bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequency and distribution of gastrointestinal oncology patient-reported symptomatic adverse events (SAEs) at a comprehensive cancer center.
Authors: McCleary Nadine Jackson , Haakenstad Ellana , Cleveland Jessica , Zhang Sunyi , Hassett Michael J. , Schrag Deborah
Published: January 2021

463

Background: In clinical trials, the systematic collection of patient (pt) reported outcomes has been shown to improve quality of life & overall survival. To develop predictive care models for symptom management, we explored the frequency & distribution of SAEs reported by pts who reported electronic patient reported outcomes (ePRO) prior to outpatient visits to the Gastrointestinal Cancer Center (GCC) at Dana Farber Cancer Institute (DFCI). Methods: ePRO is a modified NCI Patient Reported Outcomes – Common Terminology Criteria for Adverse Events instrument distributed weekly to GCC pts with a medical/surgical/radiation oncology encounter. Responses are available to the care team in the electronic health record. ePRO consists of presence/frequency/severity/interference of 15 core SAEs (fatigue, insomnia, general pain, decreased appetite, nausea, vomiting, constipation, diarrhea, shortness of breath, numbness and tingling, rash, concentration, fever, anxiety, sadness). Responses are scored 0 to 3 (with 2 and 3 indicating moderate and severe SAEs, respectively). We examined the frequency & distribution of grade 2 and 3 SAEs in ePRO responders by age, gender, race/ethnicity. All pts had gastrointestinal cancer and an outpatient visit for treatment, symptom management, follow-up care. Results: From 9/1/2018 to 8/31/2020, 1912 unique pts responded (response rate 23%). Most respondents were age 50-69 years (58% compared to 15% age <50, 27% age ≥70; range 18-95), male (53%), white (75%). Grade 3 SAE frequencies were pain (12%), fatigue (11%), anxiety/constipation/insomnia/decreased appetite (5%), sadness/numbness and tingling/diarrhea (3%), concentration/shortness of breath (2%), nausea/rash (1%), fever/vomiting (0%). Across pts, fatigue, general pain, insomnia, anxiety were the most common grade 2 and 3 SAEs. Shortness of breath, vomiting, rash, fever were least common (Table). Conclusions: In GCC pts responding to ePRO, the most frequent SAEs were pain, fatigue, insomnia, anxiety. Shortness of breath, nausea, vomiting, diarrhea were less often severe. Pts <50 were more likely to report severe anxiety but there were no other major differences based on age, sex, race/ethnicity. Ongoing efforts will increase pt/provider engagement and develop predictive models & symptom management interventions from ePRO responses. [Table: see text]
Targeting GNAS mutant appendiceal adenocarcinoma.
Authors: Haridas Valsala , Ito Ichiaki , Shen John Paul Y.C.
Published: January 2021

470

Background: Appendiceal cancers are rare, comprising just 0.5% of all intestinal neoplasia, preventing the systematic study of these tumors in randomized clinical trials. Given this absence of clinical data, no evidence-based guidelines exist regarding the best management of this disease and no drugs have been developed to specifically target appendiceal adenocarcinoma (AA). The G protein GNAS is the second most frequently mutated gene after KRAS in low-grade (49%) mucinous AA (52%), making it an attractive drug target in this orphan disease. Methods: Using CRISPR, GNAS was knocked out in KM12, SNU175 and SKCO1 gastric cell lines that harbor GNASR201C mutation. The mutant and KO pairs of cells were evaluated for their proliferation rate and ability to form colonies in a clonogenic assay. RNA sequencing of the mutant and knock out cells was performed to determine pathways potentially associated with the GNAS signaling pathway. The Sanger GDSC was used to identify drugs selectively lethal to GNAS mutant tumors. Results: KM12 cells knocked out for GNAS showed a 40% decrease in proliferation compared to the parent cells with mutant GNAS (p < 0.0001). GNAS knockout significantly reduced colony formation of all three mutant cell lines (KM12: 397 vs. 94, SNU175: 512 vs. 134, and SKCO1: 36 vs. 5, p = 0.0022). Analysis of four GNASR201C cell lines relative to matched controls identified IGF-1R, MEK and PKC as potential vulnerabilities. In vivo validation experiments are currently ongoing. Conclusions: Our findings suggest preliminarily that GNASR201C mutant cell lines are oncogene addicted to GNAS growth signal and could be targeted with inhibitor of GNAS or one of its downstream effectors.
Effect of food on exposure to napabucasin: Data from two phase I studies.
Authors: Dai Xiaoshu , Noda Naoto , Xie Yuran , Xu Bo , Hitron Matthew , Karol Michael
Published: January 2021

