bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of nivolumab (N) plus ipilimumab (I) in radioidine refractory differentiated thyroid cancer (RAIR DTC) with exploratory cohorts in anaplastic (ATC) and medullary thyroid cancer (MTC).
Authors: Lorch Jochen H. , Barletta Justine A. , Nehs Matthew , Uppaluri Ravindra , Alexander Erik K. , Haddad Robert I. , Hanna Glenn J. , Margalit Danielle Nina , Tishler Roy B. , Schoenfeld Jonathan Daniel , Goguen Laura A , Jabiev Azad , Sorensen Meredith J , Ahmadi Sara , Marqusee Ellen , Kim Matthew I , Stanizzi Darren , Harris Ethan , Kacew Alec , Barbie David Allen 
Published: May 2020

6513 Background: Treatment options for aggressive TC are limited. Pre-clinical data suggests efficacy of CTLA-4 plus PD-1 blockade in aggressive RAIR TC. Methods: This investigator initiated phase II study tested N (3mg/kg every 2 weeks) plus I (1mg/kg every 6 weeks) until disease progression or completion of 24 mo of treatment in RAIR differentiated TC including poorly differentiated TC (PDTC) with exploratory cohorts in anaplastic (ATC) and medullary TC (MTC). Radiographic response rate by RECIST v1.1 (CR+PR) was primary endpoint. At least 6 pts with disease response among n=32 DTC provided 84% power to distinguish between a 10% and a 25% RR (one-sided 9% binomial test). Results: Accrual is complete with n=32 patients with DTC, 10 with ATC and 7 with MTC enrolled between October 2017 and May 2019. Thirty-two DTC included: n=17 papillary, n=7 Hurthle, n=4 follicular TC, n=4 PDTC. Among n=49, median (range) age was 65 (30-88), 51% (25/49) were female. To date, in DTC, 3/32 achieved a PR (n=2 Hurthle and n=1 PDTC), 9.4% RR (.95CI:2%-25%). One near complete response has been observed. Among pts w ATC, 3/ 10 profound PR by RECIST occurred (30% RR, .95CI: 7%-65%). Among them, two remain without clear evidence of disease at 26 and 13 mo after treatment start. No PR's were observed in MTC. Most frequent grade 3-4 TRAEs were as expected and included increased lipase (n=8), increased serum amylase (n=4). There was an unexpected number of treatment related adrenal insufficiency (AI) (n=4) which was associated with long PFS (range 10.1—16.4+mo). Conclusions: N+I appears to have considerable activity in ATC. In unselected RAIR DTC, activity was low but responses were seen in PDTC and Hurthle cell TC. Exceptional responses with prolonged remissions were observed. Clinical trial information: NCT03246958 .
Updated analysis of the inducible T-cell co-stimulatory receptor (ICOS) agonist, GSK3359609 (GSK609), combination with pembrolizumab (PE) in patients (pts) with anti-PD-1/L1 treatment-naïve head and neck squamous cell carcinoma (HNSCC).
Authors: Angevin Eric , Groenland Stefanie L. , Lim Annette May Ling , Martin-Liberal Juan , Moreno Victor , Trigo Jose Manuel , Le Tourneau Christophe , Mathew Matthen , Cho Daniel C. , Hansen Aaron Richard , Vicente David , Maio Michele , Italiano Antoine , Bauman Jessica Ruth , Chisamore Michael Jon , Zhou Helen , Ellis Catherine Elizabeth , Ballas Marc S. , Hoos Axel , Rischin Danny 
Published: May 2020

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 .
Influence of Eastern Cooperative Oncology Group performance status (ECOG PS), tumor size and age on patient outcomes after anlotinib treatment: A subgroup analysis based on ALTER01031 trial for medullary thyroid carcinoma (MTC).
