bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1/1b trial of fruquintinib in patients with advanced solid tumors: Preliminary results of the dose expansion cohorts in refractory metastatic colorectal cancer.
Authors: Dasari Arvind , Hubbard Joleen M. , Eng Cathy , Yeckes-Rodin Heather , Ukrainskyj Stacey M , Yang Zhao , Schelman William R. , Kania Marek K. , Bekaii-Saab Tanios S.
Published: January 2022

93

Background: Fruquintinib (F) is a highly selective, novel, oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3. The phase (Ph) 3 FRESCO study (NCT02314819) that investigated F (5mg daily, 3 weeks (wks) on 1 wk off) showed improved median overall survival in patients (pts) with metastatic colorectal cancer (mCRC) in third line and beyond when compared to placebo (9.3 vs. 6.6 months); hazard ratio 0.65 (P < 0.001) and led to its approval in China. Methods: This is an ongoing Ph 1/1b open-label, dose escalation/expansion study conducted in the US. Here we present the preliminary safety and antitumor efficacy data from pts with refractory mCRC in Cohort (Coh) B (progressed on all standard therapies including TAS-102 [TAS] and/or regorafenib [R]) and in Coh C (did not receive TAS or R). Results: As of data cutoff on 27 July 2021, 81 mCRC pts had been treated (41 in Coh B and 40 in Coh C); median age of 57 years (range: 34─77), Caucasian (81.5%), female (44.4%), and ECOG PS 1 (59.3%). In Coh B, the median number of prior therapies was 5 (range: 3-9), 8 pts (19.5%) received R, 19 (46.3%) received TAS and 14 (34.1%) received both R and TAS. In Coh C, the median number of prior therapies was 4 (range: 1-10). Five pts remain on treatment; reasons for treatment discontinuation included: 56 pts (69.1%) due to progressive disease or death, 8 pts (9.9%) due to adverse events (AE), and 12 pts (14.8%) due to withdrawal of consent or physician decision. The median duration of F treatment was 4.4 months (range: 0.7– 20.0) in Coh B and 3.7 months (range: 0.02-14.3) in Coh C. The most frequently reported AEs of any grade in Coh B were fatigue (53.7%), proteinuria (51.2%), and hypertension (HTN; 48.8%). In Coh C the most frequently reported AEs of any grade were HTN (75.0%), proteinuria (40.0%), and myalgia (32.5%). Hand-foot syndrome (HFS) was reported in 29.3% of Coh B pts and 22.5% of Coh C pts. The disease control rate [DCR] was 68.3% in Coh B (1 partial response [PR] and 27 stable disease [SD]) and 59.5% for the 37 patients with at least one post-baseline tumor assessment in Coh C (2 PRs and 20 SDs). Conclusions: F is generally well-tolerated in heavily-pretreated pts with refractory mCRC. Evidence of antitumor activity was observed in cohorts B and C. The multi-cohort dose expansion is ongoing. F is being further investigated in refractory mCRC in a global Ph 3 study (NCT04322539). Clinical trial information: NCT03251378.
Oxaliplatin in metastatic colorectal cancer: Does hepatic arterial infusion reduce sensitive neuropathy compared to the intravenous route?
Authors: Valery Marine , Tanguy Marie Laure , Boige Valérie , Smolenschi Cristina , Hollebecque Antoine , Fuerea Alina , Klotz-Prieux Caroline , Benhaim Leonor , Debaere Thierry , Gelli Maximiliano , Tselikas Lambros , Ducreux Michel , Malka David
Published: January 2022

