bluuebunny/crossref_metadata_2025 huggingface dataset:
REGOMUNE: A phase II study of regorafenib plus avelumab in solid tumors—Results of the non-MSI-H metastatic colorectal cancer (mCRC) cohort.
Authors: Cousin Sophie , Bellera Carine A. , Guégan Jean Philippe , Gomez-Roca Carlos A. , Metges Jean-Philippe , Adenis Antoine , Pernot Simon , Cantarel Coralie , Kind Michèle , Toulmonde Maud , Bourcier Kevin , Soubeyran Isabelle , Bessede Alban , Italiano Antoine
Published: May 2020

4019

Background: Regorafenib (R) has been shown to modulate anti-tumor immunity by different mechanisms including reduction of tumor-associated macrophages (TAMs). Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical models. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of R (160 mg QD 3weeks/4) + Avelumab (A) (10 mg/kg every 2 weeks) combination in non MSI-H mCRC patients (pts). The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline and C2D1. Results: Between Nov. 2018 and Oct. 2019, 48 pts were enrolled in 4 centers. Median age was 61.8 (range: 26.3-78.7). Median follow-up was: 7.2 months. Median number of previous treatment lines was: 3 (range: 1-7). 41 (87.2%) pts experienced at least 1 dose modification or treatment interruption. The most common grade 3/4 adverse events were palmar-plantar erythro-dysesthesia syndrome (29.8%), hypertension (23.4%) and diarrhea (12.8%). No death was related to the treatment. Among 40 pts who had at least one imaging tumor assessment, 12 (30%) had reduction in tumor burden. Best response was stable disease for 23 pts (57.5%) and progressive disease for 17 pts (42.5%). The median PFS and OS were 3.6 months (CI95%: [1.8 – 5.4]) and 10.8 months (CI95%: [5.9 – NA]) respectively. Baseline tumor samples and paired biopsies were available for 24 and 15 pts respectively. High infiltration by TAMs at baseline was significantly associated with adverse outcome (PFS: 1.9 vs 3.7 months, p=0.045; OS: 4.8 months vs NR, p=0.027). Increased tumor infiltration by CD8+ at C2D1 compared to baseline was significantly associated with better PFS (p=0.011). Combining low TAMs infiltration and low tumor cells to CD8+ T cells distance enabled the identification of a subgroup of pts (n= 6/24, 25%) more likely to benefit from R+A combination: median PFS: 5.3 vs 1.9 months (p=0.037); median OS: NR vs 5.3 months (p=0.02). Conclusions: The R+A combination achieved PFS and OS that compared favourably with historical data of R alone in this clinical setting. High-resolution analysis of tumor samples identified a composite score based on TAMs infiltration and tumor cell to CD8+ T cells distance which could be used as a biomarker in further studies investigating this approach in mCRC pts. Clinical trial information: NCT03475953 .
Sex differences in efficacy and toxicity of first-line treatment of metastatic colorectal cancer (CRC): An analysis of 18,399 patients in the ARCAD database.
Authors: Wagner Anna Dorothea , Rakez Manel , Chibaudel Benoist , Adams Richard , Zalcberg John Raymond , Saltz Leonard B. , Venook Alan P. , Schmoll Hans-Joachim , Douillard Jean-Yves , Tournigand Christophe , Heinemann Volker , Goldberg Richard M. , Hecht J. Randolph , Cremolini Chiara , Diaz-Rubio Eduardo , Grothey Axel , Shi Qian , De Gramont Aimery
Published: May 2020

4029

Background: The clearance of 5-FU differs significantly between men (M) and women (W). Adjuvant chemotherapy (CT) for CRC has a higher toxicity in W. The impact of sex on efficacy and toxicity in first-line trials of metastatic CRC (mCRC) is unknown. Methods: We analyzed patient (pt) and tumor characteristics, toxicities (nausea (AE1), vomiting (AE2), diarrhea, neutropenia (AE3)) and efficacy (overall survival (OS), progression-free survival (PFS)) according to sex in the following treatment groups: A: CT alone, B: CT + bevacizumab, C: CT + EGFR-antibodies, with subgroup analyses in the CT alone group for single-agent, doublets and triplets, as well as irinotecan- and oxaliplatin-based regimens. Pts from trials with treatments still used today and all relevant data available were eligible. OS and PFS were assessed using Kaplan-Meier and Cox models adjusted for primary tumor location and performance status (PS). Results: We included 28 trials with 18.399 pts (11.352 M and 7.047 W). W were younger (61 vs. 63 years), had more often a PS of 1 (49 vs 45%), BRAF mutations (10 vs. 7%), right-sided tumors (42 vs. 35%) and less often rectal tumors (26 vs. 32%). Significant differences in toxicity are reported in table. Rates of diarrhea were similar. There was no sex disparity in OS in the predefined subgroups except for pts receiving triplets where OS was better in M (HRadj=1.39 (1.05 - 1.85)). Median (interquartile range) OS in months for M and W was 16.7 (9.2-27.4) and 16.2 (8.9-27.2) in group 1, 21.9 (12.7-37.5) and 22.3 (12.9 – 39.0) in group 2, and 26.8 (14.6-45.3) and 24.8 (12.3-49.2) in group 3. HRsadj (W vs M) (95% CI), p values for OS were 1.02 (0.96-1.09), .557, 0.92 (0.83-1.03), .142, 0.99 (0.85-1.14), .866. Conclusions: M and W with mCRC differ significantly regarding patient and tumor characteristics. The significant higher toxicity in W does not translate in a higher treatment efficacy. Apart from known sex differences in pharmacokinetics of 5-FU, differences in pharmacodynamics must be postulated. [Table: see text]
Inpatient outcomes and predictors of mortality in patients with gastrointestinal malignancies presenting with sepsis: A nationwide analysis.
Authors: Desai Parth , Vohra Ishaan , Attar Bashar , Katiyar Vatsala , Lingamaneni Prasanth , Moturi Krishna Rekha , Malapati Sindhu Janarthanam , Singh Sunny R K , Zia Maryam , Batra Kunnal , Gupta Shweta
Published: May 2020

