despite the recently developed cervical cancer va...

TPS5612 Background: BNC105P is a tubulin polymerization inhibitor and a vascular disrupting agent (VDA). In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia, and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells, including ovarian cancer cell lines. Pre-clinical data has demonstrated synergistic activity of BNC105P when combined with platinum or with gemcitabine, supporting the proposed study design. This study will determine the safety and efficacy of BNC105P in ovarian cancer when used in combination with gemcitabine-carboplatin. The target population is women with ovarian or primary peritoneal cancers who progressed 4 to 9 months after first-line platinum based chemotherapy, or 4 to 12 months after second line platinum based chemotherapy. Methods: A single arm phase I will be used to determine the phase II dose for the triplet combination (3-6 subjects per dose level, maximum of 24 subjects). Four dose levels of BNC105P (12-16 mg/m2) and gemcitabine (800-1000 mg/m2) will be assessed. The dose of carboplatin will be set at AUC 4. Enrolment to cohort 2 started in January 2013. The phase II component will consist of a 2-arm, randomized (1:1) study of BNC105P, gemcitabine and carboplatin versus gemcitabine and carboplatin alone. The primary endpoint for the phase II trial is objective response rate (ORR, according to RECIST 1.1 and/or GCIG CA125 criteria. An ORR of 40% or more with the experimental regimen would be considered worthy of further investigation, assuming an ORR of 20% with the control regimen. 110 phase II participants are planned (N = 55/arm). Treatment allocation will be balanced using minimization for the study site, target lesions according to RECIST (present vs. absent), progression free interval from last platinum based chemotherapy regimen (

5571 Background: We report the impact of p16 status on quality of life (QOL) for patients with stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oropharynx (OPC) treated with concurrent chemoradiotherapy in a large international phase III trial (TROG 02.02/HeadSTART). Methods: The 861 patients accrued received definitive radiotherapy (RT) (70 Gy/7 weeks) concurrently with 3 cycles of either cisplatin (100mg/m2) or cisplatin (75 mg/m2) plus tirapazamine (290 mg/m2/day) by random assignment, as previously described. QOL was measured with the FACT-H&N at baseline, 2,6,12, 23 and 38 months. No significant difference in overall or subscale QOL score change from baseline was observed between arms at any subsequent time point; results for the oropharynx subgroup by p16 status are reported for both treatment arms combined. Results: Of 853 eligible participants, 465 had OPC, for whom p16 status could be determined in 206. Of 179 who received adequate RT (≥ 60 Gy, no major deviations) and completed baseline QOL, 104 were p16+ and 79 were p16-. p16+ patients had better baseline ECOG PS, lower T-category, higher N-category, were younger and were less likely to be current smokers. Baseline mean FACT-H&N score was statistically and clinically significantly better in p16+ patients (111 vs. 102, p=0.001). The drop in QOL from baseline to 2 months was more severe in p16+ cases (-20.4 vs -9.1, p=0.001), resulting in an equalization of 2 month scores (p16+: 90.6, p16-: 93.6, p=0.16). At 6 and 12 months post-treatment, no difference in score changes from baseline by p16 status was seen (6 mo, p16+: -6.2, p16 -:-1.2, p=0.22; 12 mo, p16 +: -0.3, p16 -: +2.0, p=0.82). Conclusions: p16 associated oropharyngeal cancer has been shown to be a distinct entity with different demographic features. In our study, such patients exhibited better baseline QOL and a more severe drop immediately after treatment, but did not differ in long-term QOL response to the effects of aggressive concurrent chemoradiation. Given the favorable prognosis of p16-associated oropharyngeal cancer, efforts to reduce the QOL burden of treatment are warranted.

5506 Background: High plasma osteopontin (OPN) levels have been reported to be an adverse prognostic factor in HNSCC, to correlate with tumor hypoxia and to be predictive of benefit from hypoxia ta...

5527 Background: Human papilloma virus associated oropharyngeal SCC (HPV +ve OPSCC) is a clinically and molecularly distinct disease from HPV-negative HNSCC, with a better prognosis. We sought to determine the relationship between hypoxia, a known adverse prognostic factor in patients with locally advanced HNSCC, and HPV status. Methods: Eligible patients had: stage III and IV HNSCC treated on phase I and II chemoradiation trials with 70 Gy combined with tirapazamine and cisplatin (TPZ/CIS) or cisplatin and 5FU (CIS/5FU); pretreatment hypoxic imaging using FMISO-PET; and known HPV status as determined by p16 immunohistochemistry. Separate analyses were also conducted to consider the impact of TPZ on HPVnegative tumors in the randomized TROG 98.02 trial. Hypoxia was assessed by qualitative scoring of FMISO uptake in both primary tumors and nodes as previously described (J Clin Oncol 24:2098-2104, 2006). Results: 63 patients were included in the analysis. Both p16 +ve OPSCC tumors and p16 -ve HNSCC tumors h...

9069 Background: HL refers to the capacity to seek, understand, and utilize health information to make informed health decisions. Pts with low HL experience worse outcomes. Understanding HL issues ...

5509 Background: HGF is a hypoxia induced protein that binds to its receptor MET to regulate expression of a variety of molecules including the cytokine IL-8. Both HGF and IL-8 are associated with ...