tbuckley/cabot-search huggingface dataset:
Toxicity of PD-1/CTLA-4 inhibitor immunotherapy among elderly patients.
Authors: Vidit Kapoor, Olivier Rixe
Journal: Journal of Clinical Oncology (2019)

e14139 Background: The use of Immune check point inhibitors in advanced metastatic melanoma is becoming increasingly common especially in the elderly population. With metastatic melanoma being mostly a disease of the elderly, the safety and toxicity profile of immune check point inhibitors in this population group continues to remain controversial. Prior studies have hypothesized that due to reduced immune responses in the elderly, toxicity to immune check point inhibitors is expected to be low. In this study we aim to analyze the association of check point inhibitor induced immuno-toxicity with age. Methods: We analyzed 108 patients with stage 4 metastatic melanoma who were treated with anti-PD1 and/or anti-CTLA-4 immunotherapy. Out of these patients, 58 (53.7%) were 65 or more years old and 50 (46.3%) were &lt; 65 years old. Overall, 64 (59.3%) patients had autoimmune side effects; 35 (60.3%) were 65 years or older and 29 (48%) were &lt; 65 years old. The most common side effects were dermatitis (n = 22, 20.4%) and colitis (n = 21, 19.4%). Incidences of various autoimmune side effects were calculated in both groups (65 years or older and &lt; 65 years old). Fisher exact test was used to calculate p values Results: There was a significant difference between the incidence of dermatitis between the two groups. (51.4% in 65 years or older and 24.1% in &lt; 65 years old group, p = 0.04). The incidence of colitis was more in the 65 years or older group (37.1%) as compared to &lt; 65 years group (31.1%) however results were not statistically significant (p = 0.79). Similarly, there was no significant difference in other autoimmune side effects including hepatitis, arthritis, pneumonitis, thyroiditis, hypophysitis, adrenalitis, anemia and thrombocytopenia between the two groups. Also, there was no significant difference in the incidence of different grades of side effects (1 to 4) between the two groups. Conclusions: Patients who are 65 years or older can safely tolerate immunotherapy as compared to patients &lt; 65 years old but with an increased risk of dermatitis. These data should be validated by a larger study population.
Quantification of the financial burden of antineoplastic agent price increases.
Authors: Michail Alevizakos, Apostolos Gaitanidis, Leonard Joseph Appleman
Journal: Journal of Clinical Oncology (2019)

6519 Background: Antineoplastic medication prices are overall increasing yet this phenomenon is not limited to new medications but can also be observed in already established medications. Methods: We accessed the yearly payment files from Medicare Part B for injectable antineoplastic agents (codes J8501-J9999) for the years 2010-2017 and all costs were adjusted to 2017 USD to adjust for inflation. We then calculated the price-per-dose for every medication and compared that price with the price-per-dose that the medication would have if its initial price was only affected by inflation. We subsequently multiplied the difference with the total doses of the medication administered in order to calculate the additional cost accrued by Medicare from medications whose price had increased more than the inflation rates. Only medications with total annual payments &gt;10 million USD/yr were included in the analysis. Notably, Medicare provides reimbursement based on average U.S. market prices. Results: Price increases were noted on average in 64.5% of already established medications (median 69.6%, range 45.4-74.1%), leading to an average additional extra cost of 243 million USD per year (range 140-330 million USD), for a total of 1.7 billion USD over the 7 years of observation. Rituximab (539 million USD), trastuzumab (221 million USD), and bevacizumab (178 million USD) accrued the highest extra costs. This extra cost represented 4.6-8.9% of the annual total Medicare Part B spending for antineoplastic medications (Table). Conclusions: The majority of already established injectable chemotherapeutics demonstrate price increases that lead to substantial additional financial cost to Medicare and likely other U.S. markets as well. Price increases of Medicare Part B antineoplastic medications with cost &gt;10 million USD/yr. [Table: see text]
Clinical value of CTC in predicting the efficacy of treatment in breast cancer.
Authors: Yidong Zhou
Journal: Journal of Clinical Oncology (2019)