4045

Background: Sepsis is a frequent cause of morbidity and mortality in patients with malignancy. However, there is paucity of literature on mortality, hospital charges and overall healthcare utilization among patients with GI malignancy, which we hope to characterize in this study. Methods: We queried retrospective data from the Nationwide Inpatient Sample (NIS) database for the year 2016. Sepsis (Dx1) was identified using ICD-10 code as primary diagnosis in patients with known GI malignancies (Dx2). Univariate and multivariate Poisson regression analysis was done to study outcomes. Propensity score matching was done to minimize confounding factors. Primary outcome was inpatient mortality. Secondary outcomes were Length of Stay (LOS), Total Charge (TOTCHG) and ICU admission. Results: A total of 43,240 patients with GI malignancy were admitted in 2016 with sepsis. Two most common GI malignancies admitted with sepsis were colorectal (35%) and hepato-cellular cancer (HCC) (28.2%). Overall mortality in GI cancer was 19.8% vs 10.2% in all cancers (p<0.01). There was male (59%) and Caucasian (63%) preponderance. Out of all hospital admissions for GI malignancy, 41.4% were secondary to sepsis. E. coli (31%) infection and gram-negative bacteremia (15%) were the most common causes of sepsis. Sepsis with GI malignancy was associated with length of stay of 7.4 days vs 5.4 days (coef 2.44, 95% CI 2.3-6.7 p=0.04) and a mean hospital charge of $88,728 vs $ 54, 668 (coef 34,140, 95% CI 44,264-90,646, p<0.01) as compared to without sepsis. After adjusting for demographic and patient related variables, independent predictors of mortality were old age, uninsured, African Americans, septic shock requiring pressor support, AKI, inpatient hemodialysis, metabolic encephalopathy and acute respiratory failure. Conclusions: Sepsis poses a substantial healthcare burden in patients with GI malignancy and is a major cause of mortality. Early antibiotic treatment is necessary for sepsis control in patients with GI malignancy. [Table: see text]
Sequencing of treatment matters in synchronous liver or lung only metastatic colon cancer.
Authors: Parasramka Saurabh , Jacob Aasems , Chen Quan , Huang Bin , Hao Zhonglin
Published: May 2020

4049

Background: Per SEER database, approximately 21% of patients have synchronous metastatic disease at presentation with a median 5 year survival of 14%. Liver is by far the most common site of metastatic disease followed by lung. Metastatectomy of appropriate lesions have achieved a 5 year survival ranged between 40%-70% depending on the extent of the metastasis. For liver or lung only metastatic disease, practice varies from surgery followed by adjuvant chemotherapy to perioperative chemotherapy. Benefit of one approach versus the other has not been demonstrated. We decided to study this using the National Cancer Database (NCDB) database available from the 2010-2015 period. Methods: Adults > 20 years with primary colon cancer (excluding rectal and recto sigmoid junction) with single organ metastatic disease to liver and/or lung at diagnosis were identified. All patients had received surgery to the primary site, resection of the distant site and chemotherapy in the neoadjuvant setting (NAC) or adjuvant setting (AC) within 1 year of diagnosis. Histology except for adenocarcinoma and variants were excluded. Patients who died within 90 days of surgery were excluded. Descriptive analysis, Kaplan-Meier plots, Log-Rank tests for univariate and proportional hazards models for multivariate survival analyses were performed. To reduce biases, a sensitive analysis was also performed based on the intention to treat principle by including additional surgery only and chemotherapy only cases. Results: A total of 3175 colon cancer patients with liver or lung only metastatic disease were identified. 2487 (78%) had AC and 688 (22%) had NAC. Approximately 54% were males with 90% less than 75 years of age. More patients had private insurance and were treated in academic centers in the NC group (62 Vs 51%) and (58 Vs 42%) respectively. Both groups had similar Charlson comorbidity index. NC approach had better OS with HR of 0.75 (CI 0.65-0.85; p < 0.0001) on univariate analysis and 0.86 (0.74-0.98; P < 0.0281) on multivariate analysis. On multivariate analysis, age group > 75 years, black race, treatment outside academic research program had worse survival (p < 0.0001, 0.0139, 0.0001) respectively. The sensitive analysis showed the similar effects. Conclusions: Within the limitations of database review, our analysis suggests survival advantage of neoadjuvant chemotherapy approach over surgery first.
Development of drug resistance in colon cancer patients following chemotherapy, a contributing factor in the failure of oxaliplatin-based HIPEC to improve survival in the Prodige 7 trial.
Authors: Nagourney Robert Alan , Evans Steven Scott , Bernard Paula J , Nagourney Adam , Tran Peter , Francisco Federico , Sugarbaker Paul H.
Published: May 2020

4063

Background: Numerous studies suggest benefit for heated intra-peritoneal chemotherapy (HIPEC) in colon cancer but the Prodige 7 trial in 265 colon cancer patients randomized to HIPEC or observation after neo-adjuvant chemotherapy (NACT) didn't confirm benefit with median OS of 41.7 vs. 41.2 mos. (p = 0.99) (Proc. ASCO, 2018). One concern is that prior drug exposure selects for drug resistance blunting HIPEC effect. To test the hypothesis we examined the impact of prior chemotherapy on drug resistance in human tumor organoids isolated from colon cancer patients. Methods: Data query identified 111 colorectal cancers (87 colon & 24 rectal) tested for Oxaliplatin sensitivity by ex vivo analysis of programmed cell death (EVA/PCD), a primary culture platform that examines drug induced cell death (apoptotic & non-apoptotic) by morphology, metabolism & histology. Five-point dose response curves interpolated to provide lethal concentration 50% (LC50) were compared by Z score to distribute Oxaliplatin LC50 values around the mean using standard deviation units as the metric of sensitivity or resistance. Of 87 colon 54(62%) were untreated and 33 (38%) treated with 21/33 (64%) having received FOLFOX. To approximate Prodige 7, treated patients were separated by having received FOLFOX < 2 > months before EVA/PCD analysis and also compared Mitomycin (14 vs 41), Irinotecan (18 vs 47) & 5-FU (19 vs. 52) activity to assess cross-resistance. Results: Compared to chemo-naïve, FOLFOX-treated patients were significantly more resistant to Oxaliplatin (P < 0.01) with the degree of resistance increasing significantly for patients who received treatment < 2 months prior to EVA/PCD compared to those with chemotherapy > 2 months prior to EVA/PCD (P < 0.01). Activity for Mitomycin & Irinotecan was not significantly different for chemo-naïve vs. treated patients, but 5 FU was more resistant (P = 0.048) in previously treated. Conclusions: The failure of Prodige 7 to improve survival with HIPEC following NACT may reflect diminished Oxaliplatin activity in patients whose residual disease has been selected for Oxaliplatin & 5FU resistance. Resistance was not observed for Mitomycin or Irinotecan. This suggests that those using HIPEC may i) examine other classes of drugs or drug combinations for IP administration ii) improve the selection of candidates for HIPEC administration or iii) consider HIPEC administration earlier in the course of therapy when chemotherapy-induced drug resistance may be less evident.
Duration of FOLFOX adjuvant chemotherapy in high-risk stage II and stage III colon cancer with deficient DNA mismatch repair.
Authors: Wu Zehua , Hu Huabin , Wang Chao , Huang Yan , Deng Yanhong
Published: May 2020

