bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regorafenib, ipilimumab, and nivolumab (RIN) in chemotherapy-resistant MSS metastatic colorectal cancer (mCRC).
Authors: Fakih Marwan , Sandhu Jaideep Singh , Lim Dean , Li Sierra , Wang Chongkai 
Published: January 2023

110 Background: We recently reported on the activity of regorafenib (R), ipilimumab (I) and nivolumab (N) (RIN) in microsatellite stable (MSS) mCRC. Here, we describe mature efficacy data at the recommended phase 2 dose (RP2D) and the results of a new escalation (ESC) cohort of 40 mg to 80 mg regorafenib. Methods: Patients (pts) with chemotherapy resistant MSS mCRC received RIN at (R) at 80 mg QD x 21 days in 4-week(w) cycle, (I) at 1mg/kg Q6w and (N) at 240 mg Q 2w. If no more than 1 dose limiting toxicity (DLT) was noted in 6 evaluable pts, an expansion cohort was assessed at that dose level. Following RP2D establishment and given the increased rate of transient skin toxicity on cycle (C) 1, the protocol was amended to explore a 10-pt cohort with 40 mg/day (R) on C1 with escalation to 80mg/day on C2+. Results: 39 pts with chemotherapy resistant MSS mCRC were enrolled. 29 pts enrolled on the RP2D and 10 pts at the amended 40 to 80mg cohort. At the RP2D and ESC cohorts, 7 and 3 pts had liver metastases (LM), respectively. No significant clinical activity was noted in LM pts (ORR = 0%, median progression free survival (mPFS) = 2 months (mo)). Overall response rate (ORR), disease control rate (DCR), mPFS, median overall survival (OS) in the 22 pts with non-LM (NLM) pts in the RP2D and ESC cohorts were 36% (41% iRECIST), 68% (82% iRECIST), 5.0 mo (6.0 mo iRECIST), > 22 mo (not reached) and 0%, 57% (71.4% iRECIST), 4 mo (4 mo iRECIST), and > 10 mo (not reached). 6/22 NLM at the P2RD remain without PD at 22 mo and beyond. All 7 NLM pts in the ESC cohort progressed by 7 mo from enrollment. ctDNA (Guardant 360) assays were available at baseline and at 4-6 weeks in 23/39 pts. Early ctDNA clearance was confirmed in 8/17 pts at RP2D (4PR and 4SD > 6 mo; mPFS = 11 mo) and 2/6 pts at the ESC cohort (PFS 4.5 mo and 7mo). An ESC vs. RP2D strategy mitigated skin rash (10% vs. 38% grade (G) 3; 20% vs. 66% any G). Other immune related ≥ G3 toxicities are summarized. Conclusions: RIN (80/1/240) has substantial activity in MSS NLM mCRC patients. An ESC strategy of 40/1/240 to 80/1/240 on C2+ reduced transient skin rash and other immune-mediated toxicities but was associated with less favorable clinical outcome. These data suggest that a starting R dose of 80 mg is important in priming the immune response to RIN. The RP2D of 80/1/240 mg is recommended for further investigation in NLM mCRC. Clinical trial information: NCT04362839 . [Table: see text]
A phase1b study of navicixizumab plus FOLFIRI in second-line treatment of patients with metastatic colorectal cancer.
Authors: Lim Kian-Huat , Iglesia Michael , Culm Kerry , Koustenis Andrew G. , Mockbee Colleen M. , Mathew Lynn , Fakih Marwan , Garrido-Laguna Ignacio , Krauss John C. 
Published: January 2023

