bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab (Nivo) vs investigator’s choice (IC) for platinum-refractory (PR) recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN; Checkmate 141): Outcomes in first-line (1L) R/m patients and updated safety and efficacy.
Authors: Gillison Maura L. , Blumenschein George R. , Fayette Jérôme , Guigay Joel , Colevas A. Dimitrios , Licitra Lisa , Harrington Kevin , Kasper Stefan , Vokes Everett E. , Even Caroline , Worden Francis P. , Saba Nabil F. , Iglesias Docampo Lara Carmen , Haddad Robert I. , Rordorf Tamara , Kiyota Naomi , Tahara Makoto , Lynch Mark John , Kopit Justin , Ferris Robert L. 
Published: September 2018

6019 Background: In CheckMate 141, a randomized, phase 3 trial, nivo demonstrated superior overall survival (OS) and better tolerability in patients (pts) with PR R/M SCCHN compared with IC. Pts with SCCHN progressing within 6 mos of platinum in the primary treatment setting have dismal prognosis. We report outcomes in pts who were PR in the primary or adjuvant setting, and updated results in the overall population. Methods: Pts (N = 361) with PR R/M SCCHN were randomized 2:1 to nivo 3 mg/kg every 2 weeks or weekly IC (methotrexate, docetaxel, or cetuximab). Primary endpoint was OS estimated by Kaplan-Meier method. Cox proportional hazards models were used to estimate hazard ratios (HRs) and confidence intervals (CIs). Additional endpoints include objective response rate (ORR) and safety. Outcomes were analyzed overall and post hoc in pts who were PR in the primary/adjuvant setting and received nivo/IC as 1L R/M therapy. Results: Characteristics of the 78 (21.6%) pts who received nivo (n = 52) or IC (n = 26) in the 1L R/M setting were similar to the overall population.Nivo significantly improved OS vs IC among 1L R/M pts (median [95% CI]: 7.7 mo [3.1, 13.8] vs 3.3 mo [2.1, 6.4]; HR [95% CI] = 0.56 [0.33, 0.95]); 12-mo OS rate: 39.2% vs 15.4%. ORR was 19.2% for nivo vs 11.5% for IC in this subgroup. At 11.4-mo minimum follow-up, updated efficacy and safety in the overall population were similar to the primary analysis. Median OS (95% CI) was 7.7 mo (5.7, 8.8) for nivo vs 5.1 mo (4.0, 6.2) for IC; HR (95% CI) = 0.71 (0.55, 0.90); P = 0.0048. For nivo vs IC, the 18-mo OS rate was 21.5% vs 8.3% and ORR was 13.3% vs 5.8%. Nivo doubled the median duration of response vs IC (9.7 vs 4.0 mo). Grade 3–4 treatment-related adverse event rates for nivo vs IC were 15.3% vs 36.0% overall and 27.5% vs 32.0% for 1L R/M pts; there were no new deaths due to study drug toxicity. Conclusions: Nivo significantly improved OS and increased ORR vs IC in a 1L R/M subgroup, supporting its use as 1L therapy for pts with PR R/M SCCHN. Nivo continued to show a significant survival benefit and better tolerability vs IC in pts with PR R/M SCCHN. Clinical trial information: NCT02105636.
Nivolumab (Nivo) vs investigator’s choice (IC) in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): Efficacy and safety in CheckMate 141 by prior cetuximab use.
Authors: Ferris Robert L. , Licitra Lisa , Fayette Jérôme , Even Caroline , Blumenschein George R. , Harrington Kevin , Guigay Joel , Vokes Everett E. , Saba Nabil F. , Haddad Robert I. , Ramkumar Shanmugasundaram , Russell Jeffrey , Brossart Peter , Tahara Makoto , Monga Manish , Zhu Jin , Colevas A. Dimitrios , Gillison Maura L. 
Published: September 2018

