bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase ib trial of assessing the safety and preliminary efficacy of a combination therapy of geptanolimab (GB 226) plus fruquintinib in patients with metastatic colorectal cancer (mCRC).
Authors: Bai Yuxian , Xu Nong , An Shan , Chen Wenhui , Gao Chao , Zhang Deyong 
Published: June 2021

e15551 Background: A combination of anti-vascular endothelial growth factor receptor(anti-VEGFR) and anti-programmed cell death-1/ligand 1 (PD-1/L1) may synergize with each other and lead to better anti-tumor efficacy. We aimed to assess the safety and preliminary efficacy of combination therapy with geptanolimab (GB226, a highly selective, fully human monoclonal antibody PD-1 mAb) plus fruquintinib (a VEGFR inhibitor) in previously treated metastatic colorectal cancer (mCRC) patients. Methods: In this phase Ib trial, we enrolled mCRC patients who had failed one or two standard therapies. Patients were given geptanolimab (3mg/kg every 2 weeks) and fruquintinib (once daily for 21 days on/7 days off with planned dose cohorts of 3mg, 4mg, and 5mg) on a 28-day cycle. A standard 3+3 design was employed to determine the primary endpoints of the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) based on dose-limiting toxicities (DLT). Secondary endpoints included objective response rate (ORR), duration of response (DOR), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Results: By December 15, 2020, 15 patients were enrolled: 1 with MSI-H, 12 with MSS, and 2 with MS unknown. Ten out of 15 patients (66.7%) had received ≥2 previous lines of treatment including chemotherapy in combination with anti-EGFR (33.3%) or anti-VEGF (53.3%). Seven patients (46.7%) were found to have the PD-L1 combined positive score (CPS)≥1. Two DLTs (one patient with grade 3 ALT and AST elevation and one patient with grade 3 proteinuria) were identified in fruqintinib 5mg cohort (6 patients enrolled). No DLT was observed in either 3mg (3 patients enrolled) or 4mg (6 patients enrolled) cohorts. RP2D of this combination was identified as geptanolimab (3mg/kg, every 2 weeks) and fruquintinib (4mg, once daily for 21 days on/7 days off). In all evaluable patients, the overall ORR was 26.7% (4/15, 3 confirmed PR, 1 unconfirmed PR), and the ORR was 33.3% (2/6) in the RP2D group. The DCR for all evaluable patients was 80%, and the median PFS (mPFS) was 7.33 months (95% CI: 1.91 – NE). The median DOR and median OS was not reached at the data cut-off date. Among 12 patients with MSS, the ORR was 25.0% (3/12, 2 confirmed PR, 1 unconfirmed PR), DCR was 75% and mPFS was 5.45 months (95% CI: 1.84-9.66). All patients had at least 1 treatment related AE (TRAE). The common TRAE were proteinuria (46.7%), hypertension (46.7%), and elevated aspartate aminotransferase (40.0%). Grade 3 AEs were observed in 46.7% of patients and the most common grade 3 AE was hypertension (20.0%). No grade 4 and 5 TRAE was observed. Conclusions: The combination of geptanolimab and fruquintinib had manageable safety profiles and encouraging anti-tumor activity in mCRC patients. Clinical trial information: NCT03977090.
A phase II trial of pembrolizumab and poly-ICLC in patients with metastatic mismatch repair-proficient colon cancer.
