bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary safety analysis of phase II open-label NIVACOR trial (GOIRC-03-2018) in patients with advanced colorectal cancer RAS or BRAF mutated.
Authors: Damato Angela , Berselli Annalisa , Iachetta Francesco , Romagnani Alessandra , Larocca Mario , Garcia Arias Alicia , Antonuzzo Lorenzo , Nasti Guglielmo , Bergamo Francesca , Pinto Carmine
Published: January 2021

37

Background: NIVACOR trial is an open-label, multicentric Italian phase II trial of FOLFOXIRI/bevacizumab in association with an anti-PD1 antibody, nivolumab, in patients (pts) with metastatic colorectal cancer (mCRC). We report preliminary safety analysis by an Independent Monitoring Committee. Methods: Pts with mCRC RAS or BRAF mutated, regardless microsatellite status and eligible to receive a first line treatment will be enrolled. FOLFOXIRI/bevacizumab (BEV) in association with nivolumab (NIV) was administered every 2 weeks for 8 cycles (induction) followed by BEV plus NIV every 2 weeks (maintenance) until PD or unacceptable toxicities. BEV was administered intravenously at dose of 5 mg/kg and NIV intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint was the ORR. The safety is assessed after the inclusion of the 10th patient, receiving ≥1 dose. Results: As of September 20, 2020, 25/70 pts are enrolled. The first 10 pts were evaluated for preliminary safety analysis. Median age was 58 years (32-66), 60% of pts were male, median cycles of treatment was 5.5 (1-9). 100% were KRAS G12D mut and BRAF wild type, respectively, and 2% MSI-H/dMMR. 7/10 pts experienced at least one AE related to FOLFOXIRI/BEV and 2/10 related to NIV. The most frequent grade 1-2 AEs related to FOLFOXIRI/BEV were nausea and vomiting 4(57%), fatigue 5(71%), and diarrhea 5(71%); 3(43%) pts had grade 3-4 neutropenia, and 1(14%) febrile neutropenia. Only 2 pts developed grade 1-2 AEs related to NIV represented by rash (50%) and salivary gland infection (50%); no grade 3-4 was reported. One of pts with dose delay because of serious AES (proteinuria) BEV related, and one patient discontinued due to serious AEs (ileo-urethral fistula) not related to NIV. Conclusions: Combination of FOLFOXIRI/BEV and NIV was generally well tolerated and showed an acceptable toxicity profile. The final analysis will be scheduled at the end of enrollment. Clinical trial information: NCT04072198.
Ampullary neuroendocrine tumors: A window into a rare tumor using a national database.
Authors: Ruff Samantha M , Deutsch Gary B , Weiss Matthew John , Deperalta Danielle
Published: January 2021

373

Background: Ampullary neuroendocrine tumors (NET) make up < 1% of all gastrointestinal NETs. Information about their behavior and prognosis is reliant on small case series. This study set out to describe the population of patients who are diagnosed with ampullary NETs and compare them to patients with duodenal and pancreatic head NETs. Methods: The National Cancer Database (2004 – 2016) was queried for patients with ampullary, duodenal, and pancreatic head NETs. Clinicopathologic and treatment characteristics were compared. Subset analysis was performed on patients who underwent surgery. Kaplan Meier (KM) analysis and Cox regression were used to analyze the survival of patients with ampullary NETs. Results: Overall, 872 patients were identified with ampullary NET, 9692 with duodenal NET, and 6562 with pancreatic head NET. Patients with ampullary NET had an average age of 60.9 +/- 14.5 years, were evenly split among men and women (N = 437, 50.1% vs N = 435, 49.9%, respectively), and primarily Caucasian (N = 663, 76.0%). 72.1% underwent local tumor destruction or surgery (N = 629). Most did not receive radiation (N = 832, 95.4%), chemotherapy (N = 627, 71.9%), or hormone therapy (N = 788, 90.4%). Patients with ampullary NETs had more poorly differentiated tumors (N = 119, 13.6%) than patients with duodenal (N = 159, 1.6%) or pancreatic head (N = 602, 9.2%) NETs. Patients with ampullary NETs had more positive lymph nodes (N = 288, 33%) than patients with duodenal (N = 915, 9.4%) or pancreatic head (N = 1381, 21%) NETs. At five years, the overall survival for patients with ampullary, duodenal, and pancreatic head NETs was 57%, 68%, and 46%, respectively. Within the surgical population, five-year survival for patients with ampullary (N = 367), duodenal (N = 991), and pancreatic head (N = 1961) NETs was 60%, 74%, and 72%, respectively. When compared, there was a statistically significant difference between the mean overall survival of patients with ampullary (98 +/- 4.7 months), duodenal (112 +/- 2.5 months), and pancreatic head (108 +/- 1.7 months) NETs (p < 0.001). In the cox regression analysis, sex, Charlson-Deyo score, lymph node positivity, lymph-vascular invasion, mitotic rate, chromogranin A level, 5-HIAA level, and tumor size did not correlate with survival. Increasing age (HR 1.04, CI 1.01 – 1.07, p = 0.008) and worse tumor differentiation (poorly differentiated HR 3.33, CI 1.38 – 8.04, p = 0.008 and undifferentiated HR 8.31, CI 2.77 – 24.92, p < 0.001 compared to well differentiated) were associated with increased mortality. Conclusions: This study sheds light on a rare tumor histology. When compared to patients who underwent surgical resection for duodenal or pancreatic head NETs, patients with ampullary NETs had a significantly worse prognosis. Identifying prognostic factors allows us to create more concrete treatment recommendations and provide patients with improved prognostic information.
Impact of systemic inflammation and sarcopenia on prognosis of metastatic colorectal cancer.
Authors: da Silva Dias David , Machado Mafalda , Gosalbez Beatriz , Ravasco Paula
Published: January 2021

