bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune checkpoint inhibitor in nasopharyngeal carcinoma: Multi-institution experience.
Authors: Park Jong Chul , Wirth Lori J. , Clark John R , Durbeck Julia , Ho Won Jin , Boudadi Karim , Kang Hyunseok
Published: May 2020

6538

Background: The current standard treatment for unresectable recurrent/metastatic (R/M) nasopharyngeal carcinoma (NPC) is cytotoxic chemotherapy but prognosis remains poor. Recent phase I-II trials of anti-PD-1 therapy (aPD-1) have demonstrated promising activity in R/M NPC, but the published experience is primarily limited to Epstein-Barr virus (EBV) positive tumors in the Asian population. Here we report our three institutional real-world experience with aPD-1 in patients (pts) with R/M NPC. Methods: A retrospective analysis was conducted after IRB approval at the Massachusetts General, Johns Hopkins, and University California San Francisco Hospitals. Demographic and clinical data was collected on pts with R/M NPC who received aPD-1 at the participating institutions. Objective response rate (ORR) was the primary outcome of interest and progression free survival (PFS) and overall survival were secondary outcomes. Univariate and multivariate analyses were conducted to assess association between clinicopathologic factors and outcomes, using logistic regression models. Results: A total of 36 pts were identified: 20 pts were treated with pembrolizumab and 16 with nivolumab. Median age was 50 (15-74). Twenty-nine (81%) were male. Twenty pts (56%) were Asian. Twenty-nine pts (81%) had EBV positive disease. Nine (25%) had aPD-1 as first-line therapy (1L). Molecular profiling results were available in 16 pts: TP53 mutation was the most common alteration (25%) and was limited to EBV negative tumors. Median total mutational burden (TMB) was 3/Mb (1-28). Median PD-L1 expression was 10% (0-90). Median follow up was 13.9 months (mos). Objective response was evaluable in all 36 pts: 9 pts achieved objective response (ORR 25.0%, 95% CI 12.1-42.2) with 2 complete responses: EBV positive vs. negative (27.6% vs. 14.2%, P=0.472), Asian vs. non-Asian (25% vs. 25%, P=1.000), and 1L vs. >1L (33.3% vs. 22.2%, P=0.511). Thirteen pts had stable disease (disease control rate 61.1%). Responses were seen in both TMB high (28/Mb) and low (1/Mb) tumors and no association with PD-L1 expression was observed. One-year survival rate was 81.3%. EBV positive pts had a trend towards better survival (84.8 vs. 66.7, P=0.640). Median PFS was 5.5 mos and not different between EBV positive vs. negative pts (5.6 vs. 4.0 mos, P=0.919). Conclusions: Our multi-institutional real-world experience with checkpoint inhibitor therapy in R/M NPC confirms that a similar degree of activity is seen as reported in the phase I-II experience in diverse races, but efficacy seems more prominent in EBV positive disease.
Clinical response and biomarker analysis of POLARIS-02 a phase II study of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with metastatic nasopharyngeal carcinoma.
Authors: Wang Fenghua , Wei Xiao-Li , Feng Jifeng , Li Qi , Xu Nong , Hu Xichun , Liao Wangjun , Jiang Yi , Lin Xiaoyan , Zhang Qingyuan , Yuan Xianglin , Huang Haixin , Chen Ye , Dai Guanghai , Shi Jianhua , Shen Lin , Yang Shujun , Shu Yongqian , Liu Yunpeng , Xu Rui-hua ,   Shanghai Junshi Biosciences
Published: May 2020

6542

Background: Metastatic nasopharyngeal cancer (mNPC) patients progressed after standard therapy have limited treatment options. This study is to evaluate the clinical efficacy and safety of toripalimab in mNPC patients refractory to standard chemotherapy treatment (Clinical trial ID: NCT02915432). Methods: Patients receive 3 mg/kg toripalimab Q2W via IV infusion until disease progression, unacceptable toxicity, or voluntary withdrawal. Clinical response is assessed every 8 weeks according to RECIST v1.1. Tumor PD-L1 expression, plasma EBV titer and other biomarkers will be evaluated for correlation with clinical response. Results: From Dec 2016 to Feb 2019, 190 mNPC patients were enrolled from 17 participating centers in China. The median age was 46 years with 83% male. Patients were heavily pretreated with a median of 2 lines of prior systemic treatments. By the cutoff date of Jan 17, 2020, 97% patients experienced treatment related adverse events (TRAE). Most common TRAE included anemia, hypothyroidism, AST increased, proteinuria and fever. Grade 3+ TRAE occurred in 28% patients. Among 190 patients assessed by Independent Review Committee per RECIST v1.1, 6 CR, 33 PR and 40 SD were observed for an ORR of 20.5% and a DCR of 41.6%. The median DOR was 12.9 months. The median PFS and median OS were 1.9 months and 18.6 months respectively. PD-L1+ patients (n=48) had higher ORR than PD-L1- patients (n=134), 27.1% versus 19.4%. By tumor histology, ORR was higher in keratinizing NPC (n=8) than non-keratinizing NPC (n=168), 62.5% versus 19.0%. 144 patients had valid plasma EBV titer measured every 28 days during the study. An average drop of 101-fold plasma EBV titer from baseline was observed in patients with objective responses. Patients with 2-fold+ drop in plasma EBV titer on day 28 (n=60) went on to have 48.3% ORR and 76.7% DCR, whereas patients with less than 2-fold drop (n=88) had 5.7% ORR and 25.0% DCR. 14 responding patients who later developed progressive disease had at least 2-fold+ increase of plasma EBV tier 3-months (median) before radiographic identification of disease progression. Conclusions: Toripalimab demonstrated encouraging clinical activity with a manageable safety profile in mNPC patients refractory to standard chemotherapy. Patients with 2-fold+ drops in plasma EBV titer on day 28 from baseline had favorable clinical response of 48.3% ORR, which might be used as a predictive biomarker. Clinical trial information: NCT02915432 .
INDUCE-1: Report on safety run-in cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (5-FU/plat), with or without pembrolizumab (PE), for the treatment of advanced solid tumors.
Authors: Massarelli Erminia , Balmanoukian Ani Sarkis , Vieito Maria , Le Tourneau Christophe , Hernandez-Guerrero Tatiana , Trigo Jose Manuel , Aljumaily Raid , Chisamore Michael Jon , Rogan Debra , Sung Ruby , Henry Courtney , Turner David , Yadavilli Sapna , Franco Sonia , Ellis Catherine Elizabeth , Ballas Marc S. , Hoos Axel , Rischin Danny
Published: May 2020

