bluuebunny/crossref_metadata_2025_split huggingface dataset:
RECIST and iRECIST criteria for the evaluation of nivolumab + ipilimumab combination in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC): Results of the GERCOR NIPICOL phase II study.
Authors: Cohen Romain , Bennouna Jaafar , Henriques Julie , Tournigand Christophe , De La Fouchardiere Christelle , Tougeron David , Borg Christophe , Mazard Thibault , Chibaudel Benoist , Garcia-Larnicol Marie-Line , Svrcek Magali , Vernerey Dewi , Menu Yves , Andre Thierry 
Published: February 2020

101 Background: Immune checkpoint inhibitors (ICKi) are highly effective for MSI/dMMR mCRC pts. RECIST1.1 criteria are reported to underestimate response to ICKi. The GERCOR NIPICOL phase II study aimed to evaluate disease control rate (DCR) using RECIST1.1 and iRECIST for MSI/dMMR mCRC pts treated with nivolumab (NIVO) and ipilimumab (IPI). Methods: MSI/dMMR mCRC pts previously treated with fluoropyrimidines (FP), oxaliplatin (OX) and irinotecan (IRI) ± targeted therapies received NIVO 3 mg/kg + IPI 1 mg/kg Q3W for 4 cycles then NIVO 3 mg/kg Q2W until progression or a maximum of 20 cycles. CT-scan tumor assessments were done every 6 weeks during 24 weeks and then every 12 weeks. Primary objective was DCR at 12 weeks (12wDCR) according to RECIST1.1 and iRECIST by central review. Response rates and progression-free survival (PFS) by central review were secondary objectives. A one-stage Fleming design was used with a targeted improvement of 12wDCR from 70% to 85%. Results: Of 57 pts included between Dec 2017 and Nov 2018, 43.9% had received ≥ 3 prior lines including FP (100%), OX (100%), IRI (95.5%), antiangiogenics (57.9%) and anti-EGFRs (45.6%). 17.5% of pts had BRAF mutation and 27.5% Lynch syndrome. Grade 3-4 treatment-related adverse events were reported in 49.1% of pts, mainly hepatitis (12.3%). 12wDCR was 86.0% and 87.7% using RECIST1.1 and iRECIST respectively, with only 1 pseudo-progression (1.8%) observed during the first 12 weeks, and one later. Kappa coefficient between RECIST and iRECIST 12wDCR was 0.92 (95%CI 0.77-1.0). Best observed responses with RECIST1.1/iRECIST were: 2/2 complete responses (3.5/3.5%), 19/19 partial responses (33.3/33.3%), 30/31 stable diseases (52.6/54.4%) and 3/2 disease progressions (5.3/3.5%), with 3 pts not evaluable (cancer-related deaths before first evaluation). Conclusions: Combination of NIVO and IPI in MSI/dMMR mCRC is associated with a low frequency of pseudo-progression and high DCR rate. PFS will be evaluated in Dec 2019, with all pts having completed the predefined 1-year of ICKi therapy. Clinical trial information: NCT033501260.
A phase II study investigating cabozantinib in patients with refractory metastatic colorectal cancer (AGICC 17CRC01).
Authors: Scott Aaron James , Cohen Steven J. , Basu Mallick Atrayee , Dotan Efrat , Gold Philip Jordan , Hochster Howard S. , Subramaniam Somasundaram , Barzi Afsaneh , Blatchford Patrick Jud , Messersmith Wells A. 
Published: February 2020