4075

Background: In the IDEA collaboration, noninferiority was not confirmed for 3 months versus 6 months of FOLFOX adjuvant chemotherapy among patients with high-risk stage II and stage III colon cancer (CC). Patients with deficient DNA mismatch repair (dMMR) have a good prognosis, but for whom, whether limiting the duration of adjuvant therapy will compromise oncologic outcomes remains undefined. We evaluated the impact of 3 months of FOLFOX adjuvant chemotherapy or surgery alone in comparison with 6 months of FOLFOX on disease-free survival (DFS) in dMMR CC patients. Methods: This retrospective study included all consecutive patients who underwent curative surgical resection for high-risk stage II or III dMMR CC between May, 2011 and July, 2019. Prognostic factors were analyzed using Cox models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Results: A total of 242 dMMR CC patients were included (43.4% high-risk stage II, 56.6% stage III). The patients received 6 months of FOLFOX adjuvant chemotherapy (n = 66; median cycles [rang] = 12 [10-12]), 3 months of FOLFOX (n = 87; median cycles [rang] = 6 [4-8]), or surgery alone (n = 89). Three groups were generally well balanced, although more patients with stage III were in the 6-month therapy group (74.2%), compared with the 3-month therapy group (57.5%) and the surgery alone group (42.7%). As compared with 6 months of FOLFOX adjuvant chemotherapy in the overall population, 3 months therapy reduced DFS in multivariable analysis (HR, 2.78; 95CI, 1.18 to 6.47; P = 0.02), similar to surgery alone (HR, 2.30; 95CI, 0.99 to 5.38; P = 0.05). In the subgroup analysis, a therapy duration of 6 months was statistically superior to a duration of 3 months only in the patients with stage III, with a 3-year rate of DFS of 86.2% versus 70.8% (HR, 3.06; 95% CI, 1.14 to 8.19; P = 0.026). Conclusions: This study supports the 6-month duration of FOLFOX adjuvant chemotherapy in stage III dMMR CC.
Mutation of DNA damage repair genes confers an immune-privileged tumor microenvironment in colorectal cancer with a prognostic value.
Authors: Liang Dandan , Chen Huan , Yang Ying , Zhang Guanxiong , Zhang Jiao , Zhang Henghui
Published: May 2020

4080

Background: Microsatellite instability high (MSI-H)/mismatch-repair-deficient (dMMR) has been proved as a validated biomarker in solid tumors receiving immune checkpoint inhibitors (ICIs). Recently, mutational status of the DNA damage repair (DDR) genes has been linked to anti-tumor immune response in bladder cancer. Therefore, it would be of great interest to unravel the implications of DDR in shaping the immune responsiveness in CRC. Methods: The genomic correlates were examined in a publicly available cohort from Memorial Sloan Kettering Cancer Center (MSK ICI cohort). To explore the associations between DDR mutation and immune features, the genomic data of The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma (COADREAD) dataset was analyzed. Further, we determined DDR mutation and MSI status in a Chinese CRC cohort via a 543-gene panel sequencing. Results: First, we observed that DDR pathway was commonly mutated (21.79%) in the multi-cancer MSK ICI cohort, with the highest frequency of 36.36% in CRCs. Second, survival analysis revealed that the median overall survival (mOS) in patients with DDR mutations was significantly longer than that in the DDR wild-type subgroup, in both pan-cancer (P = 0.0008; mOS 31 vs 16 months) and CRC patients (P = 0.016; mOS 34 vs 13 months) in the MSK ICI cohort. However, in the TCGA COADREAD dataset, there was no significant difference in OS or progression free survival (PFS) between DDR mutant and DDR wild-type subgroups. These observation indicated a specific prognostic value for DDR mutation in patients with ICI treatment while not conventional treatment. Third, in the TCGA COADREAD dataset, DDR mutations were associated with increased TMB, enrichment of immune cell infiltration and immune checkpoint molecule expression, suggesting an improvement of various steps of the cancer immunity cycles in DDR mutant CRCs. Lastly, we investigated the DDR mutational pattern, and its associations with MSI-H and other genomic features in a Chinese CRC cohort. Notably, MSI-H and DDR mutation account for 5.7% and 13.4% respectively, suggesting that DDR may identify a higher proportion of potential responders than MSI-H. Conclusions: Our data suggest that DDR mutation is a potential prognostic biomarker for ICI-treated CRCs. Functional analysis in TCGA dataset revealed that DDR mutation might be an indication of enhanced cancer immunity. The higher incidence of DDR mutation in Chinese CRCs emphasized the future utility of panel-based DDR evaluation in guiding ICI treatment.
Consensus molecular subtype (CMS) as a novel integral biomarker in colorectal cancer: A phase II trial of bintrafusp alfa in CMS4 metastatic CRC.
Authors: Mehrvarz Sarshekeh Amir , Lam Michael , Zorrilla Isabel R. , Holliday Emma Brey , Das Prajnan , Kee Bryan K. , Overman Michael J. , Parseghian Christine Megerdichian , Shen John Paul Y.C. , Tam Alda , Parra Cuentas Edwin Roger , Zhang Liren , Wang Xuemei , Duose Dzifa Yawa , Luthra Rajyalakshmi , Reddy Neelima , Maru Dipen M. , Kopetz Scott , Morris Van K.
Published: May 2020