e12104 Background: Circulating tumor cells (CTCs) have proven to be underlying surrogate markers for several cancers. We aimed to investigate the diagnostic, predictive, and prognostic value of tCTCs using a four-CTC marker (CK19, surviving, Her2 and MUC1) real-time quantitative PCR (RT-PCR) assay in patients with breast cancer. Methods: In a previous study, we established a multimarker RT-PCR platform to detect and quantify CTC in colorectal cancer. By choosing four mRNA markers (CK-19/surviving/Her2/Muc1), we quantified CTC in the peripheral blood of 90 early operable breast cancer patients, 40 patients who had undergone surgery and received 6 cycles of follow-up of neoadjuvant chemotherapy, and 30 healthy volunteers. For early operable breast cancer patients, the CTC status at preoperative and postoperative time points was monitored. For the other 40 patients undergoing systemic adjuvant chemotherapy, the CTC status at six or more different time points was monitored. Results: CTCs were detected in 81% (73/90) of patients with early operable breast cancer. After surgery, 67.1% (49/73) of the patients switched to negative status. 36 out of 40 (90%) patients who received systemic adjuvant chemotherapy were CTC-positive. During follow-up, 31 out of 36 (86%,) patients became CTC-negative after 4 chemotherapy cycles. Among these 36 patients, four patients had relapsed within one year, and one had died. Three out of four relapsed patients, including the deceased one, switched into high CTC-positive status before diagnosed recurrence. Conclusions: The decrease of the levels of these CTC mRNA markers after surgery indicates that these CTC markers could be used as an indirect evaluation of tumor burden. The level of CTC mRNA markers could also help to evaluate therapeutic efficacy and disease progression.
Liver findings and risk of recurrence in locally-advanced rectal cancer (LARC): An Italian retrospective cohort study.
Authors: Angela Damato, Giulia Besutti, Candida Bonelli, Francesco Venturelli, Paolo Giorgi Rossi, Massimo Vicentini, Pierpaolo Pattacini, Carmine Pinto
Journal: Journal of Clinical Oncology (2019)

e15175 Background: Despite the combination of fluoropyrimidine chemotherapy and long course radiotherapy (50.4 Gy) followed by TME, LARC still results in 30% distant recurrence within 2-3 years after surgery. One of the most affected organs is the liver. We aimed to analyze if basal liver pathological alterations and drug-induced liver damages influence the liver recurrence. Methods: 50 patients (pts) with LARC treated with neoadjuvant chemoradiotherapy (NACRT) between June 2010 and June 2017 in a single center were included. Liver function tests (LFTs) including AST, ALT and GGT at baseline and after NACRT were evaluated. The first staging CT scan and, when available, post-NACRT CT scan were reviewed to assess steatosis (unenhanced liver density &lt; 48 HU or liver-to-spleen ratio &lt; 1.1), and liver volume. Associations of baseline LFTs and CT liver alterations and changes after NACRT with liver metastasis (LM) during follow-up were evaluated with Hazard Ratio (HR) and respective 95%CI calculated with Cox analysis. Results: The characteristics of pts were: 68% males, median age 60.4 ys (range 34-84), cTN stage II (32%) and stage III (64%). During a follow-up ranging from 1.5 to 7 ys, 17(34%) pts developed distant recurrence and 7(14%) LM. At baseline, 2 pts had GGT &gt; 73 U/l and 11(22%) had steatosis. After NACRT, 4(9%) pts had AST &gt; 40 U/I and/or ALT &gt; 49 U/l with &gt; 2-folds increase, 6 (40%) of the 15 pts with available unenhanced post-NACRT CT had steatosis development, or increase (≥10 HU density decrease), and 9 (27%) of 33 pts with available post-NACRT CT had a &gt; 10% increase in liver volume. LM was associated with female sex (p = 0.016). Baseline steatosis, post-NACRT steatosis development or increase, &gt; 10% liver volume and transaminase increase were associated with LM (HR = 3.36, 95%CI = 0.75-15.1; HR = 3.67, 95%CI = 0.33-40.7; HR = 2.91, 95%CI = 0.59-14.5; HR = 3.05, 95%CI = 0.33-27.72, respectively). All the reported associations almost disappeared, when considering all-sites of distant recurrence. Conclusions: Even if small numbers cannot exclude that associations are due to chance, baseline liver steatosis and post-NACRT liver damage may be involved in LM during follow-up of LARC.
Final PFS analysis and safety data from the phase III J-ALEX study of alectinib (ALC) vs. crizotinib (CRZ) in ALK-inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC).
Authors: Takashi Seto, Makoto Nishio, Toyoaki Hida, Hiroshi Nokihara, Masahiro Morise, Young Hak Kim, Koichi Azuma, Yuichi Takiguchi, Hiroshige Yoshioka, Toru Kumagai, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Miyako Satouchi, Toshiyuki Kozuki, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Takashi Asakawa, Tomohide Tamura
Journal: Journal of Clinical Oncology (2019)