38

Background: Systemic inflammation, evaluated with neutrophil-to-lymphocyte ratio (NLR), and sarcopenia, assessed with skeletal muscle index (SMI), appear to predict mortality in many cancers, although the optimal cut-offs are still a matter of debate. The goal of this study is to evaluate the cut-offs of NLR and SMI and their prognostic value on metastatic colorectal cancer (mCRC) under first line treatment. Methods: Retrospective cohort analysis of patients with mCRC under first-line treatment in two hospital units, between January 2015 and December 2018. Muscle mass area (MMA) was detected on computed tomography, on L3 segment, with ImageJ software. SMI was determined as MMA/height2. Statistical analysis was performed with IBM SPSS v25 software. Results: 178 patients were analysed, with mean age of 62 (±11) years old. 65% were male and 62.9% had ECOG PS 0. Two thirds of patients presented metastasis in a single organ, mainly in liver. The cut-off values were established based on ROC analysis. Systemic inflammation was defined as NLR > 2.80 and sarcopenia was defined by SMI < 49.12 cm2/m2 for men and <35.85 cm2/m2 for women. 52% of patients presented sarcopenia. In a multivariate analysis using a Cox regression model, an association was observed between overall survival and ECOG PS (p=0.014; HR 5.46, CI 95% [1.42-21.10]), systemic inflammation (p=0,038; HR 2.20, CI 95% [1,05-4.62]) and sarcopenia (p=0.01; HR 4.73, CI 95% [1.85-12.09]). Conclusions: In this study, sarcopenia and systemic inflammation showed independent prognostic value on patients with mCRC. Future prospective studies are necessary to establish a definitive cut-off value for application in clinical practice.
Real-world one-year overall survival among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan in the NAPOLI-1 based regimen.
Authors: Kim George P. , Cockrum Paul , Surinach Andy , Abushahin Laith I.
Published: January 2021

392

Background: Pancreatic cancer remains one of the most lethal cancers in the United States (US) with a 5-year relative survival of 9%. Among patients who received liposomal irinotecan + 5-fluorouracil (5-FU) and leucovorin in the NAPOLI-1 study, a randomized phase 3 study in patients with mPDAC previously treated with gemcitabine-based therapy, 25% (n = 29) were alive at ≥ 1 year. This study examines the real world one-year survival of patients with mPDAC treated with liposomal irinotecan as a doublet with 5-FU in the NAPOLI-1 based regimen. Methods: This retrospective observational study utilized the Flatiron Health EHR database from over 280 cancer clinics in the US. Data were analyzed for adult patients with mPDAC treated with liposomal irinotecan-based regimens between November 2015 and July 2020. Patient characteristics and one-year overall survival (OS) based on Kaplan-Meier estimates were assessed. Cycles were defined as unique days with an administration of liposomal irinotecan. Results: There were 669 patients (median age: 69y, IQR: 62-75) included in the study. ECOG performance status (PS) of 0-1 and 2+ were reported for 78.3% (n = 396) and 21.7% (n = 110) of patients, respectively. ECOG PS was not captured for 24.4% (n = 163) of patients. 16.3% (n = 109) of patients initiated liposomal irinotecan-based in the first line (1L) metastatic setting, 47.5% (n = 318) in second line (2L), and 36.2% (n = 242) in the third line or later (3L+). The median number of cycles received was 4 (IQR: 2 – 8). Among all patients, one-year OS was 17.2% (95% CI: 14.3% - 20.7%). One-year OS was 31.5% (22.1% – 41.3%) for patients treated in 1L, 16.4% (12.2% - 21.1%) for patients treated in 2L, and 12.2% (7.5% - 18.0%) for patients treated in 3L. The median number of cycles for 1L, 2L, and 3L were 5, 4, and 3, respectively. One-year OS increased as patients were able to receive more cycles of liposomal irinotecan. Patients who received at least 2 cycles of liposomal irinotecan (n = 551) had a one-year OS of 20.4% (16.8% - 24.2%). Among patients who received at least 4 cycles (n = 359) and at least 8 cycles (n = 170), the one-year OS estimates were 29.1% (24.0% - 34.3%) and 47.9% (39.7% - 55.7%), respectively. Conclusions: In this real-world cohort of patients with mPDAC treated with liposomal irinotecan, as expected, one-year OS increased as patients remained on therapy. Patients in this cohort were older, had more prior lines of therapy, worse ECOG PS, and similar exposure to treatment compared with patients in the registrational phase 3 NAPOLI-1 study. Among patients who received at least 4 cycles of liposomal irinotecan, one-year OS (29%) was similar to both the intent-to-treat (25%) and per protocol treated patient populations in the NAPOLI-1 trial (34%). Further studies are needed to understand the predictors of long-term survival among patients with mPDAC.
Circulating tumor DNA methylation as markers for early detection of pancreatic ductal adenocarcinoma (PDAC).
Authors: Liu Xiaoding , Guo Shiwei , Ma Chengcheng , Li Yatong , Liu Xiaoqian , Zhang Zhiwen , Yu Lianyuan , Dai Menghua , Shen Shuo , Wu Huanwen M. , Su Zhixi , He Qiye , Liu Rui , Gang Jin , Liang Zhiyong
Published: January 2021