95

Background: Oxaliplatin, a major drug in metastatic colorectal cancer (MCRC), is responsible for a cumulative and limiting peripheral neuropathy (PN). Hepatic arterial infusion (HAI) chemotherapy, which makes sense in cases of exclusive or predominant liver metastases, increases the intratumor concentration of the administered drug(s) to improve efficacy and limit systemic toxicity. Methods: We compared the frequency and severity of NP in oxaliplatin-naive patients with MCRC included in trials that evaluated treatment with oxaliplatin administered either by HAI (CHOICE, OSCAR, and PACHA-01 trials) or by intravenous (IV) route (FFCD 2000-05 trial). The primary endpoint was the occurrence of clinically significant NP (grade 2-4) according to the cumulative dose of oxaliplatin received. The secondary endpoints were the occurence of severe NP (grade 3-4) and time to onset of NP. Results: 342 patients were included (IV oxaliplatin: 300; HAI: 42). 180 patients in the IV group (60%) and 24 patients in the HAI group (57%) developed clinically significant NP, with no significant difference between the 2 groups (p = 0.85). 95 patients in the IV group (32%) and 8 patients in the HAI group (19%) developed severe NP, with no significant difference between the 2 groups (p = 0.082). NP appeared earlier in the HAI group, with more treatment discontinuations for neurotoxicity. Conclusions: The administration of oxaliplatin HAI rather than IV in the treatment of MCRC does not seem to reduce the incidence, precocity and severity of NP.
Nivolumab plus ipilimumab (N+I) in patients (pts) with colorectal cancer (CRC) with high tumor mutational burden (hTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Vaccaro Gina M. , Rothe Michael , Mangat Pam K. , Garrett-Mayer Elizabeth , Hwang Jimmy J. , Alese Olatunji B. , Khalil Maged F. , Hameed Muhammad Khurram , Duvivier Herbert Leon , Cannon Timothy Lewis , Grantham Gina N. , Halabi Susan , Schilsky Richard L.
Published: January 2022

107

Background: TAPUR is a phase II basket study evaluating the anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with hTMB treated with N+I are reported. Methods: Eligible pts had advanced CRC, no available standard treatment options, measurable disease, ECOG performance status (PS) 0-2, adequate organ function and no prior immune checkpoint inhibitor treatment. PDL-1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. hTMB was defined a priori as ≥9 mutations/megabase (Muts/Mb) reported by a FoundationOne test (n=7) or other tests (n=5) if approved by the Molecular Tumor Board. Pts received N 1 mg/kg IV every 3 weeks (wks) for 4 doses in combination with I 3 mg/kg every 3 wks for 4 doses. N was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Primary endpoint was disease control (DC), defined as complete (CR) or partial (PR) response, or stable disease at 16+ wks (SD 16+). Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 has DC, 18 more pts are enrolled; otherwise, the study stops for futility. If ≥7 of 28 pts has DC, the null DC rate is rejected. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 12 pts (9 male) with CRC with hTMB in tissue biopsy were enrolled from February 2018 to May 2020; 2 pts were not evaluable and excluded from efficacy analyses. All pts were evaluated for toxicity. TMB ranged from 9 to 233 Muts/Mb (median 13). Demographics and outcomes are summarized in the table below. Tumor microsatellite (MS) status was reported stable for 11 pts and indeterminate for 1 pt. 1 PR (88.1 wks duration, tumor 11 Muts/Mb, MS stable, PDL-1 expression not reported, KRAS mutant) and 0 pts with SD16+ were observed for a DC and OR rate of 10% (95% CI: 0%, 45%); the null DC rate of 15% was not rejected (p=0.80) and the cohort closed due to futility. 4 pts had at least one grade 3-4 adverse or serious adverse event (AE/SAE) at least possibly related to N+I including myasthenia gravis, diarrhea, glucose intolerance, hyperglycemia, and small intestinal obstruction. Conclusions: Combination therapy with N+I does not have sufficient clinical activity in pts with MS stable, hTMB CRC for further evaluation in this pt population. Other treatments should be considered for these pts, including treatments offered in clinical trials. Clinical trial information: NCT02693535. [Table: see text]
Tumor response of FOLFOXIRI plus cetuximab versus bevacizumab in RAS wild-type metastatic colorectal cancer: The subgroup-analysis of DEEPER trial (JACCRO CC-13).
Authors: Satake Hironaga , Tsuji Akihito , Tanaka Chihiro , Takahashi Takao , Wakamura Kunihiko , Yoshida Taichi , Murata Kohei , Shindo Yoshiaki , Ishikawa Yasuhide , Konishi Ken , Kochi Mitsugu , Sagawa Tamotsu , Kotaka Masahito , Kubota Yutaro , Sunakawa Yu , Sekikawa Takashi , Nakamura Masato , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi
Published: January 2022