9092 Background: The primary analysis of the J-ALEX (JapicCTI-132316) study for the ALK-inhibitor naïve ALK+ NSCLC demonstrated superior progression-free survival (PFS) of ALC compared with CRZ (HR 0.34, 99.7% CI 0.17–0.71, stratified log-rank p &lt; 0·0001) by the Independent Review Facility (IRF) (data cutoff, December 3 2015, Hida et al., Lancet 2017) . Here, we report the final PFS and OS 2 nd interim data (data cutoff, June 30 2018). Methods: ALK+ NSCLC (by IHC and FISH or RT-PCR) patients were randomized 1:1 either to receive ALC (300 mg BID, n = 103) or CRZ (250 mg BID, n = 104). Stratification factors included ECOG PS, treatment line, and clinical stage. Primary endpoint was PFS according to the blinded IRF. Secondary endpoints included OS, objective response rate, and safety. Results: After a median follow-up of 42.2 months in the ALC arm and 42.4 months in the CRZ arm, an event of disease progression or death occurred in 54% and 86% in the ALC arm and the CRZ arm, respectively. The final PFS HR was 0.37 (95%CI 0.26-0.52): median IRF-PFS was 34.1 months (95%CI 22.1– not estimated) in the ALC arm and 10.2 months (95%CI 8.3–12.0) in the CRZ arm. HRs for the time to CNS progression or death was 0.33 (95%CI 0.11–0.93) and 0.20 (95%CI 0.08–0.49) with or without CNS metastases at baseline, respectively. The 2 nd interim analysis of OS was still immature (events 30.1% in the ALC arm, 31.7% in the CRZ arm; stratified HR 0.80, 95%CI 0.35–1.82). Most of patients (77.9%) in the CRZ arm received ALC as a subsequent therapy whereas only 10.7% of patients in the ALC arm received CRZ. Proportion of patients with grade 3–4 AEs (37% vs 61%), AEs leading to interruption (40% vs 82%) or discontinuation (12% vs 23%) were lower in the ALC arm than the CRZ arm. There were no treatment-related deaths in either arm. Conclusions: In the final PFS analysis, ALC continued to demonstrate the superiority in IRF-PFS in ALK-inhibitor naïve ALK+ NSCLC regardless of baseline CNS metastases with a favorable safety profile. The updated result of OS will be presented in the future congress. Clinical trial information: JapicCTI-132316.
Supramolecular nanotheranostics based on pillarenes
Authors: Nan Song, Xin-Yue Lou, Lianjun Ma, Hui Gao, Ying-Wei Yang
Journal: Theranostics (2019)

With the rapid development of supramolecular chemistry and nanomaterials, supramolecular nanotheranostics has attracted remarkable attention owing to the advantages compared with conventional medicine. Supramolecular architectures relying on non-covalent interactions possess reversible and stimuli-responsive features; endowing supramolecular nanotheranostics based on supramolecular assemblies great potentials for the fabrication of integrated novel nanomedicines and controlled drug delivery systems. In particular, pillarenes, as a relatively new class of synthetic macrocycles, are important candidates in the construction of supramolecular therapeutic systems due to their excellent features such as rigid and symmetric structures, facile substitution, and unique host-guest properties. This review summarizes the development of pillarene-based supramolecular nanotheranostics for applications in biological mimicking, virus inhibition, cancer therapy, and diagnosis, which contains the following two major parts: (a) pillarene-based hybrid supramolecular nanotheranostics upon hybridizing with porous materials such as mesoporous silica nanoparticles, metal-organic frameworks, metal nanoparticles, and other inorganic materials; (b) pillarene-based organic supramolecular therapeutic systems that include supramolecular amphiphilic systems, artificial channels, and prodrugs based on host-guest complexes. Finally, perspectives on how pillarene-based supramolecular nanotheranostics will advance the field of pharmaceuticals and therapeutics are given.
Pembrolizumab (pembro) for recurrent head and neck squamous cell carcinoma (HNSCC): Post hoc analyses of phase 3 KEYNOTE-040 prior radiation treatment (RT) and disease state.
Authors: Kevin J. Harrington, Ezra E.W. Cohen, Denis Soulieres, José Dinis, Lisa F. Licitra, Myung-Ju Ahn, Ainara Soria, Jean-Pascal H. Machiels, Nicolas Mach, Ranee Mehra, Barbara Burtness, Jianxin Lin, Jonathan D. Cheng, Ramona F. Swaby, Christophe Le Tourneau
Journal: Journal of Clinical Oncology (2019)

