bluuebunny/crossref_metadata_2025 huggingface dataset:
Population-based, real-world prognostic factors related to survival among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Yu Kenneth H. , Cockrum Paul , Surinach Andy , Wang Shu , Chu Bong Chul
Published: January 2021

389

Background: Pancreatic cancer is expected to be the third deadliest cancer in the US in 2020. Many real-world studies of pts with mPDAC are restricted to single centers, limiting the generalizability of the insights they generate. There is a need to understand prognostic factors of survival in a broader setting to aid in tailoring treatment strategies for pts. This study aimed to identify important population-based predictors related to survival among pts diagnosed with mPDAC. Methods: Data were extracted for pts diagnosed with mPDAC between Jan 2017 and Dec 2019 from the Flatiron Health database. Predictive models for overall survival from the start of each treatment were developed using multivariable Cox proportional hazards regression. Treatment specific predictive models were generated for pts treated with first line (1L) gemcitabine + nab-paclitaxel (GNP), 1L FOLFIRINOX, 1L gemcitabine monotherapy (gem-mono), and 2L liposomal irinotecan-based regimens. The holdout method was used for cross-validation, splitting the data into 70% training / 30% validation. Age at diagnosis, sex, body mass index, smoking status, and ECOG performance score (PS) were included in all models due to clinical importance. Demographic, clinical characteristics, hematological labs, liver function tests (LFTs), and serum bilirubin levels were assessed for inclusion into the models. Uno’s concordance statistic (c-statistic) was used to assess the predictive accuracy of the models. Results: Of the 3,572 pts included in the study, 44% (n = 1,557) received 1L GNP, 27% (n = 954) received 1L FOLFIRINOX, 7% (n = 265) received gem-mono, and 22% (n = 796) received other regimens. 38% (n = 1,345) pts received 2L and of those, 17% (n = 222) received liposomal irinotecan-based regimens. Among all 1L pts, the following were included in the final model: prior surgery, white blood cell (WBC) counts, serum albumin, LFTs (ALP and ALT), serum bilirubin, and ascites (c-statistic: 0.65). The model for pts treated with GNP differed from the overall model via the addition of neutrophil counts and removal of serum bilirubin and ascites (c-statistic: 0.67). Stage at initial diagnosis was included in the model only for pts treated with 1L FOLFIRINOX (c-statistic: 0.68). Among pts treated with gem-mono the LFTs were not included in the model (c-statistic: 0.78). ALP, serum albumin, and WBC counts were important predictors of survival among pts treated with 2L liposomal irinotecan-based regimens (c-statistic: 0.70). Across all regimens the strongest predictors of survival were ECOG PS, serum albumin, and ALP. Conclusions: In one of the largest contemporary real-world studies of patients with mPDAC to date, important population predictors of survival in pts receiving systemic treatment were identified. Further validation studies are needed to understand the generalizability of these results.
Serial cell-free DNA (cfDNA) sampling in advanced pancreatic ductal adenocarcinoma (PDAC) patients may predict therapeutic outcome.
Authors: Botrus Gehan , Fu Yu , Sonbol Mohamad Bassam , Drusbosky Leylah , Ahn Daniel H. , Borad Mitesh J. , Starr Jason S. , Jones Jeremy Clifton , Raman Puneet , Mody Kabir , Bekaii-Saab Tanios S.
Published: January 2021

