bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival outcomes of adjuvant chemotherapy in elderly patients with stage III colon cancer.
Authors: Shaib Walid Labib , Khalil Lana , Akce Mehmet , Switchenko Jeffrey M. , Gao Xingyu , Diab Maria , Wu Christina , Alese Olatunji B. , El-Rayes Bassel F. 
Published: January 2021

89 Background: The survival impact of multi-agent (MAC) as compared to single-agent (SAC) adjuvant chemotherapy (AC) in elderly patients with stage III colon cancer (CC) remains controversial. The aim of this study is to evaluate the survival outcome comparing MAC to SAC in this population utilizing the National Cancer DataBase (NCDB). Methods: Patients 70 years and older with pathological stage III CC were identified between 2004 and 2015 from the NCDB using ICD-O-3 morphology and topography codes: 8140-47, 8210-11, 8220-21, 8260-63, 8480-81, 8490, and C18.0-18.8 (without C18.1). Univariate and multivariable analyses were conducted and Kaplan-Meier analysis and Cox proportional hazard models were used to identify the association between MAC vs. SAC and overall survival (OS). Results: A total of 41,707 elderly patients (≥70 years old) with stage III CC were identified. Around half of the patients (n = 20,257; 48.5%) received AC; the majority of whom (n = 12,923, 63.8%) received MAC. The median age was 79 (range 70-90). Of the patients who received AC, the majority were female (n = 11,201, 55.3 %), Caucasians (87.4%) and had a moderately differentiated tumor grade (n = 12,619, 62.3%). Tumor size more than 4 cm was identified in 11,785 (58.2%) patients and 18,496 (91.3%) had negative surgical margins. Low-risk stage III CC constituted 50.6% (n = 10,264) of the study population. High-risk stage III CC was associated with worse OS compared to low-risk disease (p < 0.001). MAC was associated with better 5-year OS compared to SAC (p < 0.001). High-risk stage III patients who received MAC had an OS of 4.2 v. 3.4 years in SAC (p < 0.001). In low risk stage III, patients who received MAC had median OS of 8.5 v. 7 years in SAC (p < 0.001). In Univariate, male sex, positive surgical margin, insurance and facility types, age, year of diagnosistumor size, and Charlson-Deyo Score of > 2 were associated with worse OS (p < 0.05). Conclusions: Multi-agent AC is associated with better survival in stage III CC patients 70 years and older compared to SAC. Enhanced benefit of MAC was shown for both low risk and high risk stage III CC.
Safety and efficacy of anti–PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: Results from GARNET study.
Authors: Andre Thierry , Berton Dominique , Curigliano Giuseppe , Ellard Susan , Trigo Pérez Jose Manuel , Arkenau Hendrik-Tobias , Abdeddaim Cyril , Moreno Victor , Guo Wei , Im Ellie , Starling Naureen 
Published: January 2021

9 Background: Dostarlimab is a humanized anti–PD-1 monoclonal antibody that binds the PD-1 receptor, blocking interaction with ligands PD-L1 and PD-L2. The ongoing phase 1 GARNET study (NCT02715284) is evaluating dostarlimab in pts with advanced solid tumors. Here we present safety and efficacy data from cohort F. Methods: Cohort F of the GARNET trial enrolled pts with dMMR or POLEmut non-endometrial solid tumors; the majority were gastrointestinal (GI) in origin. Pts must have progressed per blinded independent central review (BICR) following prior systemic therapy for advanced disease and had dMMR status by local immunohistochemistry. Pts received 500 mg dostarlimab Q3W for 4 cycles and 1000 mg Q6W until discontinuation. Objective response rate (ORR) and duration of response (DOR) were assessed by BICR per RECIST v1.1. Pts were included in the efficacy analysis if they received ≥1 dose of dostarlimab, had measurable disease at baseline, and 6 mo of follow up. All pts who received ≥1 dose were included in the safety analysis. Results: 144 pts were included in the safety analysis, with 106 dMMR pts in the efficacy analysis (1 POLEmut pt with a confirmed PR was not included in this population). Of the 106 pts, 99 (93.4%) had GI tumors. Confirmed ORR in dMMR pts was 38.7% (95% CI: 29.4, 48.6), with a complete response rate of 7.5%. ORR was consistent across tumor type (Table). At the data cutoff, median duration of follow-up (n = 107; dMMR and POLEmut pts) was 12.4 months and median DOR was not reached. The Kaplan–Meier estimated probability of maintaining response at 12 and 18 months was 91.0% and 80.9% respectively. Treatment-related adverse events (TRAEs) were reported in 68.8% of pts; 8.3% of pts experienced at least 1 grade ≥3 TRAE. The most common was lipase increased in 2 (1.4%) pts. Treatment-related serious AEs (SAEs) were reported in 6 (5.5%) pts, and 2 pts (1.8%) discontinued dostarlimab due to a TRAE. No deaths were attributed to dostarlimab. Conclusions: Dostarlimab demonstrated durable antitumor activity in a cohort of dMMR solid tumor pts, the majority of whom had GI cancers. The safety profile was consistent with other cohorts in GARNET, with immune-related TRAEs infrequent and low grade. Clinical trial information: NCT02715284. [Table: see text]
INNOVA: Interval or neoadjuvant chemotherapy in rectal cancer—A phase II randomized study comparing interval versus neoadjuvant chemotherapy in magnetic resonance imaging-defined high-risk rectal cancer.
Authors: Seshadri Ramakrishnan Ayloor , Ganesan Trivadi S. , Dhanushkodi Manikandan , M N Arunkumar , Sundersingh Shirley 
Published: January 2021