Authors: Karki Nabin Raj , Bano Kulsum , Ramses Sadek , Nayak Asha 
Published: June 2021

e15552 Background: Single agent programmed cell death protein 1 (PD1) inhibitor is ineffective against mismatch repair proficient (MMRp) colon cancer with response rates in single digits. Polyinosinic-Polycytidylic (Poly-ICLC) is a synthetic double stranded ribonucleic acid that generates inflammatory response increasing epitope recognition, develops tumor reactive T cells and induces interferon production which increases PD-L1 expression. In this trial, we test the effectiveness of combination of poly-ICLC and pembrolizumab in MMRp metastatic colon cancer. Methods: In this open label, single arm, single institution, phase 2 study, we enrolled 12 MMRp metastatic colon cancer patients from 1/25/2019 to 2/10/2021. Eligible patients had histologically confirmed MMRp metastatic colon cancer, ECOG 1-2 and progression on at least 2 lines of therapy. Treatment (Tx) consisted of Pembrolizumab (200 mg q3 weeks) and poly-ICLC (2 mg twice weekly, 3 days apart) for 1 year of treatment. Tx continued until progression, discontinuation or withdrawal. The primary endpoint was objective response rate by RECIST 1.1. Secondary endpoints included duration of response, adverse event profiling, progression free survival (PFS) and overall survival (OS). Intention-to-treat analyses (ITT) included all patient receiving at least one dose of the study agent. Results: 12 patients with median age 68.5 years (range 54-75) and 33% (4/12) male had been enrolled till 2/10/2021. Objective response rate was 8.3% (1 patient had partial response). The duration of response was 196 days. Among these 12 patients, median PFS was 63.5 days and median OS was 196 days. Treatment related adverse events of any grade were reported in 12/12 (100%) patients with the most common toxicities being nausea, vomiting, anorexia, dehydration and dizziness. 3/12 (25%) had serious (grade ≥ 3) toxicities and one patient died after experiencing leukocytosis, dehydration and hyperbilirubinemia attributed to the trial drugs. Conclusions: Poly-ICLC was not effective in combination with pembrolizumab for MMRp metastatic colon cancer in 3rd line setting and it did not seem to improve response rates to immunotherapy. Novel strategies for stimulating immunogenicity of cold tumors are needed. Clinical trial information: NCT02834052.
Dual-targeted therapy with pyrotinib and trastuzumab for HER2-positive advanced colorectal cancer: Preliminary results from a multicenter phase 2 trial.
Authors: Yuan Ying , Fu Xianhua , Ying Jieer , Yang Liu , Fang Weijia , Han Weidong , Zhang Suzhan 
Published: June 2021

e15554 Background: HER2 is an emerging treatment target for colorectal cancer (CRC). Previous phase 2 trials have demonstrated the promising antitumor activity of dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab in HER2-positive metastatic CRC. Pyrotinib, a novel irreversible HER2/EGFR dual tyrosine kinase inhibitor, has been approved for breast cancer in 2018 in China. The antitumor effect of pyrotinib was also shown in other solid tumors, such as lung cancer and gastric cancer. The randomized phase 3 PHOEBE trial proved that the efficacy of pyrotinib was better than lapatinib when in combination with capecitabine in HER2-positive local relapsed or metastatic breast cancer. We reported preliminary results of pyrotinib plus trastuzumab in patients with HER2-positive advanced CRC from an ongoing multicenter phase 2 trial (NCT04380012). Methods: Patients with confirmed recurrent/metastatic CRC, HER2-positive disease, and ECOG performance status 0-2, received oral pyrotinib 400 mg once a day plus intravenous trastuzumab 8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks. The primary endpoint was objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. The data cutoff date was December 24, 2020. Results: From December 2019 to November 2020, a total of 11 patients were enrolled. The median age was 57 (range, 44-70) years and 73% (8/11) of patients were male. The number of prior therapy lines was 0, 1, and ≥2 in 1 (9%), 2 (18%), and 8 (73%) patients, respectively. One (9%) patient only showed HER2 overexpression, 7 (64%) showed HER2 amplification and overexpression, and 3 (27%) showed HER2 mutation and overexpression. The detection of co-mutations showed that 5 (45%) patients had KRAS mutations, 1 (9%) had NRAS mutation, and none had BRAF mutation. Three patients achieved partial response, with an ORR of 27% (3/11) in the total population, 50% (3/6) in KRAS wild-type patients, and 60% (3/5) in patients with wild type of both KRAS and NRAS, respectively. The disease control rate was 45% (5/11). The most common (occurring in at least 2 patients) grade ≥3 adverse event was diarrhea (73% [8/11]). Dose interruption owing to diarrhea occurred in 7 (64%) patients, and 5 (45%) patients reduced the dose to 320 mg due to diarrhea. No treatment-related death was observed. Conclusions: Pyrotinib combined with trastuzumab showed promising ORR with acceptable safety in patients with HER2-positive advanced CRC, suggesting a potential treatment option, especially in those without co-mutations. Clinical trial information: NCT04380012.
Updated results of ALTER-C002: Anlotinib combined with CAPEOX in first-line treatment of patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer.