6544

Background: The KEYNOTE-048 study (Burtness, at al. Lancet 2019;394:1915–28) led to approval of PE in combination with 5-FU/plat for first-line (1L) treatment of head and neck squamous cell carcinoma (HNSCC). The Phase I INDUCE-1 study (NCT02723955) has shown that GSK609±PE has a manageable safety profile in patients (pts) with advanced solid tumors (Hansen, at al. Annals of Oncology 2018;29[suppl_8]:viii404) and that GSK609 combined with PE has anti-tumor activity in pts with anti-PD-1/L1-naïve HNSCC (Rischin, et al. Annals of Oncol 2019;30[Supplement_5]:v454–5). To evaluate the safety of GSK609±PE in combination with 5-FU/plat, we initiated additional safety cohorts. Methods: Pts eligible for GSK609+5-FU/plat had a diagnosis of advanced selected solid tumors and ≤5 prior lines of systemic therapy. Pts eligible for GSK609+PE+5-FU/plat had a diagnosis of recurrent or metastatic 1L HNSCC deemed incurable by local therapies. 5-FU/plat was administered every 3 weeks (Q3W) for 4-6 cycles (Burtness, at al. Lancet 2019;394:1915–28); GSK609 24 or 80 mg ±PE 200 mg were administered Q3W for up to 2 years/35 cycles or until disease progression or unacceptable toxicity. Results: Twenty-nine pts were enrolled in the 5-FU/plat safety cohorts: 10 pts in the GSK609+5-FU/plat cohort and 19 pts in the GSK609+PE+5-FU/plat cohort. With GSK609+5-FU/plat, 9/10 (90%) pts experienced ≥ 1 adverse event (AE). Of 32 AEs of any grade, 9 were Grade ≥3 and 3 were serious AEs (SAEs). Two of the 3 SAEs were related to study treatment (oral mucositis and febrile pancytopenia). With GSK609+PE+5-FU/plat, 18/19 (94.7%) pts experienced ≥ 1 AE. Of 119 AEs of any grade, 24 were Grade ≥3 and 15 were SAEs. Of the 15 SAEs, 11 were related to study treatment (febrile neutropenia [n=4], colitis [n=2], diarrhea [n=1], vomiting [n=1], acute kidney injury [n=1], cardiac chest pain [n=1] and lung infection [n=1]). For all cohorts, no Grade 5 AEs were observed. For 10 pts evaluable for confirmed best overall response in all cohorts, 2 pts had partial response, 6 pts had stable disease and 2 pts were nonevaluable. No difference in GSK609 exposure was observed relative to GSK609 monotherapy. Conclusions: The safety profile of GSK609 in combination with 5-FU/plat±PE is manageable. Most AEs were Grades 1 or 2 and consistent with PE and chemotherapy toxicities. Continued follow-up to investigate long-term safety and efficacy of this combination is warranted. Clinical trial information: NCT02723955 .
The impact of tumor hypoxia on the clinical efficacy of anti-PD-1 mAb treatment in recurrent/metastatic HNSCC patients (R/M).
Authors: Zandberg Dan Paul , Velez Maria A , Menk Ashley V. , Liu Angen , Skinner Heath Devin , Duvvuri Umamaheswar , Ohr James , Chiosea Simion I. , Nilsen Marci Lee , Clump David Anthony , Ferris Robert L. , Delgoffe Greg
Published: May 2020

6546

Background: Anti-PD-1 mAbs have changed the landscape of R/M HNSCC treatment, but physical, immunologic, and metabolic barriers present in the tumor microenvironment are likely drivers of low response rates. Hypoxia is a well-established feature of the tumor microenvironment and may act as a barrier to T cell infiltration and function. We evaluated the effect of hypoxia on the efficacy of anti-PD-1 mAb treatment in R/M HNSCC patients. Methods: We conducted a retrospective analysis of R/M patients treated with anti-PD-1 mAb that had consented to the UPMC Hillman tissue banking protocol (HCC 99-069). Pre-treatment archival FFPE samples were analyzed via immunofluorescent imaging for number of CD8+ T cells (CD8), Tregs, and the percent area (% CAIX) and mean intensity (Int) of carbonic anhydrase IX, a well-described marker of hypoxia. Tissue sections stained with PanCK, CAIX, CD8, Foxp3, and DAPI were imaged with an Olympus IX 83 microscope. ImageJ software and custom software plugins were used to determine %CAIX, Int, CD8, and Treg. PD-L1 by IHC was reported as a combined positive score (CPS) defining positive as CPS > 1. We compared non-responders (NR) i.e. PD to responders (R) i.e. PR or SD, and analyzed OS, PFS. All data were analyzed using GraphPad Prism software. Two-tailed unpaired t test was used when comparing 2 groups, 1-way ANOVA was used for multiple comparisons, and log-rank test was used for survival analysis. Results: The 36 patients included were 69% male, median age 59, 58% smokers. 61% were platinum failure. Primary site included 39% OC, 22% OPC (38% HPV positive), 17% Larynx, 17% other, 5% hypopharynx. Low %CAIX/Int, high CD8, and high CD8/Treg were all significantly associated with R. Patients with low %CAIX/Int (12 month OS Low: 75% vs. Mid: 17% vs. High:8%, p = 0.02) and high CD8/Treg had a significant increase in OS. Only high CD8 was associated with significantly higher PFS. Low %CAIX alone showed a non-significant trend towards increased R and no difference in PFS/OS. There was no difference in CD8, CD8/Treg, PD-L1 and Treg between %CAIX/Int groups. Conclusions: To our knowledge this is the first evaluation of tumor hypoxia as a predictive biomarker in anti-PD-1 mAb treated R/M HNSCC patients. Lower hypoxia by %CAIX/Int was associated with significantly increased response and OS. While further analysis in a larger dataset is needed to confirm, the lack of significant difference in CD8, Treg, PD-L1, and CD8/Treg between %CAIX/Int groups (Low, Mid, High) suggests that hypoxia may be an independent predictive marker.
CD3 and CD20 immune cell densities in primary tumors, lymph node metastasis, and recurrent disease samples of head and neck squamous cell carcinoma.
Authors: Laban Simon , Remark Romain , Idel Christian , Ribbat-Idel Julika , Schröck Andreas , Ezić Jasmin , Döscher Johannes , Theodoraki Marie-Nicole , Krupar Rosemarie , Sikora Andrew G. , Kristiansen Glen , Bootz Friedrich , Akturk Guray , Ettrich Thomas Jens , El-Osta Hazem Edmond , Schuler Patrick J , Brunner Cornelia , Hoffmann Thomas K , Perner Sven , Gnjatic Sacha
Published: May 2020