395

Background: PDAC is a cancer of high mortality and low survival. Its early detection is critical due to symptoms often occur only at advanced stages. However there is no reliable screening tool to identify high-risk patients. ctDNA methylation has recently emerged as a promising new target to differentiate PDAC plasma from normal plasma for its early detection. Methods: Reduced representation bisulfite sequencing libraries were made in 46 PDAC tissues, 30 para-PDAC tissues and 20 PDAC plasmas to screen PDAC-specific markers, which was done by quantifying and comparing methylation levels of genomic regions and individual CpG sites between those groups. Markers were validated in plasma samples from 84 PDAC patients and 64 normal controls to propose a blood classifier. The best-performing markers were developed into a targeted sequencing panel, which was tested on a larger collection of plasma samples from patients of a variety of pancreatic diseases to build and validate a PDAC-predicting model. Results: We profiled genome-wide methylation patterns of tissues samples to identify 171 PDAC-specific markers. We reiterated training and cross-validating PDAC classification models using SVM method, and achieved an average sensitivity of 86% and specificity of 88%. To prove the feasibility of a non-invasive detection in plasma, a targeted methylation assay using those markers was tested on PDAC and normal plasmas, and yielded an average sensitivity of 68.4% and a specificity of 85.8%. We refined the panel by selecting the most discriminatory markers and built the version II of the panel, which was named PANcreatic Cancer Detection Assay, or PANDA, for a more efficient target capture, which was validated in an independent cohort of plasma samples that included 94 PDAC cases, 25 chronic pancreatitis (CP) cases and 80 normal samples from multiple centers. The PANDA achieved an AUC of 0.906 when classifying PDAC from normal, and an AUC of 0.882 when separating PDAC from CPs, both of which are more accurate than CA19-9, the conventional blood marker for PDAC. We further integrated test subjects’ age and their CA19-9 level as features into the PANDA model, which further elevated their AUC to 0.882 and 0.933 when classifying PDAC plasma from either CP plasma or normal plasma, respectively. Conclusions: We have developed PANDA, an NGS based target assay covering PDAC-specific DNA methylation targets by screening and validation on PDAC tissues and plasmas. Combined with age and CA19-9 blood level, PANDA has shown encouraging results to classify PDAC plasma from non-malignant diseases, demonstrating its potential to be optimized into non-invasive diagnostics for blood-based early PDAC screening.
NACRE: A randomized study comparing short course radiotherapy with radiochemotherapy for locally advanced rectal cancers in the elderly—Preliminary results.
Authors: FRANCOIS Eric , Pernot Mandy , Ronchin Philippe , Nouhaud Elodie , Martel Lafay Isabelle , Pascal Artru , Clavere Pierre , Vendrely Veronique , Boige Valerie , Thamphya Brice , Nénan-Le Ficher Soazig , Magné Nicolas
Published: January 2021

4

Background: Neoadjuvant therapy followed by total mesorectal surgery is the standard of care for locally advanced rectal carcinoma (RC). In the elderly, often underrepresented in clinical trials, but who represent a very large number of patients, therapeutic proposals are not based on high levels of evidence. The NACRE study investigated the role of short course radiotherapy with delayed surgery in this population. Methods: The PRODIGE 42-GERICO 12 NACRE is a multicenter randomized clinical trial aimed at comparing Arm A preop radiochemotherapy (RCT) (50 Gy, 2Gy/fraction [fr]; 25 fr + capecitabine) and delayed surgery and Arm B short course radiotherapy (25 gy, 5Gy/fr, 5fr) and delayed surgery. Eligible patients (pts) had cT3 or cT4 (or cT2 of the very low rectum), M0 rectal adenocarcinomas <12 cm from the anal verge, age ≥75years, and WHO PS ≤2. Randomization was stratified by center, T (T2/T3-T4) stage and Age (≤80 or >80 years). Two primary end-points will be analyzed according to the hierarchical sequential procedure: firstly R0 resection rate (non-inferiority test with a 8% non-inferiority margin), secondly preservation of autonomy using IADL score (superiority test with 15% absolute difference margin); secondary end-point will be survival and toxicity. We present here the results for R0 resection, survival and toxicities. Results: 29 sites randomized 101 patients from 01/2016 to 08/2019, 59 were males (58.4%), median age was 80 years (range 75-91). Pts characteristics were well balanced. 14% of pts in arm A did not receive all of the planned neoadjuvant treatment compared to 0% in arm B. The R0 resection rate in arm B (86.0% [IC95% 73-94%]) was not-inferior to the R0 resection rate in arm A (89.8% [ic95% 77-97%]), p=0.04 (non inferiority test). With a median follow-up of 15.8 months (CI95%: 14.8-26.0), the 6 months death rate was 10.0% (CI95%: 3.0-22.0) in arm A and 3.92% (CI95%: 0 -13.0) in arm B. There is a significant difference in overall survival between the two arm in favor of arm B (p=0.04, LogRank test), and there is a trend in favor of arm B for specific survival (p=0.06 LogRank test). Disease free survival is not statistically different (p=0.9). 13 serious adverse events were observed in arm A during preoperative phase, 7 in arm B, 16 and 10 respectively during the post-operative phase. Conclusions: These preliminary results show that short course radiotherapy with delayed surgery is associated with better compliance than radiochemotherapy in elderly patients and could give an advantage in overall survival. This regimen may be preferred in elderly patients. Clinical trial information: NCT02551237.
Irreversible electroporation versus chemotherapy with or without radiation for locally advanced pancreatic adenocarcinoma: A systematic review and meta-analysis.
Authors: Sugumar Kavin , Hue Jonathan J. , Rothermel Luke , Hardacre Jeffrey , Ammori John Brian , Winter Jordan Michael , Ocuin Lee M
Published: January 2021