Authors: Ding Ke-Feng , Liu Yue , Du Jinlin , Zhu Yuping , Liu Zhuo , Wang Jianping , Xu Dong , Li Jun , Liao Xiujun , Sun Lifeng , He Jinjie , Xiao Qian , Wang Jianwei , Cao Hongfeng , Cai Yibo , Cai Cheng , Jin Zhekang , Yuan Ying 
Published: June 2021

e15564 Background: Antiangiogenic therapy plus chemotherapy is one of the standard treatments in mCRC. Anlotinib, an oral small multi-targeted tyrosine kinase inhibitor targeting VEGFR 1/2/3, FGFR 1-4, PDGFR α/β and c-kit, has demonstrated prolonged PFS in refractory mCRC. This trial was conducted to evaluate the efficacy and safety of anlotinib combined with CAPEOX as first-line treatment for unresectable RAS/BRAF wild-type mCRC. Methods: Patients aged 18-75, with RAS/BRAF wild-type unresectable mCRC, without prior systemic treatment and ECOG status ≤ 1were enrolled in 3 hospitals in Zhejiang, China. Enrolled patients received capecitabine (850 mg/m2 p.o., bid, on day 1-14 every 3 weeks), oxaliplatin (130 mg/m2 i.v., on day 1 every 3 weeks) and anlotinib (12 mg p.o. qd, on day1-14 every 3 weeks) as inducing therapy. After 6 cycles of combined therapy, patients who achieve complete response (CR)/ partial response (PR)/ stable disease (SD) would receive capecitabine and anlotinib as maintenance therapy until tumor progression. The primary endpoint is objective response rate (ORR); secondary endpoints included safety, disease control rate (DCR) and progression-free survival (PFS). Results: From November, 2019 to February, 2021, 31 patients had been enrolled. 1 patient was excluded for refused treatment. By now, 27 patients received at least 2 cycles of treatment and were available for efficacy evaluation: 22 patients had partial response (PR), 5 patients had stable disease (SD). The ORR was 81.5% (95% CI: 61.9–93.7%), and DCR was 100% (95% CI: 87.2–100%).1 patient received radical surgery after 6 cycles of treatment. The median PFS has not been reached yet. The most common grade≥3 AEs included hypertension (45.2%), neutropenia (25.8%) and diarrhea (12.9%). No treatment-related deaths occurred. Conclusions: The combination of anlotinib and CAPEOX showed promising antitumor activity and manageable toxicity in unresectable RAS/BRAF wild-type mCRC. Furthermore, we are launching a phase 3, multicenter, double-blind trial to further assess the efficacy of this regimen. Clinical trial information: NCT04080843. [Table: see text]
Phase I dose-escalation study of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.
Authors: Fumet Jean-David , Hervieu Alice , Hennequin Audrey , Zanetta Sylvie , Bertaut Aurelie , Ghiringhelli François 
Published: June 2021

e15573 Background: Treatment of non-resectable metastatic colorectal cancer (mCRC) involves chemotherapy based on 5-fluorouracil, oxaliplatin and irinotecan and monoclonal antibodies targeting VEGF or EGFR. Rechallenge with oxaliplatin and irinotecan bi fractionation (FOLFIRI3) have previously shown efficacy in chemorefractory patients but desynchronized triplet chemotherapy was never tested. The aim of this study was to evaluate the safety and efficacy of a new regimen so-called: FOLFIRINOX-3 bevacizumab in chemorefractory mCRC. Methods: A phase I study to test bFOLFIRINOX 3 regimen was designed using Standard “3 + 3” design for dose escalation. Patients enrolled, >18years and ECOG 0 or 1, have a pathologically confirmed mCRC and experienced treatment failure after standard chemotherapy that include 5-fluorouracil, oxaliplatin and irinotecan. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg) plus simplified FOLFOX4 (folinic acid (400mg/m2), 5-fluorouracil (400mg/m2 bolus followed by 2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (administered before and after infusional 5-fluorouracil). Three irinotecan levels were planned at 60, 70 and 90 mg/m² (day 1 and day 3). Dose limiting toxicities (DLT) were identified during the first 2 cycles. Primary endpoint was assessment of maximum tolerable dose trough evaluation of acute toxicities (CTCAE v4.03). Secondary endpoints included objective response (RECIST 1.1), progression free survival, overall survival and late toxicity. Results: Thirteen patients received experimental treatment on this study. The RP2D was irinotecan 70mg/m² day 1 and day 3. Two patients experienced DLTs (G3 diarhea ) at dose level 90mg/m² and one DLT occured (G3 diarrhea) at 70mg/m² level. The most common drug-related adverse events (all grades) were fatigue (92.3%), diarrhea (76.9%), nausea (61.5%), peripheral neuropathy (61.5%), thrombopenia (46.1%) and anemia (15.3%). Among 11 response-evaluable patients, we noticed 4 partial responses, 7 stable disease and no progression as best response. Conclusions: The combination of bFOLFIRINOX-3 at the RP2D of 70mg/m² day 1 and day 3. was well tolerated and feseably. The regimen resulted in high response rate in chemorefractory metastatic colorectal cancer. Phase II is ongoing. Clinical trial information: NCT03795311.