109

Background: Triplet regimen, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab has been shown to be superior in terms of early tumor shrinkage and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC). We 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 (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) in previously untreated mCRC patients with RAS wild-type tumors (Tsuji A, et al. ASCO 2021). Methods: The primary endpoint was DpR during the entire course. Secondary endpoints included overall response rate (ORR), disease control rate, R0 resection rate, progression-free survival, and overall survival. A post-hoc subgroup analysis by PS, tumor sidedness, age, and location of metastases was performed to evaluate the efficacy of triplet plus cet vs. bev regimen. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the full analysis set (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively. Median DpR was 57.4% vs. 46.0% ( p = 0.001), and the ORR was 69.1% vs. 71.7% ( p = 0.60), in cet vs. bev, respectively. The subgroup analysis was present in the table. There was no significant difference in terms of ORR and R0 resection rate between groups according to PS, tumor sidedness, age, and liver metastases (LM). In patients with only LM, the R0 resection rate of cet vs. bev was 25.0% vs. 14.8% ( p = 0.21). Conclusions: The m-FOLFOXIRI plus cet showed to be significantly superior to the m-FOLFOXIRI plus bev in terms of DpR in first-line treatment for RAS wild-type mCRC. The better DpR of m-FOLFOXIRI plus cet was evident for RAS wild-type mCRC patients with left-sided tumors, LM or under 70 years old. Clinical trial information: UMIN000018217.[Table: see text]
Radioembolization with chemotherapy for liver-dominant colorectal cancer: Time to subsequent treatment and quality of life in the EPOCH trial.
Authors: Salem Riad , Mulcahy Mary Frances ,   On behalf of the EPOCH Trial Investigators
Published: January 2022