103 Background: Therapeutic resistance to antiangiogenics in metastatic colorectal cancer (mCRC) inevitably develops via multiple mechanisms including upregulation of the MET kinase pathway. Cabozantinib, an oral multityrosine kinase inhibitor targeting MET, AXL, and VEGFR, demonstrated significant anti-tumor activity in CRC xenograft and cell line models. Methods: A single-arm, two-stage phase II study was conducted at 7 AGICC centers nationwide. 44 patients (pts) with mCRC who had progressed on or were intolerant of standard of care agents were treated with cabozantinib 60 mg daily in q3 wk cycles. The primary endpoint was 12-wk PFS rate. Based on the control arm of phase III CORRECT study, the Kaplan-Meier 12-wk PFS rate estimate was 13% and served as the null hypothesis. This study was powered at 0.906 to detect the alternative hypothesis of 12-wk PFS rate of 33% with a type I error rate of 0.044. Secondary endpoints were safety, RR, OS, and retrospective analysis of PFS and RR based on RAS, BRAF, and PIK3CA mutation status. Results: 44 pts were enrolled and 34 pts were response-evaluable as having undergone at least the first 6-wk restaging scan. 10 pts discontinued treatment prior to the first 6-wk scan due to clinical disease progression. Median number of cycles was 4 and median follow-up was 2.5 months. As of data-cutoff 8/23/2019, 55 Grade 3/4 AEs were reported with the most common being hypertension, fatigue, diarrhea, pain, HFS, nausea, vomiting, and proteinuria. 32 SAEs occurred in 18 pts. 5 Grade 5 AEs were reported: disease progression (3), disseminated intravascular coagulopathy, and bowel perforation. 15 pts (34%) achieved ≥ 12-wk PFS and 8 patients remain on treatment. Best response was 1 PR and 31 SD with a DCR at 6 wks of 72.7%. Of the pts who achieved ≥ 12-wk PFS, 12 had left-sided primary tumors, 5 had a RAS mutation, 1 had a PIK3CA mutation, and all pts were BRAF WT and MSI stable. Conclusions: Cabozantinib was deemed safe and demonstrates encouraging efficacy in a heavily pretreated mCRC pt population. These results support further investigation of cabozantinib in mCRC. Clinical trial information: NCT03542877.
Phase II study of panitumumab monotherapy in chemotherapy-naïve frail or elderly patients with unresectable, RAS wild-type colorectal cancer: OGSG 1602.
Authors: Ohta Katsuya , Kato Takeshi , Goto Masahiro , Terazawa Tetsuji , Noura Shingo , Satake Hironaga , Kagawa Yoshinori , Kawakami Hisato , Hasegawa Hiroko , Yanagihara Kazuhiro , Shingai Tatsushi , Nakata Ken , Kotaka Masahito , Hiraki Masayuki , Konishi Ken , Nakae Shiro , Sakai Daisuke , Kurokawa Yukinori , Shimokawa Toshio , Satoh Taroh ,   Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG)
Published: February 2020

106 Background: Single agent of panitumumab (Pmab) is expected to be well tolerated and to improve survival in first-line setting in patients (pts) who are not eligible for intensive chemotherapy, although the efficacy and safety of Pmab for chemotherapy-naïve frail or elderly Japanese pts with wild-type (wt) RAS unresectable colorectal cancer (CRC) have not been yet studied. Methods: We conducted a multi-center phase II study. Pts aged over 76 years, or over 65 who were considered unsuitable for intensive chemotherapy. Pmab 6 mg/kg was administered intravenously every 2 weeks. The primary endpoint was disease control rate (DCR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and the incidence of grade 3 or 4 toxicities. Sample size was set to 36 with exact p-value of 0.05, a power of 0.90, the null of hypothesis of 45% and alternative hypothesis of 70% based on the Clopper-Pearson method. Results: A total 36 pts were enrolled in February 2017 to August 2018. Two pts were excluded; one was a lack of image examination at baseline, and the other was a lack of measurable lesion. The median age was 81 (67-88), with 29 pts (85%) being aged over 76 years. There were 33 (92%) pts with performance status (PS) 0/1, while two (6%) and one (3%) pts were PS 2/3, respectively. Twenty-eight pts (78%) had left-sided CRC, while eight pts had right-sided CRC. The RR was 50.0% (95%CI, 32.4-67.6) including three cases (8.8%) of complete response, and SD was 26.5%, yielding 76.5% of DCR (p < 0.001, 90% confidence interval [CI], 61.5-87.7). The RR with left sided tumor was 65% (95%CI, 44.3-82.8), while that pts with right-sided tumor was 0% (95%CI, 0.0-36.9)(p = 0.003). The major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 17%), hypomagnesemia (n = 4, 11%), fatigue (n = 3, 8%), paronychia (n = 3, 6%), and hyponatremia (n = 3, 6%). The grade 3 hematologic toxicities was neutropenia (n = 1, 3%). Conclusions: Pmab monotherapy showed the favolable efficacy and feasibility in the frail or elderly pts with RAS wt, unresectable CRC. The survival analysis including OS, PFS and TTF is awaiting. Clinical trial information: UMIN000024528.
Cobimetinib plus vemurafenib (C+V) in patients (Pts) with colorectal cancer (CRC) with BRAF V600E mutations: Results from the TAPUR Study.
Authors: Klute Kelsey , Garrett-Mayer Elizabeth , Halabi Susan , Mangat Pam K. , Nazemzadeh Reza , Yost Kathleen J , Butler Nicole L. , Perla Venu , Schilsky Richard L. 
Published: February 2020