6551

Background: Immune cell (IC) infiltrates in primary tumors (PT) have been identified as prognostic markers in head and neck squamous cell carcinoma (HNSCC). IC densities may differ among PT, lymph node metastasis (LNM) and recurrent disease (RD) and by primary disease site (oral cavity- OC, oropharynx- OP, hypopharynx- HP, larynx- L). Here, we compare CD3 and CD20 IC densities in PT, LNM and RD in paired samples from different disease sites and determine the prognostic impact of IC infiltrates. Methods: Tissue microarrays with 425 PT, 198 LNM and 46 RD samples--each in triplicate--were stained immunohistochemically for CD3 and CD20 in the same slide. Immune cell densities per mm2 were determined using a digital image analysis software (QuPath). Individual means were calculated from triplicates of each sample. IC infiltrates from different sample types (PT, LNM, RD) and primary tumor sites were compared using Kruskal-Wallis and Mann-Whitney-U tests. Paired samples were compared using Wilcoxon signed rank test. IC densities were classified as CD3 high/low and CD20 high/low for each primary tumor site using the individual median as a cut-off. Overall survival (OS) was calculated using the Kaplan-Meier method. P-values for each hypothesis were corrected using a false discovery rate of 5%. Results: CD3 and CD20 IC densities differed significantly by sample type (both p<0.0001) and primary site (CD3: p=0.012, CD20: p=0.0017). CD3 and CD20 densities were significantly lower in PT compared to LNM or in RD compared to PT and LNM. Paired samples (n=172) revealed a significantly higher CD3 and CD20 density (both p<0.0005) in LNM compared to PT, but no significant differences between PT and RD (n=28, p>0.05). CD3 densities were significantly higher than CD20 densities in all sample types. CD3high patients had the best prognosis in all sites except for OC (q<0.05) independent of CD20 status. In OC, CD3 density was not prognostic, but CD3low/CD20high patients had the worst OS compared to CD3low/CD20low and CD3high/CD20high or even CD3high/CD20low patients (p=0.018) who had the best prognosis. Conclusions: IC densities of CD3 and CD20 vary by sample type and primary site. Except for OC, in all sites the prognostic impact is determined by CD3high, whereas in OSCC only the combination of CD3 and CD20 IC densities achieves a good prognostic value. Interestingly, CD3low/CD20high patients have the worst overall survival in OC patients. Further work is needed to understand the interaction of B- and T cell infiltrates in the tumor, especially in OC.
HPV ctDNA analysis in unresectable recurrent/metastatic oropharyngeal cancer.
Authors: Haring Catherine T , Brummel Collin , Jewell Brittany , Heft Neal Molly , Bellile Emily , Spector Matthew E , Mierzwa Michelle , Worden Francis P. , Tewari Muneesh , Brenner Chad , Swiecicki Paul
Published: May 2020

6554

Background: There is an increasing incidence of human papillomavirus associated (HPV+) oropharyngeal cancer (OPC). While HPV + portents improved prognosis, survival for patients with unresectable recurrent/metastatic (R/M) OPC remains poor. Extant data suggest that HPV ctDNA levels correlate with disease burden and treatment outcomes in patients with HPV + OPC in the primary setting but scant data exists in the metastatic setting. Objective: To develop a highly precise droplet digital (ddPCR) assay for quantification of plasma HPV ctDNA and to evaluate whether HPV ctDNA predicts treatment response in patients with HPV+ R/M OPC. Methods: Patients with HPV + R/M OPC starting systemic therapy were enrolled in a biorepository in which blood was collected prior to each cycle of therapy. PCR probes were created for the most common high-risk HPV subtypes, 16 and 18. HPV ctDNA was extracted from plasma and quantified with ddPCR. Percent change in HPV ctDNA was calculated after 1 and 2 cycles of treatment. Treatment response was assessed per standard of care or study protocol after 2-3 cycles of treatment. ROC curve analyses were performed. Results: A precise ddPCR assay was developed to identify plasma HPV ctDNA in 10 patients who underwent 16 distinct treatment courses. On ROC curve analysis, percent change in HPV ctDNA after 2 cycles of treatment was predictive of radiographic response (AUC 0.82, p = 0.03). The optimal cutoff point to optimize sensitive and specificity was identified as 30% change in HPV ctDNA (Table). Changes in HPV ctDNA after 1 cycle of treatment were also predictive of radiographic response (AUC 0.82, p = 0.05). Conclusions: Changes in HPV ctDNA may be predictive of treatment response in patients with R/M HPV + OPC. Furthermore, HPV ctDNA predicts response earlier than conventional imaging. While validation is needed, this assay shows promise in identifying poor responders who can be directed early towards clinical trials or alternative therapies. [Table: see text]
Molecular correlates of response to preoperative olaparib alone or with cisplatin or with durvalumab in head and neck squamous cell carcinoma (HNSCC): A Hellenic Cooperative Oncology Group study.
Authors: Psyrri Amanda , Papaxoinis George , Gavrielatou Niki , Gkotzamanidou Maria , Economopoulou Panagiota , Kotsantis Ioannis , Spathis Aris , Anastasiou Maria , Gkolfinopoulos Stavros , Nifora Martha , Fountzilas George , Foukas Periklis
Published: May 2020