91 Background: Total neoadjuvant treatment is a promising option in rectal cancer. We aim to compare neoadjuvant versus interval chemotherapy in high risk rectal cancer to identify the optimal sequencing of treatment. Methods: Using a Simon two-stage design, newly diagnosed MRI defined high risk rectal cancer patients were randomly assigned in a 1:1 ratio to receive three 21 day cycles of chemotherapy with Capecitabine 1000 mg/m2 and Oxaliplatin 130 mg/m2 either before (Arm A-neoadjuvant) or after (Arm B-interval) chemoradiation followed by surgery. Primary end point was the pathological complete response (pCR) following surgery. A heirarchial model was used to assess the primary and secondary end points (toxicity and compliance) and compare the two regimens. (Clinical Trial Registry of India No. CTRI/2015/01/005385). Results: In this single centre study conducted between November 2015 and February 2020, 42 patients were randomised in the first stage. A pCR was seen in 4 patients in Arm A and 6 in Arm B. Hence another 52 patients were randomised in the second stage of which an additional 3 and 2 patients had a pCR leading to an overall pCR of 7 and 8 patients (15.5% vs 17% and 18.4% vs 19.5% in the intent-to-treat and per-protocol populations in Arm A and B respectively. This exceeded the minimum predetermined number of 5 pCR needed to qualify for further evaluation for each arm. Grade ≥3 toxicity was observed in 2.2% of 132 cycles and 4.6% of 129 cycles of chemotherapy delivered in 45 and 43 patients in Arm A and B respectively while 11/43 (25.5%) and 10/47 (21.2%) patients experienced grade ≥3 toxicity during chemoradiation. Treatment break of > 7 days was seen in 23.2% and 29.7% of patients in Arm A and B respectively while 93.3% in Arm A and 100% of patients in Arm B completed all 3 planned cycles of pre-operative chemotherapy. A non-significant trend towards greater pathological downstaging was seen in Arm B than in Arm A (ypT1-2 39% vs 26.3%; p = 0.1 and ypN0 68.3% vs 57.9%; p = 0.5 respectively). Conclusions: In this phase two study, both neoadjuvant and interval chemotherapy emerged eligible for further evaluation against the standard of care in a future phase III study. Although we could not pick one winner based on pCR, toxicity or compliance, the greater downstaging observed with interval chemotherapy suggests it could play a greater role in an organ preservation approach. Clinical trial information:CTRI/2015/01/005385, UTN no: U111111650578.
Polymorphisms of pluripotency transcription factors for predicting cetuximab efficacy in metastatic colorectal cancer: Data from FIRE-3 and TRIBE trials.
Authors: Arai Hiroyuki , Millstein Joshua , Loupakis Fotios , Stintzing Sebastian , Wang Jingyuan , Battaglin Francesca , Kawanishi Natsuko , Soni Shivani , Wu Zhang , Cremolini Chiara , Heinemann Volker , Falcone Alfredo , Lenz Heinz-Josef 
Published: January 2021