477

Background: Napabucasin is an orally-administered NAD(P)H quinone dehydrogenase 1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. Methods: Food effects on napabucasin pharmacokinetics were evaluated in two studies: one at two sites in Japan (Study 1; JapicCTI-205447) and the other at two sites in the US and three in Canada (Study 2; NCT01775423). Study 1 enrolled healthy Japanese male volunteers (HJMV) who received napabucasin 480 mg (formula 2) per sequential design — fasting on Day (D) 1 followed by a Japanese diet (JD) on D8 — with a 6-D intervening washout. In Study 2, patients (pts) with advanced malignancies received napabucasin 500 mg (formula 1) on D1 in the fasted state, then napabucasin 500 mg (formula 2) on D4 and D8 with a high-fat breakfast [HFB] or in the fasted state per the randomized sequence per crossover design. Results: In Study 1, mean plasma napabucasin levels 6–10 h after napabucasin 480 mg administration were higher in fed (JD) vs fasted states; in the fed state, Cmax increased by 15% and AUClast by ~60% (Table), while tmax decreased by ~1.4 hours. Adverse events (AEs) in Study 1 occurred in 5/6 (83.3%) HJMVs (fasted, n=3; fed, n=5; all grade [gr] 1). In Study 2, mean concentration profiles were comparable in fasted and fed (HFB) states for napabucasin 500 mg. When comparing fasted and fed states, Cmax increased by 21% and AUClast by 39% in the fed state (Table). Interpatient variability was high: geometric CV% for CL/F was 75.9% (fed) and 141% (fasted). AEs in Study 2 occurred in 68% (17/25) of fasted pts (gr 1: n=7; gr 2: n=8; gr 3, n=2) and 50% (7/14) of pts fed an HFB (gr 1: n=2; gr 2: n=3; gr 3, n=2). Conclusions: In HJMVs, napabucasin 480 mg administered with a JD increased exposure (Cmax; AUClast; AUCinf) and decreased tmax vs the fasted state. In pts with advanced malignancies, napabucasin 500 mg administered with an HFB increased exposure (Cmax; AUClast) vs the fasted state. These exposure increases are not considered to be of clinical relevance. Clinical trial information: JapicCTI-205447; NCT01775423. [Table: see text]
Evaluating adherence to post-treatment follow-up of colorectal cancer at a reference center in Mexico: A retrospective analysis.
Authors: Hernandez-Felix Jorge Humberto , Meneses Medina Mónica Isabel , Rivera Aguilar Mauricio , Valenzuela Ana Karen , Camargo Vanessa Rosas Rosas , Cedro-Tanda Alberto , Huitzil Melendez Fidel David
Published: January 2021

51

Background: Adequate post-treatment surveillance for colorectal cancer (CRC) is recommended by all major societies with the intention to improve overall survival. However, compliance is variable and has not been studied in our country. Our aim was to evaluate the adherence to post-treatment surveillance NCCN guidelines for CRC at our Institution in Mexico City. Methods: We retrospectively reviewed charts from patients with stage I-III CRC who were diagnosed between January 2014 and December 2016. Adherence to surveillance was evaluated for the first 3 years after completion of oncologic treatment or until recurrence, whichever came first. We used an adherence composite definition previously defined by Cooper et al, where adequate compliance with guidelines was considered if patients had ≥2 physician visits per year for 3 years, ≥2 CEA tests per year for 2 years, and at least one colonoscopy in the 3-years surveillance period. Results: We included 90 patients. Mean age at diagnosis was 62 ± 12.5 years, 53% (n=48) were male, 68% (n=62) had colon cancer and 31% (n=28) rectal cancer. According to AJCC7 19% (n=17) were Stage I, 39% (n=35) II, and 42%(n=38) III. Median score for Charslon index at diagnosis was 4 (IQR 3-6). Results of follow-up adherence are presented in Table. Just 12% (n=11) of patients had a PET/CT or any other non-indicated imaging study for surveillance. Recurrence rate at the 3rd year of surveillance was 6.6% (n=6). A bivariate analysis was performed to find clinical and demographic factors associated to adherence and individual components of surveillance, we did not find any significative association. Conclusions: At our institution compliance with follow-up guidelines for CRC is good and higher than reported by other centers, though individual components have a decreasing trend in adherence every year. This could be explained because in our Institution cancer surveillance is performed by a medical oncologist. The main limitation of our study is that it involves an individual reference center in Mexico; thus, extrapolating data may not be feasible. [Table: see text]
Change in skeletal muscle index and its prognostic significance in conversion therapy for initially unresectable colorectal cancer.
Authors: Nozawa Hiroaki , Emoto Shigenobu , Murono Koji , Shuno Yasutaka , Ishihara Soichiro
Published: January 2021

