bluuebunny/crossref_metadata_2025_split huggingface dataset:
Access to innovative cancer medicines in gastrointestinal oncology: 2010 through 2020.
Authors: O Reilly David Edward , McLaughlin Ronan Andrew , Ronayne Cian , DeFrein Anne-Marie , Macanovic Bojan , Bambury Richard Martin , Power Derek Gerard , O'Reilly Seamus , Collins Dearbhaile Catherine 
Published: January 2021

469 Background: There are significant disparities in patient access to innovative cancer medicines internationally. We sought to describe global drug licensing developments in gastrointestinal (GI) oncology from 2010 – 2020. We compared US, European, UK and Irish patient access to these drugs, their cost and associated efficacy. Methods: Data was collected from public sources online including the FDA, European Medicines Agency (EMA), the UK National Institute of Clinical Excellence (NICE) and the Irish National Cancer Control Programme (NCCP). Anti-cancer compounds approved for GI malignancies between January 1, 2010 and September 1, 2020 were recorded. Approval publications and updated survival analysis outcomes were included to assess for demonstrable overall survival (OS) and/or progression free survival (PFS) benefit. Results: There were 26 regimens approved by the FDA for GI malignancies between 2010 and 2020. Slightly over half (n=15, 57.7%) of these regimens were approved by the EMA. The median time from FDA to EMA approval was 3 months (mo) +/- 5 mo. Only a small minority of these regimens were funded for patients in the UK (including the Cancer Drugs Fund, 9 regimens, 31%) or Ireland (IRL) (7 regimens, 27%). The median time from EMA approval to patient access was short in both of these countries (3.5 mo (UK) and 0.5 m (IRL)). However, the range in these countries was large (2 - 73 mo (UK) & 0-24 mo (IRL)). More than half of regimens (15, 57.7%) demonstrated an OS benefit. Of the remaining 11 regimens, a further 6 drugs (23%) demonstrated a PFS benefit. The median OS benefit (if present) was 2.3 mo +/- 3 mo. The median price of these regimens in the USA (list price) was $13,758 per month +/- $5,152. Regimens which demonstrated an OS benefit were not more expensive than those that did not (median $13,065 versus $13,758 respectively, p < 0.05). For regimens with an OS benefit, there was no statistically significant correlation between the length of OS benefit and drug cost (Pearson’s correlation = 0.32, p = 0.07). Conclusions: Less than one third of patients in the UK and Ireland have access to medicines approved by the FDA for GI malignancies between 2010 – 2020. Overall survival benefits are often modest, or absent. The cost of regimens in the USA commonly exceeds $100,000/year irrespective of OS benefit. Our work highlights the necessity to develop a value based-pricing system in GI oncology.
Clinicopathological characteristics and impact on efficacy of three versus six months of adjuvant chemotherapy in early-onset colon cancer: ACHIEVE and ACHIEVE-2 trials.
Authors: Oki Eiji , Kotaka Masahito , Manaka Dai , Shiozawa Manabu , Sakamoto Yasuhiro , Munemoto Yoshinori , Eto Tetsuya , Shitara Kohei , Kato Takeshi , Shiomi Akio , Hasegawa Junichi , Makiyama Akitaka , Yamanaka Takeharu , Mizushima Tsunekazu , Yamazaki Kentaro , Sunami Eiji , Ohtsu Atsushi , Maehara Yoshihiko , Mori Masaki , Yoshino Takayuki 
Published: January 2021

60 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s but several data such as the SEER CRC registry show that the incidence of early onset colon cancer (eoCC, age 20-49) and RC keep increasing. There is limited results suggesting eoCC may have different behaviors compared to traditional CC (tCC, age ≥ 50). Methods: Individual patient data of 1,805 high-risk stage II/III colon cancer (CC) patients (pts) as the modified ITT population in ACHIEVE and ACHIEVE-2 trials were investigated. Clinicopathological features and treatment-related data were assessed by age group. Disease-free survival (DFS) was assessed by Kaplan-Meier curves and Cox multivariable models adjusted by trials, regimen, T and N. Results: Of the 1,805 pts, eoCC were 155 pts (8.6%). Using 5% difference between age groups as clinically meaningful cutoff, eoCC had similar gender (female, 52 vs 48%), PS (PS = 1, 1 vs 4%), risk group (high-risk, 43 vs 42%) and T stage (T4, 30 vs 30%) as tCC, while eoCC were less likely right-sided colon primary (32 vs 39%), had N1 disease (48 vs 54%), and treated by FOLFOX (16 vs 23%). Overall, eoCC significantly had a worse DFS than tCC (3y-DFS, 75 vs 82%; Adjusted Hazard Ratio = 1.40: 95% Confidence Interval, 1.00-1.95: p= 0.0478); in addition, similar DFS were observed among tCC pts (age 50-69 vs >70). eoCC experienced less neutropenia, thrombocytopenia and stomatitis, but had more diarrhea, nausea and/or vomiting. There were 38 and 297 pts with an initial relapse in eoCC and tCC, respectively. Of those, peritoneal metastases were more frequently seen in eoCC (n = 13, 34%) than in tCC (n = 63, 21%) (p = 0.097), whereas liver and lung metastases were similar between the two groups. Impact on DFS of 3 versus 6 months of adjuvant chemotherapy in eoCC (3y-DFS, 75% vs 76%) is similar to that in tCC (83% vs 81%). Conclusions: eoCC had unique characteristics; the difference in DFS between eoCC and tCC were potentially due to a different metastatic spread. eoCC had a different adverse event profile compared to tCC. No impact on DFS of treatment duration in eoCC was suggested. Clinical trial information: UMIN000013036.