4084

Background: Consensus Molecular Subtype 4 (CMS4) colorectal cancer (CRC) features increased TGFβ signaling, which may account for de novo resistance to immunotherapy for patients (pts) with microsatellite stable mCRC. To date, no prior trial has incorporated CMS status as an integral biomarker. Bintrafusp alfa (M7824) is a dual PD-L1 antibody/TGFβ trap with acceptable safety. Methods: Primary tumors from pts with metastatic CRC underwent CMS testing in a CLIA setting. In this Simon two-stage phase II trial (Ho: p < .05; Ha: p≥.25) for CMS4 mCRC, pts received bintrafusp alfa 1200mg IV every 14 days. RT (8Gy/day x 3 days) to a single metastatic lesion with abscopal intent was administered between doses 2 and 3. The primary objective was to estimate response rate (RR) per iRECIST. Correlative studies including RNA sequencing were performed on pre- and on-treatment biopsies. Results: 53 of 137 tested pts (39%) between June 2018-December 2019 had CMS4 mCRC. 13 of 15 treated pts received the agent with RT. All pts were evaluable for toxicity, and 13 for response. Median number of doses was 3 (IQR, 2-4). There was one grade 3 immune-related adverse event (colitis) requiring study discontinuation. There were 2 pts with stable disease and 11 with progressive disease as best response (RR 0%, 95% CI 0-22%). Enrollment was stopped after first stage for futility. Median PFS and OS were 1.6 months and 5.0 months, respectively. In paired samples, treatment with bintrafusp alfa resulted in an increase in the expression of IFNγ signature in nonirradiated metastatic lesions ( p< .001, q< .001). Updated results will be presented. Conclusions: This is the first reported clinical trial to utilize CMS status as an integral biomarker for pts with metastatic CRC and capitalizes on treating CRC subpopulations with targeted agents based upon validated RNA-based signatures. Although the efficacy for bintrafusp alfa and RT is low, changes in IFNγ signature provides a potential signal for refining therapeutic strategies based upon TGFβ enrichment in pts with mCRC. Clinical trial information: NCT03436563 .
Treatment effects (TEs) of EGFR monoclonal antibodies (mAbs) in metastatic colorectal cancer (mCRC) patients (pts) with KRAS, NRAS, and BRAF mutation (MT) status: Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database.
Authors: Karapetis Christos Stelios , Liu Heshan , Sorich Michael , Fiskum Jack , Grothey Axel , Van Cutsem Eric , Maughan Tim , Douillard Jean-Yves , Jonker Derek J. , Bokemeyer Carsten , Sobrero Alberto F. , Chibaudel Benoist , Zalcberg John Raymond , Adams Richard , Buyse Marc E. , De Gramont Aimery , Shi Qian
Published: May 2020

4090

Background: EGFR mAbs have become incorporated into clinical practice for the management of mCRC over the last decade. KRAS and NRAS mutations are used as predictive biomarkers and BRAF V600E mutations are associated with an adverse prognosis. The observed TE within biomarker subpopulations has varied between studies. Methods: IPD from randomized trials with head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or BSC) in mCRC, across all lines of therapy (first, second and later), were pooled. Biomarker subpopulations are defined in the table. Overall survival (OS) and progression-free survival (PFS) were compared between groups by Cox model, stratified by studies and adjusted by age, gender, and performance status. TEs were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). Within each biomarker subgroup, EGFR mAb efficacy was explored according to multiple exploratory factors, including line of therapy, type of backbone chemo, gender, sidedness and site of metastasis. Interaction tests were performed. P-values < 0.01 were considered statistically significant to account for multiple comparisons. Results: 5729 pts from 8 studies with data available for ≥ 1 biomarker were analysed. PFS benefits (median 9.2 mos in EGFR mAbs, 8.0 mos in no EGFR mAbs) were confirmed in triple-WT pts, but not for OS (refer to table). No OS/PFS benefits were observed for pts with any of the MT tumors. Exploratory analyses showed a potential detrimental TE of EGFR mAbs in KRAS MT mCRC with liver metastasis (OS: HRadj 1.22, p = .003, pinteraction .0056; PFS: HRadj 1.24, p = .0009, pinteraction .0008). These results were confirmed within the subgroup of pts with all 3 biomarkers available. Conclusions: This is the largest IPD analysis to explore the predictive value of RAS/BRAF biomarkers in mCRC. Our findings demonstrate that there is no evidence of efficacy of EGFR mAbs in KRAS, BRAF and/or NRAS MT mCRC. EGFR mAbs might have a detrimental effect in KRAS MT mCRC with liver metastases. [Table: see text]
Adjunctive local therapy in metastatic colorectal cancer in an unselected cohort: Improved patient-survival in comparison to systemic therapies.
Authors: Schroeder Jan , Tasci Evrim , Nolte-Ernsting Claus , Michels Peter , Wetzel Natalie , Scheiner-Sparna Renate , Stang Andreas
Published: May 2020