6026 Background: The open-label, randomized, phase 3 KEYNOTE-040 study (NCT02252042) showed that pembro vs standard of care (SOC) chemotherapy prolonged survival in patients (pts) with recurrent and/or metastatic HNSCC whose disease progressed during/after platinum-based therapy. Post hoc analyses were conducted to evaluate pembro vs SOC by prior RT and disease state (metastatic, locoregionally recurrent [referred to as recurrent herein], or recurrent and metastatic [R/M]). Methods: Pts (N = 495) were randomly assigned (1:1) to receive pembro (200 mg Q3W) or investigator choice of methotrexate (40 mg/m 2 QW), docetaxel (75 mg/m 2 Q3W), or cetuximab (400 mg/m 2 loading dose, then 250 mg/m 2 QW). Primary end point was OS; PFS and ORR were secondary end points. Results: 175, 97, and 195 pts had metastatic, recurrent, and R/M disease, respectively (28 pts had unknown disease state); 64 pts had no prior RT; 431 pts had prior RT. As in the ITT population, prolonged survival benefit and trend toward improved PFS and ORR was observed with pembro vs SOC in pts with prior RT (Table), and prolonged survival benefit was observed with pembro vs SOC in pts with metastatic and R/M, but not recurrent, disease. Conclusions: In this post hoc analysis, patients with prior RT benefited from treatment with pembro vs SOC. For patients without RT, sample sizes are too small to draw any definitive conclusions. Survival benefit of pembro vs SOC was observed in pts with metastatic and R/M disease. Clinical trial information: NCT02252042. [Table: see text]
Intratumoral CD3<sup>+</sup> and CD8<sup>+</sup> T-cell densities in patients with deficient DNA mismatch repair (dMMR) metastatic colorectal cancer (mCRC) receiving programmed death-1 (PD-1) blockade.
Authors: Sakti Chakrabarti, Lucas J. Huebner, Heidi Diann Finnes, Andrea Muranyi, Shalini Singh, June Clements, Robert R. McWilliams, Joleen Marie Hubbard, Kandavel Shanmugam, Frank A. Sinicrope
Journal: Journal of Clinical Oncology (2019)

3532 Background: Colorectal cancer with dMMR display heterogeneity in the extent of intratumoral T-cell infiltration which may explain their variable responsiveness to PD-1 blockade. We examined the association of intratumoral CD3 + and CD8 + T-cell densities (TCD) with objective response rate (ORR) and response duration in patients with dMMR mCRCs receiving pembrolizumab (PEM). Methods: Record review was performed on 12 patients with dMMR mCRC treated with PEM (200 mg intravenously every 3 weeks) after failure of prior chemotherapy [median no. of regimens was 1 (range 1-4)] between 01/2015 and 12/2017. CD3 + and CD8 + TCDs were analyzed in the primary tumor core (CT) and at the invasive margin (IM) by immunohistochemistry and automated image analysis to determine density score (0 to 100) for each T-cell subtype and compartment (Ventana Medical Systems, Inc.). Patients were categorized as 1) responders [CR (complete response) + PR (partial response)] vs. non responders [SD (stable disease) + PD (progressive disease)] per RECIST version 1.1, and 2) by duration of response (&lt; or &gt; 12 months). Results: Median follow-up post PEM was 19.5 (9-41) months. Responders included 2 CR and 5 PR; non-responders included 4 SD and 1 PD. The ORR and median time to response were 58.3% (7/12) and 12 weeks (range 9-40), respectively. CD3 + and CD8 + TCD scores were higher in responders vs. in non-responders as well as in patients who had disease control for &gt; 12 months; differences were greatest for CD8 + CT (Table). Conclusions: Among patients treated with PEM, data suggest higher intratumoral CD3 + and CD8 + TCDs in responders versus non-responders and in those with a longer duration of disease control. If confirmed, TCDs may potentially predict responsiveness to PD-1 blockade in dMMR mCRCs. [Table: see text]
Distinct immunogenomic properties of melanomas with stable disease as best response to immune checkpoint blockade (ICB).
Authors: Natalie Vokes, Claire Margolis, David Liu, Bastian Schilling, Dirk Schadendorf, Eliezer Mendel Van Allen
Journal: Journal of Clinical Oncology (2019)