111 Background: Navicixizumab is an anti-delta-like ligand 4 (DLL4)/vascular endothelial growth factor bispecific antibody which has shown promising preclinical and clinical activity in multiple tumor types. The blockade of DLL4, a transmembrane protein acting as a ligand for Notch receptors 1 and 4, causes tumor differentiation and reduction in cancer stem cells, as well as repolarization of the tumor microenvironment. Methods: We conducted a phase 1b single-arm dose escalation study combining navicixizumab with FOLFIRI or FOLFOX as second line treatment for patients with metastatic colorectal cancer (CRC). Patients were dosed either at 3 or 4 mg/kg intravenously once every 2 weeks (Q2W). The primary endpoint was the maximum tolerated dose of navicixizumab in combination with FOLFOX or FOLFIRI. Results: Between December 2016 and August 2018, 15 patients received navicixizumab plus FOLFIRI. Median patient age was 55 years, and nine of 15 patients were female (60%). Three patients were enrolled in the 3 mg/kg dose-escalation cohort, 2 patients were enrolled in the 4-mg/kg dose-escalation cohort, and 10 patients were enrolled in the 3 mg/kg dose expansion cohort. No DLTs were observed in this study. The median duration of navicixizumab therapy was 127 days. Hypertension was the most frequent all-grade treatment-related adverse event reported (12 of 15 patients, 80%), followed by fatigue (8 of 15 patients, 53.3%). Grade 3 hypertension was reported in 3 patients (20%). Eight of the 15 patients (53.3%) experienced at least one serious adverse event, resulting in discontinuation of study for 6 (40%) patients. One patient had a bowel perforation. One patient (3 mg/kg cohort) experienced a treatment-related grade 5 cardiopulmonary arrest resulting in death. The best overall response was partial response in three patients (20%). Eleven patients (73.3%) had stable disease and one (6.7%) experienced disease progression. Conclusions: This study was stopped early to focus on the development of navicixizumab in ovarian cancer. Although the disease control rate was promising, further evaluation is needed to determine whether navicixizumab delivers efficacy greater than chemotherapy alone and assess tolerability of this regimen. [Table: see text]
Efficacy of adjuvant fluoropyrimidine with or without oxaliplatin therapy in older adults with mismatch repair deficient stage III colorectal cancer.
Authors: Sears Jerod J , Hu Zishuo Ian , Liu Jingxia , Ballentine Samuel 
Published: January 2023

112 Background: Standard adjuvant chemotherapy regimens for Stage III colorectal cancer (CRC) include FOLFOX/CAPOX, 5-FU/capecitabine, or observation alone. There is uncertainty around the therapeutic benefit of adding oxaliplatin to fluorouracil in older adults over the age of 70 with Stage III CRC, including in those with mismatch repair–deficient (MMR-D) CRC. In this single institutional study, we evaluate progression free survival (PFS) across a 12-year period in patients who receive FOLFOX/CAPOX or 5-FU/capecitabine compared to active surveillance in older adults with MMR-D Stage III CRC. Methods: We identified patients diagnosed with MMR-D Stage III CRC after the age of 70 who received care at our institution and affiliates between 2005-2019. We performed a retrospective chart review of patient outcomes during the 12-year follow up period based on chemotherapy regimen to determine PFS. Patients without MMR-D staining performed at initial time of diagnosis had MMR protein immunohistochemistry performed currently and included in the analysis. Results: Among patients with MMR-D stage III CRC, 50%, 62.5%, and 76% of patients were alive at the end of year 12 with no disease progression in the observation, 5-FU/capecitabine, and FOLFOX/CAPOX groups. The PFS probabilities at one year are 69.6%, 87.5%, and 87.0%, and at five years are 41.8%, 62.5%, and 87.0% in these groups, respectively. Finally, there was a statistically significant difference (P=0.039) in PFS across all chemotherapy regimens in the MMR-D cohort. Conclusions: Based on this study, older adult patients with stage III MMR-D colorectal cancer have an improved progression free survival when treated with oxaliplatin containing chemotherapy compared to active surveillance alone. [Table: see text]
Final analysis of a prospective controlled trial of the efficacy of uracil and tegafur/leucovorin for stage II colon cancer with risk factors for recurrence using propensity score-based methods (JFMC46-1201).
Authors: Kondo Ken , Sadahiro Sotaro , Sakamoto Kazuhiro , Tsuchiya Takashi , Takahashi Takao , Ohge Hiroki , Sato Toshihiko , Ogata Yukata , Baba Hideo , Itabashi Michio , Ikeda Masataka , Hamada Madoka , Maeda Kiyoshi , Masuko Hiroyuki , Takahashi Keiichi , Sakamoto Junichi , Kusano Mitsuo , Hyodo Ichinosuke , Taguri Masataka , Morita Satoshi 
Published: January 2023