98 Background: Cancer stem cells are subpopulation of cancer cells characterized by the self-renewal ability, and primarily maintained by a network of pluripotency transcription factors (PTFs). Despite their chemo-resistant phenotype, recent clinical trials data show cetuximab (Cet) is more beneficial for a subset of metastatic colorectal cancer (mCRC) categorized in a mesenchymal/stem-like subtype based on transcriptomic classifications. We investigated whether single nucleotide polymorphisms (SNPs) in PTF encoding genes have predictive values for the efficacy of Cet in mCRC patients. Methods: Genomic and clinical data from three independent cohorts of patient treated with first-line chemotherapy ( n = 451, in total) were tested: Cet cohort (FOLFIRI+Cet arm in FIRE-3 trial, n = 129); bevacizumab (Bev) cohort 1 (FOLFIRI+Bev arm in FIRE-3 trial, n = 107) and Bev cohort 2 (FOLFIRI+Bev arm in TRIBE trial, n = 215), as controls. Genomic DNA extracted from blood samples was genotyped using an OncoArray (Illumina, Inc., San Diego, CA, USA). Eight SNPs in PTF encoding genes ( NANOG rs11055786, NANOG rs11055767, NANOGP8 rs2168958, NANOGP8 rs9944179, POU5F1 rs3130501, POU5F1 rs3130932, SOX2 rs11915160, and MYC rs3891248) were tested for association with progression-free survival (PFS) and overall survival (OS), using Cox proportional hazards model. Results: In the Cet cohort, three SNPs were significantly associated with PFS in univariate analysis: NANOG rs11055767 (C/C vs any A allele, hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.42–0.94, log-rank p = 0.02), NANOGP8 rs2168958 (A/A vs any C allele, HR = 2.12, 95% CI = 1.36–3.29, log-rank p < 0.01), and NANOGP8 rs9944179 (G/G vs any A allele, HR = 3.68, 95% CI = 1.46–9.31, log-rank p < 0.01). Multivariate analysis confirmed the significance in NANOGP8 rs2168958 and NANOGP8 rs9944179. Furthermore, two SNPs were significantly associated with OS in multivariate analysis: POU5F1 rs313051 (G/G vs any A allele, HR = 0.46, 95% CI = 0.22–0.99, adjusted p = 0.04) and POU5F1 rs3130932 (A/A vs any C allele, HR = 0.46, 95% CI = 0.22–0.93, adjusted p = 0.03). Both in the Bev cohorts 1 and 2, no significant associations between the SNPs and clinical outcomes were observed. Conclusions: The current findings suggest that polymorphisms in the PTF genes could be predictive markers for Cet in patients with mCRC. Further studies are warranted to validate the predictive utility.
PULSE: A randomized phase II open label study of panitumumab rechallenge versus standard therapy after progression on anti-EGFR therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC).
Authors: Strickler John H. , Ou Fang-Shu , Bekaii-Saab Tanios S. , Parseghian Christine Megerdichian , Cercek Andrea , Ng Kimmie , Sanchez Federico Augusto , Bruggeman Sarah , Larson Joseph J. , Finley Gene Grant , Hubbard Joleen M. , Wu Christina , Lenz Heinz-Josef , Kopetz Scott , Corcoran Ryan Bruce 
Published: January 2021