Tissue and plasma tumor mutation burden (TMB) as predictive biomarkers in the CO.26 trial of durvalumab + tremelimumab (D+T) versus best supportive care (BSC) in metastatic colorectal cancer (mCRC).
Authors: Loree Jonathan M. , Topham James T. , Kennecke Hagen F. , Feilotter Harriet , Keshavarz-Rahaghi Faeze , Lee Young S , Li Weimin , Quinn Katie , Banks Kimberly , Renouf Daniel John , Jonker Derek J. , Tu Dongsheng , O'Callaghan Christopher J. , Chen Eric Xueyu 
Published: January 2021

61 Background: Pembrolizumab was recently granted tissue agnostic FDA accelerated approval for metastatic cancers with TMB≥10 mut/Mb. However, limited data supports immunotherapy in microsatellite stable (MSS) mCRC with TMB≥10 mut/Mb. We assessed tissue TMB and contrasted it to plasma derived TMB in the CO.26 trial. Methods: CO.26 was a phase 2 trial (2-sided ⍺ = 0.1 and 80% power) that randomized 180 patients (pts) 2:1 to D+T or BSC in refractory mCRC. Pre-treatment plasma was sequenced with the GuardantOMNI assay and archival tissue underwent exome sequencing with TMB assessed per the TMB harmonization project. MSI-H cases were excluded. For plasma TMB, we used a previously published cut point (≥28). Results: Overall survival (OS) but not progression free survival (PFS) was improved with D+T in the entire population. Of 180 pts, 163 were evaluable for plasma and 110 for tissue TMB. Median time between archival tissue and plasma collection was 3.1 yrs (IQR 1.9-5.1). Median tissue TMB was 6.6 muts/Mb (IQR 4.1-12.0), while median plasma TMB was 16.3 muts/Mb (IQR 9.4-25.9). Tissue and plasma TMB (r = -0.039, P = 0.69) were not correlated. Tissue TMB≥10 was not prognostic in the BSC arm (HR 1.01, 90%CI 0.52-1.92, P = 0.99) and OS was not improved in pts with tissue TMB≥10 (32/110 pts) following D+T vs BSC. A test of interaction suggested this threshold was not predictive (P = 0.85). Using a minimum P-value approach, no threshold supported high tissue TMB as predictive in MSS mCRC. In fact, the optimal cut point suggested low tissue TMB ( < 4.1 muts/Mb) had the greatest benefit from D+T (P-interaction = 0.048) and pts with TMB ≥4.1 mut/Mb (HR 0.50, 90%CI 0.26-0.96, P = 0.083) trended to better OS in the BSC arm. In contrast, 35/163 pts (21%) were identified in a high plasma TMB group associated with worse OS (HR 2.56, 90%CI 1.45-4.54, P = 0.007) in the BSC arm but improved OS following D+T compared to BSC with P-interaction = 0.082. Only 1 response was noted following D+T in a pt with tissue TMB = 16 mut/Mb and plasma TMB = 13 mut/Mb. Conclusions: Archival tissue TMB≥10 mut/Mb does not appear predictive of D+T benefit in MSS mCRC. Plasma derived TMB may better reflect evolutionary changes following intervening therapy than archival tissue. Clinical trial information: NCT02870920. [Table: see text]
Response to PD-1 and PD-L1 based immunotherapy in MSS advanced colorectal cancer is impacted by metastatic disease sites.