408

Background: Multi-agent chemotherapy (CT) with or without radiotherapy (RT) is the standard of care for non-metastatic Type B locally advanced pancreatic cancer (LAPC). Irreversible electroporation (IRE) has been described as a treatment modality in patients with LAPC but published postoperative morbidity and mortality rates are high for a non-curative procedure. There have been few studies that have compared directly IRE with standard of care CT ± RT. We performed a meta-analysis of the available literature to compare the outcomes between these treatment groups in LAPC. Methods: A systematic literature search was performed in Medline, Embase, and the Cochrane Library in September 2020. Studies that focused on comparing outcomes between IRE and CT ± RT for LAPC were selected for further study. The impact of IRE versus CT ± RT was evaluated using forest plot analysis. Overall survival (OS) and progression free survival (PFS) served as the primary endpoints. As a secondary objective, short term morbidity and mortality data in both groups was evaluated. Results: Our search yielded 326 papers. After excluding duplicates, 3 studies met inclusion criteria. All were retrospective. Combined, these studies included clinical data on 3,862 patients. The meta-analysis indicated that patients with LAPC who underwent IRE had better OS (HR = 0.46, 95% CI: 0.28-0.74) and PFS (HR = 0.38, 95% CI: 0.24-0.60) compared to patients who received CT ± RT. Due to incomplete morbidity, 30-, and 90- day mortality information reported in the included studies, further analysis was not performed for the same. Conclusions: There is a striking paucity of studies comparing IRE with the standard of care treatment approaches for LAPC. Our meta-analysis reveals that IRE has been associated with longer OS and PFS compared to CT ± RT. However, these studies are limited by retrospective study design, heterogeneity of population and chemotherapy regimens, and incomplete morbidity data, precluding any conclusions. Until higher quality, comparative retrospective studies, or more importantly, prospective studies with standardized indications are conducted, IRE should be used with caution and remains experimental in the treatment of PDAC.
Investigate the efficacy of immunotherapy for treatment of pancreatic adenocarcinoma (PDAC) with mismatch repair deficiency (dMMR).
Authors: Noor Arish , Aguirre Luis E. , Blue Kirsten , Avriett Trenton , Carballido Estrella M. , Kim Richard D. , Kim Dae Won
Published: January 2021

415

Background: Immune checkpoint inhibitors (ICI) have been approved in solid tumors with dMMR. However, only limited data are available for PDAC with dMMR given the rarity of dMMR in PDAC. We evaluated efficacy of ICIs in PDAC with dMMR. Methods: Retrospective clinical and pathologic data were collected for patients (pts) with pancreatic adenocarcinoma from May 2017 to June 2020 at Moffitt cancer center. Results: We identified 10 pts with dMMR PDAC. The median age was 64.5 years (range: 42-86) and 4 pts were male. 4 pts had resectable disease, 3 had locally advanced and 3 had metastatic disease at initial diagnosis. MSH6 deficiency (def) was found in 2 cases, PMS2 def in 2, MLH/PMS2 def in 5, and MSH2/MSH6 in 1. 7 pts were treated with ICIs. 3 pts had locally advanced and 4 had metastatic disease when they started ICIs. 5 received Pembrolizumab (pem), 1 received ipilimumab/ nivolumab (ipi/nivo), and 1 received pem then ipi/nivo after progressive disease (PD) on pem. The median number of prior lines of chemotherapy was 1 (range 0-2). 6 pts were evaluable, and 1 had rapid disease progression after 1 dose of pem. Among 6 evaluable pts, 3 had an objective response (1: complete response and 2: partial response), and 2 had stable disease (SD). Median progression-free survival was 8.2 mo, and median overall survival was not reached with median follow-up (FU) of 6.8 mo. The median duration of response was not reached with a median FU of 22.6 mo. The pt with CR remained disease-free for up to 22 months. The pt whose treatment was switched to ipi/nivo after PD on pem achieved SD > 4mo on ipi/nivo. While on immunotherapy, one patient with ipi/nivo developed immunotherapy associated rash requiring systemic steroids, and another on pem developed hypothyroidism requiring levothyroxine. Conclusions: This series suggest ICIs can provide durable clinical efficacy in pts with dMMR PDAC.
The impact of multi-agent chemotherapy in metastatic pancreatic adenocarcinoma: A population-based study utilizing the SEER database.
Authors: Sugumar Kavin , Gupta Shreya , Hue Jonathan J. , Ocuin Lee Mayer , Rothermel Luke , Hardacre Jeffrey , Ammori John Brian , Winter Jordan Michael
Published: January 2021

416

Background: Over the last decade, various landmark trials have demonstrated the impact of multi-agent chemotherapy in the treatment of PDAC. However, the impact in the ‘real world’ has been less clear. The ACCORD trial (2011) was a phase III trial comparing combination chemotherapy (FOLFIRINOX) and single agent (gemcitabine) for advanced disease. The MPACT trial introduced another beneficial regimen (nab-paclitaxel and gemcitabine) in 2013. Subsequently, multi-agent chemotherapy became standard of care for medically appropriate patients. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with PDAC between 1998 and 2017. The cohort was divided into two groups: 1998-2011 (pre-ACCORD) and 2012-2017 (post-ACCORD). We analyzed all patients with metastatic PDAC for overall survival and compared results in the two groups using Kaplan Meier analysis and multivariate Cox proportional hazards models. An interrupted time series analysis was also used to compare the temporal trends in 2-year survival between 1998 and 2017. Results: A total of 47,134 patients were diagnosed with PDAC between 1998 and 2017. Nearly two-third of patients (26,438; 57%) had distant disease. On univariate survival analysis, there was a significant increased overall survival probability in the 2012-17 group compared to the 1998-2011 group (p<0.05). The one- and two-year survival rates were 11% and 3% in the pre-ACCORD period compared to 14% and 4 % after the ACCORD trial respectively. This difference remained significant on multivariate analysis while adjusting for covariates (HR=0.08, 0.78-0.92, p=0.05). On interrupted time series analysis, we observed a steady rise in 2- year survival between 1998 and 2017. There was a significant jump in the two-year survival probability from 16% at 2011 to 20% at 2012 in metastatic PDAC (β=0.02, 0.009-0.03, p<0.0001, Table). Conclusions: Beyond the randomized clinical trial arena, overall survival has increased over time, with a statistically significant jump around the time of the ACCORD trial. However, the absolute increase in the ‘real world’ is smaller than the gains observed in prospective clinical trials. [Table: see text]
Characteristics and growth rate of lung metastases in patients with primary gastrointestinal malignancies: A retrospective cohort analysis.
Authors: Burns Shohei , Vella Maya , Paciorek Alan , Zhang Li , Atreya Chloe Evelyn , Collisson Eric Andrew , Feng Mary Uan-Sian , Kelley Robin Kate , Tempero Margaret A. , Van Loon Katherine , Ko Andrew H.
Published: January 2021