6556

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors drive increased DNA damage and tumor cell death, particularly in tumors with existing defects in DNA repair. Furthermore,they promote immune priming, through a range of molecular mechanisms. Foremost, among candidate intracellular pathways is STING (stimulator of interferon genes), an innate immune response activated by cytosolic DNA (perhaps a consequence of DNA damage) that can lead to enhanced interferon (IFN) production. PARP inhibitor-induced DNA damage also leads to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. To this end, there is increasing rationale for testing PARP inhibitors alone or in combination with chemotherapy or PD1 checkpoint inhibitors in HNSCC. Methods: 39 patients were enrolled in OPHELIA phase II trial in which pts were randomized 3:3:3:1 to Cisplatin (C) 60 mg/m2 on d1 followed by Olaparib (O) 75mg d 1-5 (Arm A), O 300 mg bid for 21-28 days (Arm B), no treatment (ARM C) orD 1500 mg on d1 followed by O 600 mg daily for 21-28 days (Arm D). Response was defined as tumor reduction noted on exam, imaging or pathology. Pretreatment biopsies were subjected to 310 gene OncoDNA NGS panel. Double Stranded Brakes/Repair (DSB/R) was measured by evaluating phosphorylation of histone H2AX by immunochistochemistry (IHC). In addition, IHC for PD-L1 (CPS) and STING was performed in paired pre- and post-treatment biopsies. Results: 17/36 pts in (O) treatment arms (6/11 evaluable pts Arm A, 9/11 evaluable pts Arm B, 2/11evaluable\ pts arm D) developed a response. One patient in D+O arm developed path CR. Low γH2AX staining at pretreatment biopsies was associated with progression (p=0.029). Higher PD-L1 expression (CPS≥1) was associated with disease progression (p=0.014). CPS PD-L1 was upregulated following (O) treatment. STING expression was not significantly upregulated post treatment in (O) treatment arms. Alterations in genes that have been previously reported to be associated with (O) sensitivity, namely DNA damage Response/Repair (DDR) genes and genes involved in chromatin remodeling ( CHK2, KMT2D, KMT2C, ARID2 and AJUBA), were identified in responders. Conclusions: This window study demonstrated promising signs of activity of (O) in HNSCC, particularly in tumors with high expression of γH2AX and alterations in DDR or chromatin remodeling genes. Clinical trial information: NCT02882308 .
Computational discovery of non-mutational tumor-restricted antigens reveals evidence of immunoediting in head and neck squamous cell carcinoma.
Authors: Kemnade Jan Ole , Wheeler Thomas M. , Cardenas Maria , Sikora Andrew G. , Frederick Mitchell
Published: May 2020

6564

Background: We previously identified 107 expression-based tumor antigens (EbTAgs) defined as genes with negligible expression in healthy tissue and overexpression in cancer. EbTAgs present novel targets for the adaptive anti-tumor immune response and exhibit evidence of immunoediting in highly immune infiltrated oral cavity tumors. To detail the landscape of EbTAgs in head and neck squamous cell carcinoma (HNSC) and further elucidate EbTAg immunoediting, we compared the expression EbTAgs in the context of tumor immune infiltration among four HNSCC subtypes: oral cavity (OC), HPV+ oropharyngeal (HPV+OP), HPV- oropharyngeal (HPV-OP), and laryngeal/hypopharyngeal (LH). Methods: Upper quartile FPKM gene expression values of all protein coding genes were calculated for all HNSC samples using RNAseq data from The Cancer Genome Atlas (TCGA). TCGA HNSC tumors were divided into subtypes and analyzed for EbTAg expression. Individual tumor sample immune infiltrate was determined using unsupervised clustering of 14 immune cell signature ssGSEA scores for the HNSC dataset as a whole and for each subtype. Results: LH tumors expressed significantly more EbTAgs than other subtypes (p=0.0014), specifically HPV+OP (p=0.0008, Tukey’s test). Immune clustering analysis showed that LH tumors were significantly more likely to be in the low than the high immune cluster whereas the reverse was true for HPV+OP tumors (p<0.0001). Hypothesizing that EbTAg expression was a function of tumor immune infiltration rather than HNSC subtype, we compared EbTAg expression between tumors in low and high immune clusters of the entire HNSC dataset as well as of each HNSC subtype. Significantly more EbTAgs were expressed in low immune tumors compared to high immune tumors of the HNSC dataset (p<0.0001). Similarly, significantly more EbTAgs were expressed in low immune tumors compared to high immune tumors of the OC, OP-all tumors, and HPV+OP datasets (p=0.0003, p<0.0001, p=0.0006) with a trend of more EbTAgs in the immune low versus high tumors in the HPV-OP and LH datasets (p=0.12, p=0.095). Conclusions: EbTAg expression in TCGA HNSC samples correlates with tumor immune infiltration resulting in lower expression under greater immunological pressure. These results reinforce the hypothesis that EbTAgs undergo immunoediting and are immunologically relevant. Exploration of EbTAgs as antigenic targets of modular vaccines or adoptive T-cell therapy as well as biomarkers of immune checkpoint inhibition therapy response is warranted.
DURTRERAD: A phase II open-label study evaluating feasibility and efficacy of durvalumab (D) and durvalumab and tremelimumab (DT) in combination with radiotherapy (RT) in non-resectable locally advanced HPV-negative HNSCC—Results of the preplanned feasibility interim analysis.
Authors: Klinghammer Konrad Friedrich , Gauler Thomas Christoph , Stromberger Carmen , Kofla Grzegorz , de Wit Maike , Gollrad Johannes , Rauer Izabella , Martus Peter , Tinhofer Inge , Budach Volker , Keilholz Ulrich , Burock Susen
Published: May 2020