117 Background: The usefulness of adjuvant chemotherapy for stage II colon cancer with high-risk factors for recurrence has not been established. Methods: This was a prospective, non-randomized controlled study based on patients’ selection of treatment options, including randomized therapeutic decision-making. High-risk factors were defined as having at least one of the following factors: T4, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, and < 12 dissected lymph nodes. UFT (300 mg/m2/day) plus LV (75 mg/day) were orally administered for 6 months after surgery. The primary endpoint was disease-free survival (DFS) after adjusting for risk factors using propensity sore matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. The secondary endpoints were overall survival (OS) and safety. Results: 1902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively between May 2012 and April 2016. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Eligible patients were divided into two groups: A, patients who selected surgery alone (n = 641); B, patients who selected UFT/LV treatment (n = 1239). Of the eligible patients, 402 in group A and 804 in group B were propensity score-matched. The 5-year DFS rate (95% confidence interval) was significantly higher in group B (76.3% [73.1-79.1]) than in group A (68.8% [63.9-73.2]) {hazard ratio [HR] 0.66 [0.51–0.84, P = 0.0008]}. The 5-year OS rates were not significantly different between group B and group A [HR 0.74 (95% CI 0.50–1.10, P = 0.1391)]. Using IPTW, significantly higher 5-year DFS [HR 0.71 (95% CI 0.59–0.86, P = 0.0006)] and overall survival [HR 0.66 (95% CI 0.49–0.90, P = 0.0122)] rates were observed in group B compared with group A. Multivariate analysis revealed that male sex, over 70 years old, T4, < 12 dissected lymph nodes, and no adjuvant chemotherapy were significant risk factors for recurrence. Conclusions: Adjuvant chemotherapy with UFT/LV significantly improves DFS. Oral UFT/LV as adjuvant chemotherapy shows efficacy with an acceptable safety profile for stage II colon cancer with risk factors. Clinical trial information: UMIN000007783 .
Modified (m)-FOLFOXIRI plus cetuximab versus m-FOLFOXIRI plus bevacizumab as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer: Survival analysis of the phase II randomized DEEPER trial by JACCRO.
Authors: Sunakawa Yu , Shiozawa Manabu , Watanabe Takanori , Ota Hirofumi , Yasui Hisateru , Yabuno Taichi , Tei Mitsuyoshi , Kochi Mitsugu , Manaka Dai , Ohori Hisatsugu , Yamaguchi Tatsuro , Sagawa Tamotsu , Kotaka Masahito , Kubota Yutaro , Sekikawa Takashi , Nakamura Masato , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi , Tsuji Akihito 
Published: January 2023

120 Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .
Prognostic and predictive impact of metastatic organ involvement on maintenance therapy in advanced metastatic CRC: Analysis of patients treated within the PanaMa trial (AIO KRK 0212).
Authors: Karthaus Meinolf , Sommerhäuser Greta , Kurreck Annika , Beck Alexander , Fehrenbach Uli , Fruehauf Stefan , Graeven Ullrich , Müller Lothar , Koenig Alexander , Fischer von Weikersthal Ludwig , Goekkurt Eray , Haas Siegfried , Stahler Arndt , Heinemann Volker , Held Swantje , Alig Annabel Helga Sophie , Kasper Stefan , Stintzing Sebastian , Trarbach Tanja , Modest Dominik Paul 
Published: January 2023