122 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with BRAF V600E mutation treated with C+V are reported. Methods: Eligible pts had advanced CRC, no standard treatment (tx) options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts had BRAF V600E/D/K/R mutation and no MAP2K1/2, MEK1/2, NRAS mutations. Recommended dosing was C, 60 mg orally once daily for 21 days, 7 days off and V, 960 mg orally twice daily. Simon two-stage design was used to test the null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16 weeks (wks) according to RECIST (SD16+)), 18 more pts enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Thirty pts enrolled from August 2016 to August 2018; 2 were not evaluable for efficacy. Demographics and outcomes are summarized in Table. All pts had BRAF V600E mutations. Eight PR and 8 SD16+ were observed for DC and OR rates of 57% (90% CI, 43% to 67%) and 29% (95% CI, 13% to 49%), respectively. Twelve pts had at least 1 grade 3 AE or SAE at least possibly related to C+V including elevated liver enzymes, decreased lymphocytes, dyspnea, diarrhea, fatigue, hypercalcemia, hypophosphatemia, rash, photosensitivity, upper GI hemorrhage, and vomiting. Conclusions: The combination of C+V showed anti-tumor activity in heavily pre-treated CRC pts with BRAF V600E mutations . Further study is warranted to confirm the efficacy of C+V in this population. Clinical trial information: NCT02693535. [Table: see text]
Sociodemographic disparities in young adults with colorectal cancer (CRC): Analysis of 26,768 patients in the National Cancer Database (NCDB).
Authors: Matusz-Fisher Ashley , Trufan Sally Jeanne , Kadakia Kunal C. , Nazemzadeh Reza , Chai Seungjean , Salmon Stuart , Worrilow William Mills , Musselwhite Laura W. , Hill Joshua , Salo Jonathan C. , Kim Edward S. , Hwang Jimmy J. , Salem Mohamed E. 
Published: February 2020

13 Background: The incidence of colorectal cancer (CRC) in young adults (YA) is rising. Impact of sociodemographic status on YA with CRC is not well described. Methods: Data obtained from the NCDB were used to examine the impact of sociodemographic status on clinicopathological features and outcomes of YA with CRC. Patients (pts) were categorized based on whether they lived in areas of low or high income and education. Logistic regression and chi-square were used to examine the differences between the groups. Results: In total, 26,768 YA (≤40 yrs) pts diagnosed with CRC between 2004 and 2016 were retrospectively studied. The majority of pts were male (51.6%), and 78.7% were white, 14.6% black, and 6.6% of other races. Of the entire cohort, 32.3% pts resided in the highest income areas (median ≥$68,000), whereas 18.4% were in the lowest ( < $38,000); 23% lived in areas that had the highest high school graduation rate ( > 93%), while 20% lived in areas of the lowest graduation rate ( < 79%); and 32.3% came from metropolitan areas, while 18.4% came from urban areas. Pts in the lowest compared to highest income and education areas were more likely to be black (OR: 6.4, 5.6-7.4), not have private insurance (OR: 6.3, 5.6-7.0), have T3/T4 stage (OR: 1.4, 1.3-1.6), have positive nodes (OR: 1.2, 1.1-1.3), be rehospitalized within 30 days (OR: 1.3, 1.1-1.6), or have a Charlson-Deyo score ≥ 1 (OR: 1.6, 1.4-1.9), and were less likely to have surgery (OR: 0.63, 0.6-0.7). After adjusting for race, insurance status, T/N stage, and Charlson-Deyo comorbidity scores, pts from lowest vs. highest income and education areas had a 24% increased risk of death (HRadj: 1.24, CI 1.1-1.44, p = 0.004), and pts from urban vs. metropolitan areas had a 10% increased risk of death (HRadj = 1.10 (1.01-1.20), P = 0.02). Pts with stage IV disease in the lowest vs. highest income populations had worse mOS (1.72 vs. 2.17 years, p < 0.001). Conclusions: YA with CRC in the lowest income and education population were more likely to have worse OS. Furthermore, regardless of income, pts in metropolitan areas seemed to have a lower risk of death likely due to greater access to care. More efforts are needed to eliminate disparities and achieve health equity.
Pertuzumab plus trastuzumab (P+T) in patients (Pts) with colorectal cancer (CRC) with ERBB2 amplification or overexpression: Results from the TAPUR Study.
Authors: Gupta Ranju , Garrett-Mayer Elizabeth , Halabi Susan , Mangat Pam K. , D'Andre Stacy D. , Meiri Eyal , Shrestha Sagun , Warren Sasha L. , Ranasinghe Shamika , Schilsky Richard L. 
Published: February 2020

