bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

7 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

77 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

79 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

83 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

84 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.
PARADIGM study: A multicenter, randomized, phase III study of mFOLFOX6 plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer.
Authors: Yoshino Takayuki , Uetake Hiroyuki , Tsuchihara Katsuya , Shitara Kohei , Yamazaki Kentaro , Watanabe Jun , Oki Eiji , Sato Takeo , Naitoh Takeshi , Komatsu Yoshito , Kato Takeshi , Mori Ikuo , Yamanaka Kazunori , Hihara Masamitsu , Soeda Junpei , Yamanaka Takeharu , Akagi Kiwamu , Ochiai Atsushi , Muro Kei 
Published: January 2021

85 Background: The optimal choice of monoclonal antibodies (mAbs) for first-line treatment in patients (pts) with RAS ( KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC) remains controversial. The meta-analyses of subgroup analyses in phase III studies of pts with KRAS exon 2 wild-type mCRC suggested a longer overall survival (OS) with an anti-EGFR mAb over bevacizumab in pts with RAS wild-type mCRC or with left-sided primary tumors. However, there has been no prospective study comparing the two mAbs in these pt populations. This randomized phase III study was originally designed to demonstrate the superiority of panitumumab versus bevacizumab, both in combination with mFOLFOX6, for RAS wild-type mCRC, but we have revised the protocol to analyze efficacy in pts with a left-sided primary tumor as the primary (final) analysis. Methods: Eligible pts are aged 20-79 years with histologically/cytologically confirmed RAS wild-type chemotherapy-naive mCRC, and ECOG performance status 0-1. Between May 29, 2015 and Jun 8, 2017, 823 pts were randomized 1:1 to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6 by the minimization method and the randomisation was stratified by institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). The primary analysis was revised to adopt a hierarchical testing procedure; we first compare OS between the two arms in left-sided primary tumor population, and only if there is statistically significant difference, then ITT population analysis will be performed. In this revised plan, the expected number of deaths is 420 in the left-sided population to provide 80% power to detect an OS hazard ratio of 0.74 at a one-sided significance level of 0.02101 determined on the alpha spending function approach after one interim analysis. A large-scale exploratory biomarker substudy to identify potential biomarker candidates using tumor tissue and circulating tumor DNA is also underway (Clinical trial no.: NCT02394834). The data cut off for the primary analysis is expected to be during 1Q 2021. Results: Results are expected in 2021. Conclusions: Results are expected in 2021. Clinical trial information: NCT0239475.
Demographics and clinical characteristics of metastatic colorectal cancer patients treated with bevacizumab-awwb in real-world oncology clinics.
Authors: DeClue Richard , Rhodes Whitney , Accortt Neil A , Jin Ran , Sandschafer Darcie , Wertz Debra , Patel Kashyap B. 
Published: January 2021

90 Background: Bevacizumab-awwb is a biosimilar to bevacizumab approved by the FDA based on evidence obtained in a phase 3 study in non-squamous non-small cell lung cancer. The present real-world evidence study evaluated experience with bevacizumab-awwb (launched 07/19/2019) in patients with metastatic colorectal cancer (mCRC) in a real-world oncology setting to gain insight into biosimilar use for a bevacizumab-awwb approved indication lacking clinical trial data. Methods: This retrospective analysis identified patients, age ≥ 18 years (y), within existing medical records diagnosed with mCRC who initiated bevacizumab-awwb as first- or later-line treatment. Patients were identified from the ConcertAI Definitive Oncology Dataset, a consolidated EMR database of CancerLinQ and Vector Oncology, representing geographically diverse practice locations, including rural and urban centers, within the United States. Results: A total of 304 patients were eligible for this analysis. First use of bevacizumab-awwb in mCRC occurred within 20 days of product launch. Most patients (n = 262, 86%) were treated in a community setting and more than half of all eligible patients received prior bevacizumab (n = 162, 53%). Among 42 patients treated in academic settings 29 (69%) had not received bevacizumab prior to receiving bevacizumab-awwb. In the 162 patients with prior bevacizumab use, 134 (83%) had no recorded disease progression between the last bevacizumab infusion and start of bevacizumab-awwb. Among these 134 patients, 111 (83%) received bevacizumab-awwb within 28 days of last bevacizumab dose. Demographic and clinical characteristics of patients stratified by prior bevacizumab use were comparable (Table). In both subgroups most patients had an adenocarcinoma histological diagnosis with primary tumors in the rectum or sigmoid colon. Overall, most frequent comorbidities of mCRC patients were diabetes (24%), chronic obstructive pulmonary disease (10%), and renal disease (8%). Conclusions: Patients with mCRC who received bevacizumab-awwb in this real-world oncology setting in the first year post product launch were similar regardless of prior bevacizumab use. Among patients with prior bevacizumab use, 83% continued with bevacizumab-awwb in the same line. In the subset of patients without progression post bevacizumab, most received bevacizumab-awwb within 28 days of last bevacizumab dose demonstrating use of bevacizumab-awwb in new and continuing patients. [Table: see text]