423

Background: Advanced PDAC remains a deadly disease with a 5-year survival rate of less than 10%. cfDNA - based next generation sequencing (NGS) may identify actionable alterations in patients with PDAC. In this study, we aim to determine the feasibility of utilizing serial cfDNA NGS testing and its potential relevance in predicting therapeutics outcomes. Methods: A total of 23 PDAC patients with PDAC cfDNA isolated from plasma collected at diagnosis and upon disease progression to first line SOC therapy and were analyzed on a 73-74 gene NGS panel (Guardant Health). Changes in molecular profiles from baseline to progression were analyzed for overall survival, progression free survival (PFS), and treatment response. PFS and OS were analyzed using the Kaplan-Meier method and the log-rank test was used to compare the survival of different groups of patients. All p-values were two-sided. Analyses were performed using R (version 3.5.1, R Foundation, Vienna, Austria). Results: In this retrospective study, the 1-year probability of survival was 71% (median 473 days) and the 1-year PFS was 14% (median 212 days). TP53 and KRAS were the most frequently mutated genes identified in baseline samples, with 78% prevalence for each. Patients with clearance of TP53 17% (3/18) patients and/or KRAS 33% (6/18) patients clones after first line therapy significantly increases PFS (p=0.0056 and p=0.037, with HR of 0.087 and 0.32, respectively). However, appearance of TP53 or KRAS alterations upon progression does not significantly affect overall survival or PFS. Conclusions: The preliminary results from this study suggest that cfDNA clearance of TP53 and/or KRAS alterations may predict for improved PFS in PDAC. Confirmation of these findings in larger studies is warranted.
Familial pancreatic cancer (FPC) status as a clinical biomarker in patients receiving platinum-based systemic therapy: A case-control analysis.
Authors: Kelly Deirdre , Borgida Ayelet , Perera Sheron , Denroche Robert Edward , Holter Spring , Liu Zhihui (Amy) , Liu Zijin , Zhang Amy , Dodd Anna , Ramotar Stephanie , Hutchinson Shawn , Wilson Julie , Notta Faiyaz , Knox Jennifer J. , Gallinger Steven , Grant Robert C , O'Kane Grainne M.
Published: January 2021

430

Background: Familial pancreatic cancer (FPC) is broadly defined as kindreds with at least a pair of first-degree relatives with pancreatic ductal adenocarcinoma (PDA). The role of DNA damage response agents, including platinum has not been well studied in this patient population. Methods: In this retrospective analysis, treatment details and clinical outcomes were analyzed in pts with FPC with advanced, unresectable or recurrent disease enrolled in the Ontario Pancreatic Cancer Study database. The primary outcome, overall survival (OS) was calculated from the initial diagnosis of advanced disease until death. 179 non-FPC patients from the COMPASS trial [NCT02750657] served as a control cohort all of whom had full molecular profiling and family history documented. OS between pts that received platinum-based therapy, and those that did not was compared using multivariable Cox proportional hazards model adjusting for age, sex, diagnosis year and FPC status. Interaction between FPC status and platinum was evaluated. Results: A total of 205 FPC pts were identified, 71% of pts had full germline testing and 16 (8%) had germline pathogenic variants in BRCA1/2. 104 (51%) were female and 101 (49%) male. Median age was 63 years (20-93) and 58 (28%) received platinum-based chemotherapy. Within the control arm (n=179), 71 (40%) were female, and 108 (60%) male; the median age was 64 years (29-84) and 106 (59%) received platinum-based therapy. In univariable analysis, median OS in pts with FPC was 16.9 months compared to 9.6 months (HR 0.46 [95% CI 0.37-0.58]). FPC patients receiving platinum had a superior median OS of 19 months compared to 15.5 months without platinum. In a multivariable analysis, both FPC (HR 0.33 [95% CI 0.21-0.51]) and receipt of platinum HR 0.53 [95% CI 0.38-0.73]) were prognostic. No interaction was seen with FPC and receipt of platinum (p=0.15). Conclusions: FPC status is prognostic but not predictive of platinum response in this study. Further molecular profiling of this unique cohort of patients will provide insights into putative predisposing germline alterations, and novel treatment strategies.
Shared DNA-based copy number with divided methylation changes differentiate and clinically associate early stage pancreatic cancer tumors.
Authors: Chao Eva , Aung Kyaw Lwin , Xu Qi , Matsui William H. , Kowalski Jeanne
Published: January 2021