6574

Background: DURTRERAD is a randomized phase II study evaluating feasibility and efficacy of durvalumab (anti-PD-L1) vs. durvalumab and tremelimumab (anti-CTLA-4) in combination with radiotherapy as primary treatment for locally advanced HPV negative HNSCC. (NCT03624231). Concurrent chemo-RT with a platinum-based regimen is considered the standard treatment, although efficacy and long-term toxicity are not satisfactory. Combining immunotherapy with RT might result in improved efficacy with limited long-term toxicity. Methods: The phase II study planned to enroll 120 pts, 60 pts (1:1) in each treatment arm. Treatment with DT (1500mg/75 mg, arm DT),or D (1500mg, arm D) both in combination with RT (70Gy) was considered to be feasible if less than 10% of the patients treated will discontinue treatment due to on-treatment toxicities. A first interim analysis for feasibility and efficacy was planned after randomisation of 20 patients. Results: So far 23 patients have been screened, 16 patients have been randomised and started their allocated treatment, 10 in arm D and 6 in arm DT. Of 10 patients in arm D 1 patient stopped infusional treatment due to immune related toxicity. Out of 6 patients in the DT arm, however, 5 patients stopped treatment due to treatment related AEs, 2 pts due to immune related toxicity with one Grade 5 AE. Three patients stopped due to non-immune related AE. The grade 5 AE prompted the interim analysis, which revealed non-feasibility as well as safety-issues of the DT+radiotherapy combination . As a result, the DT arm was prematurely terminated. Conclusions: Even though in the recurrent/metastatic setting DT was not associated with increased toxicity, DT in combination with RT was not feasible in our poor prognostic, vulnerable patient cohort of advanced HPV negative unresectable HNSCC, warranting early disclosure of these results. No increase in toxicity was observed in the D monotherapy arm, and the trial continued with D monotherapy in combination with RT. Clinical trial information: NCT03624231 .
Single-cell multiplexed proteomics to identify novel polyfunctional CD8+ T cell signatures induced by nivolumab in head and neck cancer patients after salvage surgery.
Authors: Gulati Shuchi , Haque Sulsal , Palackdharry Sarah , Steele Aubrey , Allen Casey , Takiar Vinita , Riaz Muhammad Kashif , Lehn Maria , Jandarov Roman , Zender Chad , Patil Yash , Tang Alice L , Cervenka Brian , Sukari Ammar , Nagasaka Misako , Wise-Draper Trisha Michel
Published: May 2020

6576

Background: Immune checkpoint inhibitors (ICIs) are FDA approved for use in head and neck squamous cell cancer (HNSCC), however, only ~20% patients achieve a response. Identification of biomarkers of response or toxicity remains a challenge. Polyfunctional T-cells, or T-cells producing multiple cytokines, have been recognized as contributors to durable immunity against various cancers. However, their role has not been studied prospectively in HNSCC patients receiving ICIs. To look for an early predictor of response, we used single-cell functional proteomic profiling (IsoPlexis) on blood samples pre- and post- first dose of nivolumab (nivo) in patients on our phase-II study of locally recurrent HNSCC (NCT03355560). Methods: HNSCC patients who failed definitive radiation +/-chemotherapy and were subsequently treated with curative intent salvage resection were enrolled to receive 6 months of nivo beginning 4 to 11 weeks after surgery. Blood samples were collected before and after the first dose of nivo. Peripheral blood mononuclear cells were isolated, enriched for CD8+ T cells and using the 32-plex IsoCode technology, single-cell cytokine signals were captured and polyfunctional strength of CD8+ T cells was evaluated across four groups (effector, stimulatory, regulatory, inflammatory). A comparison analysis was performed between pre- and post- nivo treatment and between patients who relapsed (non-responders) vs those who did not (responders). Results: Thirty-three of 39 planned patients have been enrolled, of which 28 are evaluable and 5/28 (18%) developed recurrence. Median age is 68 years (range 51-85), 9/28 (32%) patients are female, 26/28 (93%) are white, disease sites include oropharyngeal 6/28 (21%), oral cavity 11/28 (39%) and larynx 11/28 (39%). Samples were evaluated at a median follow up of 5.9 months from enrollment. Single-cell analysis demonstrated a strong upregulation of polyfunctional human CD8+ T cell subsets in responders. Polyfunctional Strength Index (PSI) was enhanced in CD8+ T cells across the responders’ samples, composed largely of effector cytokines (granzyme-β, IFN-γ, MIP-1α, perforin, TNF-α). Conclusions: Single-cell functional proteomic analysis revealed significantly upregulated polyfunctional profiles and an increase in effector cytokines in patients who responded to nivo. This data provides important insights into PD-1 inhibitor triggered T-cell activity and may be used to predict response to ICIs in HNSCC patients using a blood test. Clinical trial information: NCT03355560 .
Risk of chronic opioid use after radiation for head and neck cancer: A systematic review and meta-analysis.
Authors: Zayed Sondos , Lin Cindy , Boldt Gabriel , Read Nancy , Mendez Lucas , Venkatesan Varagur , Sathya Jinka , Moulin Dwight , Palma David A.
Published: May 2020