442

Background: There are no formal guidelines for the management of GI cancer pts with lung-exclusive or lung-predominant metastases (LM), which generally take a more indolent course than metastatic disease occurring at other anatomic sites. We performed a retrospective analysis at a high-volume tertiary care center to evaluate host and tumor characteristics of this pt population, describe treatment approaches, and model patterns and rates of growth. Methods: Eligible pts were identified through Cancer Center registry data, provider recall, and electronic record review. Criteria included LM occurring either synchronously (SLM) or metachronously (MLM) w/primary cancer diagnosis; nodal, but not visceral or peritoneal, mets allowed. Data re: demographics, tumor characteristics, and rx modalities were collected. We reviewed all eligible CT +/- PET scan reports to gather data on #, location, and size of pulm mets, with all images subsequently reviewed by an independent radiologist. Up to 5 pulm mets were tracked through each pt’s clinical course. Growth rate was estimated using a linear mixed model analysis considering patients as the random. Results: Forty pts were identified between 9/2009 - 12/2019 (23 F/17 M; 28 white/7 Asian/5 other/multi; median age 62 y.o.; n = 15 w/tobacco hx). Tumor types: pancreatic (n = 18), colorectal (n = 12), hepatobiliary (n = 7), other (n = 3). SLM vs MLM:13/27; intact vs resected primary = 16/24. Median time from orig cancer dx to onset of MLM = 16 mos (range, 1 to 60 mos). No. of pulm mets at 1st appearance: 1 (n = 7); 2-5 (n = 17); 6-10 (n = 16). Median size of largest pulm met at 1st appearance = 6 mm (range, 0-39 mm); avg growth rate of largest pulm met = 0.18 mm/month (95% CI, 0.08-0.27). Avg growth rate of up to 5 largest lesions (sum) = 0.35 mm/month (95% CI, 0.07-0.64). Median f/u time prior to rx initiation for MLM = 172 days (range, 25-1547 days); 18 pts developed additional mets during their observation period. Rx modalities for LM: surg (n = 6), radiation (n = 18), systemic rx (n = 32). Addn details specific to cancer type, progression patterns, and pt outcomes will be presented at the meeting. Conclusions: The natural hx of LM varies across the spectrum of GI malignancies. Further larger-scale efforts to define patterns of growth of LM for different GI cancers, informed by size, #, and clinical/molecular features, are needed to guide appropriate timing and selection of rx as well as surveillance strategies.
Final results of the ACTS-CC 02 trial: A randomized phase III trial of S-1/oxaliplatin (SOX) versus UFT/leucovorin as adjuvant chemotherapy for high-risk stage III colon cancer.
Authors: Tomita Naohiro , Sasaki Shin , Kusumoto Tetsuya , Watanabe Jun , Sakamoto Yoshiyuki , Yoshida Kazuhiro , Maeda Atsuyuki , Teshima Jin , Yokota Mitsuru , Tanaka Chihiro , Yamauchi Junichiro , Uetake Hiroyuki , Itabashi Michio , Takahashi Keiichi , Baba Hideo , Kotake Kenjiro , Boku Narikazu , Aiba Keisuke , Morita Satoshi , Sugihara Kenichi ,   ACTS-CC 02 Study Group
Published: January 2021

59

Background: As previously reported (Sunami E, et al. Clin Colorectal Cancer. 2020), the ACTS-CC 02 trial demonstrated that S-1 and oxaliplatin (SOX) was not superior to UFT/leucovorin (LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) after a median follow-up of more than 6 years. Methods: A total of 966 patients with high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300–600 mg/day of UFT according to body surface area [BSA] and 75 mg/day of LV on days 1-28, every 35 days, 5 courses) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80–120 mg/day of S-1 according to BSA on days 1-14, every 21 days, 8 courses). The primary endpoint was DFS. Patients’ data were updated in February 2020. Results: The subjects of this final efficacy analysis were 955 patients (478 in the UFT/LV group and 477 in the SOX group). Totally, Stage IIIA/IIIB/IIIC were 1.3%/50.2%/48.6% and T1/2/3/4 were 1.5%/4.0%/61.8%/32.7%. With median follow-up time of 74.3 months, the 5-year OS rate was 78.3% in the UFT/LV group and 79.1% in the SOX group (HR: 0.97; 95% CI: 0.76-1.24; p = 0.8175). The 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group (HR: 0.92; 95% CI: 0.76-1.11; p = 0.3973). In an exploratory analysis, the 5-year OS rate in patients with T4 disease was 65.2% and 70.8% in the UFT/LV group and SOX group, respectively (HR: 0.81; 95% CI: 0.56-1.17), and the 5-year DFS rate was 45.4% and 50.5% (HR: 0.87; 95% CI: 0.65-1.19), respectively. Notably, in patients with T4N2b disease, the 5-year OS rate was 51.0% and 64.1% in the UFT/LV group and SOX group, (HR: 0.72; 95% CI: 0.40-1.31) and the 5-year DFS rate was 31.1% and 37.2% (HR: 0.87; 95% CI: 0.50-1.31), respectively. Conclusions: In Japanese patients with high-risk stage III colon cancer, the 5-year OS rate was similar in the UFT/LV group and SOX group. However, the oxaliplatin-based regimen was suggested to be more effective for DFS and OS in patients with advanced disease, such as T4N2b. Clinical trial information: JapicCTI-101073.
The efficacy and safety of anlotinib in refractory colorectal cancer: A double-blinded, placebo controlled, randomized phase III ALTER0703 trial.
Authors: Chi Yihebali , Shu Yongqian , Ba Yi , Bai Yuxian , Qin Baoli , Wang Xiuwen , Xiong Jianping , Xu Nong , Zhang Helong , Xu Jianming , Cheng Ying , Feng Jifeng , Hu Chunhong , Chen Yigui , Chen Zhendong , Wang Jufeng , Dang Chenxue , Cai Jianqiang
Published: January 2021