TPS143 Background: Patients with KRAS and NRAS ( RAS) wild-type mCRC benefit from the epidermal growth factor receptor (EGFR) monoclonal antibodies (Abs) panitumumab and cetuximab, but nearly all patients experience resistance. Blood-based profiling of cell free DNA (cfDNA) can identify genomic alterations that drive acquired EGFR Ab resistance. After discontinuation of anti-EGFR Abs, acquired genomic alterations decay over time to undetectable levels. Some studies have suggested clinical benefit from EGFR Ab rechallenge, but there is limited evidence that EGFR Ab rechallenge improves survival compared to standard of care (SOC) therapies. We hypothesize that cfDNA profiling will identify patients appropriate for panitumumab rechallenge, and that these molecularly selected patients will have improved survival compared to current SOC therapies. Methods: This is a randomized phase II, open label study designed to compare the overall survival (OS) of panitumumab rechallenge versus SOC (investigator choice TAS-102 or regorafenib). Secondary objectives include comparisons of progression free survival, objective response rate, clinical benefit rate, and quality of life as measured by the linear analogue self-assessment (LASA) questionnaire. Eligible patients have radiographically measurable KRAS, NRAS, and BRAF codon 600 wild-type mCRC based on tumor tissue testing, and must have experienced progression or intolerance to treatment with a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF Ab, and an anti-PD-1 Ab if the tumor has mismatch repair deficiency or is MSI-H. Progression after at least 4 months treatment with an anti-EGFR Ab is required. All patients must be enrolled in the COLOMATE cfDNA screening protocol (NCT03765736) and meet molecular eligibility based on Guardant360 cfDNA profiling (absence of amplification of ERBB2, KRAS, NRAS, and MET; absence of mutations of BRAF, EGFR, ERBB2, KRAS, NRAS, and MET [mutant allele frequency > 0.5%]). Greater than 90 days must have elapsed between the most recent treatment with an anti-EGFR Ab and cfDNA profiling. Dosing for all study drugs is according to clinical SOC. 120 patients will be randomized 1:1 to panitumumab rechallenge or SOC. With 83 OS events, this study will have 80% power to detect an improvement in median OS from 6.5 to 10 months (HR=0.65; 1-sided α= 0.15). This study began enrollment in 6/2020. Recruitment is ongoing at 16 sites in the Academic and Community Cancer Research United (ACCRU) network (ACCRU-GI-1623). Clinical trial information: NCT03992456.
Conversion from unresectable to resectable liver metastases in real-world patients with liver-only metastatic colorectal cancer (mCRC) treated with FOLFOXIRI plus bevacizumab: The Conversion trial.
Authors: Ahmed Shahid , Anderson Deborah , Chalchal Haji I. , Dwernychuk Lynn , Gill Dilip , Gitlin Josh , Hammond Austin , Kanthan Rani , Le Duc , Lim June , Rakheja Rajan , Sari Nazmi , Vizeacoumar Franco , Zaidi Adnan , Moser Michael 
Published: January 2021

TPS147 Background: Patients with mCRC generally have a limited life expectancy, however, a small number of patients with liver-only mCRC could be cured following metastasectomy. In highly selected patients with mCRC, FOLFOXIRI (5FU, oxaliplatin, and irinotecan) plus bev results in high response rates. However, very limited evidence is available about efficacy of this regimen in real-world patients with liver-only mCRC. Furthermore, there is paucity of biomarkers that predict liver metastasectomy in such patients. The current study aims a) to evaluate rate of conversion from unresectable to resectable liver metastases in real-world patients with liver-only mCRC following FOLFOXIRI-bev, b) to identify predictive markers including an early PET-FDG response that correlate with curative surgery, & c) to determine disease control rate, overall survival, quality of life, treatment toxicities, and cost-effectiveness of surgery. Methods: In this pragmatic phase 2 study, 37 patients with liver-only unresectable mCRC who are deemed eligible for FOLFOXIRI-bev by their oncologist will be recruited at the two major cancer centers in Saskatchewan. Patients will receive FOLFOXIRI-bev every two weeks for a total of 12 cycles and will undergo periodic imaging tests. The resectability of liver metastases will be determined by a multidisciplinary team. For those patients who are not able to undergo a curative surgery, a doublet chemotherapy regimen ±bev will be continued at the discretion of treating oncologist. . The prognostic and predictive value of mutations in specific genes involved in cell proliferation, cell death resistance, angiogenesis, and invasion in colorectal cancer along with the relationship between the abundance and characteristics of exRNA and conversion rate and survival will be assessed. Logistic regression and Cox proportional analyses will be performed to assess correlation between an eight-week FDG-PET/CT response to chemotherapy and other biomarkers and rate of removal of metastases and survival, respectively. This pragmatic study will help to determine conversion rate in real-world patients with FOLFOXIRI plus bev and role of early FDG-PET/CT scan response and other biomarkers in predicting metastasectomy along with cost-effectiveness of this approach. Clinical trial information: NCT03401294.
Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer:NRG-GI005 (COBRA).
Authors: Morris Van K. , Yothers Greg , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Iqbal Atif , Boland Patrick M , Deming Dustin A. , Scott Aaron James , Lim Howard John , Wolmark Norman , George Thomas J. 
Published: January 2021