6579

Background: Opioid overuse is a major international public health concern. The prevalence and risk factors for chronic opioid use (COU) in radiation-induced head and neck pain are poorly understood. The aim of this study was to estimate the rates of COU and to identify risk factors for COU in head and neck cancer (HNC) patients undergoing curative-intent radiotherapy (RT) or chemoradiotherapy (CRT). Methods: We performed a systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, using the PubMed (Medline), EMBASE, and Cochrane library databases, queried from dates of inception until present. COU was defined as persistent opioid use ≥3 months after treatment completion. Studies in the English language that reported on COU in HNC patients who received RT/CRT were included. Meta-analyses were performed using random effects models. Heterogeneity was assessed using the I2 value. Results: A total of 134 studies were identified, with 7 retrospective studies (reporting on 1841 patients) meeting inclusion criteria. Median age was 59.4 years (range 56.0-62.0) with 1343 (72.9%) men and 498 (27.1%) women. Primary tumour locations included oropharynx (891, 48.4%), oral cavity (533, 29.0%), larynx (93, 5.1%), hypopharynx (32, 1.7%), and nasopharynx (29, 1.6%). 846 (46.0%) patients had stage I/II disease and 926 (50.3%) had stage III-IV disease. 301 (16.3%) patients had RT alone, 738 (40.1%) received CRT, and 594 (32.3%) underwent surgery followed by adjuvant RT/CRT. The proportion of HNC patients who received radiotherapy and developed COU was 40.7% at 3 months (95% CI 22.6%-61.7%, I2= 97.1%), 15.5% at 6 months (95% CI 7.3%-29.7%, I2= 94.3%) and 7.0% at 1 year. There were significant differences in COU based on primary tumor sites (P < 0.0001), with the highest rate (46.6%) in oropharyngeal malignancies. Other factors associated with COU included history of psychiatric disorder (61.7%), former/current alcohol abuse (53.9%), and start of opioids prior to radiation treatment (51.6%). There was no significant difference in the proportion of COU by gender (P = 0.683), disease stage (I/II vs III/IV; P = 0.443), or treatment received (RT, CRT, or adjuvant RT/CRT; P = 0.711). Conclusions: A significant proportion of patients who undergo radiotherapy for head and neck cancer suffer from COU. High-risk factors for COU include an oropharyngeal primary tumour, history of psychiatric disorder, former/current alcohol abuse, and pre-treatment opioid use. New strategies to mitigate opioid use are needed.
Effect of ARMS-qPCR on detection sensitivity of earlier diagnosis of papillary thyroid cancers with worse prognosis determined by BRAF V600E and TERT promoter mutation coexisting.
Authors: Yu Peng-cheng , Tan Li-cheng , Shi Xiao , Ma Ben , Wei Wen-jun , Wang Yu , Ji Qing-hai , Wang Yu-long
Published: May 2020

6588

Background: Co-existing of BRAF V600E and TERT promoter C228T/C250T mutation has been extensively related to prognosis in thyroid cancer. Our study aimed to establish a more sensitive method for mutation detection and explore the correlation more in-depth. Methods: BRAF and TERT promoter mutation status of 250 papillary thyroid cancer was detected by both Amplification Refractory Mutation System quantitative PCR (ARMS-qPCR) and Sanger sequencing to compare the sensitivity. The associations between the mutation status and the clinicopathological features were analyzed. Results: ARMS-qPCR displayed higher sensitivity than Sanger ( BRAF V600E: 75.2% vs. 52.4%, p< 0.001; TERT promoter C228T/C250T: 12.0% vs. 3.6%, p= 0.001; Co-mutation (9.6% vs. 3.2%, p= 0.005). Both methods indicated that patients with BRAF V600E and TERT promoter co-mutation were higher in age at diagnosis (ARMS-qPCR: 51.0 ± 14.2 vs. 40.2 ± 12.6, p <0.001; Sanger: 64.3 ± 7.1 vs. 40.5 ± 12.6, p <0.001), and the recurrence rate (16.7% vs. 3.1%, p= 0.014; 50.0% vs. 2.9%, p< 0.001), besides, the co-mutation group were related to more advanced TNM stage ( p< 0.001; p< 0.001) and higher MACIS score (5.1 ± 1.5 vs. 4.2 ± 0.7, p= 0.006; 6.6 ± 1.1 vs. 4.2 ± 0.8, p< 0.001). In addition, compared with the co-mutation results of Sanger, it seems that ARMS-qPCR has identified an earlier stage of group, which were younger (43.3 ± 10.1 vs. 66.4 ± 6.1, p< 0.001), and with smaller tumor (1.8 ± 1.5 vs. 4.0 ± 1.3, p= 0.002), as well as lower recurrence rate ( 0.0% vs. 50%, p= 0.007). Besides, the newly identified group were lower in MACIS score (4.2 ± 0.8 vs. 6.9 ± 0.7, p= 0.002) and with lower TNM stage ( p= 0.001). Conclusions: Patients with BRAF V600E and TERT promoter C228T/C250T co-mutation have a worse prognosis. Using ARMS-qPCR, the more sensitive method could identify earlier stages of patients with a potentially worse prognosis. [Table: see text]
Benefits of an early mobility program for hospitalized cancer patients: A pilot study.
Authors: Smith Cardinale B. , Gunning Melissa , Hubman Margie , Conklin Christine , Wells Nicole , Theroux Haley Hines , Liu Mark , Wolfe Jennifer
Published: May 2020

7008

Background: Cancer patients are often hospitalized with complications from cancer and cancer treatment. Many experience a decline in physical functioning which likely contributes to increased length of stay (LOS) and excess days, increased readmissions and decreased patient experience. We aimed to determine whether a mobility program project would improve quality of care and decrease healthcare utilization. Methods: We implemented a mobility aide program on an oncology unit in a large academic medical center between April 2, 2019 to December 31, 2019. The program consisted of nursing evaluation using the Activity Measure for Postacute Care (AMPAC), an ordinal scale ranging from bed rest to ambulating ≥250 feet, was used to quantify mobility. Plan of care was determined in a multidisciplinary manner with physical therapy (PT), nursing and a mobility aide, a medical assistant with enhanced rehabilitation training. Patients were then mobilized two times per day seven days a week. Using descriptive statistics we evaluated the programs impact on excess days, readmissions, changes in mobility and patient experience as measured by Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) during this time period compared to the 6 month interval prior to implementation. Results: During the study interval, 988 patients were admitted and received the mobility program. There was a 6% reduction in excess days (p = 0.04). Similarly, readmission rates decreased from 25% to 19% (p = 0.03). Overall 76% of patients wither maintained or improved their mobility score. During this time period HCAHPS scores (willingness to recommend hospital) increased from 63% at baseline to 91% (p = 0.01). Conclusions: Use of this mobility program resulted in a significant decrease in healthcare utilization and improvement in patient experience. This demonstrates that non-PT professionals can mobilize hospitalized cancer patients decreasing the burden of PT and nursing resources. Future work will evaluate the sustainability of the program and evaluate association with healthcare costs.
Going off pathway: Problem or good care?
Authors: Edge Stephen B. , Liu Lu , Stefaniak Nessa , Murphy Monica L. , Thompson James E. , Hillengass Jens , Dy Grace K. , Kuvshinoff Boris W. , McKinney Mishellene
Published: May 2020