114

Background: The primary objective of the EPOCH trial evaluated potential benefit of adding second-line transarterial radioembolization (TARE) with yttrium-90 glass microspheres to chemotherapy compared to chemotherapy alone in patients with liver-dominant metastatic colorectal disease (mCRC). Secondary endpoints included time to deterioration of quality of life (TTDQoL). Methods: EPOCH was a 1:1 randomized, open-label, global, multicenter phase 3 trial. TTDQoL was assessed using the Functional Assessment of Cancer Therapy-colorectal (FACT-c) questionnaire and defined as the time from randomization to the change from baseline in FACT-c total score ≤ -7 points or date of death and was estimated using Kaplan-Meier analysis. Time to subsequent therapy was defined as the time from randomization to the start of subsequent therapy and was estimated using Kaplan-Meier analysis. Restricted mean survival time (RMST) analysis was used to estimate the area under Kaplan-Meier curves (AUC) for progression-free survival (PFS), hepatic PFS (hPFS), and TTDQoL, and the difference in AUC estimates between the two arms were assessed. The use of TheraSphere in the USA in the trial was under Investigational Device Exemption from FDA. Results: The EPOCH trial included 428 patients. Both primary endpoints of PFS (HR = 0.69, 95% CI: 0.54, 0.88; 1-sided p=0.0013) and hPFS (HR = 0.59, 95% CI: 0.46, 0.77; 1-sided p<0.0001) were met in the EPOCH study. Median time to subsequent therapy in the TARE plus chemotherapy arm was 21.0 months, compared to 10.1 months in the chemotherapy only arm (HR = 0.49, 95% CI: 0.37, 0.67). TTDQoL before subsequent therapy was reported in 53.5% (115/215) patients in the TARE plus chemotherapy arm, compared to 43.7% of patients in the chemotherapy only arm (93/213). Median TTDQoL was 3.8 months in both the TARE plus chemotherapy arm and the chemotherapy alone arm (1-sided p=0.1513; HR = 0.86, 95% CI: 0.65, 1.14). AUC for PFS until 22.1 months was 9.4 months (95% CI: 8.4, 10.4) for the TARE plus chemotherapy arm, compared to 7.4 months (95% CI: 6.6, 8.1) for the chemotherapy only arm (1-sided p=0.0008). AUC for hPFS until 22.1 months was 10.3 months (95% CI: 9.2, 11.3) for the TARE plus chemotherapy arm, compared to 7.4 months (95% CI: 6.7, 8.2) for the chemotherapy only arm (1-sided p<0.0001). AUC for TTDQoL until 18.5 months was 6.6 (95% CI: 5.6, 7.6) for the TARE plus chemotherapy arm, compared to 5.5 (95% CI: 4.4, 6.5) for the chemotherapy only arm (1-sided p=0.0663). Conclusions: These results suggest that the addition of TARE to second-line chemotherapy in patients with liver-dominant mCRC extended PFS, hPFS, and time to subsequent treatment without compromising quality of life. Clinical trial information: NCT01483027.
SONCAR study: A prospective randomized controlled study on optimized neoadjuvant chemotherapy-oxaliplatin plus CRT in patients with locally advanced rectal cancer.
Authors: Zhang Rong-Xin , Zeng Zhifan , Gao Yuan-Hong , Wu Xiao-Jun , Chen Gong , Li Liren , Ding Pei-Rong , Liu Min , Wang Qiaoxuan , Xiao Weiwei , Pan Zhi-Zhong , Wan De-Sen , LU Zhen-Hai
Published: January 2022

117

Background: The benefit of adding Oxaliplatin to neoadjuvant chemoradiotherapy in Locally Advanced Rectal Cancer (LARC) patients remains controversial. The present study investigated whether induction chemotherapy (CapOX), 2 cycles of CapOX combined with standard radiation (Oxa-CRT) concurrently and consolidation chemotherapy (CapOX) could improve OS compared with standard treatment (nCRT) for locally advanced rectal cancer. Methods: We conducted this randomized, single center, open-label, phase III trial in China. Eligible patients were pathologically confirmed rectal adenocarcinoma, clinical T3-4 with or without regional N + and no sign of distance metastasis determined by pelvic MRI, chest and abdominal CT scan. All patients were randomly allocated to the experimental group: pelvic radiation of 50Gy/25 fractions with 4 cycles of oxaliplatin and capecitabine (1 cycle of CapOX (oxaliplatin: 130mg/m2, cape: 1000mg/m2, bid, Day 1 to Day 14) administrated before radiotherapy as induction chemotherapy, 2 cycles of CapOX (oxaliplatin: 100mg/m2, cape: 1000mg/m2, bid, Day 1 to Day 14) administrated concurrent with RT, and 1 cycle of CapOX (oxaliplatin: 130mg/m2, cape: 1000mg/m2, bid, Day 1 to Day 14) conducted as consolidation chemotherapy); or control group: radiation with capecitabine. The primary end point was OS. This trial was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02031939). Results: From January 2014 to June 2020, 556 patients enrolled in this study (n=278 in both groups), and 536 patients were evaluable (269 in experimental group and 267 patients in control group). Surgery was performed in 235 patients (84.5%) in experimental group and 242 patients (87.1%) in control group. The pCR rates were 27.8% (75 in 269) and 19.4% in control group (52 in 267) (p = 0.025). 16 and 5 patients achieved clinical complete response (cCR) in experimental and control group, respectively. Grade 3-4 toxicities were recorded in 42 (21.8%) and 6 (5.1%) patients in experimental and control group. The most common grade 3-4 toxicities were leukopenia, thrombocytopenia and neutropenia. The overall surgical complication rate was not significantly different between two groups (12.1% vs. 11.9%). Conclusions: Four cycles of CapOX combined with RT in LARC significantly increased complete tumor response in Chinese patients with acceptable toxicities. Clinical trial information: NCT02031939.
Periop-01: A randomized controlled trial of extended perioperative tinzaparin to improve disease-free survival in patients with resectable colorectal cancer.
Authors: Auer Rebecca Ann C , Karanicolas Paul Jack , Ott Michael , Brackstone Muriel , Ashamalla Shady , Asmis Timothy R. , Boutros Marylise , Caycedo Marulanda Antonio , Jayaraman Shiva , Jonker Derek J. , Moloo Husein , Patel Sunil , Spadafora Silvana , MacLellan Steven , Mallick Ranjeeta , Stotland Peter , Tagalakis Vicky , Trottier Daniel C. , Weaver Joel , Carrier Marc
Published: January 2022