127 Background: Despite molecular selection, patients with RAS wildtype mCRC represent a heterogeneous population, including different metastatic patterns and number of organs involved. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial. Methods: The study population was stratified according to number of organs involved and also to different patterns including liver metastases alone or in combination with additional organs. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints (i.e. progression-free survival (PFS) and overall survival (OS) of maintenance therapy) in the aforementioned populations. Results: Of 248 patients (pts) receiving maintenance therapy, 133 pts had a one-metastatic site disease (53.6%). Of those, 102 pts had liver-only metastases. Furthermore, liver metastases plus one additional involved organ was observed in 61/248 patients (24.6%), and liver metastases plus two or more organs in 40/248 patients (16.1%). In general, one organ disease was associated with favourable PFS of maintenance therapy compared to patients with ≥2 organs involved (HR 0.68, 95% CI 0.52–0.88; P = 0.004). A predictive impact of disease spread in terms of pmab-containing maintenance therapy was present for the PFS of maintenance therapy in patients with ≥ 2 organ disease (HR 0.58, 95% CI 0.39–0.86; P = 0.006) unlike in patients with only one-organ disease (HR 0.83, 95% CI, 0.57-1.21; P = 0.332) and also specifically in patients with a 2-organ disease including the liver (HR 0.57, 95% CI 0.33–0.99; P = 0.046). Conclusions: Consistent with previous reports, organ spread has prognostic impact in mCRC. The efficacy of more intensive maintenance therapy (including pmab and 5-FU/FA) is predominantly seen in patients with more than one organ involved in the metastatic spread, while less striking effects were seen in patients with only one organ disease. These data may support clinical decisions when EGFR-based maintenance therapy is considered. Clinical trial information: NCT01991873 .
The EPOCH trial: Identifying key patient subgroups to optimize treatment planning.
Authors: Harris William P. , Salem Riad ,   on behalf of the EPOCH Investigators
Published: January 2023

130 Background: The primary objective of the original EPOCH trial was to evaluate the potential benefit of adding transarterial radioembolization (TARE) with yttrium-90 glass microspheres to second-line chemotherapy (chemo) versus chemo alone in patients with liver-dominant metastatic colorectal cancer (mCRC). Randomization was stratified by key prognostic factors, including KRAS status; however, it did not account for ECOG status and baseline CEA levels. We present post-hoc analyses investigating the impact of prognostic factors on primary and secondary endpoints to help optimize patient selection. Methods: EPOCH was a 1:1 randomized, open-label, global, multicenter Phase 3 trial. Primary endpoints were progression-free survival (PFS) and hepatic PFS (hPFS). Overall survival (OS) and time to deterioration of quality of life (TTDQOL) were secondary. Post-hoc analyses of the following subgroups were performed: Subgroup A (excluding patients with both ECOG=1 and CEA≥35ng/mL) and Subgroup B (patients with KRAS wild-type and either ECOG=0 or CEA<35ng/mL). Kaplan-Meier analyses, hazard ratios (HRs) and log-rank tests were used to compare outcomes between TARE plus chemo and chemo only groups. Results: In Subgroup A, 160 (75.1%) patients were randomized to chemo only, versus 143 (66.5%) to the TARE arm. In Subgroup B, 91 (42.7%) patients were randomized to chemo only, versus 77 (35.8%) to the TARE arm. Results are shown for PFS, hPFS, OS, and TTDQOL in the intent-to-treat population. In both subgroups A and B, PFS, hPFS, and TTDQOL were significantly improved for the TARE plus chemo arm as compared to the chemo only arm; no OS difference was found. Conclusions: Careful patient selection using multiple prognostic factors is necessary to identify those who will benefit most from TARE with second-line chemo. Prognostic factors were important in identifying the level of benefit seen in patients treated with TARE and chemo versus chemo alone. Clinical trial information: NCT01483027 . [Table: see text]
SOX plus bevacizumab versus SOX plus cetuximab as initial treatment of recurrent advanced colorectal cancer with wild-type KRAS (MCSGO-1107 study): A phase II randomized study.
Authors: Okamura Shu , Nishizawa Yujiro , Kagawa Yoshinori , Imasato Mitsunobu , Miyake Masakazu , Ohara Nobuyoshi , Ide Yoshihito , Nonaka Ryoji , Tamai Koki , Konishi Ken , Kato Takeshi , Sawada Genta , Tei Mitsuyoshi , Satoh Taroh , Miyoshi Norikatsu , Uemura Mamoru , Takahashi Hidekazu , Murata Kohei , Doki Yuichiro , Eguchi Hidetoshi 
Published: January 2023

