bluuebunny/crossref_metadata_2025 huggingface dataset:
The successful phase 3 niraparib ENGOT-OV16/NOVA trial included a substantial number of patients with platinum resistant ovarian cancer (OC).
Authors: Del Campo Jose Maria , Mirza Mansoor Raza , Berek Jonathan S. , Provencher Diane M. , Emons Guenter , Fabbro Michel , Lord Rosemary , Colombo Nicoletta , Petru Edgar , Wenham Robert Michael , Herrstedt Jorn , Gilbert Lucy , Heubner Martin Leonhard , Gonzalez Martin Antonio , Follana Philippe , Benigno Benedict B. , Dørum Anne , Rimel Bj , Hazard Sebastien , Matulonis Ursula A. ,   For the ENGOT-OV16/NOVA Investigators
Published: September 2018

5560

Background: Niraparib is a highly selective poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor (PARPi); in preclinical studies, it concentrates in the tumor relative to plasma to deliver durable, near complete PARP inhibition and persistent antitumor effects.Niraparib demonstrated significantly longer progression free survival (PFS) vs placebo in patients (pts) with recurrent OC who were randomized following a complete response (CR) or partial response (PR) to platinum based chemotherapy in the controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. To more fully characterize the NOVA trial population, we assessed platinum resistance status, defined as a duration of response to platinum < 6 months to the most recent (ultimate) platinum regimen. Analysis was limited to pts in the placebo arm, as inclusion of pts receiving active treatment (niraparib) would have confounded the ability to determine duration of response to platinum alone. Methods: Pts with recurrent OC, no prior PARPi use, ≥2 prior courses of platinum based chemotherapy, and CR or PR to the most recent platinum based chemotherapy were eligible. Pts were assigned to one of two cohorts based on g BRCA testing (g BRCAmut or non-g BRCAmut) and randomized 2:1 within each cohort to niraparib 300 mg or placebo qd until progressive disease (PD). Randomization occurred up to 8 weeks following the last dose of the most recent platinum based chemotherapy. PFS was measured from time of randomization to death or earliest PD as assessed by independent review committee. Estimated probability of pts having disease progression in each cohort and pooled across cohorts 6 months after the last dose of their most recent platinum therapy was calculated using the Kaplan-Meier methodology. Results: 181 pts were randomized to placebo (65 g BRCAmut and 116 non-g BRCAmut). Platinum resistance rate estimates for the g BRCAmut, non-g BRCAmut, and pooled cohorts were 42%, 53%, and 49%, respectively. Conclusions: Approximately half of the pts in the NOVA study, where niraparib treatment met its primary endpoint of prolonging PFS following a response to platinum, had developed platinum resistance to their last line of chemotherapy. Clinical trial information: NCT01847274.
Prognostic implications of lymph node metastasis in advanced ovarian cancer: Analysis of National Cancer Database.
Authors: Saha Sukamal , Ramanathan Sabarina , Mukkamala Suresh , Salib Hayman S. , Oza Rajen , Lee Jeen , Bajaj Vinay , Arora Madan L. , Wiese David
Published: September 2018

5567

Background: During debulking surgery (Surg) for advanced ovarian cancer (OvCa), lymph node (LN) sampling are not routinely performed. Hence, prognostic implications of LN involvement following debulking surg and chemotherapy (ChemoRx) were analyzed from National Cancer Database (NCDB). Methods: Only Stage III and Stage IV patients (pts) from 2004 –2014 NCDB pts undergoing Debulking surg. and ChemoRx were included. Group A included pts with debulking surg without bowel resection; Group B with major bowel resection and Group C with bowel and bladder resection. Pts were further subdivided according to the use of 1) NeoAdjuvant (NeoAdj) 2) Adjuvant (Adj) and 3) Neo Adj and Adj ChemoRx. Survival analysis was done based on -ve or +ve LN status. using Pearson Chi Square testing. Results: Out of 10,737 Stage III and 3,102 Stage IV pts, there were 6828 Group A, 6413 Group B and 598 Group C pts. Five year overall survival (OS) for all pts in Stage III with LN-ve vs LN +ve was 59.9% vs 53.9% and Stage IV was 48.7% vs 41.2%. In Group A, B, and C, the 5 yr OS was better in LN – ve than LN +ve pts (Table1). The OS for both LN –ve and LN +ve groups were better in Adjuvant chemoRx in all 3 groups. OS was slightly better in Stage III vs Stage IV pts. Conclusions: Even though LN dissection are not routinely done during debulking surg, overall pts with LN metastasis do worse than LN –ve pts irrespective of the timing of ChemoRx. Hence, LN sampling during debulking surg should be strongly considered as it may provide important prognostic information. [Table: see text]
INNOVATE: A phase II study of TTFields (200 kHz) concomitant with weekly paclitaxel for recurrent ovarian cancer—Updated safety and efficacy results.
Authors: Vergote Ignace , Moos Roger von , Manso Luis , Sessa Cristiana
Published: September 2018