Postoperative PET-CT in patients (pts) with pathological stage III colon cancer (CC): Interim results from the first prospective validation study.
Authors: Tschernichovsky Roi , Perl Gali , Finkel Inbar , Peretz Idit , Jacobi Oded , Sternschuss Michal , Ulitsky Olga , Kundel Yulia , Sulkes Aaron , Bernstine Hanna , Groshar David , Brenner Baruch 
Published: June 2021

e15599 Background: A substantial number of pts with pathological stage III CC recur despite the absence of metastatic disease on pre-operative CT. In a previous large retrospective study from our institution on 348 pts, we reported that early postoperative PET-CT modified the staging and management of 13.4% of assumed stage III CC pts. The aim of the current study was to prospectively validate these results. Methods: A prospective, single-center study of pts with pathological stage III CC who underwent early postoperative PET-CT between the years 2013-2021. Results: 83 pts were accrued and 81 (48.1% males, median age 66y) were evaluable for the primary endpoint i.e. PET-CT results. Pathological stage was IIIA, IIIB and IIIC in 7 (8.6%), 56 (69.1%) and 17 (21%) of pts, respectively. Median number of lymph nodes examined and of positive nodes were 17 (range, 9-134) and 2 (range, 0-15), respectively. Post-operative PET-CT findings were significant in 7 pts (8.6%): 4 pts (4.9%) were upstaged to stage IV, 2 (2.5%) were diagnosed with a second primary malignancy, and 1 (1.2%) was both upstaged and diagnosed with another cancer. Three additional pts (3.7%) are currently undergoing evaluation for suspicious PET-CT findings. At a median follow-up of 30.6 months (range, 6.2-92), 13 of the 71 pts with true stage III CC recurred; the estimated 3y disease-free survival rate was 81%. The estimated 5y overall survival rates for the entire cohort and for true stage III pts were 82% and 90%, respectively. Of the 5 pts found to have metastatic disease based on PET-CT findings, one is scheduled to undergo potentially curative surgical removal of a solitary liver metastasis. Conclusions: Interim results from the first prospective study to evaluate the impact of early postoperative PET-CT in pts with pathological stage III CC seem to support earlier retrospective data: the use of PET-CT in this setting changed the staging and management of 8.6% of pts, including the possibility for early detection of potentially curable metastatic disease. Additional data, with more pts and longer follow-up, will be presented at the meeting.
Association of colon adenocarcinoma in situ in polyp with subsequent colon cancer: A population-based retrospective study.
Authors: Wang Shuai , Jayarangaiah Apoorva , Kaur Anahat , Elrafei Tarek N. , Steinberg Lewis , Kumar Abhishek 
Published: June 2021

e15605 Background: Adenocarcinoma in situ (pTis) of the colon is defined as malignant cells confined within epithelium or mucosa. Since pTis is not invasive, polypectomy alone is usually adequate, especially if resection margins are cancer-free. We performed a population-based study to investigate the association of intrapolyp pTis and subsequent colon cancer. Methods: We queried the SEER database (1975-2017) for patients with pTis in adenoma. We further filtered patients with subsequent colon cancers. Standard incidence ratios (SIRs) were used to evaluate the excess risk of developing subsequent colon cancers comparing to the general population. Difference between patients who did or did not develop colon cancer were analyzed using Chi-square test. Results: A total of 15164 patients with pTis were identified. Among them, 736 (4.85%) patients developed subsequent colon cancer. Age ≥70 years, pTis in villous adenoma, polyp in hepatic flexure, splenic flexure, transverse colon, descending colon, and diagnosis year before 2000 were associated with increased risk of developing subsequent colon malignancy (all p< 0.05). Polypectomy comparing to colectomy (total, subtotal or partial) is associated with a higher rate of developing subsequent colon cancers ( p < 0.05). In patients with intrapolyp pTis, observation/expectation (O/E) of developing colon cancers are elevated to 4.76, 1.84, 1.66, and 1.28 within one year, 1-5 year, 5-10 year, and after ten years, respectively (all p< 0.05). O/E for the male and female is 1.80 and 1.63 (both p< 0.05); for the white and black is 1.64 and 2.21(both p< 0.05). Conclusions: Subsequent colon cancers developed in 4.85% of pTis patients. Excess risk of developing subsequent colon cancers is highest in the first year, and declines with time but persists beyond ten years. Male and black have the highest excess risk. Factors like older age, villous adenoma, location from hepatic flexure to descending colon, and polypectomy are associated with developing subsequent colon cancers.