132 Background: TAPUR is a phase II basket trial evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with ERBB2 overexpression or amplification treated with P+T are reported. Methods: Eligible pts had advanced CRC, no standard treatment (tx) options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts had ERBB2 overexpression or amplification, or certain ERBB2 mutations. Recommended dosing after initial dosing was P, 420 mg IV over 30-60 mins every 3 weeks (wks) and T, 6 mg/kg over 30-60 mins every 3 wks. Simon two-stage design was used to test a null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16+ wks per RECIST (SD16+)), 18 more pts enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Twenty-eight pts enrolled from November 2016 to September 2018 were evaluable for efficacy and safety. Demographics and outcomes are summarized in Table. All pts had ERBB2 amplification; 1 also had an ERBB2 mutation. 79% of pts had at least 3 prior txs. Four PR and 10 SD16+ were observed for DC and OR rates of 50% (90% CI, 36% to 60%) and 14% (95% CI, 4% to 33%), respectively. Two pts had at least one grade 3 AE or SAE at least possibly related to P+T including anemia, infusion reaction, and left ventricular dysfunction. Conclusions: The combination of P+T showed anti-tumor activity in heavily pre-treated CRC pts with ERBB2 amplification . Additional analyses by RAS mutation status are pending. Further study is warranted to confirm efficacy of P+T in this population. Clinical trial information: NCT02693535. [Table: see text]
Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab: Results of the expansion part of a phase I study in patients with metastatic colorectal cancer.
Authors: Bordonaro Roberto , Calvo Aitana , Auriemma Alessandra , Hollebecque Antoine , Rubovszky Gabor , Saunders Mark P. , Papai Zsuzsanna , Prager Gerald W. , Stein Alexander , Andre Thierry , Argiles Guillem , Cubillo Antonio , Dahan Laetitia , Edeline Julien , Leger Catherine , Amellal Nadia , Cattan Valerie , Tabernero Josep 
Published: February 2020

140 Background: Trifluridine/tipiracil (FTD/TPI) is approved for use in patients (pts) with pretreated mCRC. In vivo studies have shown an increase in anti-tumor activity when combining FTD/TPI, oxaliplatin or bevacizumab, and an increase in tumor immunogenicity after treatment with FTD/TPI and oxaliplatin (Ghiringhelli, 2018). The recommended dose for expansion had been defined as FTD/TPI 35 mg/m² bid, days 1–5 q14, together with oxaliplatin 85 mg/m² (day 1). Methods: In addition to FTD/TPI and oxaliplatin, eligible pts received bevacizumab 5 mg/kg (Cohort A) or nivolumab 3 mg/kg (Cohort B) on day 1. Eligibility criteria included measurable disease, performance status (PS) 0-1, normal organ function, progression after > 1 prior anti-tumor therapy (excluding oxaliplatin), and confirmed MSS status (Cohort B). A Bayesian design was used for futility and efficacy assessments. Efficacy endpoints of objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and adverse events (AEs) were assessed for each cohort; biomarkers of immune function including PD-L1 expression for Cohort B. Results: A total of 37 and 17 pts were enrolled in Cohorts A and B respectively; with a median age of 64 years (range 33 to 83 years), 61% and 39% had an PS of 0 and 1. At baseline, no pt showed PD-L1 expression on tumor cells, and only 1 pt on immune cells (5% threshold). At data cutoff, 32 and 12 pts were evaluable for response in Cohorts A and B. In Cohort A, ORR was 13% (1 CR; 3 PR), and DCR was 91%. The mPFS was 6.9 months (95% IC, 4.3-9.3). In Cohort B, ORR was 8% (1 PR), DCR was 67%. The mPFS was 6.5 months (95% IC, 1.8-8.6). Overall, the most common treatment-related AEs (≥20% of pts) included neutropenia, nausea, diarrhoea, and fatigue; only 1 pt reported grade 3 febrile neutropenia; 5 pts discontinued due to AEs and no treatment-related death were reported. Conclusions: In this study, bevacizumab in addition to FTD/TPI and oxaliplatin showed antitumor activity. The cohort of nivolumab was prematurely discontinued due to lack of efficacy. Both cohorts showed an acceptable safety profile in pretreated mCRC pts. Clinical trial information: NCT02848443.
Complete neoadjuvant treatment for rectal cancer: A single institution experience.
Authors: Baekey John , Brunault Robert , Safran Howard , Breakstone Rimini , Vrees Matthew , DiPetrillo Thomas A. , Leonard Kara Lynne , Yu Esther , Almhanna Khaldoun 
Published: February 2020