5580

Background: TTFields are a non-invasive, regional antimitotic treatment modality, which have been approved for the treatment of recurrent and newly diagnosed glioblastoma by the FDA. TTFields act by delivering intermediate frequency alternating electric fields to the tumor, predominantly by disrupting the formation of the mitotic spindle during metaphase. INNOVATE was the first trial testing TTFields (200kHz) in ovarian cancer patients. Methods: Thirty-one recurrent, platinum-resistant, unresectable ovarian cancer patients were enrolled in the INNOVATE trial and treated with TTFields in combination with weekly paclitaxel. The primary endpoint was treatment emergent adverse events. Secondary endpoints included progression free-survival, overall survival and radiological response rate. Results: The median age was 60 (range – 45-77), most patients (77%) had serous histology. 52% had an ECOG score of 0. The median number of prior chemotherapy regimens was 4.1 (range 1-11). All patients were platinum-resistant, and 97% of patients received prior taxane-containing regimens. Ten (32%) patients suffered from serious adverse events (SAEs) during the study, none were related to TTFields. Of all reported SAEs, 31% were related to gastrointestinal disorders (ileus, jaundice and ascites) and 31% were respiratory events (dyspnea, pleural effusion and pulmonary embolism). Only one SAE which, related to the tumor, led to permanent discontinuation of the device. Most patients were reported to have mild-moderate, TTFields-related skin irritation, out of whom only two patients (6.4%) had severe-grade events. The median PFS was 8.9 months (95% CI 4.7, NA). Of the evaluable tumors, 25% had partial response and another 46.4% stable disease – a clinical benefit of 71.4%. Six patients (19.4%) had a CA 125 response, translating into a decrease of 50% or more in serum levels. The median OS was not reached. Conclusions: TTFields concomitant to weekly paclitaxel are tolerable and safe in heavily pre-treated platinum-resistant ovarian cancer ovarian cancer patients. These data support further clinical testing of TTFields with chemotherapy in ovarian cancer. Clinical trial information: NCT02244502.
Outcome of patients with advanced endometrial and cervical cancer treated in a phase 1 unit.
Authors: Miller Rowan , Devlin Michael-John , Brown Nicholas Fraser , Grunewald Tami , McCormack Mary , Lockley Michelle , Ledermann Jonathan A. , Meyer Tim , Forster Martin David , Kristeleit Rebecca Sophie
Published: September 2018

5597

Background: Patients (pts) with advanced endometrial (EC), cervical and vulval (CVC) cancer have limited therapeutic options and poor prognosis. Early phase trials may be a suitable option for pts with good performance status aided by molecular selection. We sought to determine the outcome of EC and CVC pts treated in a phase 1 unit. Methods: Medical records of pts with EC and CVC treated within an early phase trial between 2010 and 2016 were reviewed. Data comprised pt and tumor characteristics, prior therapy, trial therapy and outcome. Results: 38 pts, median age 59 years (21-74) with EC (19) or CVC (19) were identified. Median prior therapies for advanced disease: 1 (1-3). Histological subtypes: endometrioid (4), high grade serous (HGS 7), carcinosarcoma (CS 4), clear cell (1), and adenosquamous (3) for pts with EC; adenocarcinoma (5), squamous (11), clear cell (2) and neuroendocrine (1) for CVC pts. 20 pts (53%) had Next Generation Sequencing (NGS) using a targeted panel with actionable mutations identified in 10 (KRAS (4), PIK3CA (6) and EGFR (1)). Pts were allocated in order of priority to a trial (1) on the basis of NGS (‘genomic’ 8%), (2) within a ‘tumor specific’ expansion cohort (45%) or (3) a ‘generic’ study (47%). The overall response rate (ORR) was 21% with 34% stable disease (SD) and median progression free survival (PFS) and overall survival (OS) of 11 and 42 weeks respectively, with 10 pts still on study. Within the EC cohort ORR was 21% with 32% SD and PFS and OS of 9 and 38 weeks respectively. For the CVC cohort ORR was 21% with 37% SD and PFS and OS of 12 and 42 weeks respectively. Outcomes were better for the pts in the genomic and tumour specific groups. Both PFS and OS were longer with median PFS of 42, 32 and 8 weeks and OS of 91, not reached and 37 weeks for genomic, tumor specific and generic trials respectively. Conclusions: Early phase trials represent a good option for pts with advanced EC and CVC with meaningful clinical benefit observed even in this small cohort. Encouraging RR and PFS were observed in these pts with limited standard treatment options. This includes pts with difficult to treat histological subtypes such as HGS and CS EC and clear cell and adenocarcinoma CVC. NGS is feasible in real time and increasing use may benefit pts further.
Pathologic complete response (pCR) rates after neoadjuvant pertuzumab (P) and trastuzumab (H) administered concomitantly with weekly paclitaxel (T) and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) chemotherapy for clinical stage I-III HER2-positive breast cancer.
Authors: Foldi Julia , Mougalian Sarah Schellhorn , Silber Andrea , Lannin Donald R. , Killelea Brigid K. , Chagpar Anees B. , Horowitz Nina Ruth , Frederick Courtney , Rispoli Lawrence , Abu-Khalaf Maysa M. , Sabbath Kert D. , Sanft Tara Beth , Fischbach Neal A. , Brandt Debra S. , Hofstatter Erin Wysong , DiGiovanna Michael , Pusztai Lajos
Published: September 2018