65

Background: The efficacy of late line treatments for metastatic colorectal cancer (mCRC) is still limited. Antiangiogenic therapy is one of standard treatments in mCRC. Anlotinib is a multitarget tyrosine kinase inhibitor, mainly targets VEGFR1-3. This phase III trial was conducted to evaluate anti-tumor efficacy and safety of anlotinib monotherapy in refractory mCRC. Methods: Aged 18 years or older mCRC patients were enrolled in 33 Chinese hospitals. They had received at least 2 lines of chemotherapy based treatments; had ECOG PS 0-1and adequate bone marrow, liver and renal function. Enrolled patients were 2-to-1 randomly assigned into anlotinib or placebo group and stratified by previous VEGF-targeting therapy (y/n) and time from diagnosis to metastases (</≥18 months). Anlotinib (12 mg/d, oral, d1-14, q3w) or matched placebo was administered plus best supportive care. Primary end point was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Disease Control Rate (DCR), safety and quality of life. Results: Between December 2014 and August 2016, 421 patients were enrolled (282 in anlotinib and 137 in placebo group). By the cut-off date (August 31, 2018), the median OS was 8.6 months (95% CI 7.8-9.7) in anlotinib and 7.2 months (6.2-8.8) in placebo without statistical difference (p=0.87; HR=1.02 [0.82-1.27]). The median PFS in anlotinib group (4.1 months; 3.4-4.5) was significantly improved over that in placebo (1.5 months; 1.4-1.5), with a p<0.0001 and a HR of 0.34 (0.27-0.43). Improvements of ORR and DCR were observed in anlotinib over placebo (Table). In subgroup patients with RAS/KRAS/BRAF wildtype, the median OS was statistically prolonged in anlotinib (11.0 months; 8.6-14.1; n=103) than that in placebo (6.7 months; 3.5- 11.1; n=46), HR=0.68 (0.47, 0.99), p=0.043. 52.5% of patients in anlotinib and 19.7% in placebo group experienced grade 3 or above treatment related adverse events (TRAEs). The most common grade ≥3 anlotinib related adverse events were hypertension (20.9%), increased γ-GT (7.1%) and hand-foot syndrome (6.4%), which were recovered by reducing dosage. Only 2 patients in anlotinib group had grade 5 TRAE, which were both hemorrhage. Conclusions: Anlotinib could provide clinical benefits by substantially prolonged PFS with manageable toxicity for Chinese refractory mCRC patients. Although median OS did not reach significant improvement. Those with RAS/KRAS/BRAF wildtype might be the potential patients in anlotinib treatment. Clinical trial information: NCT02332499. [Table: see text]
Phase II study of ipilimumab, nivolumab, and panitumumab in patients with KRAS/NRAS/BRAF wild-type (WT) microsatellite stable (MSS) metastatic colorectal cancer (mCRC).
Authors: Lee Michael Sangmin , Loehrer Patrick J. , Imanirad Iman , Cohen Stacey , Ciombor Kristen Keon , Moore Dominic T. , Carlson Cheryl Ann , Sanoff Hanna Kelly , McRee Autumn Jackson
Published: January 2021

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Background: Panitumumab is a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR) and is a standard therapy in KRAS/NRAS/BRAF WT mCRC. Preclinical data shows that anti-EGFR therapy causes a tumor-specific adaptive immune response and immunogenic apoptosis, with functional adaptive immunity required to mediate efficacy. However, resistance to anti-EGFR antibody therapy inevitably develops and is associated with increased expression of CTLA-4 and PD-L1. We hypothesized that addition of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) to panitumumab will increase response rate in patients with KRAS/NRAS/BRAF WT MSS mCRC. Methods: LCCC1632 was a multicenter, single-arm, Simon’s two stage phase II clinical trial with a pre-specified safety run-in of panitumumab, ipilimumab, and nivolumab in KRAS/NRAS/BRAF WT, MSS mCRC (NCT03442569). Eligible patients must have received 1-2 prior lines of therapy and no prior anti-EGFR or immune checkpoint inhibitor therapy. Subjects received ipilimumab 1 mg/kg IV q6wk, nivolumab 240 mg IV q2wk, and panitumumab 6 mg/kg IV q2wk until progression, toxicity, or patient withdrawal. The primary endpoint was response rate at 12 weeks per RECIST 1.1, and key secondary endpoints included progression-free survival and duration of response. Results: A total of 56 subjects were enrolled 3/2018-6/2020. This included the 6-subject safety run-in, with 0/6 dose-limiting toxicities in first 12 weeks. The first stage of the Simon’s two-stage clinical trial (n=32) had sufficient response rate to merit full enrollment. There were 7 unevaluable subjects for the primary endpoint of 12-week response rate. Among 49 evaluable subjects, 12-week response rate was 35% (95% CI 21-48; n=17 responses). Twenty subjects had at least an unconfirmed response at any time. Median PFS was 5.7 months (95% CI 5.5-7.9). There was one treatment-related grade 5 adverse event of myocarditis. The most common treatment-related grade 3-4 AEs included lipase increased (9%), amylase increased (7%), ALT increased (5%), AST increased (5%), diarrhea (5%), hypophosphatemia (5%), and maculopapular rash (5%). Conclusions: The combination of panitumumab, ipilimumab, and nivolumab demonstrated evidence of activity and met its prespecified primary endpoint of 12-wk response rate criteria to merit further study. The PFS in this single-arm study compares favorably to expected PFS for anti-EGFR monotherapy in RAS wild-type patients, and results suggest activity of immune checkpoint inhibitors combined with anti-EGFR therapy in MSS mCRC. Clinical trial information: NCT03442569.
Phase II study of pembrolizumab plus capecitabine and bevacizumab in microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Interim analysis.
Authors: Bocobo Andrea Grace , Wang Renee , Behr Spencer , Carnevale Julia C. , Cinar Pelin , Collisson Eric Andrew , Fong Lawrence , Kidder Wesley Allen , Ko Andrew H. , Kolli Kanti Pallav , Kennedy Megan , Laffan Angela , Lindsay Sheila , Nalla Sneha , Schwartz Gabriel , Whitman Julia , Zendejas Patricia , Zhang Li , Van Loon Katherine , Atreya Chloe Evelyn
Published: January 2021