4096

Background: Patients with distant metastases in colorectal cancer have a poor prognosis and a low overall survival (OS). In addition to systemic treatments and irradiation, the tumor burden can be reduced by loco-regional therapeutics, including microwave ablation (MWA), radiofrequency therapy (RFA) and trans-arterial chemoembolization (TACE) available. To evaluate the benefit of such local therapies, we compared OS of a single-centre study population to a reference population of patients who underwent no loco-regional treatment within the German Tumor Registry Colorectal Cancer (TKK). Methods: The study population consists of a cohort of 51 patients (n = 51) treated loco-regionally in addition to systemic therapy. The patients were recruited in a single cancer centre in Mülheim, Germany during the years 2006 to 2015. A reference population of 788 patients was chosen from a prospective, longitudinal registry of the TKK. Time to event data analysis included the estimation of Kaplan-Meier cumulative survival probabilities and hazard ratios (HR) with corresponding 95% confidence intervals (95% CI) from Cox proportional hazards regression. Results: The median OS was 31.3 months (95% CI 26.8 - 41.6) in the study population, as compared to the reference population, where it was 21.9 months (95% CI 20.1 – 24.6). Patients with liver and lung metastases in the study population had an OS of 41.6 months (95% CI 30.5 – 78.2), the corresponding patients from the reference population 21.7 months (95% CI 16.7 – 24.6). Furthermore, patients in the reference group had a 1.79-fold death-rate, as compared to patients treated with additional loco-regional therapy (HR = 2.02; 95% CI: 1.29-3.16). Conclusions: Additional treatment with loco-regional therapies of distant metastases in patients with metastatic colorectal cancer appears to be associated with improved OS by nearly 10 months compared to systemic treatments only. [Table: see text]
Immunoscore as a parameter predicting time to recurrence and disease-free survival in T4N0 stage II colon cancer patients.
Authors: Galon Jerome , Hermitte Fabienne , Mlecnik Bernhard , Lugli Alessandro , Bifulco Carlo Bruno , Nagtegaal Iris D. , Hartmann Arndt , Marliot Florence , Van Den Eynde Marc , Roehrl Michael H. A. , Ohashi Pamela S , Zavadova Eva , Torigoe Toshihiko , Patel Prabhudas S. , Wang Yili , Kawakami Yutaka , Marincola Francesco , Ascierto Paolo Antonio , Fox Bernard A. , Pages Franck
Published: May 2020

4105

Background: Risk assessment is particularly important to decide when to propose an adjuvant treatment for Stage II Colon Cancer (CC) patients. However, the current tumor risk features are imperfect and additional risk factors are needed to guide treatment decisions. The consensus Immunoscore is an alternative and powerful approach that could be used in the T4N0 Stage II colon cancer population. Immunoscore is an in vitro diagnostic test that predicts the risk of relapse in patients with CC by measuring the host immune response at the tumor site. Methods: From the international Immunoscore consortium study (n = 2681) (Pagès et al. The Lancet 2018), a subgroup analysis was performed on T4N0 Stage II colon cancer patients (n = 208). Results: In stage II T4N0, Int+Hi Immunoscore represented 65.4% of the population and low-Immunoscore only 34.6%. T4N0 patients with Int+Hi Immunoscore presented a significantly prolonged survival for TTR compared to low Immunoscore patients (5 years recurrence rate Int+Hi: 84.6% (78.3-91.5), Lo: 46.3% (35.1-61); unadjusted HR [Int+Hi vs Lo] = 0.21; (95% CI 0.11-0.4); P< 0.0001), representing a restricted mean survival time (RMST) difference of 80.9 months (95% CI 51.1-110.6) ( P< 0.0001). The DFS was significantly different between Int+Hi and Low Immunoscore (5 years recurrence rate Int+Hi: 70.5% (95% CI 62.7-79.1), Lo: 38.5% (95% CI 28.2-52.5); unadjusted HR [Int+Hi vs Lo] = 0.31; (95% CI 0.19-0.49); P< 0.0001). Using restricted mean survival time (RMST) a significant ( P< 0.0001) difference of 60.4 months (95% CI 32.6-88.1) was observed between the 2 groups Importantly, Cox multivariate analysis in Stage II T4N0 colon cancer patients, revealed that Immunoscore was the only remaining significant parameter (HR [Int+Hi vs Lo] = 0.15; (95% CI 0.05-0.46); P= 0.0009). In contrast, all other parameters, gender, sidedness, mucinous, grade, T-stage, VELIPI, MSI were not significant in multivariate analysis. Finally, Immunoscore showed the highest relative contribution to predict relapse (76.2% chi2 relative contribution), stronger than all the other parameters, MSI (16.1%), Grade (5%), sidedness (2%), gender (2%), VELIPI (1%). Conclusions: Immunoscore is the most powerful parameter to predict the risk in T4N0 population, and could be a good tool for adjuvant treatment decision in Stage II patients.
Intrathoracic versus cervical anastomosis after minimally invasive esophagectomy for esophageal cancer: A randomized controlled trial.
Authors: Verstegen Moniek , van Workum Frans , Klarenbeek Bastiaan , Gisbertz Suzanne , Hannink Gerjon , Haveman Jan Willem , Heisterkamp Joos , Kouwenhoven Ewout , Van Lanschot Jan , Nieuwenhuijzen Grard , Van der Peet Donald , Polat Fatih , Rovers Maroeska , Rosman Camiel ,   ICAN Trial Study Group
Published: May 2020