577

Background: Inclusion of H with chemotherapy has increased pathologic complete response (pCR) rates in HER2 positive breast cancer, and dual HER2 blockade involving H + P further increased efficacy. With dual HER2 blockade and taxane-based (+/-carboplatin followed by anthracycline) chemotherapies, pCR rates reach, 75% in estrogen receptor (ER) negative and 45% in ER+ patients. HER2 targeted therapies also increase the efficacy of anthracyclines but are not routinely combined due to potential cardiotoxicity. The goal of this phase II study was to assess pCR rate when H+P is administered during the entire treatment duration, including the anthracycline phase, of weekly T (80 mg/m2) x 12 followed by FE(75 mg/m2)C x 4 neoadjuvant chemotherapy. Methods: pCR (ypT0/is and ypN0) rate was assessed separately in ER+ and ER- cancers following Simon’s two-stage design to detect improvement in pCR rates to 90% and 70% in the ER- and ER+ cohorts, respectively. Eligibility included age <65, stage I-III, HER2+ disease, and normal cardiac function. Results: The ER- cohort completed full accrual of 25 patients: 23 completed therapy and surgery, 2 patients are still receiving treatment. The pCR rate is 78% (n=18, 95% CI:58-90%). The ER+ cohort was closed after 23 patients were accrued to the first stage due to lower than expected pCR of 26% (n=6, 95% CI:13-46%) at interim analysis. The incidence of grade 3/4 adverse events was 48% (n=24/50), the most common being neutropenia (n=12) and diarrhea (n=7). No patient experienced symptomatic congestive heart failure, one patient had a drop in LVEF to < 50% following completion of chemotherapy. Thirteen patients (27%) had a >10% asymptomatic drop in their LVEF but remained above 50%, LVEF returned to baseline by the next assessment in half of these cases. Conclusions: Neoadjuvant P and H administered concomitantly with weekly T followed by FEC resulted in 78% pCR rate in ER-/HER2+ cancers. This pCR rate is among the highest reported in the literature. The pCR rate was substantially lower in ER+ cancers. Clinical trial information: NCT01855828.
Phase III randomized trial of chemotherapy with or without bevacizumab (B) in patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN): Survival analysis of E1305, an ECOG-ACRIN Cancer Research Group trial.
Authors: Argiris Athanassios , Li Shuli , Savvides Panayiotis , Ohr James , Gilbert Jill , Levine Marshall A. , Haigentz Missak , Saba Nabil F. , Chakravarti Arnab , Ikpeazu Chukwuemeka , Schneider Charles , Pinto Harlan , Forastiere Arlene A. , Burtness Barbara
Published: September 2018

6000

Background: The addition of B, an anti-VEGF monoclonal antibody, to chemotherapy has improved outcomes in several solid tumors. Pemetrexed plus B showed promising efficacy in R/M SCCHN (Argiris et al. JCO 2011). E1305 was designed to evaluate the addition of B to a platinum doublet in R/M SCCHN. Methods: B-eligible pts with performance status 0-1, not having received chemotherapy for R/M SCCHN (prior chemotherapy for locally advanced disease allowed ≥ 4 months) and without factors predisposing to bleeding (history of bleeding due to SCCHN, anticoagulation, central cavitary lung metastasis, carotid invasion) were randomized to: A) one of 4 regimens (investigator's choice) given every 3 weeks: A1, cisplatin (C) 100 mg/m2, 5-FU 1000 mg/m2/day x 4 days; A2, carboplatin (Cb) AUC 6, 5-FU 1000 mg/m2/day x 4 days; A3, C 75 mg/m2, docetaxel (D) 75 mg/m2; A4, Cb AUC 6, D 75 mg/m2, or B) the same regimen (B1, B2, B3, B4) plus B 15 mg/Kg IV, every 3 weeks, until progression. Chemotherapy could be stopped after 6 cycles after maximum response. All pts received prophylactic antibiotics. The primary endpoint was overall survival (OS). Control median OS of 8.5 months (mo) was projected; the addition of B was hypothesized to increase median OS to 11.5 mo with a hazard ratio (HR) of 0.74. Results: 403 pts were randomized (200 in arm A; 203 in arm B). Baseline characteristics were well balanced. 38% in arm A/42% in arm B had an oropharyngeal primary; 87% received C or Cb plus D. With a median follow-up of 23.1 mo, median OS was 11 mo in arm A and 12.6 mo in arm B; HR 0.84 (95% CI 0.67-1.05), p = 0.13. The 1-, 2-, 3-, and 4-year OS were 46% vs 51%, 18% vs 26%, 8% vs 16%, 6% vs 13%, in arm A vs B, respectively. Median PFS was 4.4 mo in arm A and 6.1 mo in arm B (HR 0.71, 95% CI 0.58-0.87; p = 0.0012). Objective response rate was 25% in arm A vs 36% in arm B (p = 0.013). Grade 3-5 bleeding occurred in 3.5% in arm A vs 7.7% in arm B (p = 0.08). Conclusions: B added to a standard platinum doublet improved response rate and PFS but not OS in first-line treatment of R/M SCCHN. The control arm in this study performed better than expected. Clinical trial information: NCT00588770.
Impact of prophylactic human papillomavirus (HPV) vaccination on oral HPV infections among young adults in the U.S.
Authors: Gillison Maura L. , Broutian Tatevik , Graubard Barry , Pickard Robert , Tong Zhen-Yue , Xiao Weihong , Kahle Lisa , Chaturvedi Anil
Published: September 2018

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.
Genomic determinants of response to pembrolizumab in head and neck squamous cell carcinoma (HNSCC).
Authors: Haddad Robert I. , Seiwert Tanguy Y. , Chow Laura Quan Man , Gupta Shilpa , Weiss Jared , Gluck Iris , Eder Joseph Paul , Burtness Barbara , Tahara Makoto , Keam Bhumsuk , Kang Hyunseok , Muro Kei , Albright Andrew , Huang Lingkang , Ayers Mark , Mogg Robin , Cristescu Razvan , Cheng Jonathan D. , Mehra Ranee
Published: September 2018