Authors: Fakih Marwan , Sandhu Jaideep Singh , Wang Chongkai , Ouyang Ching 
Published: January 2021

72 Background: Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) has been associated with immunotherapy resistance. However, the impact of metastatic diseases sites on clinical outcome with checkpoint inhibition has not be adequately investigated. Methods: Following IRB approval (14361), we performed a retrospective study to assess the response and progression-free survival (PFS) to PD-1 or PD-L1 based therapy in patients with MSS mCRC who progressed following standard chemotherapy and targeted therapy. Patients were included if they received an FDA approved anti-PD1 or anti-PD-L1 agent, alone or in combination with other investigational agents. Exclusion criteria included concurrent cytotoxic therapy. Response and PFS were determined by RECIST guidelines. Results: 97 patients with refractory MSS mCRC satisfied the inclusion criteria were evaluable for analysis. 57, 17, 13, and 10 received nivolumab, atezolizumab, pembrolizumab, and durvalumab, respectively. 47, 8, 10, 10, 17 received concurrent VEGFR, MEK, CTLA-4, radiation, or other targeted therapies. Among tested variables, including age, gender, primary tumor location, ECOG status, RAS, BRAF, APC, TP53, TMB, and sites of metastasis, only ECOG status (0 vs. 1) and metastatic disease to the liver were associated with disease control (partial response and stable disease; p = 0.005 and < 0.001 respectively). Disease control rates in patients without liver metastases (n = 43) was 56% (95% CI: 40-71%), compared with 2% (95% CI: 0.1-10%) in patients with liver metastases (n = 54) (p < 0.001). Also, liver involvement was predictive for PFS based on multivariate Cox regression model (p < 0.001). The median PFS in patients with liver involvement was 1.5 vs 4.5 months for no liver involvement (HR = 4.41, p = < 0.001). Amongst patients without liver metastases, 35% (15/43) remained without progression at 6 months. These patients were characterized by lung metastases (n = 8) and/or lymph node metastases (n = 4). Conclusions: The presence of liver metastases is MSS mCRC is predictive for lack of benefit from PD-1/PD-L1 inhibitors. Patients without liver metastases can derive a meaningful clinical benefit, with 35% being progression-free at 6 months. Future PD-1/PD-L1 drug development should consider metastatic sites of disease in study design and development.
A phase Ib study of NUC-3373 in combination with standard therapies in advanced/metastatic colorectal cancer (NuTide:302).
Authors: Coveler Andrew L. , Kazmi Farasat , Ciombor Kristen Keon , Graham Janet , Rodgers Lisa Jane , Myers Michelle , Berlin Jordan , Blagden Sarah Patricia , Evans T.R. Jeffry 
Published: January 2021

93 Background: 5-FU is a key anti-cancer agent used across a broad range of tumors. The anti-cancer metabolite of 5-FU, fluorodeoxyuridine-monophosphate (FUDR-MP), binds and inhibits thymidylate synthase (TS), disrupting DNA synthesis and repair. 5-FU is often dosed with leucovorin (LV) to enhance the binding of FUDR-MP to TS. NUC-3373 is a targeted inhibitor of TS designed to bypass 5-FU resistance mechanisms associated with transport, activation and breakdown and avoid the generation of toxic metabolites such as FUTP and FBAL. NUC-3373 has a longer plasma t1/2 (~10 hours) than 5-FU (8-14 minutes), generating substantially higher intracellular levels of FUDR-MP and lower levels of the toxic metabolites FUTP and FBAL. Part 1 interim data from the NuTide:302 study demonstrated NUC-3373’s favorable PK and safety profile was unaffected by LV. Therefore, all subsequent patients in NuTide:302 are receiving NUC-3373 + LV. Here we present the next data series from NuTide:302. Methods: NuTide:302 is a 3-part, Phase Ib study in patients with advanced CRC who have relapsed after ≥2 prior lines of fluoropyrimidine- containing therapies. In Part 1, patients are receiving NUC-3373 with or without LV. In Part 2, NUC-3373 +LV is being administered in dose-escalation cohorts with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). In Part 3, the NUFOX and NUFIRI regimens selected from Part 2 will be combined with biologics targeting VEGF and EGFR pathways. Results:36 patients have been treated in Part 1: 21 received 1500 mg/m2 NUC-3373 ± LV q2w; 11 received 1500 mg/m2NUC-3373 + LV q1w; and 4 received 2500 mg/m2 NUC-3373 + LV q1w. Clinical activity has been observed including tumor shrinkages and stabilization of disease for up to 5 months following rapid progression (≤2 months) on prior lines of therapy. One fluoropyrimidine-refractory patient demonstrated a 28% reduction in target lesions and achieved a stable disease of 5 months after rapid progression on CAPOX (2 months) and FOLFIRI (1.5 months). Safety data for all patients treated with NUC-3373 ± LV in Part 1 of NuTide:302 is shown below. Updated data on the clinical activity and safety of NUC-3373 will be presented. Clinical trial information: NCT03428958. Conclusions:NUC-3373 ± LV has shown clinical activity in heavily pre-treated CRC patients, including tumor shrinkage in a fluoropyrimidine-refractory patient. The safety profile of NUC-3373 ± LV is very encouraging: no neutropenia or hand-foot syndrome of any grade and no diarrhea or mucositis above Grade 2. NUC-3373 +LV is currently being dose escalated further in Part 1 and dosed with either oxaliplatin (NUFOX) or irinotecan (NUFIRI) in Part 2 of NuTide:302. [Table: see text]
Phase II trial of nivolumab and metformin in patients with treatment refractory microsatellite stable metastatic colorectal cancer.