56

Background: Systemic chemotherapy can cause loss of skeletal muscle mass in colorectal cancer (CRC) patients in the neoadjuvant and palliative settings. However, it is largely unknown how the body composition is changed by chemotherapy rendering unresectable CRC to resectable disease or how it affects the prognosis. This study aimed at elucidating the effects of systemic chemotherapy on skeletal muscles and survival in stage IV CRC patients who underwent conversion therapy. Methods: We reviewed 98 stage IV CRC patients who received systemic chemotherapy in our hospital. According to the treatment setting, patients were divided into the ‘Conversion’, ‘Neoadjuvant chemotherapy (NAC)’, and ‘Palliation’ groups. The cross-sectional area of skeletal muscles at the third lumbar level and changes in the skeletal muscle index (SMI), defined as the area divided by height squared, during chemotherapy were compared among patient groups. The effects of these parameters on prognosis were analyzed in the Conversion group. Results: The mean SMI increased by 8.0% during chemotherapy in the Conversion group (n = 38), whereas it decreased by 6.2% in the NAC group (n = 18) and 3.7% in the Palliation group (n = 42, p < 0.0001). Moreover, patients with increased SMI during chemotherapy had a better overall survival (OS) than those whose SMI decreased in the Conversion group (p = 0.021). The increase in SMI was an independent predictor of favorable OS on multivariate analysis (hazard ratio: 0.26). Conclusions: Stage IV CRC patients who underwent conversion to resection often had an increased SMI. As such an increase in SMI further conveys a survival benefit in conversion therapy, it may be important to make efforts to preserve muscle mass by meticulous approaches, such as nutritional support, muscle exercise programs, and pharmacological intervention even during chemotherapy in patients with metastatic CRC.
Quadruplet regimen with capecitabine, irinotecan, oxaliplatin, and bevacizumab in chemo-naive patients with metastatic colorectal cancer: Results from the safety lead-in of QUATTRO-II study.
Authors: Bando Hideaki , Kotani Daisuke , Kotaka Masahito , Kawazoe Akihito , Masuishi Toshiki , Satake Hironaga , Taniguchi Hiroya , Yamazaki Kentaro , Yamanaka Takeharu , Oki Eiji , Yoshino Takayuki , Muro Kei , Komatsu Yoshito , Kato Takeshi , Tsuji Akihito
Published: January 2021