7014

Background: Clinical oncology pathways (COP) provide decision support and benchmarking against national standards. Some organizations provide financial incentives for using COP-recommended treatment (on pathway: OnP). Treatment (Rx) other than COP recommended Rx (off pathway: OffP) is appropriate for some cases. There are limited data on the appropriateness of OffP Rx. This study examines rates and reasons for OffP Rx in one cancer center. Methods: All systemic Rx decisions entered in the ClinicalPath COP from 10/1/18 - 9/30/19 were classified as OnP (including Rx on a clinical trial) or OffP and as adjuvant/neoadjuvant therapy (ADJ) or for metastatic cancer (MET). Oncologists must provide free text reasons for OffP Rx. Records of all OffP care were reviewed by a senior nurse-led team and physician to verify and classify OffP reasons. Cases without clear documentation were referred to the treating oncologist and/or multidisciplinary team for review. Justified OffP reasons (R1-6) were classified as: R1. Documented drug toxicity and/or treatment-limiting co-morbidity; R2. Prior treatment precluding pathway Rx; R3. New drug indication or molecular targeted therapy not in COP; R4. Continuation of Rx started prior to referral; R5. Other clearly documented and reviewed provider or multidisciplinary team rationale; and R6. Patient preference. Results: There were 2,997 COP treatment decisions for 2,389 patients. The OnP rate was higher for ADJ than for MET Rx (87% vs. 78%). Non-justified OffP care accounted for 1% of cases. 69% of OffP Rx was because of known drug toxicity, co-morbidity limiting therapy, prior therapy precluding COP choice, and new drug indications (Table). Conclusions: COPs provide decision support and practice benchmarking. Lower OnP rates for MET Rx likely reflect the nuances of Rx for advanced cancer. Most OffP care was justified and appropriate. Financial incentives that focus on the percentage of COP OnP care could paradoxically harm the quality of care, especially given the high percentage of OffP decisions for reasons of drug toxicity, co-morbidity and new drug indications. [Table: see text]
Subjective cognition in chimeric antigen receptor T-cell therapy recipients.
Authors: Barata Anna , Hoogland Aasha , Hyland Kelly , Kommalapati Anuhya , Jayani Reena , Irizarry-Arroyo Nathalie E. , Rodriguez Yvelise , Alla Raviteja , James Brian , Lafranchise Elizabeth , Jain Michael D. , Locke Frederick Lundry , Jim Heather S.L.
Published: May 2020

7020

Background: Chimeric antigen receptor T-cell (CAR-T) therapy can lead to durable responses in chemorefractory patients with hematologic malignancies. CAR-T, however, can be associated with neurotoxicity. There is a significant body of literature describing patient-reported concerns with cognition in hematopoietic cell transplant (HCT) recipients, a similar treatment group. However, little is known about subjective cognition in CAR-T patients. This study examined changes in subjective cognition over time in CAR-T recipients and compared their outcomes with allogeneic HCT recipients. Methods: At baseline and 90 days after infusion, participants completed the Everyday Cognition Questionnaire (ECog). The ECog provides scores for total cognition, memory, language, visuospatial abilities, planning, organization, divided attention, and satisfaction with cognition. Comparison data from allogeneic HCT recipients came from a previous observational study. Linear mixed models compared changes in subjective cognition between recipients of CAR-T and allogeneic HCT over time. Models were adjusted by age, marital status, education, and Karnofsky performance status. Results: Participants were 111 CAR-T recipients (mean age 60 years, 37% female) and 190 allogeneic HCT recipients (mean age 53, 42% female). Linear mixed models indicated CAR-T recipients’ subjective cognition didn’t change within the 90 days after infusion (p’s > .05). At baseline, there were no group differences between CAR-T and allogeneic HCT recipients in subjective cognition (p’s > 0.05). Over time, however, subjective cognition between groups differed. Specifically, CAR-T recipients reported stable subjective cognition whereas allogeneic HCT recipients reported worsening total subjective cognition (p = 0.04), memory (p = 0.02), visuospatial abilities (p = 0.01), planning (p = 0.01), and divided attention (p = 0.01). At follow-up, CAR-T recipients reported better total subjective cognition (p < 0.01), memory (p < 0.01), language (p = 0.01), visuospatial abilities (p < 0.01), planning (p < 0.01), and divided attention (p < 0.01) than allogeneic HCT recipients. Conclusions: Despite the neurotoxicity associated with CAR-T, patients can expect to perceive similar subjective cognition at day 90 compared to baseline. Future studies should also evaluate objective cognition in CAR-T recipients.
Global perspectives on clinical cancer research: A comparison of randomized controlled trial (RCT) design and outcomes across high income and low-middle income countries.
Authors: Wells Connor , Sharma Shubham , Del Paggio Joey C. , Hopman Wilma M. , Gyawali Bishal , Pramesh CS , Sullivan Richard , Booth Christopher M.
Published: May 2020