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Background: MSS mCRC rarely responds to pembrolizumab monotherapy, but capecitabine and bevacizumab may induce immune-stimulatory effects. This study evaluates the safety, tolerability and preliminary efficacy of pembrolizumab in combination with capecitabine and bevacizumab in MSS mCRC. We present results at the planned interim analysis. Methods: Design:single-arm, open-label, single-site phase 2 trial with a safety lead-in to confirm the recommended phase 2 dose (RP2D) for capecitabine and expansion cohorts. Per the Simon’s 2-stage design, ≤1 response in 29 patients (pts) requires trial suspension. Key eligibility criteria: MSS mCRC with stable disease (SD) or progressive disease (PD) on prior fluoropyrimidine-based therapy. Treatment: RP2D PO capecitabine on days 1-14 plus 200 mg IV pembrolizumab and 7.5 mg/kg IV bevacizumab on day 1 in 21-day cycles. Pts are followed for toxicity and radiographic response. Results: From 04/2018-09/2020, 29 pts were enrolled, of whom 15 (52%) were female; 21 (72%) white; and median age was 55 years (range 36-77 years). Prior therapies: 2 (7%) pts had SD and 27 (93%) pts had PD on fluoropyrimidine-containing regimens; 24 (83%) pts had prior exposure to bevacizumab. The RP2D for capecitabine was 1000 mg/m2 PO BID, with no dose limiting toxicities observed. Complete toxicity data are available for 25 off-treatment pts. The most common related adverse events (AEs) were palmar-plantar erythrodysesthesia (PPE) (64%) and fatigue (68%). Grade ≥3 related AEs occurred in 9 (36%) pts, including immune-related AEs of Grade 3 dyspnea, hypophosphatemia, and pancreatitis in 1 pt each. Treatment related AEs leading to dose interruptions, reductions, or delays occurred in 15 (60%) pts, most commonly PPE in 13 (52%) pts. No pt had a related AE leading to treatment discontinuation or death. Disposition: of 29 pts enrolled, 24 were removed for PD and 1 was removed for an unrelated AE. Best response by RECIST 1.1 in 23 evaluable pts: partial response (PR) in 2 (9%); SD in 14 (61%); PD in 7 (30%). Median time on treatment was 6 months (range 2-26 months). Conclusions: Combination of pembrolizumab with capecitabine and bevacizumab was found to be tolerable with an expected toxicity profile in MSS mCRC pts. With 2 responses, the study met interim analysis criteria to continue accrual. Tissue and blood-based immune correlatives are planned. Clinical trial information: NCT03396926.
Phase II trial of bintrafusp alfa in patients with metastatic MSI-H cancers following progression on immunotherapy.
Authors: Morris Van K. , Lam Michael , Wang Xuemei , Overman Michael J. , Johnson Benny , Kee Bryan K. , Wolff Robert A. , Dasari Arvind , Zorrilla Isabel R. , Tam Alda , Maru Dipen M. , Kopetz Scott
Published: January 2021

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Background: Microsatellite instability-high (MSI-H) tumors are characterized by deficient mismatch repair, high tumor mutation burden, and exceptional anti-tumor responses to immunotherapy. While durable disease control is often observed for advanced MSI-H cancers treated with immune checkpoint blockade (ICB), some patients (pts) experience treatment resistance. In melanoma and urothelial cancer, acquired resistance to ICB has been associated with increased signaling of the immunosuppressive TGF-β pathway. Bintrafusp alfa (BA) is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking PD-L1. Methods: In this phase II study (NCT03436563), pts with MSI-H metastatic solid tumors who had progressed on prior ICB were eligible. Pts received 1200 mg BA intravenously every 14 days. Paired tumor biopsies were collected for biomarker analysis. The primary objective was to estimate response rate (RR) per iRECIST. Median progression-free survival (PFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Adverse events (AEs) were assessed according to CTCAE v5.0. Results: 15 pts [arising from the colon/rectum (12), pancreas (1), duodenum (1), appendix (1)] were enrolled. Median duration of prior ICB before progression was 7.2 months (range, 1.8-24). All pts were evaluable for toxicity, and 14 for response. There was 1 grade 3 treatment-related AE (adrenal insufficiency) and 1 grade 5 treatment-related immune AE (hepatic failure). Median number of doses with BA was 4 (interquartile range, 2-4). There were 3 pts with stable disease and 11 with progressive disease as best response. RR was 0% (95% confidence interval (CI), 0-24%), and disease control rate was 21% (95% CI, 5-51%). Median PFS and OS were 1.8 months (95% CI, 1.5-5.7) and 9.1 months (95% CI, 5.3-not estimable), respectively. One pt with colorectal cancer demonstrated sustained stable disease (20.5 months) with BA. Conclusions: Dual inhibition of TGF-β and PD-L1 by BA did not demonstrate significant anti-tumor activity in the majority of pts with MSI-H metastatic cancer who had progressed on prior ICB. One pt did experience prolonged clinical benefit from BA. Ongoing correlative studies may inform on the effect of TGF-β and PD-L1 modulation by BA within the tumor microenvironment. Clinical trial information: NCT03436563.
Incidence of hypertension and proteinuria in patients treated with bevacizumab versus bevacizumab biosimilar
Authors: Man Yun , Yu Han , Mukherjee Sarbajit , Zalewski Olivia
Published: January 2021