6020 Background: In CheckMate 141, nivo resulted in significantly prolonged overall survival (OS), favorable safety, and stable quality of life vs IC in patients (pts) with platinum-refractory (PR) R/M SCCHN. Cetuximab, a formal trial stratification factor, permits exploratory subgroup assessment. Outcomes by prior cetuximab use are described. Methods: CheckMate 141 was a randomized, open-label, phase 3 trial (NCT02105636) in which pts (N = 361) with PR R/M SCCHN were randomized 2:1 and stratified by prior cetuximab use to nivo 3 mg/kg every 2 weeks or IC of methotrexate, docetaxel, or cetuximab. The primary endpoint was OS; additional endpoints were progression-free survival (PFS), objective response rate (ORR), and safety. A multivariate analysis will explore influence of additional factors. Results: Nivo improved OS vs IC regardless of prior cetuximab, and improvement was greater in pts without prior cetuximab (Table). Median OS was longer for nivo vs IC in pts with PD-L1 expression ≥ 1% regardless of prior cetuximab, and in pts with PD-L1 expression < 1% without prior cetuximab. Among pts with PD-L1 expression ≥ 1%, ORR was higher with nivo vs IC with/without prior cetuximab. PFS was similar regardless of prior cetuximab. Grade 3–4 treatment-related adverse event rates for nivo vs IC were 11.7% vs 40.9% with prior cetuximab and 15.4% vs 26.7% without prior cetuximab. Conclusions: OS and ORR improved with nivo vs IC regardless of prior cetuximab use, and the magnitude of benefit was greater in pts without prior cetuximab exposure. These results support the use of nivo for R/M SCCHN regardless of prior cetuximab use. Clinical trial information: NCT02105636. [Table: see text]
Cost-effectiveness of nivolumab for treatment of platinum-resistant recurrent or metastatic squamous cell carcinoma of the head and neck.
Authors: Carroll Kate , Tringale Kathryn Ries , Zakeri Kaveh , Sacco Assuntina Gesualda , Barnachea Linda , Murphy James Don 
Published: September 2018

6026 Background: The Checkmate 141 randomized trial found that patients with platinum-refractory, recurrent or metastatic (R/M) squamous-cell carcinoma of the head and neck (SCCHN) treated with nivolumab had significantly longer overall survival than those treated with standard, single-agent therapy. However, nivolumab is more expensive than standard treatment. We conducted a cost-effectiveness analysis of nivolumab for the treatment of R/M SCCHN. Methods: We constructed a Markov model to simulate treatment with nivolumab or other single-agent therapy (docetaxel, cetuximab, or methotrexate) for patients with R/M SCCHN. Transition probabilities including disease progression, survival, and toxicity were derived from clinical trial data, while costs (in 2016 US dollars) and health utilities were estimated from the literature. Incremental cost-effectiveness ratios (ICERs), expressed as dollar per quality-adjusted life-year (QALY), were calculated with values less than $100,000/QALY considered cost-effective from a healthcare payer perspective. We conducted one-way and probabilistic sensitivity analyses to examine model uncertainty. Results: Our base-case model found that treatment with nivolumab increased overall cost by $59,000 and improved effectiveness by 0.2443 QALYs compared to single-agent therapy, leading to an ICER of $241,100/QALY. In sensitivity analyses, the model was most sensitive to the cost of nivolumab and assumptions about survival. Nivolumab would become cost-effective if the cost per cycle decreased from $13,432 to $5,716. If we assumed that all patients alive at the end of the Checkmate 141 trial were cured of their disease then nivolumab was still not considered cost-effective (ICER $160,000/QALY). Probabilistic sensitivity analysis also demonstrated relative stability of the cost-effectiveness model and found that treatment with nivolumab was cost-effective 0% of the time at a willingness-to-pay threshold of $100,000/QALY. Conclusions: While nivolumab significantly improves overall survival, at the current cost it would not be considered a cost-effective treatment option for patients with R/M SCCHN.
Nimotuzumab combined with cisplatin plus fluorouracil chemotherapy in patients with metastatic nasopharyngeal carcinoma after radical radiotherapy: A multicentre, open-label, phase II clinical trial.
Authors: Zhao Chong , Miao Jingjing , Shen Guanzhu , Li Jin-Gao , Zhang Ning , Shi Mei , Wang Lin , Hu Guoqing , Chen Xiaozhong , Hu Xuefeng , Wu Shi Xiu , Chen Jiaxin , Shao Xunfan , Xie Conghua 
Published: September 2018