124

Background: Cancer patients undergoing surgical resection of their tumor are hypercoagulable beyond the period of hospitalization. Preclinical studies demonstrate that the postoperative hypercoagulable state promotes metastases, an effect that is abrogated by administration of perioperative low molecular-weight heparin (LMWH). Methods: We conducted a randomized, open label clinical trial to determine if extended duration thromboprophylaxis using subcutaneous LMWH (tinzaparin 4,500 IU daily), beginning at decision to operate and continuing for 56 days postoperatively, compared to inpatient postoperative thromboprophylaxis only, increased the 3-year disease-free survival (DSF) in patients undergoing resection for colorectal cancer. Secondary outcomes included 5-year overall survival (OS), postoperative bleeding and venous thromboembolism (VTE). Results: Trial recruitment was stopped prematurely after 614 of the planned 1075 patients were registered, following a pre-defined interim analysis for futility. The intention-to-treat analysis included 602 patients with demographics in the table. The 3-year DFS was 78.9% (63/299 recurrences) in the tinzaparin group and 80.5% (59/303 recurrences) in the control group (hazard ratio (HR) 1.09; [95% CI 0.91,1.31; p=0.3]). The 5-year OS was 91.3% in the tinzaparin group and 92.4% in the control group (HR 1.08; [95% CI 0.66,1.79; p=0.1]). The incidence of postoperative VTE was 1.7% and 1.3% in the tinzaparin and control groups, respectively (HR 1.3; [95% CI 0.30,5.69; p=0.7]. The incidence of major bleeding in the first postoperative week was 0.3% and 2% in the tinzaparin and control groups, respectively (HR 0.16; [95% CI 0.02,1.15; p=0.07]. Conclusions: Extended duration perioperative anticoagulation with tinzaparin did not improve DFS or OS in colorectal cancer patients undergoing surgical resection. The incidences of postoperative bleeding and VTE were low. Funded by Canadian Institute of Health Research and Leo Pharma Clinical trial information: NCT01455831. [Table: see text]
Safety and efficacy of pressurized intraperitoneal aerosolized chemotherapy in appendiceal and colorectal cancer patients with peritoneal carcinomatosis: A first-in-US phase I study.
Authors: Raoof Mustafa , Frankel Paul Henry , Fakih Marwan , Chao Joseph , Lim Dean , Woo Yanghee , Paz Isaac Benjamin , Lew Michael , Cristea Mihaela C. , Rodriguez-Rodriguez Lorna , Fong Yuman , Solass Wiebke , Thomas Rebecca Meera , Chang Sue , Blakely Andrew M. , Whelan Richard L. , Deperalta Danielle , Reymond Marc A. , Merchea Amit , Dellinger Thanh Hue
Published: January 2022