148 Background: Full dose adjuvant chemotherapy following preoperative chemoradiation and surgery is poorly tolerated in stage II and III rectal cancer. We reviewed our institution’s experience with complete neoadjuvant treatment for rectal cancer since publication of the BrUOG R-224 trial results. Methods: After obtaining IRB approval, Data on patients with stage II and III rectal cancer who underwent complete neoadjuvant therapy were collected.. Patients who were planned to receive 8 cycles of modified FOLFOX6, chemoradiation with capecitabine 825 mg/m2 twice daily and 50.4 Gy intensity-modulated radiation therapy, then surgery were included. Results: Thirty-five patients were treated with complete neoadjuvant therapy between January 2014 and December 2017. Median age was 58 years (27 to 75 y); 1 patient (3%) was clinical stage II and 34 (97%) stage III. Twenty-seven patients (77%) received all 8 cycles of mFOLFOX6, of whom 24 completed subsequent chemoradiation. Therefore 69% of patients completed therapy according to the BrUOG R-224 protocol. Pathologic complete response (ypT0N0) was observed in 9 patients (26%). Treatment related toxicities resulted in dose reductions or treatment interruption in 57% and 29% of patients receiving chemotherapy and chemoradiation respectively. Conclusions: Complete neoadjuvant therapy for clinical stage II to III rectal cancer is well-tolerated in routine practice and offers an alternative to preoperative chemoradiation, surgery, then adjuvant full dose chemotherapy.
Phase II study of lamivudine in p53 mutant metastatic colorectal cancer (mCRC).
Authors: Parikh Aparna Raj , Rajurkar Mihir , Van Seventer Emily E. , Gemma Angelo J. , Allen Jill N. , Blaszkowsky Lawrence Scott , Clark Jeffrey William , Goyal Lipika , Hong Theodore S. , Wo Jennifer Yon-Li , Corcoran Ryan Bruce , Solovyov Alexander , Greenbaum Benjamin , Szabolcs Annamaria , Tai Eric C. , Joseph Jasmin , Thapar Vishal , Zheng Hui , Ryan David P. , Ting David Tsai 
Published: February 2020

149 Background: Non-coding repeat RNAs in cancers are pervasive and “mimic” viruses with activation of pattern recognition receptors and the innate immune response. Many repeat RNAs replicate in cancer genomes through a reverse transcriptional intermediate analogous to retroviruses. Nucleoside reverse transcriptase inhibitors (NRTIs) block this retroviral life cycle to increases repeat RNAs in p53 mutant colon cancer cell cancer lines. We initiated a Phase 2 study of lamivudine (3TC) in TP53 mutant mCRC. Methods: Two-stage design with target accrual of 20 patients (pts) in stage 1 and total of 32. Eligibility: pts with p53 mutant refractory mCRC with progression on or intolerance to 5FU, oxaliplatin and irinotecan and anti-EGFR if RAS WT. RNA sequencing was performed on pre-treatment (tx) and on tx biopsy to evaluate for repeat RNA expression and expression of other genes linked to 3TC response/resistance. Radiation was allowed. 9 pts were treated with 3TC 150 mg po bid for 28-day cycles, the maximum FDA approved dose of 3TC in HIV. Subsequent pts were treated at 600 mg po bid, previously tested in P1 trials. Tumor assessments were performed every 8 weeks until documented disease progression by RECIST 1.1 criteria or drug intolerance. Results: 29/32 pts have been treated. Median age: 60 yrs. (27-82) 18 males, 11 females. 2/ 9 (22%) pts on standard 3TC dosing had stable disease (SD) on single agent 3TC with a duration of tx of 169 and 167 days, respectively. Both pts had an initial drop in CEA upon initiation of 3TC. Of the next 20 pts on high dose 3TC, 19 were evaluable. 4 had SD, for 110, 159, 130 and 228+ days. 14 pts had tx-related adverse events (TRAE). 1 pt with a definite Grade 1 TRAE (fatigue). No pts with Grade ≥3 TRAEs. We obtained pre-tx fresh frozen biopsies on 24/29 pts. Of those with SD, 4 had biopsies and differential expression identified significantly higher HSATII repeat RNA in pts with SD compared to PD. There was an association of decreased epigenetic gene expression in HSATII repeat RNA high tumors. Conclusions: This proof-of-concept study demonstrates the safety and activity of single-agent 3TC. Repeat RNA levels appear to correlate with clinical benefit and can be measured in biopsies. Further combination studies and correlatives are planned. Clinical trial information: NCT03144804.