136 Background: Although clinical outcomes of chemotherapy in patients with locally advanced or metastatic colorectal cancer (CRC) have improved over the last decade, the standard-of-care chemotherapy regimens for patients with unresectable RAS wild-type CRC remain to be discussed. The aim of this study was to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated, unresectable, locally advanced, or metastatic CRC with wild-type KRAS. Methods: This phase II, randomized, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated, unresectable, locally advanced, or metastatic CRC with wild-type KRAS. Forty-five patients were enrolled in this study between February 2012 and October 2016. Results: The overall response rate (ORR) for the SOX+B-mab group was 59.1%, whereas that for the SOX+C-mab group was 43.5% (p = 0.29). The disease control rate (DCR) for the SOX+B-mab group was 90.9%, whereas that of the SOX+C-mab group was 91.3% (p = 0.96). For all patients, median OS were 25.3 months (95% CI: 16.5–39.4 months) in the SOX+B-mab group and 15.5 months (95% CI: 7.30–30.4 months, p = 0.167) in the SOX+C-mab group. Median PFS were 11.7 months (95% CI: 7.37–18.2 months) in the SOX+B-mab group and 5.5 months (95% CI: 3.36–10.1 months, p = 0.077) in the SOX+C-mab group. In the SOX+B-mab group, OS and PFS were not significantly different with and without early tumor shrinkage (ETS). However, in the SOX+C-mab group, patients with ETS had significantly better OS (30.4 months [95% CI: 8.0–44.3 months, p = 0.032]) and PFS (12.0 months [95% CI: 5.1–19.7 months, p = 0.003]) than those without ETS. Conclusions: The safety and efficacy of SOX+B-mab and SOX+C-mab as initial treatment for unresectable CRC with wild-type KRAS were almost the same. ETS was more correlated with PFS in the SOX+C-mab group than in the SOX+B-mab group, suggesting consideration of treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. Clinical trial information: UMIN000006706 .
Updated results from ALTER-C001 study: Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC.
Authors: Yan Jin , Han Yunwei , Zhang Li , Jin Yongdong , Sun Hao 
Published: January 2023

137 Background: The standard first-line therapy followed by maintenance treatment is an optional approach to balance the efficacy and toxicity for metastatic colorectal cancer (mCRC). In general, this approach had been seen PFS benefit in some trials, but probably lack of OS benefit, which indicating that new regimens needed to be explored. Anlotinib, a novel multi-targeted TKI, significantly prolonged the PFS of refractory mCRC in a phase III clinical trial (NCT02332499). Previous results of this study exhibited antitumor efficacy and manageable toxicity for mCRC. Here we report an update results with a longer follow up. Methods: 29 patients with unresectable mCRC, aged 18-75, without prior systemic treatment and ECOG performance status 0-1 would be prospectively included. Anlotinib 10mg and capecitabine 1000mg/m2 was given orally for 14 days in 3-week cycles; oxaliplatin 130mg/m2 was given by intravenous infusion on day 1 in 3-week cycles. After 6 cycles of induction therapy, patients would receive anlotinib (12mg, po, d1~14, q3w) until disease progression or intolerable adverse events. The primary endpoint was PFS. Secondary endpoints included ORR, DCR, DOR and safety. Results: At data cut-off date (June 30, 2022), a total of 31 patients were enrolled, the median age was 57 years, 23 (74%) were males, ECOG PS 0/1 was 18 (58%)/13 (42%), 28 (90%) had more than one metastatic tumor. Among them, 24 patients were available for efficacy assessment. The median PFS was 8.28 months (95% CI: 6.29-10.27) and the median DOR was 6.01 months (95% CI: 4.59-7.43). The ORR was 62.5% (95% CI: 40.6-81.2) and DCR was 91.7% (95% CI: 73.0-99.0) in best overall response assessment, of which the longest duration of treatment was 17.5 months. The treatment-related adverse events (TRAEs) occurred in 31 pts (100.0%) including nausea (58.1%), vomiting (51.6%), neutropenia (51.6%), leukopenia (35.5%), hypertension (35.5%). The Grade 3/4 TRAEs were neutropenia (12.9%), hypertension (12.9%), lipase elevated (9.7%), hypertriglyceridemia (6.5%), and leukopenia (3.2%). Conclusions: The updated results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy as maintenance therapy showed a promising clinical benefit and favorable safety profile for mCRC, and the results needed to be confirmed in trials continued subsequently. Clinical trial information: ChiCTR1900028417 .