7021

Background: Cancer clinical trials have become increasingly international in scope. There are limited data regarding trial variation based on the economic status of the country in which they are conducted. Here we describe trial characteristics, design, and results of all RCTs published globally during 2014-2017. Methods: A structured literature search was designed using PUBMED to identify all RCTs evaluating anti-cancer therapies published during 2014-2017. Data captured included authorship, participants, study characteristics, design, and results. RCTs were classified based on the World Bank country-level economic classification of the first author [low-middle/upper-middle income countries (LMIC) and high-income countries (HIC)]. Among superiority RCTs that met the primary endpoint (i.e. statistically “positive”), we calculated the ESMO-MCBS to identify trials with substantial clinical benefit (MCBS scores 4/5 or A/B). Outcomes were compared with Chi Square or Fisher’s Exact tests. Results: The study cohort included 694 RCTs; 636 (92%) were led by HIC and 58 (8%) were led by LMIC. Compared to LMIC, RCTs in HICs were more likely to be funded by industry [73% vs 41%, p<0.001] and more likely to test novel systemic therapies [87% vs 78%, p=0.027]. LMIC studies were typically smaller (median N=220 vs N=474 participants, p<0.001) and more likely to meet their primary endpoints [66% vs 44%, p=0.002]. In “positive” superiority trials, the effect size was larger in LMICs compared to HICs (median HR 0.62 vs HR 0.84, p<0.001). The proportion of trials identifying treatments with substantial clinical benefit (ESMO MCBS 4/5/A/B) was 45% (LMIC) and 31% (HIC, p=0.291). Studies from LMIC were published in journals with lower impact factors (IF) (median IF 7 vs 21, p<0.001); a publication bias persisted when adjusted for whether a trial was positive or negative: median IF LMIC negative trial=5 vs HIC negative trial=18 (p<0.001); median IF LMIC positive trial=9 vs HIC positive trial= 26 (p<0.001). Conclusions: Only a small minority of oncology RCTs are led by investigators in LMIC; these trials are less likely to be funded by industry and more likely to meet their primary endpoint. “Positive” RCTs from LMIC identify therapies with a substantially larger effect size than HIC. These data identify a substantial publication bias against RCTs conducted in LMIC.
Racial disparities in immune-related adverse events (irAE) of immune checkpoint inhibitors (ICPi) and association with survival based on clinical and biochemical responses.
Authors: Peravali Monica , Gomes-Lima Cristiane , Tefera Eshetu , Baker Mairead , Sherchan Mamta , Farid Saira , Burman Kenneth D , Constantinescu Florina , Veytsman Irina
Published: May 2020

7025

Background: ICPi cause various irAE with thyroid dysfunction as a commonly reported abnormality. There is increasing evidence showing positive association with development of irAE and survival. However, prior trials with ICPi had underrepresentation of minorities with <5% African Americans (AA). Methods: We retrospectively reviewed patients (pts) with stage IV solid malignancies treated with PD1/PDL1 blockers between 1/2013-12/2018 across MedStar Georgetown Cancer Institute facilities. Pts treated with CTLA-4 inhibitors were excluded. Progression free survival (PFS) and overall survival (OS) were primary endpoints and were calculated using Kaplan-Meier methods and Wilcoxon rank sum test for comparison. Results: 293 pts met eligibility criteria. 91 pts (31%) had any grade irAE; most common AE were endocrine (40.7%) specifically TSH elevation, dermatological (23.1%) and rheumatologic (18.7%). Proportion of irAE was significantly higher in Caucasians versus AA (60.4% vs 30.8%), in pts with low PDL1, lower LDH, older age, and those who had more treatment cycles with ICPi. Rate of progression was lower in pts with irAE (30.8% vs 46.0%, p-0.0140). Median PFS (5.8 vs 3.0 months (mo), p- 0.0204) and OS (17.1 vs 7.2 mo, p value- <0.0001) were higher with irAE. Statistically significant difference in OS (17.1 vs 8.6 mo, p- 0.0002) but not in PFS (5.8 vs 3.3 mo, p: 0.0545) was noted with endocrine irAE. No differences in survival were observed among other commonly reported irAE. Differences in survival among subgroups of pts with irAE are detailed in table. Conclusions: Development of irAE positively correlated with improved PFS and OS as reported in previous studies. To our knowledge, this is the first study observing differences in OS favoring endocrine AE and Caucasian race. These factors may be potential surrogate markers of prognosis pending replication of these results in large-scale studies. [Table: see text]
Health insurance status and cancer stage at diagnosis and survival in the United States.
Authors: Zhao Jingxuan , Han Xuesong , Nogueira Leticia , Jemal Ahmedin , Halpern Michael T. , Yabroff K Robin
Published: May 2020

7026

Background: While previous studies demonstrated associations between Medicaid coverage or no health insurance with both advanced stage at cancer diagnosis and worse survival, access to health care in the U.S. has changed substantially in the past decade. This study examined associations of health insurance status with stage at diagnosis and survival among 17 common cancers using recent national data. Methods: We identified 1,427,532 cancer patients aged 18-64 years newly diagnosed with 17 common cancers from the 2010-2013 National Cancer Database. Multivariable logistic regression models were used to examine the distribution of stage at diagnosis by health insurance status (private, Medicare, Medicaid, dual Medicare/Medicaid, and uninsured) overall and for each cancer site. Cox models compared stage-specific survival by health insurance for each site. Results: Compared to privately insured patients, Medicaid and uninsured patients were significantly more likely to be diagnosed with advanced-stage cancer (III/IV) for all the 17 cancers combined (adjusted odds ratio [AOR]: 2.27, 95% confidence interval [95CI]: 2.24-2.29; AOR: 2.39, 95CI: 2.36-2.42, respectively) and for all included cancer sites separately. Medicare and Medicare-Medicaid patients were also more likely to be diagnosed at advanced-stage for all the 17 cancers combined, but results varied by cancer site. Compared to the privately insured patients, worse survival was observed for patients with all other insurance types and uninsured at each stage for all the 17 cancers combined and most cancer sites. For example, among patients diagnosed at stage I, adjusted mortality hazard ratios for Medicare, Medicaid, Medicare-Medicaid, and uninsured patients were 1.72 (95CI: 1.70-1.75), 1.73 (95CI: 1.71-1.76), 2.07 (95CI: 2.02-2.17) and 1.56 (95CI: 1.53-1.58), respectively, compared with privately-insured patients. Conclusions: Patients with non-private insurance were more likely to be diagnosed with cancer at advanced stage and have worse survival. Improving access to health insurance with adequate coverage is crucial for receiving appropriate cancer screening, diagnosis, and quality care.