4509

Background: Robust evidence is lacking whether Ivor Lewis minimally invasive esophagectomy (MIE) or McKeown MIE should be preferred for patients with mid to distal esophageal or gastro-esophageal junction Siewert I-II (GEJ) cancer. Methods: In this multicenter randomized controlled trial, patients with esophageal (below the level of the carina) or GEJ cancer planned for curative resection were recruited. Eligible patients were randomly assigned (1:1) to either Ivor Lewis MIE or McKeown MIE. The primary endpoint was anastomotic leakage (AL) requiring endoscopic, radiologic or surgical intervention. Secondary outcome parameters were overall AL rate, postoperative complications, length of stay and mortality. Results: A total of 262 patients were randomly assigned to Ivor Lewis MIE (n = 130) or McKeown MIE (n = 132). Seventeen patients were excluded from the trial due to not meeting inclusion criteria (n = 2), physical unfitness for surgery (n = 3), patients’ choice (n = 3), interval metastases (n = 5) or peroperative metastases (n = 4). AL necessitating reintervention occurred in 15 (12.3%) of 122 patients after Ivor Lewis MIE and in 39 (31.7%) of 123 patients after McKeown MIE (relative risk 0.39, 95% CI 0.22-0.65; risk difference 19.4%, 95% CI 7.9%-31.8%). Overall AL rate was 12.3% after Ivor Lewis MIE and 34.1% after McKeown MIE. Severe complications (Clavien-Dindo ≥ 3b) were observed in 10.7% after Ivor Lewis MIE and in 22.0% after McKeown MIE. Pleural effusion requiring drainage occurred in 9.8% of patients after Ivor Lewis MIE and 21.1% of patients after McKeown MIE. RLN palsy rate was 0% after Ivor Lewis MIE and 7.3% after McKeown MIE. Median length of hospital stay was 10 days (IQR 8 – 15 days) after Ivor Lewis MIE and 12 days (IQR 9 – 18 days) after McKeown MIE. ICU length of stay and mortality rates were comparable between groups. Conclusions: These findings provide evidence for a lower rate of AL requiring reintervention after Ivor Lewis MIE compared to McKeown MIE for patients with mid to distal esophageal or GEJ cancer. Clinical trial information: NTR4333 .
Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: A randomized, phase II, multicenter, open-label study (DESTINY-Gastric01).
Authors: Shitara Kohei , Bang Yung-Jue , Iwasa Satoru , Sugimoto Naotoshi , Ryu Min-hee , Sakai Daisuke , Chung Hyun Cheol , Kawakami Hisato , Yabusaki Hiroshi , Lee Jeeyun , Saito Kaku , Kawaguchi Yoshinori , Kamio Takahiro , Kojima Akihito , Sugihara Masahiro , Yamaguchi Kensei
Published: May 2020

4513

Background: T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor. In a phase 1 trial of T-DXd (5.4 or 6.4 mg/kg), the objective response rate (ORR) was 43.2% (19/44) and median progression-free survival (mPFS) was 5.6 mo in patients with advanced HER2+ gastric cancer (GC). DESTINY-Gastric01 (DS8201-A-J202; NCT03329690) is an open-label, multicenter, randomized, phase 2 study of T-DXd in HER2-expressing advanced GC or GEJ adenocarcinoma; results are from the primary analyses for ORR and interim overall survival (OS) in HER2+ patients. Methods: Patients with centrally confirmed HER2+ (IHC 3+ or IHC 2+/ISH+ on archival tissue) GC that progressed on ≥ 2 prior lines were randomized 2:1 (T-DXd 6.4 mg/kg q3w or physician’s choice [PC] irinotecan or paclitaxel). All patients received prior HER2 therapy. Stratification factors were region, ECOG PS (0;1), and HER2 status. The primary endpoint was unconfirmed ORR by independent central review. Secondary endpoints were OS (alpha controlled), PFS, disease control rate (DCR), duration of response (DOR), and safety. Results: 187 patients received T-DXd (n = 125) or PC (n = 62 [55 irinotecan; 7 paclitaxel]); 79.7% Japan, 20.3% Korea. Patients had a median of 2 prior lines of therapy, and 44.4% had ≥ 3. At data cutoff (8 Nov 2019), 22.4% of T-DXd and 4.8% of PC patients remained on treatment. ORR was 51.3% (61/119; 11 CR and 50 PR) with T-DXd vs 14.3% (8/56; all PR) with PC ( P < .0001); confirmed ORR, 42.9% vs 12.5% ( P < .0001); DCR, 85.7% vs 62.5% ( P = .0005); mDOR, 11.3 vs 3.9 mo; mPFS, 5.6 vs 3.5 mo (HR, 0.47 [95% CI, 0.31-0.71]; P = .0003). OS was significantly prolonged with T-DXd (mOS, 12.5 vs 8.4 mo; HR, 0.59 [95% CI, 0.39-0.88]; P = .0097; prespecified O'Brien Fleming boundary, P = .0202); 12-month OS, 52.1% vs 28.9%. Grade ≥ 3 AEs occurred in 85.6% of patients with T-DXd vs 56.5% with PC; the most common were neutrophil count decreased (51.2%; 24.2%), anemia (37.6%; 22.6%), and white blood cell count decreased (20.8%; 11.3%). 12 patients (9.6%) had T-DXd–related interstitial lung disease (ILD; 2 grade 3, 1 grade 4, no grade 5) vs 0 with PC. 1 drug-related death (pneumonia [non-ILD] in the T-DXd arm) occurred. Conclusions: T-DXd demonstrated statistically significant and clinically meaningful improvements in ORR and OS compared with standard chemotherapy (paclitaxel or irinotecan) in patients with HER2+ advanced gastric or GEJ adenocarcinoma. Clinical trial information: NCT03329690 .
A phase II study of rh-endostatin combined with paclitaxel and nedaplatin in treating patients with recurrent or metastatic esophageal squamous cell carcinoma (ESCC).
Authors: Wang Zhiqiang , Li Yu-Hong , Wang De-Shen , Wang Fenghua , Ren Chao , Tan Qiong
Published: May 2020

4522

Background: For patients (pts) with metastatic ESCC, the prognosis is poor. Rh-endostatin (endostar), a potent inhibitor of angiogenesis, has shown clinical activity when combined with chemoradiotherapy in treating locally advanced ESCC. This single-arm phase 2 study was designed to assess the efficacy and safety of endostar combined with paclitaxel and nedaplatin in treating pts with recurrent or metastatic ESCC. Methods: Eligible pts had recurrent or metastatic ESCC and Karnofsky score ≥70. Endostar (30 mg/day, continuous infusion, day 1-14) plus paclitaxel (150 mg/m2, day 4) and nedaplatin (80 mg/m2, day 4) were administered every 3 weeks for 6 cycles followed by maintenance therapy with endostar. Primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and adverse events (AEs). Results: From January 2015 to August 2019, 53 pts were enrolled. 44 (83%) pts were male. The median age was 59 years. 43 (81%) pts had pathology of poor or moderate differentiated ESCC. The middle and lower thirds of the esophagus (81%) were the most common primary tumor sites. 11 (21%) patients had undergone esophagectomy. At the time of treatment, 49 (93%) pts were diagnosed with clinical stage IVB. The most common metastatic sites were lymph node (91%), lung (32%) and liver (26%). 50 pts were assessable for response. No complete response was observed. 21 pts achieved a best response of partial response and 14 pts had stable disease. ORR was 42% and DCR was 70%. The median PFS and OS was 5.1 months (95% CI 3.7-6.6 months) and 13.2 months (95% CI 8.0-18.4 months) respectively. The most common AEs observed during this study were anemia (49.1%), neutropenia (34%), fatigue (28.3%) and anorexia (26.4%). The most common Grade 3/4 AE observed was neutropenia (17%). Conclusions: The combination of endostar plus paclitaxel and nedaplatin is a well tolerated treatment modality with promising activity in previously untreated recurrent or metastatic ESCC. Its efficacy and safety could be further studied in randomized trials. Clinical trial information: NCT02350517 .
Tumor response and growth rate of nivolumab treatment in advanced gastric cancer: Real-world data from a large observational/translational study, JACCRO GC-08 (deliver trial).
Authors: Kawabata Ryohei , Sakamoto Yasuhiro , Inoue Eisuke , Ishiguro Atsushi , Akamaru Yusuke , Kito Yosuke , Takahashi Masazumi , Matsuyama Jin , Yabusaki Hiroshi , Makiyama Akitaka , Suzuki Takahisa , Tsuda Masahiro , Yasui Hisateru , Kawakami Hisato , Matoba Ryo , Muro Kei , Nakajima Takako Eguchi , Ichikawa Wataru , Fujii Masashi , Sunakawa Yu
Published: May 2020