434

Background: There is no known molecular taxonomy of pancreatic cancer that can guide therapeutic strategies. Understanding the fundamental molecular mechanism underlying pancreatic cancer biology remains an unmet need. We explore the extent to which combinations of DNA-based molecular changes in copy number (CN) and methylation separate early stage PAAD tumors and associated with survival outcomes. Methods: We performed genome-wide combined cluster analyses on DNA-based CN and methylation changes using TCGA data. We examined cluster associations with clinical outcomes by comparing in months (mos), Kaplan--Meier estimated overall survival (OS) and disease-free interval (DFI) using a log-rank test. We performed additional comparisons among CN-Methylation derived clusters with respect to PAAD phenotypes. Results: Using 78 early stage pancreatic cancer tumors from TCGA with CN, methylation and clinical outcomes data, we identified two patient clusters with distinct gene copy number signatures that when combined with three methylation signatures, resulted in three additional clusters. Thus, the same gene CN signature, when combined with different methylation signatures, further differentiated tumors into sub-clusters with varying levels of associations with clinical outcome. Among them, analogous to current gene-expression based subtypes, we also identified an immune-rich subtype that was associated with improved overall survival (n=21, median OS=16mos; DFI=16mos), and an extracellular matrix (ECM)-rich with worse survival (n=19, median OS=12mos; DFI=8mos). Unlike previous expression subtypes, we identified another metabolic-enriched subtype with the same worse median OS and DFI, differentiated by methylation with the ECM-rich subtype. The improved OS cluster had a signature of CN neutral and increased methylation, while the poor cluster had a signature of CN gains and increased methylation among a set of genes distinct from the improved cluster. No significant differences in age, site, microsatellite instability and KRAS status among clusters were noted. Notably, in a multivariable model that included gene expression-based subtypes, only our DNA-level subtypes remained significantly associated with overall survival. Conclusions: While RNA-level changes often display large variations, DNA-level changes are more robust. Copy number changes appear to separate tumors into poor and improved prognosis clusters, while methylation appears to inform on the further separation of poor prognosis into various levels. A DNA-based molecular taxonomy for early stage pancreatic cancer could prove invaluable when used in combination with methylation-based circulating tumor DNA assays for clinical trial monitoring of tumor responses.
Exploring cancer clinical trial participation in the new normal of COVID-19: The patient perspective.
Authors: Raymond Martha Ann , Simonetta Margaret-Ann
Published: January 2021

461

Background: The impact of coronavirus (COVID-19) has significantly affected cancer patients seeking to enroll in a clinical trial. The pandemic has led to an unprecedented disruption across the cancer research community pausing trial operations. Data from the National Institute of Health and the National Library of Medicine indicates 988 cancer clinical trials were suspended from March  September 1, 2020, with 60% of institutions enrolling patients at a lower rate. Our research underscores the patient perspective of clinical trial participation amid COVID-19. Methods: July  September 2020 Nationwide eight-week online survey and interviews. Research goals: gain a better understanding of barriers and cultural attitudes of ethnically diverse communities regarding trial participation; learn the enhanced safety measures needed for patients to feel comfortable returning to the clinic; better understand the importance of effective patient-clinician communication. Results: 511 patient participants reported the following insights: 86% reported their healthcare team had not discussed trial participation; 99% reported being comfortable with telehealth visits for pre-screening and monitoring; 82% receive care at community-based hospitals. Barriers to enrollment and additional safety considerations include gaps in outreach and education services for ethnically diverse communities; absence of cultural sensitivity and disregard of historical perspective; financial insecurity and travel; and the need for increased COVID-19 testing, enhanced safety protocols and a proven vaccine. Participants identified their ethnicity as 38% Caucasian; 24% Black/African American; 19% Hispanic/Latino; 16% Asian; 2% Native American/Pacific Islander. Conclusions: Clinical trials provide patients access to the newest treatments, and yet only 2%-3% of adult cancer patients enroll in a trial. Common barriers to trial participation have been widely researched, but now amongst the coronavirus pandemic, additional barriers are evident. Based on our research, our call to action is clear: work with key opinion leaders in ethnically diverse populations to help build trust and mutual respect when discussing research studies; and engage patients and clinicians to openly discuss clinical trial enrollment working toward patient-centered communication. The coronavirus pandemic is a devastating public health threat, and it will take a collective effort from the entire cancer community to minimize the effect of COVID-19 on cancer clinical trial participation.
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.
Pembrolizumab plus chemotherapy for previously untreated, HER2-negative unresectable or metastatic advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: KEYNOTE-859.
Authors: Tabernero Josep , Bang Yung-Jue , Van Cutsem Eric , Fuchs Charles S. , Janjigian Yelena Y. , Bhagia Pooja , Li Kan , Adelberg David E. , Qin Shu Kui
Published: January 2021