6028 Background: Cisplatin plus fluorouracil (PF) is main therapy for metastatic nasopharyngeal carcinoma (NPC). However, the efficacy is not satisfactory, especially in patients with metastasis after radical radiotherapy. The purpose of this study was to investigate the efficacy and toxicity of Nimotuzumab combined with PF in patients with metastatic NPC after radical radiotherapy. Methods: Patients with untreated metastatic NPC after radical radiotherapy were recruited from 9 hospitals in China with Simon’s two-stage design. All patients received Nimotuzumab (200mg/w) and cisplatin (100mg/m2, day 1) plus fluorouracil (4g/m², day 1-4) every 3 weeks until progressive disease (PD) or unacceptable toxicity or a maximum of 6 cycles. If patients had still not progressed at this stage, Nimotuzumab (200mg/w) as monotherapy would be delivered until PD. This study was registered in ClinicalTrials.gov, Number NCT01616849. Results: Between Jun, 2012 and April, 2015, 35 patients were enrolled (Table). The objective response rate (ORR) and disease control rate (DCR) were 71.4% and 85.7%, and the median time of progression free survival (PFS) and overall survival (OS) were 6.97 and 11.01 months. The most common toxicities were leukopenia (94.1%), vomiting (97.1%) and nausea (97.1%); the grade 3/4 toxicities were leukopenia (62.9%) and mucositis (20.0%). There was only 1 patient have mild hypotension which related to Nimotuzumab. The ORR, DCR, median time of PFS and OS were 88.9%, 100.0%, 7.29 and 11.47 months in patients who received a total dose of Nimotuzumab ≥ 2400mg, respectively. Conclusions: Nimotuzumab combined with PF has achieved encouraging efficacy with an acceptable safety profile in metastatic NPC after radical radiotherapy. A phase III randomised study is needed. Clinical trial information: NCT01616849. [Table: see text]
Impact of early trials in molecularly-characterized patients (pts) with head and neck cancer (HNC).
Authors: Baste Neus , Dienstmann Rodrigo , Brana Irene , Viaplana Cristina , Jimenez Jose , Ruiz-Pace Fiorella , Bescos Coro , Lorente Juan , Giralt Jordi , Alberola Margarita , Nuciforo Paolo , Vivancos Ana , Del Campo Jose Maria , Tabernero Josep , Felip Enriqueta , Rodon Jordi 
Published: September 2018

6031 Background: Multiple genomic alterations were described in HNC, including squamous cell carcinomas (SCC), salivary gland (SG) and nasopharyngeal (NF) tumors. Tumor molecular profiling (TMP) may increase therapeutic alternatives in early trials for pts with refractory metastatic (met) HNC. We evaluate the impact of matched/unmatched therapy (mT/uT) in HNC with potentially targetable alterations. Methods: From 2010-16, 47 met HNC pts were treated in 57 early trials after TMP. Clinical benefit was measured by: time to progression (TTP); clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] > 4months [m]); progression-free survival [PFS] ratio≥1.3 (PFS under molecular therapeutics/PFS upon last prior chemotherapy [pT]). Results: Median age was 51 years; median number of pT lines was 1 (0-5). In total, 26 SCC, 11 SG, 8 NF and 2 nasosinusal pts (mostly with lymph nodes and lung met) were treated with small kinases (SK) inhibitors (inh) (50%; main targets PI3K/HER/FGFR), immune-oncology (IO) drugs (40%, PD-1/PD-L1), angiogenesis inh (5%) or chaperone, cytidine analog, RNA polymerase (5%). 14/57 trials were mT including CDKinh (1 CDKN2A mutation [mut]), PI3Kinh (5 PIK3CA mut, 2 PTEN mut), PI3K/MEKinh (1 NRAS mut), HERinh (1 ERBB3mut), FGFRinh (2 FGFR1mRNA high, 1 FGF3/4/19 ligand amplified) and porcupine inh (1 ZNFR3mut). Distribution by tumor: IO (16 SCC/5 NF), SKmT (8SG/4SCC/2NF) and SKuT (9SCC/4SG). Responses: 1CR in SCC (IO), 5 PR in SCC (4 IO, 1 FGFRinh), 3 PR in NF (1 cytidin analog, 1 IO, 1 PI3K/MEKinh). Benefit: median TTP 9.33m (CI95% 7-20) with upward trend in NF and SG vs SCC (HR 0.6;p = 0.28), without differences according to target therapies (HR 0.8; p = 0.9); CBR of 58%, without differences by tumor type (p = 0.42) or therapy (SKmT, SKuT, IO; p = 0.5); 60% with PFS ratio≥1.3, significantly higher in SCC and SG (p = 0.016), particularly with IO drug and SKmT, respectively. Conclusions: Considering our preselected fit population as bias selection, individualized treatment selection with novel therapeutics based on TMP, especially in NF and SG irrespective of targets (SKmT, SKuT, IO), and in SCC with IO drugs, seems to confer substantial clinical benefit.
Comprehensive targeted next-generation sequencing to reveal limited clonal evolution after concurrent chemoradiation in patients with squamous cell carcinoma of the head and neck.
Authors: Tinhofer Inge , Eder Theresa , Konschak Robert , Niehr Franziska , Jöhrens Korinna , Keilholz Ulrich , Budach Volker 
Published: September 2018