2515 Background: ICB has improved survival in melanoma. Patients with stable disease (SD) as best treatment response represent an intermediate response phenotype whose biology has been incompletely characterized. Methods: Whole exome and transcriptome sequencing from pre-treatment tumors in melanoma patients treated with ICB (anti-CTLA-4 and/or anti-PD-1) were assembled and uniformly analyzed (WES n = 293; WES+RNA-seq n = 159). RECIST (v1.1) was used to determine complete or partial response (CR/PR; n = 94), SD (n = 42), or progressive disease (PD; n = 157). Gene set enrichment analysis (GSEA) was performed on 50 “hallmark” gene sets to identify pathways differentially expressed in patients with SD. CIBERSORT was used to infer relative proportions of 22 immune cell types in each sample. Mutation antigenicity was determined by calculating patient-specific mutation affinity for MHC class I peptides. Results: GSEA identified enrichment of multiple immune-related gene sets in SD tumors, including TNF-α signaling and interferon-ɣ response (FDR q &lt; 0.1, SD vs CR/PR and SD vs PD). SD tumors had higher HLA and antigen presentation pathway expression, and increased cytolytic T cell activity compared to CR/PR and PD. CIBERSORT analysis identified higher total immune infiltrate in SD patients compared to CR/PR and PD (Mann-Whitney U p = 0.03 and p &lt; 0.001, respectively) but not in patients with CR/PR vs PD (p = 0.124). However, checkpoint expression, including PD-1, PD-L1, and LAG3, was also higher in SD patients. Mutation load did not differ between SD and CR/PR or PD patients (SD median 2.87 vs CR/PR median 7.98, Mann-Whitney U p = 0.104; PD median 3.42, p = 0.210). However, SD patients had more antigenic passenger mutations (SD vs CR/PR, p = 0.001; vs PD, p &lt; 0.001); there was no difference in antigenicity of driver mutations. Conclusions: Pre-treatment melanomas from patients with SD contain more antigenic passenger mutations and demonstrate a global increase in immune signaling. This may describe a subset of patients with pre-existing dysfunctional immune response that is minimally responsive to ICB. Further characterization of the tumor-immune interaction in these patients may inform improved interventions.
Defining an IBD-like subgroup in consensus molecular subgroups of colorectal cancer and transcriptomic biomarker development for at-risk patients.
Authors: Enya Scanlon, Seamus J Murphy, Richard D. Kennedy, Jaine K. Blayney
Journal: Journal of Clinical Oncology (2019)

e15142 Background: Ulcerative colitis (UC), is a known risk-factor for colorectal cancer (CRC). 10% of UC-patients develop UC-specific CRC yet there are currently no biomarkers for early detection or understanding of drivers of disease. Unresolved inflammation is key in UC-CRC development, yet the aetiology is unclear. It is unknown if UC-CRC falls into a specific consensus molecular subgroup in the CMS classification (Guinney et al 2015). This bioinformatics approach aimed to identify patients at-risk of developing UC-CRC, whilst informing biological and clinical understanding of the disease. Methods: We used publicly available UC data and in-silico, cross platform, class label transfer (GECA) to determine mRNA similarity between UC/UC-CRC and sporadic CRC (sCRC) and to identify a UC-predominant CMS. Pathogenic mutations were identified for each CMS as well as gene set enrichment and survival analysis to determine UC-CRC behaviour comparative to sCRC. Transcriptional relationships were assessed via unsupervised and semi-supervised clustering by immune-signatures and scores to determine molecular patterns between phenotypes. We derived a gene list from UC data informed by clustering to stratify patients based on risk to UC-CRC progression. Results: UC-CRC featured predominantly in the NA group, with 3 attributed pathogenic mutations, an oxidative stress environment and neuroendocrine dysregulation. The subgroup had UC-like clinical features; younger age, distal tumour location and TP53 mutations along with the highest rate of cancer recurrence (~20%) and a unique cellular composition in CMS being highly immune and stromal. Importantly this immune signal was distinct from the interferon type signalling observed in CMS1 and was not associated with PD-L1 activation. Clustering revealed a loss of IFN-type gene expression in colon tissue as UC progressed to UC-CRC. Conclusions: The NA group was thought to be unclassifiable samples between CMS however, analysis shows UC-CRC enrichment with defined biological characteristics. We have identified novel biology that may inform the risk of developing UC-CRC and guide potential preventative and therapeutic approaches.