Authors: Gao Ming , Chi Yihebali , Zheng Xiangqian , Li Dapeng , Tang Pingzhang , Xu Zhengang , Chen Xiaohong , Ge Minghua , Zhang Yuan , Guo Zhuming , Wang Jun , Chen Jie , Zhang Jiewu , Cheng Ying , Li Zhendong , Liu Hui , Qin Jianwu , Zhu Jingqiang , Cheng Ruochuan 
Published: May 2020

6527 Background: Anlotinib is a newly developed TKI achieved a nearly 2-fold PFS prolongation in a randomized, placebo-controlled phase 2b trial (NCT02586350) for MTC, the results of which were firstly published in 2019 ASCO annual meeting. This subanalysis examined the influence of baseline demographic (ECOG PS score, age) and tumor size on efficacy in this study. Methods: Kaplan-Meier method was applied to estimate the median PFS (mPFS) for subgroups of patients (pts) received anlotinib or placebo based on ECOG PS score (0 vs. 1), median tumor lesion diameter ( < 67 vs. ≥67mm) and age ( < 55 vs. ≥55 years old). Results: 91 eligible pts were randomly assigned in a 2:1 ratio to receive anlotinib or placebo. The numbers of pts in each subgroup were summarized in the table below. In placebo arm, mPFS did not differ significantly between pts with ECOG PS 0 and 1 (11.3 vs. 11.1months; HR = 0.895 [95% CI 0.347, 2.312], P = 0.821) or between pts with tumor lesion diameter < 67mm and ≥ 67mm (7.0 vs. 11.1 months; HR = 1.168 [95% CI 0.463, 2.945], P = 0.737). Conversely, pts in anlotinib arm with ECOG PS 0 obtained more PFS benefits (34.6 vs. 14.0 months; HR = 0.331 [95% CI 0.163, 0.671], P = 0.002). Similarly, anlotinib treated pts with tumor lesion diameters < 67mm achieved a longer mPFS (Not reached vs. 14.0 months, HR = 0.567 [95% CI 0.280, 1.147], P = 0.111). Consistent with that has been verified in differentiated thyroid cancer, high age predicted poor prognosis as mPFS were 14.3 months and 6.8 months in pts < 55 and ≥ 55 years old respectively in placebo arm (HR = 0.322 [95% CI 0.116, 0.893], P = 0.007).). Anlotinib treatment exhibited PFS improvement to pts in both age groups but higher PFS prolongation was observed in pts < 55 years old (22.4 vs. 14.0 months; HR = 0.720 [95% CI 0.321, 1.614], P = 0.381). Conclusions: This analysis showed that for pts in placebo arm, PFS was similar regardless of functional status (ECOG PS) or tumor size while older pts had higher progression risk. Treatment with anlotinib exhibited greater PFS benefits for pts with better functional status (ECOG PS = 0), younger age or lower tumor burden. These results indicated that it is reasonable to start anlotinib treatment at a relative earlier disease stage before the worsen of ECOG PS, increase of tumor size or ageing. Clinical trial information: NCT02586350 . [Table: see text]
Initial analyses of a phase I/II trial of durvalumab (D) plus tremelimumab (T) and stereotactic body radiotherapy (SBRT) for oligometastatic head and neck carcinoma.
Authors: Bahig Houda , Aubin Francine , Nguyen-Tan Phuc Felix , Souliere Denis , Palma David A. , Charpentier Danielle , Debenham Brock J , Jamal Rahima , Sultanem Khalil , Ballivy Olivier , Filion Edith , Wong Philip 
Published: May 2020

6531 Background: PD-1/PD-L1 +/- CTLA-4 blockade in head-and-neck carcinoma (HNSCC) has shown signs of clinical activity. SBRT aims to reduce tumor burden and perhaps be immune-stimulatory. This analysis seeks to assess the safety and efficacy signal of the triple treatment combination (TTC) consisting of SBRT sandwiched between cycles of D (αPD-L1) and T (αCTLA-4) in oligometastatic (2-10) HNSCC. Methods: This is a single arm multi-institutional phase I/II trial (NCT03283605). D (1500 mg) and T (75 mg) were given for 4 monthly cycles, followed by monthly D. SBRT to 2-5 lesions was administered during cycle 2. The median prescribed and maximum SBRT doses were 40 Gy (range:18-50) and 49 Gy (range:28-61), respectively, given in 3-5 fractions. Global health status was derived from EORTC QLQ C30 questionnaires. Results: At data cut-off (Dec 31, 2019), 20 patients were recruited, of which 16 had a study treatment and were analyzed. Table describes the patient characteristics. There were 1 CTCAE V5.0 Grade 2 and 1 Grade 3 (both GI) serious adverse event (SAE) attributable to D and T. Two patients had unrelated SAEs (1 Grade 3-hypercalcemia and 1 Grade 5-GI). The Grade 5 SAE was a gastric hemorrhage that occurred the night of the first D + T infusion. There was no Grade 3+ AE secondary to SBRT. Thus, SBRT did not add to the 2/16 patients who had D + T related SAEs. Global health status scores did not differ statistically between baseline (75) and cycle 3 (73). Of the 14 patients that received SBRT, 7 patients had RECIST target lesions untreated by SBRT. The best responses for these 7 patients were: 1 CR, 3 PR, and 3 SD. When SBRT treated lesions are included and analyzed per RECIST (n = 14), there were 9 PR, 3 SD and 2 PD. The estimated median progression free survival was 7.2 months. Conclusions: The first 16 evaluable patients demonstrated tolerable profiles to the TTC (D + T + SBRT) for the treatment of oligometastatic (≤10 lesions) HNSCC. Best response rates were encouraging and could be due to the addition of SBRT during immunotherapy that served to either stimulate the immune system or annihilate slow responding or immunotherapy resistant lesions. Smaller overall tumor burden and 7/16 patients being treated in first line could also have contributed to better results. Clinical trial information: NCT03283605 . [Table: see text]
Efficacy and tolerance of carboplatin-cetuximab in patients with metastatic or recurrent head and neck squamous cell carcinoma unfit for extreme regimen.