6059 Background: Recent next-generation sequencing (NGS) studies revealed a wide mutational spectrum in SCCHN. However, little is known about spatial intratumoral heterogeneity and temporal clonal evolution. Precise understanding of the genomic architecture of primary and recurrent/metastatic (R/M) tumors will be crucial for the development of personalized treatment and molecular biomarkers. Methods: In this pilot study, paired tumor samples (primary, R/M lesions) from 10 patients with locally advanced SCCHN who progressed after concurrent chemoradiation (CTRX) were included. Mutational profiling was performed by NGS targeting the exonic regions of 327 genes. Only somatic mutant variants with a difference of ≥0.15 in allele frequency (AF) between primary and R/M tumors were considered for further analysis. Results: Median time to progression was 6.2 months (range: 2.5-30.2). Overall, the difference in mutational patterns of primary and R/M tissue was very small. On average, one mutant variant (range: 0-2) was selectively detected in only one of the paired samples or differed in AF for ≥0.15. Nonetheless, clonal selection of mutant variants previously linked to disease progression was observed in 8 of 10 cases. In line with their gain of function, an increase in AF of TP53 missense mutations (R175H, R248Q) in the recurrent tumor - suggestive of the selection of treatment-resistant mutant TP53 subclones - was observed in two patients. Further variants with increased mutant AF in recurrent tumors were found in ADCY2, CDKN2A, FGFR3, MET, NOTCH1, PIK3CA and TGFBR2. Conclusions: We here provide first evidence that treatment-induced clonal selection after CRTX frequently occurs in SCCHN but is limited to only few gene alterations associated with an aggressive phenotype. This result is surprising given CRTX being a DNA-damaging regimen with inherent risk of de-novo mutagenesis and abundant time for clonal tumor evolution. Further investigations of spatial intratumoral heterogeneity and clonal evolution in larger patient cohorts are required for improving our understanding of treatment resistance and disease progression in SCCHN.
Standard of care vs reduced-dose chemoradiation after induction chemotherapy in HPV+ oropharyngeal carcinoma patients.
Authors: Rainey Hope , Roy Elizabeth , Selkridge Isaiah , Misiukiewicz Krzysztof , Gupta Vishal , Bakst Richard Lorne , Zhang David Y. , Kotz Tamar , Som Peter , Anderson Karen S. , Miles Brett A. , Genden Eric , Teng Marita , Bonomi Marcelo , Sikora Andrew Gregory , Demicco Elizabeth , Jia Rachel , Posner Marshall R. 
Published: September 2018

6069 Background: Locally advanced Human Papillomavirus (HPV) + oropharyngeal carcinoma (OPC) has a significantly better response, locoregional control and survival compared to non HPVOPC. Standard-dose chemoradiotherapy (sdCRT) results in significant side effects, leading to acute and life-threatening late morbidity. We studied whether reduced dose chemoradiation (rdCRT) after induction chemotherapy (IC) resulted in equivalent progression-free survival (PFS) compared to sdCRT + IC with decreased late morbidity. Methods: Patients with locally advanced OPC and < 20 pack years (py) smoking history were tested for p16 and then HPV by type-specific PCR. After 3 cycles of docetaxel, cisplatin and fluorouracil (TPF) IC all HPV+/p16+ subjects underwent clinical and radiographic evaluation. Clinical responders were randomized to either sdCRT (70Gy) or rdCRT (56Gy) with weekly carboplatin (AUC 1.5) at a 1:2 ratio. The primary endpoint was 2 year PFS; the secondary endpoint was 2 year overall survival (OS). Toxicity, late morbidity and swallowing were monitored. Results: 23 patients were enrolled and 20 randomized, 8 to sdCRT and 12 to rdCRT; 2 were HPV- and 1 refused further therapy after IC and were not randomized. Median age was 56.5 yrs (range 36-78); 30% were African-American, 10% were Hispanic, 5% were female; 16 were HPV 16+ and 4 were other high risk (HR) variants; 60% never smoked, 25% were < 10 py, and 15% were 10-20 py; 70% had high risk features: T4, N2c, or N3. Clinical response to TPF was 100%; 70% had a clinical complete response. As of February 1, patients have been followed for a median of 37.5 months (range 21.7 – 49.5). 2 year PFS/OS for sdCRT and rdCRT are 87.5% vs 83.3% (log-rank test p = 0.85), respectively. All 3 failures were local or regional and 2 of 3 occurred in non HPV16 HR variants. Conclusions: HPV+ OPC patients who received rdCRT after TPF IC had similar PFS/OS compared to those receiving sdCRT. These results uphold the potential clinical benefit of radiation dose reduction as a treatment option with comparable survival to the standard radiation dose. A Phase III trial comparing IC plus rdCRT to sdCRT alone or with IC is warranted in this population. Non-HPV16 HR variants may have a worse outcome. Clinical trial information: NCT01706939.
Association of activating NOTCH1 mutations in adenoid cystic carcinoma with shorter progression-free survival to systemic therapy.
Authors: Ferrarotto Renata , Duran Alper H , Wei Wei , Carter Brett W. , El-Naggar Adel K. , Su Shirley Y , Bell Diana , Kies Merrill S. , William William N. , Glisson Bonnie S. , Godoy Myrna , Heymach John 
Published: September 2018