Authors: Akce Mehmet , Rupji Manali , Switchenko Jeffrey M. , Shaib Walid Labib , Wu Christina , Alese Olatunji B. , Diab Maria , Lesinski Gregory B. , El-Rayes Bassel F. 
Published: January 2021

95 Background: Preclinical data suggests metformin can improve immune exhaustion of tumor infiltrating lymphocytes and potentiate the effects of PD-1 blockade. By normalizing the hypoxic TME, metformin was shown to improve cytotoxic T cell function and efficacy of anti-PD-1 antibody in highly aggressive B16 melanoma and MC38 colon adenocarcinoma tumor models. Based on this preclinical rationale we conducted a phase II study with nivolumab and metformin combination in treatment refractory MSS metastatic colorectal cancer (mCRC). Methods: Nivolumab 480 mg IV every 4 weeks and Metformin 1000 mg po twice daily was administered in 28-day cycles following a 14-day metformin only lead-in phase.Eligible patients included stage IV metastatic treatment refractory MSS mCRC (patients must have received oxaliplatin, irinotecan, and fluoropyrimidine), age ≥18 years, ECOG PS 0-1, adequate organ function, no prior anti PD-1 agent. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS) and progression free survival (PFS). Simon’s two-stage Minimax design was employed (H0: ORR =4%; H1: ORR=15%; alpha = 0.1; power =80%). If ≥1 objective response was observed in the first evaluable 18 patients, 10 additional patients would be included in the cohort. ≥3 objective responders in 28 patients would be required to be considered positive study. Pre-treatment and on-treatment research biopsies and correlative peripheral blood specimens were collected. Results: A total of 24 patients were enrolled, 6 patients were replaced per protocol, and 18 patients had evaluable disease. Of the 18 evaluable patients 11/18 (61%) were female, median age 58 [IQR 50-67]. 2 patients had prolonged stable disease (4 and 10 cycles). No patients had objective response based on RECIST 1.1. Median OS and PFS was 5.1 months [95% CI (2-11.7)] and 2.3 months [95% CI (1.7-2.4)], respectively. Most common grade 3 and 4 toxicities were anemia (n=2) and diarrhea (n=2). Conclusions: In treatment refractory MSS mCRCnivolumab and metformin combination was well tolerated. Two patients achieved stable disease, but no objective response was seen; therefore, the study did not proceed with the second stage of enrollment. Immunologic correlative analysis of this study is ongoing. Clinical trial information: NCT03800602.
Folate pathway gene expression in metastatic colorectal cancer patients treated with arfolitixorin/5-FU-based chemotherapy.