Authors: Le Roy Charlotte , Vernerey Dewi , Evin Cecile , Crespel Celine , Samaille Thomas , Le Tourneau Christophe , Huguet Florence 
Published: May 2020

6539 Background: Head and neck squamous cell carcinoma (HNSCC) is the fourth cause of death by cancer in France. For metastatic patients, the standard first line treatment is the EXTREME regimen. However, a lot of these patients have a poor performance status (PS) and/or several comorbidities making them unfit for this regimen. We have treated them with carboplatin and cetuximab (simplified EXTREME regimen) since 2007. The aim of this study is to assess the efficacy and tolerance of this regimen in this frail population. Methods: We retrospectively reviewed the medical charts of all patients treated with simplified EXTREME regimen for recurrent or metastatic HNSCC in three French academic hospitals between 2007 and 2017. The primary endpoint was overall survival (OS) and secondary endpoints were progression free survival (PFS), overall response rate (ORR), identification of prognostic factors, and toxicity. Results: 103 patients were included with a median age of 63 y.o., 60% had a PS 0-1 and 40% a PS 2-3. With a median follow-up of 30.2 months, median OS was 7.2 months and median PFS 3.7 months. ORR was 39% and 24% of patients had disease stabilization. On univariate analysis, a PS of 2 or more was significantly associated with a worse OS (median OS 10.1 months if PS 0-1 versus 4.6 months if PS 2-3; HR = 1.68; 95%CI = 1.11-2.57; p = 0.01). Acute grade 3-4 hematologic and non-hematologic toxicity rates were 25.2% and 27.2%, respectively, with 11.8% of thrombopenia, 9.7% of neutropenia, 10% of skin toxicity, and 12.6% of asthenia. Patients with grade 1 or more skin toxicity had a higher ORR (HR = 3.44; 95%CI = 1.16-10.23; p = 0.03) and a prolonged OS (HR = 0.37; 95%CI = 0.23-0.58; p < 0.0001) and PFS (HR0.29; 95%CI = 0.19-0.47; p < 0.0001). During treatment, 29% of patients had a pain decrease, 13.5% a gain of weight, and 17.2% an improvement in PS. Conclusions: This is the largest cohort of patients treated with simplified EXTREME for HNSCC. Simplified EXTREME was well tolerated in this frail population with a high ORR. Patients with a good PS had prolonged survival. Interestingly, skin toxicity of any grade was significantly correlated with treatment efficacy.
Phase I dose escalation of stereotactic body radiation therapy and concurrent cisplatin for re-irradiation of unresectable, recurrent head and neck squamous cell carcinoma.
Authors: Echevarria Michelle , Chung Christine H. , Kirtane Kedar , Muzaffar Jameel , Arrington John , Farinhas Joaquim , Caudell Jimmy J. 