6089 Background: We previously reported that activating NOTCH1 mutations occurs in approximately 20% of ACCs and drive a phenotype with solid histology, liver and bone metastases, poor prognosis, and potential responsiveness to Notch1 inhibitors; however the impact of NOTCH1mutations on responsiveness to systemic therapy in ACC is unknown. The aim of this study was to evaluate the ORR and median PFS (mPFS) to systemic therapy in patients with metastatic ACC according to their Notch1 status. Methods: We identified 20 ACC patients with measurable disease that underwent treatment at MDACC and had tumor molecular profile. A radiologist blinded to the patient’s NOTCH1status performed review of all images. Measurement of target lesions was captured by a quantitative imaging analysis tool for ORR assessment by RECIST 1.1. PFS was estimated by Kaplan-Meier method. Comparisons of PFS between groups were performed using log-rank test. P≤0.05 was considered statistically significant. Results: Out of 20 patients, 4 (20%) were NOTCH1 mutant. Notch1 pathway activation status by immunohistochemistry (NICD) was available for 15 patients, 10 were positive. The median number of therapy lines was 2 (range 1-6). Best ORR among 49 treatment plans across all lines of systemic therapy including chemotherapy (15), anti-EGFR (10), anti-VEGFR (11), and others (13) was PR in 2 (4%), SD in 29 (59%), and PD in 18 (37%). During first line treatment, patients with NOTCH1 mutations had significantly shorter mPFS compared to NOTCH1 wild-type (2.97 vs. 6.92 months, P = 0.02). The PFS rate at 3 months was 25% for NOTCH1mutants vs. 81% for wild-type. A trend towards shorter PFS was seen in NICD positive vs. negative (3.58 vs. 6.74 months, P = 0.2). Conclusions: NOTCH1 mutations in ACC are associated with shorter PFS during first-line treatment. Validation of these findings is warranted in larger patient cohorts.
Racial composition in trials supporting the U.S. approval of anti-cancer new molecular entities (NMEs): 2011- 2016.
Authors: Fashoyin-Aje Lola A. , Fernandes Laura L. , Lemery Steven , Keegan Patricia , Sridhara Rajeshwari , Bull Jonca C. , Pazdur Richard 
Published: September 2018

6518 Background: In New Drug- and Biologics License Applications, clinical trials provide the primary safety and efficacy data upon which approval decisions are made. Low numbers of patients from racial groups that experience higher incidence and/or mortality from some cancers compared to the overall US population, may limit the generalizability of trial results. The Census estimates that the US population is 77.1%White, 13.3% Black/ African American (AA), 5.6% Asian, 1.2% American Indian/ Alaska Native (AIAN), and 0.2% Native Hawaiian/ Other Pacific Islander (NHPI). FDA conducted an analysis to compare the racial composition in trials supporting the approval of NMEs for the treatment of solid tumor malignancies. Methods: We reviewed the marketing applications of the 33 NMEs approved between 2011- 2016 to identify trials that provided the primary evidence of safety and efficacy. Results: A total of 29941 patients were enrolled. The table below illustrates enrollment by race (excluding Non-Hispanic, Hispanic, Other, Mixed Race & Missing) and approval year. Conclusions: The proportion of White patients enrolled in the US (88%) is higher than the proportion of Whites in the US population. However, the enrollment of AA and NHPI/AIAN patients is low and below the proportional representation of AA and NHPI/AIAN in the US. While enrollment targets may differ across cancer type and by race, the racial composition of patients enrolled in the trials that support the approval of cancer therapeutics should be reflective of the likely US patient population for whom these agents will be prescribed. The majority of Asian patients enrolled were from RoW while the majority of AA and NHPI/AIAN patients were enrolled from the US. Increasing the representation of racial minority patients in oncology trials will require targeted recruitment and enrollment of these patients in US sites. [Table: see text]