6009

Background: Somatic mutational load (ML) is associated with response to anti CTLA-4 and PD-1/-L1 immunotherapies in select tumors, due to formation of neoepitopes not subject to central immune tolerance. Neoepitopes specific to HPV, EBV virus infection are also present in some HNSCC. An IFNγ gene expression profile (GEP) characteristic of tumor inflammation is also related to response to anti PD-1/-L1 therapy. This study evaluated relationships between ML and clinical outcome and independent predictive values of ML and GEP in patients with HNSCC treated with pembrolizumab. Methods: Whole exome sequencing (WES) and GEP were assessed in FFPE tumor specimens of patients with HNSCC (KEYNOTE 012; subsets of B1 [PD-L1+, n = 34] and B2 [PD-L1+/‒, n = 73] cohorts). ML, neoantigen load (NL), HPV/EBV status and clonality were assessed by standard WES analytical methods. GEP score is a weighted sum of normalized expression values of 18 genes. Statistical testing of ML and response, and ML and GEP relationship by HPV/EBV status was prespecified. Results: There were 73 patients identified as HPV‒ and EBV‒ (n = 25 in B1; n = 48 in B2). In HPV‒ and EBV‒ patients in B1 and B2 cohorts, respectively, associations between ML and objective response (OR) (P = 0.029 and 0.055; AUROC 0.89 and 0.63), and GEP and OR (P = 0.064 and 0.01; AUROC 0.82 and 0.74) were statistically significant. In combined cohorts of HPV‒ and EBV‒ patients, ML and GEP were significantly associated with OR (P = 0.009 and 0.002; AUROC 0.70 and 0.76, respectively). ML and GEP were only weakly correlated (r = 0.173). In a joint model, ML was significantly associated with response (p = 0.020) after adjusting for GEP (also significant, p = 0.006). NL and clonality weighted ML were also significantly associated with response (P = 0.026 and 0.006, respectively). In HPV+ or EBV+subjects, OR association was not significant for ML, possibly due to a dominance of viral vs somatic neoepitopes; GEP was significant, likely due to tumor inflammation. Conclusions: ML and GEP are independently predictive of response to pembrolizumab in HPV‒/EBV‒ patients with HNSCC; GEP was predictive regardless of viral status. ML and GEP may have utility in characterizing responses to anti PD-1 therapies and novel cancer regimens in HNSCC. Clinical trial information: NCT01848834.
Epacadostat plus pembrolizumab in patients with SCCHN: Preliminary phase I/II results from ECHO-202/KEYNOTE-037.
Authors: Hamid Omid , Bauer Todd Michael , Spira Alexander I. , Olszanski Anthony J. , Patel Sandip Pravin , Wasser Jeffrey S. , Smith David C. , Balmanoukian Ani Sarkis , Aggarwal Charu , Schmidt Emmett V. , Zhao Yufan , Gowda Hema , Gangadhar Tara C.
Published: September 2018

6010

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that induces immune tolerance by T-cell suppression. IDO1 overexpression has been associated with poor survival in SCCHN. Epacadostat (E) is a potent, selective oral IDO1 inhibitor. ECHO-202/KEYNOTE-037 is an open-label, phase I/II (P1/2) study evaluating E plus PD-1 inhibitor pembrolizumab (P) in multiple tumor types. We report preliminary P1/2 efficacy, safety, and tolerability findings in the SCCHN cohort as of a 29OCT2016 data cutoff. Methods: Eligible adult patients (pts) had metastatic SCCHN and received ≥1 prior chemotherapy regimen that included a platinum agent. Prior checkpoint inhibitor therapy (tx) was not permitted, and pts with carcinoma of the nasopharynx or salivary gland were excluded. In P1 dose escalation (3+3+3), pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for P2 cohort expansion. Response was assessed in RECIST 1.1 evaluable pts. Results: A total of38 pts (P1, n = 2; P2, n = 36) were evaluated. Median age was 63 years, 87% of pts were men, 95% were white, and 66% received prior cetuximab. Of 36 efficacy-evaluable pts, 81% (n = 29) received 1–2 prior lines of tx and 19% (n = 7) received ≥3 prior lines of tx. ORR (CR+PR) and DCR (CR+PR+SD) for pts with 1–2 prior tx were 34% (2 CR, 8 PR) and 62% (8 SD), respectively; for pts with ≥3 prior tx, ORR and DCR were 14% (1 PR) and 43% (2 SD). Response was observed regardless of HPV status. At data cutoff, 9/11 responses were ongoing (range, 1+ to 563+ days). PFS and biomarker analyses are ongoing. The most common TRAEs in all 38 pts were fatigue (24%), nausea (11%), and decreased weight (11%). Grade ≥3 TRAEs occurred in 11% of pts; only increased amylase and lipase (both asymptomatic) were grade ≥3 TRAEs that occurred in > 1 pt. TRAEs led to discontinuation in 1 pt (increased amylase and lipase). Conclusions: In pts with advanced SCCHN, E + P was generally well tolerated and associated with encouraging response rates, particularly in pts with 1–2 prior lines of tx. A phase III SCCHN study is planned. Clinical trial information: NCT02178722.
Safety of pembrolizumab with chemoradiation (CRT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN).
Authors: Powell Steven Francis , Gitau Mark Mutuota , Sumey Christopher Joseph , Reynolds John T. , Lohr Michele , McGraw Steven , Nowak Ryan Kenneth , Terrell Andrew M , Jensen Ashley Wayne , Blanchard Miran Joel , Ellison Christie , Black Lora Jane , Thompson Paul A. , Gold Kathryn A. , Cohen Ezra E.W. , Lee John H. , Spanos William Charles
Published: September 2018