125

Background: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is being evaluated as a novel minimally invasive palliative treatment of peritoneal metastases (PM). Prior studies have established the feasibility and safety of repeated PIPAC treatments in gastrointestinal and gynecologic cancers. The goal of the present phase 1 trial was to establish the safety and feasibility of PIPAC oxaliplatin in a highly chemotherapy refractory colorectal and appendiceal cancer patient population. Methods: Patients with biopsy-proven peritoneal metastases from colorectal or appendiceal cancer underwent up to three PIPAC treatments using oxaliplatin (92 mg/m2) with a six-week interval at two academic centers. Patients with bowel obstruction, extra-peritoneal metastases, or poor performance status (ECOG>2) were excluded. PIPAC was nebulized over 5 min with a 30 min aerosol dwell time. Apart from the first PIPAC cycle, the patients also received a sensitizing dose of 5FU/LV (400mg/m2) within 24 hours of the procedure. Primary end point was safety as assessed by dose limiting toxicities within 6 weeks of the first PIPAC. Secondary endpoints included safety with the addition of 5FU/LV, efficacy, surgical morbidity, technical failure rate, progression-free and overall survival, pharmacokinetics (PK), and quality of life assessment. Results: A total of 8 patients were included: 5 colorectal; and 3 appendiceal. Median number of prior chemotherapy cycles was 2 (Interquartile range – IQR; 1.5-3.5). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median time from diagnosis to PIPAC was 16 months (IQR; 5.6, 17.5) and Peritoneal Carcinomatosis Index was 29 (IQR; 20.5, 31.5). Five (62.5%) patients completed 3 PIPAC cycles while in 3 (37.5%) patients PIPAC was discontinued due to disease progression within the peritoneal cavity. No surgical complication or dose limiting toxicity was observed. Only one patient developed grade 3 treatment-related toxicity after first PIPAC (anemia), and another patient after second PIPAC (abdominal pain and anemia). At the completion of PIPAC treatment 5 patients had stable disease and 3 had disease progression. Pharmacokinetic, histologic response and preliminary survival data will be presented at the meeting. Conclusions: PIPAC with oxaliplatin is safe and feasible in a highly chemotherapy refractory cohort of appendiceal and colorectal carcinomatosis patients with or without sensitizing 5-FU/ LV. Clinical trial information: NCT04329494.
Intensification of local therapy with high-dose rate intraoperative radiation therapy (HDR-IORT) and extended resection for locally advanced and recurrent colorectal cancer.
Authors: Agas Ryan Anthony Francisco , Tan Jennifer , Xie Sophia , Van Dyk Sylvia , Heriot Alexander Graham , Ngan Samuel Y
Published: January 2022

126

Background: This study reports our long-term experience with high dose rate intraoperative radiotherapy (HDR-IORT) in a single, quaternary institution. Methods: From 2004-2020, 138 consecutive patients with 141 total resections for locally advanced rectal cancer (LARC) (n=60, 43%) defined as T4Nx or T3N+ or locally recurrent rectal cancer (LRRC) (n=81, 57%) were retrospectively reviewed. The median age was 61 years (range 31-83) with 30 patients aged >70 years during surgery. Most patients had preoperative radiotherapy (RT) +/- concurrent chemotherapy (n=125). Thirty-two recurrent cancers received preoperative pelvic reirradiation to a median dose of 36 Gy (range 34.2 – 41.4). HDR-IORT was delivered using isotope iridium-192 in a remote afterloader, and a Freiburg applicator, after macroscopic resection of the tumour. A single 10 Gy fraction was delivered. Fifty-eight of 84 patients who underwent pelvic exenterations had >3 en bloc organs resected, and 96 patients underwent pelvic sidewall dissections. IORT sites included the primary tumour bed (33%), nodal regions (28%) and wider pelvic areas (70%). Resection margin status were R0 in 76 patients (54%) and R1 in 65 (46%). R1 resection was defined as positive (n=53) or close (n=12). R1 resection patients accounted for 61% of pelvic relapses. Results: With a median follow-up time of 4 years, 3-, 5-, and 7- year, overall survival (OS) rates were 75%, 48%, and 45%, respectively (84%,58%, 58% for LARC and 68%,39%, 35% for LRRC). Local progression-free survival (LPFS) of all patients were 88%, 85%, and 85%, respectively (97%, 93%, 93% for LARC and 80%, 80%, 80% for LRRC). On multivariable analysis, an R1 resection was associated with a trend toward poorer OS (p=0.05), while a trend towards worse LPFS (p=0.07) was noted for those without preoperative RT. The most common severe (grade ≥3) adverse events were postoperative abscess (n=25) and bowel obstruction (n=11). Overall, there were 49 (34%) grade 3-4 and no grade 5 adverse events. No intraoperative complications were attributed to IORT. The 30-day mortality rate was 0%. Conclusions: Favorable OS and LPFS can be achieved with intensive local therapy. As R1 resection may be associated with worse survival, optimisation of IORT, surgical resection, and systemic therapy are required. [Table: see text]
BREAKWATER safety lead-in (SLI): Encorafenib + cetuximab (EC) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC).
Authors: Kopetz Scott , Yoshino Takayuki , Kim Tae Won , Desai Jayesh , Yaeger Rona , Van Cutsem Eric , Ciardiello Fortunato , Wasan Harpreet Singh , Maughan Tim , Zhang Yuanyuan , Usari Tiziana , Chung Chin-Hee , Zhang Xiaosong , Tabernero Josep
Published: January 2022