Authors: Tell Roger , Di Cara Alessandro , Odin Elisabeth , Carlsson Göran Ulf , Wettergren Yvonne 
Published: January 2021

99 Background: Arfolitixorin is the natural, biologically active form of the marketed folates and is expected to be efficacious in a larger proportion of patients with less inter- and intra-individual variability compared with e.g. leucovorin. We have previously found a positive correlation between survival and expression of folate pathway genes in stage III/IV CRC treated with 5-fluorouracil/leucovorin (5-FU/LV). Low expression of folate-related genes may lead to poor response to 5-FU/LV-based treatment, since suboptimal transport and metabolization of LV yield insufficient active [6R]-5,10-methylenetetrahydrofolate and weak inhibition of the target enzyme thymidylate synthase (TYMS). The aim of the present study was to investigate possible confounders and biomarkers of arfolitixorin/5-FU-based treatment in relation to safety and response in a phase I/IIa metastatic colorectal cancer (mCRC) trial. Methods: ISO-CC-005 is a multi-center, phase I/IIa study in mCRC patients eligible for 5-FU/folate therapy alone or in combination with irinotecan or oxaliplatin ± bevacizumab. Patients were also treated with different doses of arfolitixorin as a single or double bolus. The study investigated safety and tolerability of arfolitixorin, and anti-tumor activity was evaluated by overall response rate (ORR) per RECIST v1.1 after 4 cycles of chemotherapy. RNA was prepared from FFPE tumor tissue, reverse transcribed and used for gene expression profiling. The following genes of interest were evaluated: ABCC3, MTHFD2, SLC46A1, SLC19A1, SLC25A32 and TYMS. An ANOVA test was used to rule out potential biases in the baseline expression levels of the genes and to assess the potential association with clinical response. Results: Eighty-one (77.1%) of 105 patients provided material for this analysis. A lower pre-treatment expression of TYMS was associated with clinical benefit (PR and SD; p = 0.021). No clear association was identified between the gene expression markers and the number of adverse events. Gender was not significantly associated with differences in gene expression. Conclusions: Low pre-treatment expression levels of TYMS were associated with clinical benefit (PR and SD) following treatment. Given the role of this gene in the folate metabolic pathways we plan to further assess its predictive potential on a larger cohort during our ongoing global phase III AGENT study. In parallel an assessment of the expression of the other candidate genes on specific patient sub-groups is currently ongoing. These studies will provide additional cues on the use of these genes as predictive markers for treatment outcome and their role in the mode of action of the drug. Clinical trial information: NCT02244632.
NRG Oncology NRG-GI007 trial-in-progress: Phase I study of OBP-301 (Telomelysin) and definitive chemoradiation (CRT) for patients with locally advanced esophageal and gastroesophageal adenocarcinoma who are not candidates for surgery.
Authors: Ku Geoffrey Yuyat , Winter Kathryn A. , Williams Terence Marques , Adusumilli Prasad S. , Nishimura Makoto , Yock Adam , Ilson David H. , Hong Theodore S. 
Published: January 2021

TPS262 Background: Definitive CRT is a standard-of-care for patients with medically inoperable esophageal cancer (EC, NEJM 326:1593). The NRG/RTOG 0436 study of cisplatin/paclitaxel and RT (+/- cetuximab) as definitive therapy showed that about ½ of patients have locally persistent disease (JAMA Oncol 3:1520). OBP-301 is a conditionally-restricted, replication-competent adenovirus derived from human adenovirus type 5 (Ad-5) that adds a human Telomerase Reverse Transcriptase (hTERT) gene promoter; it replicates only in tumor cells to cause lysis. It may enhance RT and may cause immunogenic cell death. A phase I study with RT in Japanese patients with inoperable EC showed tolerability and activity. Methods: In NRG-GI007, OBP-301 is added to weekly carboplatin/paclitaxel and RT to 50.4 Gy (1.8 Gy/fx ×28 fx) for patients with medically inoperable esophageal or gastroesophageal junction (GEJ) adenocarcinoma. Patients receive intratumoral OBP-301 1×1012 virus particles (vp)/ml via endoscopy (EGD) 3 days prior to CRT, then at days 12 and 26 of CRT, for a total of 3 doses. Restaging with PET and EGD occur 6-8 weeks later. Blood and tumor tissue are collected for immune- and viral-based correlative assays. Patients must be assessed to be medically inoperable and have ECOG performance status <1. The primary endpoint is safety, and clinical complete response (cCR) rate is a secondary endpoint. Initially, 6 patients are enrolled. If protocol-defined dose-limiting toxicity (DLT) occurs in <1 of 6 patients, the dose will be deemed to be safe and 9 more will be enrolled to further assess safety and obtain a preliminary assessment of cCR rate. If >2 of 6 patients have DLT, the dose of OBP-301 is reduced to 1×1011 vp/ml and another 6 patients will be treated. If <1 of 6 patients has a DLT at the lower dose, that dose will be deemed to be safe and 9 more will be enrolled. If >2 of 6 patients have DLT, then neither dose level will have met the safety rule and the trial will be ended. This trial opened to accrual on June 29, 2020. Clinicaltrials.gov NCT04391049. Funding: This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA180803 (IROC), from the National Cancer Institute (NCI) and Oncolys BioPharma. Clinical trial information: NCT04391049.