TPS263

Background: For patients with unresectable, locally advanced recurrent or metastatic G/GEJ cancer, the standard of care includes a fluoropyrimidine plus a platinum-based agent as first-line therapy. The PD-1 inhibitor pembrolizumab has demonstrated durable antitumor activity in this patient population across lines of therapy. Herein, we describe the randomized, double-blind, phase 3 KEYNOTE-859 trial (NCT03675737) of first-line pembrolizumab plus chemotherapy in patients with advanced G/GEJ adenocarcinoma. Methods: Patients with histologically or cytologically confirmed, locally advanced unresectable or metastatic G/GEJ adenocarcinoma with known PD-L1 expression status, HER2-negative disease, measurable disease per RECIST v1.1, and ECOG performance status of 0 or 1 will be randomly assigned 1:1 to receive pembrolizumab plus chemotherapy or placebo plus chemotherapy. Randomization will be stratified by geographic region (Europe/Israel/North America/Australia vs Asia vs rest of world), PD-L1 tumor expression status (combined positive score < 1 vs ≥1), and combination chemotherapy (FP vs CAPOX). Pembrolizumab or placebo will be administered at 200 mg IV every 3 weeks (Q3W). The chemotherapy regimen will be investigator’s choice of FP (continuous infusion of 5-fluorouracil [800 mg/m2/day on days 1-5 of each cycle] plus IV cisplatin [80 mg/m2] Q3W) or CAPOX (oral capecitabine [1000 mg/m2 twice daily on days 1-14 of each cycle] plus IV oxaliplatin [130 mg/m2 on day 1 of each cycle] Q3W). Duration of cisplatin or oxaliplatin may be capped at 6 cycles per local country guidelines; treatment with 5-fluorouracil or capecitabine may continue per protocol. Treatment with pembrolizumab or placebo will continue for ≤35 administrations (~2 years) or until disease progression, unacceptable toxicity, intercurrent illness that prevents further administration of treatment, investigator decision, or noncompliance. Imaging will be performed at screening and subsequently every 6 weeks until disease progression, start of new anticancer treatment, withdrawal of consent, or death. Adverse events will be monitored throughout the study from the time of randomization to 30 days after the last dose of study treatment (90 days for serious adverse events). The dual primary end points are OS and PFS per RECIST v1.1 as assessed by blinded independent central review (BICR). Secondary end points include ORR and DOR per RECIST v1.1 as assessed by BICR, safety, and tolerability. Enrollment is ongoing. Clinical trial information: NCT03675737.
Trial-in-progress: A pilot study of combined immune checkpoint inhibition in combination with ablative therapies in subjects with hepatocellular carcinoma (HCC).
Authors: Carroll Hailey Kathryn , Aleem Umair , Varghese Pooja , Galligan Marie , Bourke Michele , Hoey Katherine , Ryan Ronan , Doran Peter , Stewart Stephen , O'Farrelly Cliona , Greten Tim F. , Houlihan Diarmaid , McDermott Raymond S. , Duffy Austin G.
Published: January 2021

TPS355

Background: Locoregional therapies for hepatocellular carcinoma, such as transcatheter arterial chemoembolization (TACE) or ablation, can induce a peripheral anti-tumor immune response. This may be amplified by immune checkpoint inhibitors (ICI). Early and higher anti-CTLA4 dosing could potentially lead to better priming and a stronger immune response. Recent data has suggested that early (day 1 only), increased doses of anti-CTLA4 therapy, was associated with encouraging clinical activity and a tolerable safety profile. This study will evaluate dual immune checkpoint, CTLA4 (tremelimumab, day 1-only dosing) and PD-L1 (durvalumab) blockade in combination with TACE in patients with advanced HCC. Intensive peripheral immune-monitoring and longitudinal on-treatment tumor biopsies will focus on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Methods: Patients with HCC (Childs Pugh A/B7; Barcelona Clinic Liver Cancer Stage B/C; ECOG 0/1; sorafenib-naïve or experienced) are being enrolled in a pilot study (Study Number UCDCRC/19/01) of tremelimumab at 2 dose levels (DL1 and DL2) in combination with durvalumab and TACE until disease progression (per irRECIST). DL1: tremelimumab (75mg q28 days for 4 doses) and durvalumab (1500mg q28 days). DL2: tremelimumab (300mg in a single dose on day 1) and durvalumab (1500mg q28 days). Subtotal TACE will be performed during study week 6 with the dose-limiting toxicity (DLT) evaluation period encompassing the first 8 weeks of the study. Primary endpoint is 6-month progression-free survival with secondary efficacy endpoints being safety, tolerability and overall survival. Exploratory objectives will evaluate changes in immune parameters in the tumor and peripheral blood of patients undergoing anti-CTLA4 therapy pre- and post-RFA or TACE. A major focus will be on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Patients will be enrolled and treated at St Vincent’s University Hospital in Dublin, Ireland. This study is currently open and actively recruiting. Clinical trial information: EudraCT Number 2019-002767-98.
Randomized phase II trial of olaparib + pembrolizumab versus olaparib alone as maintenance therapy in metastatic pancreatic cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2+) mutations: SWOG S2001.
Authors: Chung Vincent , Guthrie Katherine A , Pishvaian Michael J. , Lowy Andrew M. , Chiorean Elena Gabriela , Duong Mai T. , O'Reilly Eileen Mary , Philip Philip Agop
Published: January 2021