Published: May 2020

6543 Background: For patients with unresectable, previously radiated, locoregionally recurrent head and neck cancer, stereotactic body radiation therapy (SBRT) has become an attractive option. The use of high daily doses of radiotherapy may overcome the inherent radioresistance of these recurrent cancers. Given the resistant and advanced nature of many of these cancers, the addition of chemotherapy to radiotherapy is typically recommended as a radiosensitizer. We therefore performed a phase I clinical trial in order to establish a maximum tolerated dose of SBRT with concurrent chemotherapy in locoregionally recurrent head and neck cancer. Methods: Major inclusion criteria were recurrence of previous squamous cell carcinoma of the head and neck in patients who had previously undergone radiotherapy to doses ≥ 45 Gy to the area of recurrence, ≥ 6 months prior to enrollment, and who were medically unfit for surgery, deemed unresectable, or refused surgery. Patients were treated with radiation therapy every other day for five fractions at three dose levels; 30 Gy, 35 Gy, and 40 Gy. Cisplatin was given prior to every SBRT fraction at a dose of 15 mg/m2. Patients were monitored for safety and tolerability for any grade 4 or greater toxicity (per CTCAE v4.0) that occurred within 3 months from the start of SBRT. Primary end point was maximum tolerated dose (MTD). Results: Twenty patients were enrolled and of those 17 patients were evaluable for the primary endpoint. Nine patients had a primary tumor in the oropharynx, four patients in the oral cavity, three in the neck, one in the larynx, and one simultaneously in the larynx and neck. Of the three patients that were not evaluable two withdrew consent, and one patient in the 30 Gy dose level died of unknown causes two weeks following completion of treatment. Due to safety concerns the 30 Gy dose level was expanded an additional three patients, and no further dose limiting toxicities (DLTs) were observed. At the 35 Gy and 40 Gy dose level there were no reported grade 4 or 5 adverse events (per CTCAE v4.0). There were 5 (27%) reported grade 3 toxicities and 12 (66%) grade 2 toxicities. Conclusions: This phase I study demonstrates that 40 Gy SBRT with concurrent cisplatin at a dose of 15mg/m2 is feasible, safe, and well tolerated. Patients continue to be followed for secondary outcomes of local control and overall survival. Clinical trial information: NCT02158234 .
Molecular biomarkers to identify patients (pts) who may benefit from durvalumab (D; anti-PD-L1) ± tremelimumab (T; anti-CTLA-4) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) from HAWK and CONDOR studies.
Authors: Li Weimin , Matakidou Athena , Ghazoui Zara , Si Han , Wildsmith Sophie , Morsli Nassim , Mann Helen , Wrona Magdalena , de Los Reyes Melissa , Raja Rajiv , Barker Craig , Whiteley Jessica , Zhang Qu , Fayette Jerome , Zandberg Dan Paul , Mesia Ricard , Siu Lillian L. 
Published: May 2020

6548 Background: Baseline tumor and germline biomarkers in R/M HNSCC were analyzed for predictive potential in pts benefitting from D or D+T. Methods: In HAWK (NCT02207530), 112 pts (PD-L1 tumor cells [TC]≥25%) received D (10 mg/kg Q2W for ≤12 m); in CONDOR (NCT02319044), 67 pts (PD-L1 TC < 25%) received D (10 mg/kg Q2W for ≤12 m), 133 pts received D+T (D 20 mg/kg Q4W, T 1 mg/kg Q4W for ≤12 m), and 67 pts received T (10 mg/kg Q4W [7 doses] then Q12W [2 doses] for ≤12 m) VENTANA PD-L1 (SP263) Assay determined PD-L1 status. Paired FFPE archival tumor and PBMC samples (as germline control) in the HAWK and CONDOR trials were evaluated by whole exome sequencing (WES). Tumor mutation burden (TMB) was number of somatic mutations/megabase. HLA class I types were obtained via WES of PBMCs (CONDOR only). HPV and neutrophil-to-lymphocyte ratio (NLR) were tested locally in CONDOR. Wilcoxon, log-rank tests, and COX-PH models were used. Pooled D & D+T data were analyzed unless noted. Results: 153 pts had paired evaluable FFPE tumor and PBMC samples (HAWK, n = 48; CONDOR, n = 105). TMB distributions were similar between studies ( P= 0.43). TMB correlated with smoking ( P= 0.02) but not HPV ( P= 0.24), NLR ( P= 0.66), or PD-L1 status ( P= 0.43). Overall, high TMB (≥upper tertile) trended with longer OS vs low TMB in all evaluable pts (N = 153; 9.0 vs 5.6 m; HR = 0.70; 95% CI = 0.48-1.01); P= 0.06). In HAWK, there was no association of TMB with OS. In CONDOR, pts (D and D+T arms) with high TMB vs low had significantly longer OS (N = 76; 16.3 vs 5.3 m; HR = 0.53; 95% CI = 0.31-0.92). TMB and OS association was further assessed by increasing TMB cutoffs. Improved HRs trended with higher cutoffs; cutoffs ≥upper quartile significantly linked to OS.TMB was not associated with PFS or ORR. Pts with low PD-L1 and low TMB had worse OS compared to pts with high PD-L1 or high TMB. Pts with high NLR (≥median) and low TMB had significantly worse OS than pts with low NLR and high TMB (HR = 2.63, P< 0.001). Analysis of germline HLA alleles revealed significantly poorer survival for carriers of the HLA-B*15:01 allele (9.4%) (HLA-B variant status did not affect TMB and OS association in CONDOR). Germline HLA heterozygosity did not impact OS. Pts with mutations in ATM (5%), a DNA damage repair gene, also trended with prolonged OS. Conclusions: TMB is a possible predictive biomarker of IO HNSCC therapy. Combined analysis of NLR and TMB may provide additional PD-L1 data in assessing pts most likely to have long-term benefit. Clinical trial information: NCT002207530, NCT02319044 .