6011

Background: Pembrolizumab (pembro) is a humanized monoclonal antibody that blocks the programmed death receptor-1 (PD-1) interaction with its ligands (PD-L1, PD-L2). While pembro is approved for platinum-refractory, recurrent/metastatic SCCHN, its role in definitive therapy for LA-SCCHN is not yet defined. Here we present the safety results of pembro with cisplatin-based CRT for patients (pts) with LA-SCCHN (NCT02586207). Methods: 27 pts with oropharyngeal (OP), hypopharyngeal (HP), and laryngeal (L) stage III-IVB SCCHN (any HPV status) eligible for cisplatin-based, definitive CRT were enrolled from November 2015 to August 2016 as part of a safety cohort. Pembro was given at a fixed dose of 200 mg IV 4-7 days prior to initiation of CRT and then every 3 weeks during CRT (2 concomitant doses) and then following CRT for 5 additional doses. CRT consisted of weekly cisplatin 40 mg/m2 IV x 6 doses (240 mg/m2 maximum) given concurrently with radiation at a dose of 2 Gy once daily for 35 fractions (total 70 Gy). Safety was determined by the occurrence of CRT or pembro dose-limiting adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on imaging or with salvage surgery at 100 days post-CRT completion. Results: 20 (74%) pts with OP HPV+ and 7 (26%) pts with HPV- (4 L, 2 OP, 1 HP) tumors were enrolled. 21 (78%) completed all planned doses of pembro. 3 discontinued due to irAEs (G2 peripheral motor neuropathy, G3 AST elevation, G1 Lhermitte-like syndrome). 3 discontinued due to protocol reasons (early neck dissection -2 pts, prolonged hospitalization-1 pt). All pts completed the full radiation dose (70 Gy) without significant delay (defined as > 5 days). 23 (85%) received the goal target dose of cisplatin (≥200 mg/m2). There was one pt death due to concurrent illness, unrelated to treatment. The study has been reopened with expansion cohorts of 34 HPV+ pts and 23 HPV- pts to evaluate efficacy. Conclusions: Pembro in combination with weekly cisplatin-based CRT is safe and does not significantly impair radiation or chemotherapy dosing. Efficacy of this combination is being explored further in this study and through larger phase III clinical trials. Clinical trial information: NCT02586207.
An open-label, multicohort, phase I/II study to evaluate nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC).
Authors: Delord Jean-Pierre , Hollebecque Antoine , De Boer J. P. , De Greve Jacques , Machiels Jean-Pascal H. , Leidner Rom S. , Ferris Robert L. , Rao Shangbang , Soumaoro Ibrahima , Cao Z. Alexander , Kang Hyunseok , Topalian Suzanne Louise
Published: September 2018

6025

Background: Treatment options for patients (pts) with R/M NPC are limited to palliative chemotherapy. NPC is often associated with the Epstein–Barr virus (EBV), a potential antigen for immune recognition, and high expression levels of the immune checkpoint receptor programmed death-1 (PD-1) and its major ligand PD-L1. Nivolumab disrupts PD-1–mediated signaling, restoring T-cell antitumor function. Methods: In CheckMate 358 (NCT02488759), PD-L1–unselected adults with R/M NPC, ECOG PS of 0–1, and ≤2 prior systemic therapies in the R/M setting were eligible to receive nivolumab 240 mg every 2 weeks until progression or unacceptable toxicity, as part of an ongoing multicohort study of 5 virus-associated cancers. Human papillomavirus-associated NPC and keratinizing squamous cell carcinoma (WHO Type 1) were excluded. Primary endpoints were objective response rate (ORR) and safety; secondary endpoints were duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results: Of 24 treated pts with R/M NPC, median age was 51 years, 88% were male, 62% were white, 88% were European, and 88% had EBV+ tumors. At a median follow-up of 26 weeks (range: 4–40), ORR was 20.8% and appeared to be higher in pts with no prior R/M therapy (Table). The disease control rate (ORR + SD) was 45.8%. Responses were observed regardless of PD-L1 or EBV status. Median PFS was 2.4 mo (95% CI: 1.5, NR); median OS was NR. Conclusions: Nivolumab demonstrated clinical activity and a manageable safety profile in R/M NPC, supporting ongoing research with nivolumab in this disease. Updated efficacy and biomarker data will be presented. Clinical trial information: NCT02488759. [Table: see text]
The impact of HPV infection on survival of patients with non-oropharyngeal head and neck cancer.
Authors: Alsidawi Samer , Westin Gustavo Figueiredo Marcondes , Chintakuntlawar Ashish V. , Okuno Scott H. , Price Katharine Andress Rowe
Published: September 2018

6048

Background: The role of Human Papilloma Virus (HPV) infection in non-oropharyngeal squamous cell carcinoma (non-OPSCC) of the head and neck is unknown. Current available studies have yielded conflicting results due to limited number of patients. We present a large analysis from the National Cancer Database (NCDB) evaluating HPV-positive non-OPSCC. Methods: Using the NCDB registry, we included adults diagnosed with non-OPSCC from 2004-2012 with available HPV status. A cohort of patients with OPSCC was analyzed for HPV prevalence comparison. Survival analysis was performed using Kaplan-Meier method and stratified using HPV-status. The prognostic effect of variables was studied using Cox proportional hazards models. The JMP software was used for statistical analysis. Results: A total of 8726 non-OPSCC patients were identified and primary sites included the oral cavity (50%), larynx (41%) and hypopharynx (9%). 11% of non-OPSCC patients had evidence of infection with high-risk HPV strains compared to 61% of OPSCC patients. HPV-positive non-OPSCC patients presented at slightly younger age, had more advanced stage and higher tumor grade compared to HPV-negative patients (P < 0.01). HPV-positive non-OPSCC patients had better survival than HPV-negative patients (HR 0.82, 95% CI 0.72-0.93, P < 0.01) and this was most pronounced in patients with locally advanced disease (5-year survival 50% versus 40%, HR 0.69, 95% CI 0.6-0.8, P < 0.01). A univariate and multivariate analysis were performed adjusting for age, sex, race, stage, primary site, Charlson/Deyo comorbidity score, financial income, tumor grade, surgery, radiation and chemotherapy administration. Smoking history was unavailable. HPV positivity was an independent predictor of better survival in non-OPSCC in multivariate analysis (HR 0.69, 95% CI 0.59-0.8, P < 0.01). Conclusions: HPV infection is seen in a subset of patients with non-OPSCC head and neck cancer and these present with more advanced tumors. The survival of patients with HPV-positive non-OPSCC is significantly better than HPV-negative tumors. Routine HPV testing and enrollment in treatment de-intensification clinical trials similar to OPSCC might be appropriate for this patient population.
Cell-free DNA for treatment monitoring and outcome predictor in head and neck cancer.
Authors: Beck Julia , Schirmer Markus , Rave-Fraenk Margret , Urnovitz Howard , Bornemann-Kolatzki Kirsten , Mitchell William Marvin , Oellerich Michael , SchÃ¼tz Ekkehard , Canis Martin
Published: September 2018