TPS447

Background: Olaparib was approved in 2019 as maintenance therapy for g BRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression free survival (mPFS) with olaparib compared to placebo (7.4 versus 3.8 months) for g BRCA1/2+ mPDA pts following either stable disease/response on first-line platinum chemotherapy. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Several clinical studies in solid tumors have shown preliminary efficacy with the combination of PARP plus immune checkpoint inhibitors. Based upon these data, SWOG S2001 aims to further improve the PFS of g BRCA1/2+ mPDA pts. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing will be eligibleif no progression after receiving 4 to 6 months of platinum chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin). Zubrod performance status (PS) 0 or 1 pts are eligible. Pts will be stratified according to first line chemotherapy, PS 0 versus 1, and disease status after first-line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha=0.10, this design requires 78 evaluable pts to be accrued over 3 years. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support:NIH/NCI grants U10CA180888 and U10CA180819. Clinical trial information: TBD.
MEKiAUTO: A phase I/II open-label study of combination therapy with the MEK inhibitor cobimetinib, Immune-checkpoint blockade with atezolizumab, and the AUTOphagy inhibitor hydroxychloroquine in KRAS-mutated advanced malignancies.
Authors: Raufi Alexander , Wong Winston , Lee Shing Mirn , Manji Gulam Abbas
Published: January 2021

TPS450

Background: Pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma (CRC) are aggressive diseases which account for the third and second leading causes of cancer-related death, respectively. Limited progress has been made towards effective treatments or cure. K RAS is mutated or amplified in nearly 30% of all cancers, including up to 95% of PDAC and 45% of CRC. Although no successful KRAS directed therapy has been approved to date, data has emerged demonstrating that inhibition of downstream targets of KRAS, namely MEK/ERK, increases autophagic flux in KRAS-mutated tumors. This catabolic process is used by many tumors to maintain viability and recent preclinical studies have shown that combining MEK/ERK and autophagy inhibitors in KRAS-mutated tumors can synergistically suppress cancer cell proliferation. Inhibition of autophagy has demonstrated an increase in antigen presentation which sensitize tumors to immune checkpoint inhibitors. Presented here is a trial-in-progress that will evaluate combination of cobimetinib (MEK inhibitor), atezolizumab (anti-PDL1), and hydroxychloroquine (autophagy inhibitor) in KRAS-mutated advanced malignancies. Methods: This is a phase 1/2 multicenter, open-label study of combination cobimetinib (40-60mg) orally once daily on days 1-21, hydroxychloroquine (600mg) orally twice daily on days 1-28, and atezolizumab 840 mg IV on days 1 and 15 of each 28 day cycle. Patients with histologically confirmed metastatic or unresectable KRAS-mutant adenocarcinoma for which standard curative or meaningful life-prolonging treatment options do not exist or are no longer effective will be enrolled. The primary objective of the phase I portion of this trial, which seeks to enroll 18 patients, is to estimate the maximum tolerated dose (MTD) of these agents using a two-stage time-to-event continual reassessment method (TITE-CRM). The primary objective of the phase II portion of this trial, which seeks to enroll approximately 66-157 patients, is to evaluate the preliminary efficacy of this combination, based on the objective response by 16 weeks. Secondary endpoints include PFS, OS, and safety. Correlative aims include analyses of pre- and on-treatment biopsies with quantitative multiplex immunofluorescence, RNA-sequencing, reverse phase protein array for association with clinical benefit and to determine mechanisms of action/resistance. An interim analysis will be performed at the conclusion of the phase I portion of the study. This study is open with 4 patients enrolled at the time of submission. Clinical trial information: NCT04214418 . This trial is being conducted as part of the imCORE collaboration. Clinical trial information: NCT04214418.