Prognostic role of pre-treatment magnetic resonance imaging (MRI) radiomic analysis in patients with squamous cell carcinoma of the head and neck (SCCHN).
Authors: Alfieri Salvatore , Romanò Rebecca , Bologna Marco , Calareso Giuseppina , Mirabile Aurora , Ferri Andrea , Marcantoni Alessandra , Grosso Enrica , Tarsitano Achille , Valerini Sara , Vecchio Stefania , Deantonio Letizia , Blengio Fulvia , Ibrahim Toni , Mancinelli Moela , Ascoli Francesco , Bossi Paolo , Locati Laura Deborah , Mainardi Luca , Licitra Lisa F. 
Published: May 2020

6553 Background: Emerging data suggest that radiomics can be used to predict outcomes in SCCHN. At present, only few data are available for pre-treatment MRI. Methods: Study population was retrieved from an ongoing multicenter, randomized, prospective trial (NCT02262221, HETeCo) evaluating health and economic outcomes of two different follow-up (FUP) strategies (intensive vs non-intensive) in effectively cured stage III-IV (VIII TNM ed.) SCCHN. We selected only patients with both pre- and post-contrast enhancement T1 and T2-weighted baseline MRI (b-MRI) and at least 2 years (2y) of FUP. A radiomic model was developed to identify high risk (HR) and low risk (LR) of disease recurrence. Radiomic features (RF) were extracted from the primary tumor in the b-MRI. The best RF combination was selected by Least Absolute Shrinkage and Selection Operator (LASSO). Ten-fold cross-validation was used to compute sensitivity, specificity and area under the curve (AUC) of the classifier. Kaplan-Meier (KM) curves were estimated for HR and LR, for both overall survival (OS) and disease-free survival (DFS) and log rank test was performed. Three years (3y)-DFS and OS were also estimated for the two groups. The radiomic risk class was used as a new variable in a multivariate Cox model including well established prognostic factors in SCCHN (TNM stage, subsite and HPV). Results: Out of 155 enrolled HETeCO patients, 98 baseline imaging were retrieved of which 57 b-MRI. Of these, 51 met the eligibility criteria (25 in intensive and 26 in non-intensive arm). Baseline patients’ characteristics were: median age 66 yr (38-86); sex (M 42; F 9); median smoking history: 30 packs/y (1-100); 25 oral cavity (49%), 18 oropharynx (35%, 14 HPV+), 6 larynx (12%), 2 hypopharynx (4%). At a median FUP of 42 months (25-64), 45 (88%) patients are still alive. The recurrence rate was 20% (10/51, of which 2 distant). In total, 1608 RF were extracted. The sensitivity, specificity and AUC of the classifier were 90%, 76%, and 80%, respectively. The radiomic risk class was found to be an independent prognostic factor for both DFS and OS (p=0.01 and p=0.046, respectively). KM curves for DFS and OS were significantly different between HR and LR groups (p=0.002 and p=0.04, respectively). In HR vs LR, 3-y DFS and OS were: 78% [61-100%] vs 97% [90-100%], and 88% [75-100%] vs 96% [88-100%], respectively. Conclusions: Radiomics of pre-treatment MRI can predict outcomes in SCCHN. External validation of this preliminary radiomics-based model is currently ongoing.