57

Background: FOLFOXIRI plus bevacizumab (BEV) is regarded as the standard of care for selected patients (pts) with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea. The AXEPT phase III study showed that the modified capecitabine (CAP) + irinotecan (IRI) + BEV (CAPIRI+BEV) [CAP 1600 mg/m2, IRI 200 mg/m2, and BEV 7.5 mg/kg q3wk] treatment was non-inferior to FOLFIRI+BEV, with a lower incidence of hematologic toxicity. We hypothesized that the modified CAPIRI combined with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) would be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods: The QUATTRO-II study is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses (RD) of OX and IRI were investigated as a safety lead-in. In Step 2, pts are randomized to either the RD of CAPOXIRI+BEV or FOLFOXIRI+BEV. In Step 1, four dose levels of CAPOXIRI (fixed dose of CAP 1600 mg/m2 and BEV 7.5 mg/kg plus escalated or de-escalated doses of OX and IRI, q3wk) were investigated in a 3+3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results: A total of 9 pts (3 at Level 0, 6 at Level 1) were included in Step 1. The baseline characteristics were as follows: the median age was 62 years; 6 were male; 6 presented with a left-sided tumor; 8 had a performance status of 0; all wild type/ RAS mutant/ BRAF V600E mutant were 8/1/0; and UGT1A1 wild type/*6 single hetero/*28 single hetero were 7/0/2. In Level 0 (IRI 200 mg/m2, OX 100 mg/m2), one grade 4 neutropenia and one grade 3 anorexia were observed, but without DLT. In Level 1 (IRI 200 mg/m2, OX 130 mg/m2), two grade 4 neutropenia and one grade 3 colitis were observed, with 1 DLT (febrile neutropenia) case, fully recovered without G-CSF administration. No treatment-related deaths were observed. Although dose modifications were needed in 4 of the 6 pts, no further safety concerns related to treatment continuity were observed in the 2nd or subsequent cycles. Thus, we determined that the dose administered in Level 1 is the RD for Step 2. According to the preliminary efficacy results at 8 weeks after initiating study treatment, 6 pts achieved a partial response (2 in Level 0 and 4 in Level 1). Conclusions: The RD of CAPOXIRI+BEV was 200 mg/m2 IRI, 130 mg/m2 OX, 1600 mg/m2 CAP, and 7.5mg/kg BEV. The randomized phase II Step (Step 2) of QUATTRO-II is ongoing. Clinical trial information: NCT04097444.
Anlotinib combined with CAPEOX in first-line treatment of patients with RAS and BRAF wild-type unresectable metastatic colorectal cancer: A single-arm, phase II study (ALTER-C-002 trial).
Authors: Ding Ke-Feng , Liu Yue , Chen Jiaqi , Sun Lifeng , Xu Dong , Liao Xiujun , Xiao Qian , LI JUN , Yuan Ying
Published: January 2021

75

Background: Anlotinib is an oral small molecule multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR1/2/3, FGFR1-4, PDGFR α/β and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. In a previous trial, Anlotinib had been demonstrated to be safe and efficacious in advanced colorectal cancer after failure of recommended treatment. We aimed to evaluate the efficacy and safety of Anlotinib combined with CAPEOX as first-line treatment for unresectable RAS and BRAF wild-type metastatic colorectal cancer (mCRC). Methods: ALTER-C-002 is a single-arm phase II clinical trial. A total of 30 patients with RAS/BRAF wild-type unresectable mCRC, aged 18-75, without prior systemic treatment and ECOG performance score ≤ 1 will be prospectively included. Patients received Capecitabine (850 mg/m2, p.o., on day 1-14 every 3 weeks), Oxaliplatin (130 mg/m2, i.v., every 3 weeks) and Anlotinib (12 mg, p.o., 2 weeks on/1 week off). After 6 cycles of inducing therapy, patients will receive Capecitabine and Anlotinib as maintenance therapy until tumor progression. Primary endpoint was objective response rate (ORR); secondary endpoints included safety, disease control rate (DCR) and progression-free survival (PFS). Results: As of Sep.15th, 2020, 19 patients had been enrolled. 12 of 19 patients were evaluable for antitumor activity: 10 patients had partial response, 2 patients had stable disease. The ORR was 83.3% (95% CI: 51.6–97.9%), and DCR was 100% (95% CI: 73.5–108.1%). 9 patients (47.4%) developed grade Ⅲ adverse events with 1 (5.3%) grade Ⅳ AE. The grade Ⅲ AEs included hypertension (n = 8), diarrhea (n = 3), hypertriglyceridemia (n = 2), leukopenia and neutropenia (n = 3), alanine aminotransferase increase (n = 1), intestinal obstruction (n = 1), nausea and vomiting (n = 1), and grade Ⅳ AE was blood bilirubin increase. 1 patient received emergent surgery for relieving intestinal obstruction after 14 days of Anlotinib treatment discontinuation. No extra bleeding or wound healing risk were observed during the perioperative period. No treatment-related deaths occurred. Conclusions: The combination of Anlotinib and CAPEOX displayed promising antitumor activity and manageable toxicity in unresectable RAS and BRAF wild-type mCRC, which should be merited further evaluation in randomized studies. Clinical trial information: NCT04080843.
NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)—Pembrolizumab experimental arm (EA) primary results.
Authors: Rahma Osama E. , Yothers Greg , Hong Theodore S. , Russell Marcia McGory , You Y. Nancy , Parker William , Jacobs Samuel A. , Colangelo Linda H. , Lucas Peter C. , Gollub Marc J , Hall William Adrian , Kachnic Lisa A. , Vijayvergia Namrata , Wolmark Norman , George Thomas J.
Published: January 2021