The preliminary efficacy of KN026 (Anti-HER2 BsAb) in advanced gastric and gastroesophageal junction cancer patients with HER2 expression.
Authors: Xu Jianming , Zhang Yun , Wu Jun , Xu Nong , Ying Jieer , Xiang Xiaojun , Zhang Yanqiao , Wang Jianhong , Zhao Rusen , Ye Feng , Wu Qiong , Guo Baohong , Liu Yuchen , Liu Juan , Xing Shuning , Xu Ting 
Published: June 2021

e16005 Background: HER2 overexpression or amplification has been proven to be a validated therapeutic target for HER2-positive gastric and gastroesophageal junction cancer (GC/GEJ) in ToGA trial. However, there is a huge unmet medical need in the HER2-positive GC/GEJ patients who progressed or were refractory to trastuzumab treatment. In HER2 low expression patients, the benefit of novel HER2-targeted therapeutics, eg. Bispecifics, ADC and CAR-T, remain to be explored. Here we report the preliminary results of KN026, a bispecific antibody binds two distinct epitopes of HER2 receptors, in GC/GEJ patients with prior at least one line treatment. Methods: GC/GEJ patients who failed to ≥first-line treatment were enrolled into two cohorts according to HER2 overexpression (Cohort 1: IHC3+ or IHC 2+ ISH+) and low expression (Cohort 2: IHC 1+/2+ ISH- or IHC 0/1+ISH+), and treated by KN026 QW10mpkor Q2W(20mpk) or Q3W(30mpk) until progression of disease (PD) or intolerable toxicity or 2 years. Results: As of 2020/12/25, a total of 31 pts received KN026 treatment including 20 pts in Cohort 1 and 11 pts in Cohort 2. The median drug exposure period was around 20 wks and 6 wks in two Cohorts, respectively. Among 18 efficacy-evaluable pts in Cohort 1, 11 pts were stilling receiving treatment with 55.6% (10/18) ORR and 72.2% DCR (13/18). The 9-m PFS rate was 60.4% (95%CI: 24.4 to 83.5) in Cohort 1, while the DOR, mPFS and mOS were not reached. Of 9 pts receiving prior-HER2 treatment, the median time from the first dose of KN026 to last prior HER2 treatment was 55 days. The ORR was 44.4% (4/9) with 4.1m DoR, and DCR was 66.7% (6/9). The mPFS and mOS were 5.6m(95%CI:1.3 to NE) and 11.0m(95%CI: 1.4 to NE), respectively. In Cohort 2, two partial response was observed out of 9 efficacy-evaluable pts. The ORR and DCR were both 22.2% (2/9) with 1.4 m mPFS (95%CI: 1.0 to 5.9) and 9.6m mOS (95%CI: 3.0 to NE). The overall incidence of KN026 related adverse events was 87.1%, with 9.7% Gr 3 TRAE. The most common KN026-related treatment emergent adverse events (≥10% TRAE) were aspartate aminotransferase increased (n=8,25.8%), rash (n=6,19.4%), anaemia (n=5,16.1%),alanine aminotransferase increased (n=4, 12.9%) and weight decreased(n=4, 12.9%). The ≥Gr 3 TEAE that KN026 related were infusion related reaction(n=1, 3.2%), blood pressure increased (n=1, 3.2%), ureteral stricture with hydronephrosis (n=1, 3.2%). Conclusions: KN026 demonstrated promising efficacy in HER2 overexpressing GC/GEJ pts and in anti-HER2 treated GC/GEJ pts with a favorable safety profile. Clinical trial number: NCT03925974. Clinical trial information: NCT03925974.