4527

Background: Nivolumab (Nivo) demonstrated survival benefit in previously treated gastric cancer (GC) patients (pts), with a response rate (RR) of 11% and a disease control rate (DCR) of 40% (Kang YK, et al. Lancet 2017). There are few real-world data of Nivo and its predictive markers are needed in GC. It has been demonstrated that some tumors grow rapidly after Nivo treatment, but the proportion is uncertain. Methods: DELIVER trial was a prospective, multicenter, observational/translational study which assessed pts with advanced GC treated with Nivo alone and ECOG Performance Status (PS) 0-2 (UMIN000030850). The aims were to evaluate the efficacy and safety of Nivo in real world, and to discover novel host-related immune-biomarkers (gut microbiome, genetic polymorphism, gene expression, and metabolome) using fecal and blood samples which were collected before and after Nivo treatment. The RR, DCR, progression-free survival, overall survival, and tumor growth rate (TGR) were estimated as the efficacy. The response was evaluated by first imaging based on RECIST version 1.1. The TGR was calculated as a percentage increase in tumor volume during 1 month (Champiat et al. Clin Cancer Res 2017). Results: A total of 501 pts was enrolled in this study from Mar 2018 to Aug 2019, and 487 pts were evaluable for analysis (median age 70-y, 71% male, ECOG PS0/1/2 42%/44%/14%, tub/por/sig 45%/41%/5%, 21% HER2-pos, 42% pts with ascites). The DCR was 39.2% (95%CI 34.9-43.7) in evaluable pts. In 282 pts with measurable lesions, the RR was 6.7% (95%CI 4.1-10.3) and DCR was 36.5%. Sub-analysis by patient background indicated that DCR was 41% for PS0, 42% for PS1, and 24% for PS2. In addition, the DCR was lower in pts with ascites compared to those without ascites (28.6% vs. 47.0%, p= 0.005). The TGR decreased after introduction of Nivo in 124 (56.6%) of 219 evaluable pts for TGR; however, 20.5% pts were identified as experiencing hyper-progressive disease (HPD) which was defined as a ≥2-fold increase of the TGR before and after Nivo. When defining HPD as a ≥2-fold increase of tumor growth kinetics ratio and 50% increase of tumor burden, 9.6% pts experienced it. Conclusions: The real-word data of the large observational trial showed a comparable DCR to that of clinical trial in advanced GC treated with Nivo. This trial revealed the tumor behavior and some pts who experienced rapid tumor growth after Nivo treatment in clinical practice; biomarkers for HPD and the definition should be established. Clinical trial information: UMIN000030850 .
Phase II study of intraperitoneal paclitaxel combined with S-1 plus cisplatin for gastric cancer with peritoneal metastasis: SP + IP PTX trial.
Authors: Kobayashi Daisuke , Fukushima Ryoji , Ota Mitsuhiko , Fushida Sachio , Yamashita Naoyuki , Yoshikawa Kozo , Ueda Shugo , Yabusaki Hiroshi , Kusumoto Tetsuya , Arigami Takaaki , Hidemura Akio , Omori Takeshi , Yamaguchi Hironori , Hirono Yasuo , Tsuji Yasushi , Kishi Kentaro , Tomita Toshihiko , Ishigami Hironori , Kitayama Joji , Kodera Yasuhiro ,   Japan Intraperitoneal Chemotherapy Study Group (JIPG)
Published: May 2020

4529

Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. Although a phase III study failed to show a statistically significant superiority of IP paclitaxel (PTX) combined with S-1 and intravenous PTX over S-1/cisplatin (SP), the standard of care as a first-line treatment in Japan, the sensitivity analysis suggested clinical efficacy of the IP PTX. Thus, attempts to combine IP PTX with other systemic therapies with higher efficacy have been warranted. After a dose-finding study, we sought to explore efficacy of a new regimen that combined IP PTX with SP. Methods: Gastric cancer patients with peritoneal metastasis confirmed by diagnostic imaging, laparoscopy or laparotomy were enrolled in the phase II multi-institutional prospective trial. In addition to the established SP regimen (S-1 administered orally at a dose of 80 mg/m2 bid for 21 days followed by a 14-day rest and cisplatin administered intravenously at a dose of 60 mg/m2 on day 8), IP PTX was administered on days 1, 8 and 22 at a dose of 20 mg/m2. The primary endpoint is overall survival (OS) rate at one year after treatment initiation. Secondary endpoints are progression free survival (PFS), response rate and toxicity. Results: Fifty-three patients were enrolled and fully evaluated for OS and toxicity. The median number of courses was 7 (range 1-20). The 1-year OS rate was 74% (95% CI, 60-83%). The median survival time was 19.4 months (95% CI, 16.7 months-). The 1-year PFS rate was 57% (95% CI, 42-69%). The overall response rate was 20% (95% CI, 1-72%) in 5 patients with target lesions. Cancer cells ceased to be detected by peritoneal cytology in 23 (64%) of 36 patients. Fourteen (26%) patients underwent gastrectomy after response to chemotherapy. The incidences of grade 3/4 hematological and non-hematological toxicities were 43% and 47%, respectively. The frequent grade 3/4 toxicities included neutropenia (23%), anemia (29%), diarrhea (13%) and anorexia (17%). Intraperitoneal catheter and implanted port-related complications were observed in 4 patients. There was 1 treatment-related death. Conclusions: IP PTX combined with SP is well tolerated and active in gastric cancer patients with peritoneal metastasis. Clinical trial information: UMIN000023000 .
Gastric inflammatory prognostic index (GIPI) to predict efficacy of PD-1/PD-L1 immune checkpoint inhibitors in metastatic gastroesophageal junction (GOJ)/gastric cancer (GC) patients.
Authors: Morelli Cristina , Formica Vincenzo , Patrikidou Anna , Murias Carmen , Butt Sabeeh-Ur-Rehman , Nardecchia Antonella , Lucchetti Jessica , Renzi Nicola , Shiu Kai-Keen , Roselli Mario , Arkenau Tobias
Published: May 2020