6055

Background: Copy number instability (CNI) signatures of cancers can be readily detected by Next Generation Sequencing of plasma cell-free DNA (cfDNA). HPV detected in oropharyngeal carcinomas is currently the only prognostic biomarker available. We report here CNI scores for disease monitoring of Head and Neck Cancers (HNC) with potential predictive value for personalized therapeutic options. Methods: A total of 132 plasma samples were collected from 54 HNC patients under informed consent and IRB approval. cfDNA was extracted from plasma, ~20M paired-end NGS mappable reads (reference: HG19) per sample were generated and CNI scores were calculated by read counting statistics. After unblinding CNI scores were evaluated as diagnostic parameter for association with disease characteristics and progression. Survival analysis was conducted after dichotomization of baseline CNI scores at a value of 31 corresponding to the 97.5thpercentile of a normal reference group (RG, n = 141). Results: CNI scores above the 97.5th RG percentile were detected in 40 out of 54 (74%) treatment naïve baseline samples. 29 patients with tumors ≤ T3 (62%, n = 42) and 11 out of 12 (92%) with T4 tumors had CNI scores > 31, with significantly higher CNI scores (p = 0.04) seen for T4 tumors. Higher CNI scores were also found in patients with tumor lymph node invasion (n = 37; median: 381, Q25-Q75: 57-1573) compared to negative lymph nodes (pN0, n = 17; 27, 19-64, p= 0.0004). A steep decline of CNI scores was detected after surgical resection, with increasing CNI scores in later disease progression. The pre-operative CNI scores were a stronger predictor of time to recurrence (p = 7*10-5) than the pN status (p = 0.05) (Cox regression). High baseline CNIs ( > 31) strongly correlated with time to recurrence (Kaplan-Meier log-rank p = 0.018) with a median of 20 months and median overall survival of 30 months in the high CNI group, neither reached in the low CNI-score group (60 m follow-up). Conclusions: Chromosomal instability within HNC was quantified from plasma cfDNA as CNI score. The CNI score may serve as better predictor for the time to recurrence interval than pN status. The data suggests that cfDNA analysis as CNI score may serve as real-time marker of treatment efficacy and outcome.
FGFR3 correlation with mutant p53 and its prognostic value in oropharyngeal squamous cell carcinoma (OPSCC).
Authors: Chen Zhuo Georgia , Nannapaneni Sreevinas , Griffith Christopher C , Wang Dongsheng , Zhang Chao , Magliocca Kelly R. , Wang Xu , Chen Zhengjia , Patel Mihir , Steuer Conor Ernst , Shin Dong Moon , Saba Nabil F.
Published: September 2018

6057

Background: Fibroblast growth factor receptor 3 (FGFR3) is expressed in squamous cell carcinoma of the head and neck (SCCHN) including oropharyngeal squamous cell carcinoma (OPSCC) and is a potential therapeutic target. Information on its prognostic value and its correlation with other relevant cancer related proteins is limited. Methods: We performed immunohistochemistry (IHC) analyses of p16, mutant p53 (mp53), and FGFR3 on 221 retrospectively collected OPSCC tissue samples. mp53, and FGFR3 were semi-quantified as weighted index [WI = % positive x intensity (0. 1+, 2+, and 3+)]. Correlations of FGFR3 WI with p16 status, and mp53 WI were analyzed. Association of FGFR3 with disease-free survival (DFS) or overall survival (OS) was assessed. Results: A total of 144/221 (65%) were p16 +, 93/172 (54%) had mp53, and 140/221 (63%) expressed FGFR3. FGFR3 was highly correlated with mp53 (p < 0.001), which was true in both p16 + and – OPSCC (p < 0.0001 and p = 0.0006, respectively).mp53 level was significantly lower in p16 positive versus p16 negative group (p < 0.0001). Univariate analysis revealed an association of p16 negative and high mp53 with worse OS (p < 0.001 and p < 0.001, respectively) and DFS (p < 0.001 and p = 0.004, respectively). FGFR3 was associated with worse OS and DFS (p = 0.014 and p = 0.047, respectively). On multivariable analysis FGFR3 was associated with worse DFS (p = 0.005), but not OS. Kaplan-Meier plot using medians of both FGFR3 and mp53 as the cut-off values showed that higher FGFR3 and mp53 correlated to worst DFS (p = 0.025) and OS (p = 0.009). Conclusions: Our results suggest that FGFR3 is associated with mp53 and p16 – OPSCC and correlates with worse clinical outcome. The biologic relation of FGFR3 and mp53 in OPSCC deserves further investigation. (This research was supported by a grant NCI R21 CA182661-01A1to NFS and GZC).
Resource utilization in patients with head and neck cancer: Analysis of CCTG HN6 (NCT00820248).
Authors: Ghate Ketan , Parulekar Wendy R. , Chen Bingshu E. , Montenegro Alexander , Khaouam Nader , McCarthy Joy S. , Walker John , Waldron John , Siu Lillian L. , Johnson Ana
Published: September 2018