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Background: Biosimilar products are proven to have no clinically meaningful differences in terms of safety and effectiveness with the reference product, however, to our knowledge, there is limited comparative analysis regarding adverse events for the bevacizumab biosimilars and the reference product. The purpose of this study was to evaluate the incidence of hypertension and proteinuria in patients treated with reference versus biosimilar bevacizumab to potentially streamline clinical management. Methods: A retrospective study was conducted with data consisting of gastrointestinal cancer patients who initiated either reference bevacizumab or biosimilar bevacizumab between January 2019 and July 2020 at Roswell Park Comprehensive Cancer Center. For the primary composite endpoint, Electronic Health Records were searched for the presence or absence of hypertension and proteinuria, as well as time to event analysis. In patients treated with bevacizumab biosimilar, demographics, hypertension and proteinuria related risk factors, bevacizumab containing chemotherapy regimen, and bevacizumab dosing were also identified to assess the risk association with hypertension and proteinuria. Results: 75 patients were included with 42 patients received bevacizumab and 33 patients received bevacizumab biosimilar. Hypertension occurred in 52.4% of reference bevacizumab group versus 36.4% of bevacizumab biosimilar group. Median time to hypertension is 84 days (bevacizumab) versus 24.5 days (bevacizumab biosimilar) following the first treatment (p= 0.0064). Proteinuria developed in 35.7% of reference bevacizumab patients compared to 30% of bevacizumab biosimilar patients. Median onset of proteinuria was 213 days (bevacizumab) versus 53.5 days (bevacizumab biosimilar) (p= 0.0022). In patients with a history of hypertension or underlying renal dysfunction, there was an increased risk of further hypertension and proteinuria, respectively. Conclusions: Higher risk of hypertension and proteinuria was associated with the bevacizumab reference product group, although not statistically significant. A shorter onset of hypertension and proteinuria was associated with the bevacizumab biosimilar group. Our results need further validation in larger cohorts, especially due to the more recent implementation of bevacizumab biosimilar products. [Table: see text]
Outcomes of isolated distant lymph node metastases in colorectal cancer.
Authors: Kalapurackal Mathai Vinod , Aung Soe Yu , Wong Vanessa , Dunn Catherine , Shapiro Jeremy David , Jalali Azim , Wong Rachel , Lee Margaret , Tie Jeanne , Ananda Sumitra , Kosmider Suzanne , Lim Stephanie Hui-Su , Caird Susan , Burge Matthew E. , Dean Andrew Peter , Gibbs Peter , Nott Louise M.
Published: January 2021

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Background: The optimal management of isolated distant lymph node metastases (IDLNM) in metastatic colorectal cancer (mCRC) is not clearly established. Small case series and prior data from the TRACC (Treatment of Recurrent and Advanced Colorectal Cancer) registry support the use of radical treatment with curative intent (local resection, chemo-radiation or stereotactic radiotherapy), which may lead to better outcomes in mCRC patients with IDLNM. Aims: This study investigates the clinical characteristics and outcomes of mCRC patients with IDLNM treated with systemic therapies plus locoregional therapy with curative intent versus systemic therapies with palliative intent. Methods: Clinical data were collected and reviewed from the TRACC registry, a prospective, comprehensive registry for mCRC from multiple tertiary hospitals across Australia from 01/07/2009 to 30/06/2020. Clinicopathological characteristics, treatment modalities and survival outcomes were analyzed in patients with IDLNM and compared to patients with other organ metastases. Fisher exact test was used for significance tests and Kaplan Meier curves for survival analyses. Results: Of 3408 mCRC patients with a median follow-up of 38.0 months, 93 (2.7%) were found to have IDLNM. Compared to mCRC with other organ metastases, patients with IDLNM were younger (mean age: 62.1 vs 65.6 years, p=0.0200), more likely to have metachronous disease (57.0% vs 38.9%, p=0.0005), be KRAS wild-type (74.6% vs 53.9%, p=0.0012) and BRAF mutant (12.9% vs 6.2%, p=0.0100). There was no overall survival difference between with IDLNM and those with other organ metastases (median OS 27.24 vs 25.92 months, p=0.2300). Twenty-four patients (25.8%) with IDLNM received treatment with curative intent, with a trend towards improved overall survival compared to those with other organ metastases treated with curative intent (73.5 vs 62.7 months, p=0.8200). Amongst mCRC patients with IDLNM, those who received treatment with curative intent had a significantly better overall survival than those treated with palliative intent (73.5months vs 23.2 months, p=0.0070). Conclusions: Our findings suggest that there are differences in the patterns of presentation of IDLNM and other organ metastases. Radical treatment with curative intent options should be considered for mCRC patients with IDLNM where appropriate.