TPS148 Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features as a prognostic factor to assess risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N=1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for no adjuvant chemotherapy will be randomized 1:1 into 2 arms:standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the GuardantHealth LUNAR panel, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. The trial is actively accruing towards the phase II endpoint across all US and Canadian cooperative groups. Support:U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: NCT04068103.
ARC-9: Phase Ib/II study to evaluate etrumadenant (AB928)-based treatment combinations in patients with metastatic colorectal cancer (mCRC).
Authors: Cecchini Michael , Krishnan Kartik , Giafis Nick , Scott Jennifer , Quah Cheng Seok , Bendell Johanna C. 
Published: January 2021

TPS150 Background: ATP release from dying cancer cells in response to platinum-based chemotherapy increases extracellular immunosuppressive adenosine, which binds and activates the A2a and A2b receptors on immune cells. Adenosine-mediated signaling impairs activation, proliferation, and cytotoxic activity of effector T cells, resulting in inhibition of antitumor activity. Concomitant adenosine receptor blockade may therefore enhance the therapeutic efficacy of chemo/immunotherapy regimens. Etrumadenant (AB928), the first clinical-stage, small-molecule, dual adenosine receptor antagonist, is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Recently, results were reported for the ARC-3 phase 1/1b study of etrumadenant + modified 5-fluorouracil + oxaliplatin (mFOLFOX-6) in patients (pts) with mCRC. In this study, etrumadenant + mFOLFOX-6 was well tolerated without significant additive toxicity. Disease control was observed in patients with RAS/BRAF mutated mCRC, as well as 3L+ disease previously treated with FOLFOX and/or FOLFIRI (PR and/or SD >4 mo). Due to deep responses in 1L-3L+ pts, 6 pts had the opportunity to pursue surgery and radiotherapy with curative intent. The encouraging results from ARC-3 warrant further evaluation of etrumadenant-based combination therapy for mCRC. Methods: ARC-9 is a phase 1b/2, multicohort, open-label, randomized platform study designed to evaluate safety and clinical activity of etrumadenant (150 mg orally once daily [QD]) in combination with standard-of-care (SOC) regimens or novel therapeutics in pts with mCRC (Table). Cohort eligibility is based on prior anticancer treatment history. Pts enrolled in Cohorts A and B will be randomized (2:1) into the experimental vs SOC arms. Cohort C consists of a single arm to allow inclusion of novel agents as they become available with built in early stopping rules for futility. Pts who progress on the SOC arm of Cohort A can enroll in Cohort B; pts who progress on the SOC arm of Cohort B can crossover to the experimental arm. Primary endpoints across cohorts are shown in Table. Safety monitoring will occur throughout the trial, disease assessments will occur every 8 weeks, and correlative study pre- and on-treatment biopsies will be performed. [Table: see text]
NRG-GI004/SWOG-S1610: Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) Study—A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC).
Authors: Overman Michael J. , Yothers Greg , Jacobs Samuel A. , Sanoff Hanna Kelly , Cohen Deirdre Jill , Guthrie Katherine A , Henry Norah Lynn , Ganz Patricia A. , Kopetz Scott , Lucas Peter C. , Blanke Charles David , Wolmark Norman , Hochster Howard S. , George Thomas J. , Rocha Lima Caio Max Sao Pedro 
Published: January 2021

TPS158 Background: Despite activity of programmed cell death-1 (PD-1) pathway inhibition in dMMR/MSI-H mCRC, approximately one-third of patients demonstrate progressive disease as best response to anti-PD1 monotherapy. Preclinical models have demonstrated synergistic interactions between FOLFOX, anti-VEGF, and anti-PD-1. We hypothesize that the dMMR/MSI-H mCRC subset may be more effectively targeted by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-1 therapy (atezo) alone. Methods: Initially a three-arm study, the mFOLFOX6/bev arm was closed to new enrollment on 6-4-20 due to emerging data; the redesigned COMMIT is a prospective phase III open-label trial that will randomize (1:1) mCRC dMMR/MSI-H pts (N=211) to either atezo monotherapy or mFOLFOX6/bev+atezo combination. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is progression-free survival (PFS) as assessed by site investigator. Secondary endpoints include OS, objective response rate, safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Support: U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.