6067

Background: As new treatments for head and neck cancer arise, further information is required regarding resource utilization. The Canadian Cancer Trials Group HN.6 study included collected resource utilization data prospectively on patients with locally advanced squamous cell carcinoma of the head and neck treated with cisplatin or panitumumab plus radiotherapy (RT). Methods: The HN.6 phase III trial enrolled 320 patients across Canada between 2008-2011. The economic analysis was conducted from the societal perspective. Resource utilization was collected prospectively for 3 categories: outpatient, hospitalization and institutionalization (end of life care) at baseline, 8 weeks, every 3 months(mo) for 2 years and every 4 mo until 3 years. Lost productivity questionnaires were collected in the last week of RT. Descriptive statistics were used to summarize the outcomes. Categorical variables were reported by percentage and continuous variables were reported by mean and standard deviation. Results: Of 320 pts randomized, resource utilization and lost productivity data were available for 317 (99%) and 285 (89%) pts, respectively. Eighty nine pts required 130 emergency room visits (mean 1.46±0.85). There were 696 (mean 3.74±3.22) office visits among 186 pts and 367 (mean 3.95±6.43) outpatient visits among 93 pts. Surgeons, radiation oncologists and emergency room physicians were the top three providers of outpatient care with 234 (mean 2.05±1.54), 137 (mean 1.67±1.19) and 118 (mean 1.4±0.78) visits for 114, 82 and 84 pts, respectively. CT scans (286), lab tests (418), x-rays (182) and other tests (400) were conducted in 136, 180, 120 and 194 pts, respectively. Three pts were institutionalized for end of life care (mean 28 days±26.06), and 214 pts were hospitalized (mean 14.5 days±28.8). One hundred and thirteen (41%) pts reported a change in work status at the end of RT. Conclusions: Radical treatment for locally advanced SCCHN is resource intensive. Tracking resources utilized prospectively in clinical trial settings and reporting this information consists of an efficient way to inform health resource allocation decisions. Clinical trial information: NCT00820248.
A personalized approach using hypoxia resolution to guide curative-intent radiation dose-reduction to 30 Gy: A novel de-escalation paradigm for HPV-associated oropharynx cancers (OPC).
Authors: Riaz Nadeem , Sherman Eric Jeffrey , Katabi Nora , Leeman Jonathan Eric , Higginson Daniel S. , Boyle Jay , Singh Bhuvanesh , Morris Luc G. , Wong Richard J. , Tsai C. Jillian , Schupak Karen , Gelblum Daphna Y. , McBride Sean Matthew , Hatzoglou Vaios , Baxi Shrujal S. , Pfister David G. , Dave Amita , Humm John , Schöder Heiko , Lee Nancy Y.
Published: September 2018

6076

Background: We conducted a pilot study using functional imaging to guide reduction in radiation (RT) to 30Gy with concurrent chemotherapy in patients with HPV+ OPC. Methods: 19 patients were enrolled prospectively from 7/2015-10/2016. Primary tumors were excised and analyzed for DNA repair foci ex-vivo. A pre-RT dynamic 18F-FMISO (fluoromisonidazole) PET was then used to assess tumor hypoxia (defined as > 1.2 tumor to muscle SUV ratio) in cervical lymph nodes. Patients without hypoxia on baseline or repeat scan done 5-10 days after initiation of chemoRT received 30Gy (57% reduction) over 3 weeks to the tumor bed and neck with 2 cycles of concurrent chemotherapy (high-dose cisplatin or carboplatin/5-FU). Patients with persistent hypoxia received the standard dose of 70Gy over 7 weeks with chemo. Neck dissection (ND) was done 4-months post chemoRT. Weekly DWI MRI, ctDNA, whole exome & RNA sequencing were performed. Results: 19 patients (11 tonsil, 5 BoT, 3 unknown primaries) were enrolled. Staging: 11 T1, 5 T2, 3 Tx; 5 N1, 3 N2a, 11 N2b; all M0. On pre-RT 18F-FMISO scans, 13 were positive and 6 were negative for hypoxia. Of the 12 intra-treatment 18F-FMISO scans (1 not done due to intermittent illness, this patient received 70Gy), 3 were positive and these patients received 70Gy chemoRT. 15 patients were de-escalated to 30Gy. To date, analysis showed complete pathologic response in 8 of 9 patients (all 15 expected to have ND by April 2017. The one positive case received only 1 cycle of cisplatin. To date, 18 of 19 patients (95%-6 pending ND) remain disease free. Correlative analysis with sequencing, DNA repair foci, ctDNA, and results from pathologic and intra-treatment imaging response will be presented. Conclusions: This is the first report of apersonalized approach to a major decrease in RT dosing for definitive treatment of HPV+ oropharyngeal carcinoma guided by patient-specific imaging-based treatment response. De-escalation to 30Gy informed by intra-treatment imaging for hypoxia appears feasible, safe and efficacious. A multi-center trial to validate these pilot results is planned. Clinical trial information: NCT00606294.
Quantifying gender ascertainment bias in hereditary cancer testing.
Authors: Chen Anthony , Anguiano Allison , Bernhisel Ryan , Brown Krystal , Gorringe Heidi , Manley Susan
Published: September 2018