4530

Background: ICIs demonstrated improved overall survival (OS) in heavily pre-treated mGOJ/GC pts. Pts selection exclusively based on PD-L1 tissue expression appears to be suboptimal, despite data from subgroup analyses of KEYNOTE trials. Strong rationale suggests a potential predictive role of inflammatory biomarkers in ICIs treated mGOJ/GC pts. Methods: Ten systemic inflammatory markers [platelets, monocytes, neutrophil/lymphocyte ratio (NLR), platelets-lymphocyte ratio, lymphocytes, sum of mononuclear cells, albumin, lactate dehydrogenase, c-reactive protein (CRP) and serum globulin] were retrospectively analyzed at baseline in 57 mGOJ/GC pts with unknown PD-L1 status treated in second-line with ICIs, and correlated with OS. Least Absolute Shrinkage and Selection Operator (LASSO) method was used to select variables (preliminarily subject to optimal coding using HR smoothed curves for OS) with the highest prognostic value. Selected variables were then analyzed in a multivariate Cox Regression Model and used to build a GIPI nomogram. Results: NLR and CRP taken as continuous variables and albumin categorized as < vs > 30 g/dL were found as the most meaningful independent predictors of OS and used to build the GIPI nomogram. Nomogram-based lowest (l), mid-low, mid-high and highest (h) risk quartiles were associated with median(m)OS of 14.9, 7.1, 5.6 and 2.1 months (mos), respectively [HR of l vs h 4.94, p 0.0002]. By optimally dichotomizing CRP and NLR, pts with one or more of the following risk factors: NLR >6, CRP >15 mg/L, albumin <30 g/dL (n: 29) had a mOS of 3.9 mos vs 14.2 mos of pts with no risk factor (n: 28) (HR 2.48, p 0.001). Conclusions: GIPI, combining NLR, CRP and Albumin, is the first inflammatory index with a significant prognostic value in mOGJ/GC pts receiving second-line ICIs. Its implementation in correlation with PD-L1 expression in the present cohort is ongoing. GIPI merits validation in independent cohorts and prospective clinical trials.
Impact of frontline doublet versus triplet therapy on clinical outcomes: Exploratory analysis from the RAINBOW study.
Authors: Klempner Samuel J , Wainberg Zev A. , Muro Kei , Chao Joseph , Catenacci Daniel V.T. , Ajani Jaffer A. , Al-Batran Salah-Eddin , Toms Nikki , Knoderer Holly , Wei Ran , Liepa Astra M. , Chatterjee Anindya , Ohtsu Atsushi
Published: May 2020

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Background: Treatment (tx) of advanced gastric cancer (GC/GEJ) is highly heterogeneous, with substantial variability in tx patterns. Frontline tx choice may affect outcomes of subsequent tx, thereby influencing choice/efficacy of second-line (2L) tx. In RAINBOW, 2L ramucirumab(R) plus paclitaxel(P) significantly improved overall survival (OS) of patients (pts) with GC/GEJ. Here we explore efficacy, safety and quality of life (QoL) based on prior tx. Methods: Pts were grouped into doublet (DB) or triplet (TP) regimens based on prior cytotoxic tx received. OS and PFS were estimated using Kaplan-Meier method and tx effects on OS and PFS were evaluated by Cox PH model; safety and QoL were assessed descriptively for DB vs TP. Results: Use of DB and TP was similar between arms, with 23% in R+P and 26% in placebo (PB)+P arm receiving TP. Baseline characteristics were generally balanced between tx arms within DB and TP subgroups, with majority of TP administered in western regions (91%). Pts ≥65 years of age was 40% for DB and 28% for TP. DB pts (n = 498; 75%) received S1+cis (n = 97, 15%) and cape+ox (n = 71; 11%) as most common prior tx, while TP pts (n = 163; 25%) received epi+cape+ox (n = 74, 11%) and epi+cis+5FU (n = 53, 8%). Similar to ITT population, R+P improved OS and PFS in both DB and TP subgroups (Table). Patterns of overall and Grade ≥3 TEAEs between arms were similar regardless of prior tx. Higher rates of serious TEAEs were reported in TP pts (57%, 49%) than DB pts (44%, 40%) in R+P and PBO+P arms, respectively. Similar trend was observed for TEAEs leading to discontinuation for TP (40%, 30%) vs DB (29%, 22%) in respective tx arms. Baseline QoL scores were similar between tx arms within subgroups, but mean scores were > 5 points worse (range 0-100) for prior TP for role functioning, fatigue, pain, and appetite loss. Changes in mean scores were generally similar between arms and within subgroups. Conclusions: This exploratory analysis of RAINBOW suggests that although safety-related outcomes were less favorable in pts with prior TP, regardless of tx arm, similar improvements in efficacy were noted for R+P irrespective of prior DB or TP. Clinical trial information: NCT01170663 . [Table: see text]