8

Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk pt population with correlative biomarkers. Here we report the primary and available secondary endpoints (EPs). Methods: Stage II/III LARC pts (with ONE or more of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy +/- pembrolizumab 200mg IV Q3 wks x 6 doses) → surgery 8-12 wks following last dose of radiotherapy. Primary EP: Improvement in Neoadjuvant Rectal Cancer (NAR) score for EA v control potentially representing a 3-4% absolute OS improvement. Secondary EPs: Comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter sparing surgery (SSS), and exploratory assessments of molecular and radiographic predictors of response and distant failure. Binary EPs compared by Fisher’s exact test. Reported p-values are two-sided. Results: From 8/2018-5/2019, 185 pts were randomized to control (n=95) or pembrolizumab (n= 90). Baseline characteristics were relatively well balanced. 137 pts were evaluable for NAR (68 control, 69 pembrolizumab). Mean NAR was 14.08 for control (95% CI: 10.7-17.4) v 11.53 for pembrolizumab (CI: 8.5-14.6) (p=0.26). pCR=29.4% v 31.9% (p=0.75); cCR=13.6% v 13.9% (p=0.95); and SSS=71.0% v 59.4% (p=0.15). The side effects on Arm 3 were consistent with both CRT and pembrolizumab safety profile. Grade 3/4 AEs were slightly increased on the pembrolizumab arm during and after CRT (48.2 v 37.3%). There were 2 deaths during FOLFOX, one on the control arm due to sepsis; the other on the EA due to pneumonia. There were no statistically significant differences in RT (fractions, dose, boost fractions, or boost dose), FOLFOX or capecitabine doses. Conclusions: Pembrolizumab added to chemoRT as part of TNT was safe and without unexpected short-term toxicities but failed to improve the NAR score. The secondary endpoints including PFS and OS have not been reached. Correlative analysis for both T-cell and myeloid cell populations in the tissue and blood in addition to comprehensive cytokine analysis is ongoing. NCT02921256. Support: U10CA180868, -180822; UG1-189867; U24-196067. Clinical trial information: NCT02921256.
Is antiangiogenic therapy necessary for patients with metastatic colorectal cancer (mCRC) and mutation in the BRAF gene? Results of the systematic review and meta-analysis.
Authors: Fedyanin Mikhail , Polyanskaya Elizaveta , Elsnukaeva Kheda , Tryakin Alexey , Pokataev Ilya , Tjulandin Sergei
Published: January 2021

88

Background: There are no direct prospective randomized studies supporting the need for antiangiogenic drugs in the treatment of patients with the m BRAF mCRC. However, subgroup analysis of different studies showed conflicting results. Therefore, we performed systemic review and meta-analysis to compare efficacy anti-angiogenic targeted therapy with chemotherapy and chemotherapy alone in patients with m BRAF mCRC in terms of progression free survival (PFS), and overall survival (OS). Methods: We performed a search of all prospective randomized phase III studies in PubMed, ASCO and ESMO congresses for all years before September, 2020, compared chemotherapy (CT) plus bevacizumab or aflibercept or ramucirumab and CT alone at the first-line or second-lines with information of the BRAF status. Primary outcome was hazard ratio (HR) for PFS and 95% confidence interval (CI); secondary–HR for OS and 95%CI. Fixed effects were used for analysis. Meta-analysis was conducted by "Review Manager" Ver. 5.3. Results: We identified 4 trials (AVF2107g, AGITG MAX, VELOUR and RAISE), which included 120 patients with mBRAF (anti-angiogenic plus CT–65 (54%) and CT alone–55 (46%). According to results of the meta-analysis there was a tendency for significant improvement in PFS (HR 0.64, 95% CI 0.4-1.02; p = 0.06; I2 = 0%, p for heterogeneity 0.7; 53trials) and significant improvement in OS (HR 0.51, 95% CI 0.32-0.82; p = 0.005; I2 = 0%, p for heterogeneity 0.52; 4 trials) in group of ani-angiogenic therapy. Conclusions: Addition of anti-angiogenic therapy to chemotherapy showed improvement in the PFS and OS in pts with m BRAF compared with chemotherapy alone. A prospective randomized trial is needed to determine the optimal regimen of systemic therapy for pts with m BRAF mCRC.
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.