6516

Background: Historically, hereditary cancer genetic testing has been much more prevalent among women, in part due to gender-specific cancer risks associated with Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Despite expanded genetic testing that includes hereditary cancer syndromes that affect both men and women, the gender gap still persists. Here we report on gender ascertainment bias in hereditary cancer testing by evaluating the proportion of test cancellations in men and women who were not affected with cancer at the time of testing. Methods: A commercial testing cohort was queried to identify individuals for whom genetic testing with a multi-gene pan-cancer panel was ordered between September 2013 and December 2016. Individuals who were ascertained for testing based on a clinical suspicion of HBOC or Lynch syndrome (LS) and did not have cancer at the time of testing were included. Test cancellations (i.e. a test order that did not yield any reported result) due to lack of insurance coverage were assessed, as this is directly related to clinical testing criteria. Results: Genetic testing was ordered for 259,919 individuals who did not have cancer at the time of testing, which included 6007 men (2.3%) and 253,912 women (97.7%). Overall, 21.2% of tests ordered for men were cancelled due to lack of insurance coverage, which is significantly higher than the cancellation rate among women (14.4%, p < 0.001). This trend was observed among individuals tested for suspicion of HBOC (18.7% for men vs. 13.2% for women; p < 0.001), but not for those tested for LS (26.6% for men vs. 25.1% for women; p = 0.137). Among those whose tests were not cancelled, the positive mutation rate was twice as high for men compared to women (9.6% vs 4.6%, respectively; p < 0.001). Conclusions: In this analysis, the proportion of genetic tests ordered was substantially biased towards women. Cancellation rates for men were significantly higher compared to women, while the mutation positive rate was twice as high. Although men and women who are unaffected with cancer have an equal probability of having a family cancer history that meets HBOC testing criteria, the data presented here suggests that there is a higher clinical standard for men to receive genetic testing.
Asymptomatic distant recurrence detection and survival in early stage breast cancer: A nationally representative study.
Authors: Schumacher Jessica R. , Neuman Heather B. , Zhang Ying , Yu Menggang , Vanness David J. , Si Yajuan , Burnside Elizabeth S , Ruddy Kathryn Jean , Partridge Ann H. , Schrag Deborah , Edge Stephen B. , Jacobs Elizabeth A , Havlena Jeffrey , Francescatti Amanda B. , Spears Patricia , Winchester David P , McKellar Daniel P. , Chang George J. , Kozower Benjamin D. , Greenberg Caprice Christian
Published: September 2018

6520

Background: Breast cancer follow-up guidelines recommend imaging for distant metastases only in the presence of signs/symptoms. However, data supporting this recommendation predates the current era of improved imaging and targeted therapies based on molecular subtype. The objective was to assess the relationship between mode of distant recurrence detection and survival. Methods: A stage-stratified random sample of Stage II-III breast cancer patients diagnosed in 2006-7 was selected from NCDB records from 1,217 CoC-accredited facilities (10/hospital n = 10,853). Women were categorized by subtype: 1) ER or PR+/HER2-; 2) ER and PR-/Her2- (triple negative); 3) HER2+. Medical records abstracted for 5-years post-surgery supplemented NCDB data and assessed distant recurrence and mode of detection (prompted by signs/symptoms or surveillance imaging), imaging (chest CT, abdomen/pelvis CT/MRI, head CT/MRI, bone scan, PET/CT), death date. The relationship between mode of recurrence detection and days from initial cancer diagnosis to death was assessed using propensity-weighted multivariable Cox proportional hazards regression stratified by subtype. Propensity weights, based on receipt of surveillance systemic imaging, accounted for sociodemographic and tumor/treatment factors. Results: 5-year distant recurrence was 22.3% for triple negative, 14.8% HER2+, and 11.2% for ER or PR+/ HER2- patients. Asymptomatic imaging detected recurrence in 22.9% and signs/symptoms in 77.1%. Patients with asymptomatic as compared to sign/symptom detected recurrences had reduced risk of death in 5 years if triple negative (HR = 0.68, 95% CI = 0.50-0.93) or HER2+ (HR = 0.40, 95% CI = 0.24-0.65) with no significant association for ER or PR+/HER2- (HR = 1.2, 95% CI = 0.88-1.51). This translated to a between-group difference in weighted median survival of 5 months for triple negative and 13 months for HER2+ patients. Conclusions: This is the first nationally representative study to show a survival advantage with asymptomatic detection of distant metastases for patients, with the benefit limited to triple negative and HER2+ disease. Further research to confirm observational findings is warranted.
Mammography use in breast cancer survivors: An administrative claims study.
Authors: Ruddy Kathryn Jean , Sangaralingham Lindsey R. , Neuman Heather B. , Greenberg Caprice Christian , Freedman Rachel A. , Jemal Ahmedin , Mougalian Sarah Schellhorn , Hunt Katie N. , Haddad Tufia C. , Lemaine Valerie , Ghosh Karthik , Hieken Tina J. , Vachon Celine , Gross Cary Philip , Shah Nilay D.
Published: September 2018

6531

Background: Annual mammography is recommended to screen residual breast tissue for new cancers and recurrent disease after treatment for early stage breast cancer. This study aimed to assess mammography rates over time in breast cancer survivors. Methods: We used administrative claims data from a large U.S. commercial insurance database, OptumLabs, to retrospectively identify privately- and Medicare Advantage-insured women with operable breast cancer who had residual breast tissue after definitive breast surgery between 2006 and 2015. We required coverage for at least 13 months following surgery. For each subsequent 13-month time period, we only included women without a loss of coverage, bilateral mastectomy, metastatic breast cancer diagnosis, or non-breast cancer diagnosis. We calculated the proportion of patients who had a mammogram during each 13-month period following breast surgery. We used multivariable logistic regression to test for factors associated with mammography in the first 13 months. Results: The cohort included 26,011 women followed for a median of 2.9 years (IQR 1.9-4.6) after surgery; 63.1% were less than 65 years of age, and 74.4% were white. In their first year of follow-up, 86% underwent mammography, but by year 7, this decreased to 73%. Fewer than 1% underwent MRI instead of mammography. In multivariable analysis, mammograms were less likely during the first year after surgery among women aged < 50 years (odds ratio [OR], 0.7; 95% confidence interval [CI], 0.6 to 0.8), African Americans (OR, 0.7; 95% CI, 0.7 to 0.8), patients who underwent mastectomy (OR, 0.7; 95% CI, 0.6 to 0.7), and patients residing in the Western part of the country (OR, 0.9; 95% CI, 0.7 to 0.9). Those with 1-2 comorbidities were more likely (OR, 1.1; 95% CI 1.1-1.2) than those with none to have a mammogram during that period. Mammography use did not differ significantly by year of diagnosis (2006-2015). Conclusions: Even in an insured cohort, a substantial proportion of breast cancer survivors do not undergo annual surveillance mammography. Mammography use falls as the time from the early stage breast cancer diagnosis increases. Understanding factors associated with lack of mammographic screening may help improve survivorship care.