134

Background: Currently, there are no 1L tx options indicated specifically for patients (pts) with BRAFV600E mCRC. Based on results of BEACON CRC (NCT02928224), BRAF inhibitor encorafenib + EGFR inhibitor cetuximab was approved for tx of previously treated pts with BRAFV600E mCRC. BREAKWATER (NCT04607421), an ongoing, open-label, global, multicenter, randomized phase 3 study, evaluates 1L EC ± chemotherapy for tx of pts with BRAFV600E mCRC. Here we present preliminary data on safety and pharmacokinetics (PK) from the BREAKWATER SLI, which aimed to identify the chemotherapy backbone for EC for the phase 3 portion of BREAKWATER. Methods: SLI inclusion criteria were BRAFV600E mCRC (determined using tumor tissue or blood); evaluable disease (RECIST v1.1); ≤1 prior systemic tx for mCRC; European Cooperative Oncology Group performance status (ECOG PS) 0/1; and adequate bone marrow, hepatic, and renal function. Pts previously treated with BRAF/EGFR inhibitors or both oxaliplatin and irinotecan were excluded. Pts received encorafenib 300 mg daily + cetuximab 500 mg/m2 every 2 weeks (Q2W) + either FOLFIRI Q2W or mFOLFOX6 Q2W in 28-day cycles. The primary endpoint was frequency of dose-limiting toxicities (DLTs). PK were a secondary endpoint. Data cutoff date: Sep 13, 2021. Results: 57 pts were enrolled (EC + FOLFIRI, n = 30; EC + mFOLFOX6, n = 27). Median (range) age was 57 (28–78) years; 25% were Asian; 65% had ECOG PS 0; 37% had ≥3 organs involved; 58% were treatment naive. At cutoff date, tx was ongoing in 45 (79%) pts. Median (range) duration of tx for encorafenib in EC + FOLFIRI and EC + mFOLFOX6 was 15 (0–31) and 14 (0–27) weeks, respectively. One DLT was observed: grade 4 neutropenia in 1 pt in EC + FOLFIRI. Tx-emergent all-cause serious adverse events (AEs) occurred in 20% and 19% and grade ≥3 AEs in 33% and 56% of pts in EC + FOLFIRI and EC + mFOLFOX6, respectively. The table shows frequent (all grade in ≥30% pts or grade ≥3 in ≥10% with either tx) tx-emergent all-cause AEs. One pt died due to disease progression. In EC + FOLFIRI, in the presence of steady-state encorafenib, AUCinf of irinotecan and its active metabolite, SN-38, significantly decreased ̃25% and ̃40%, respectively, compared with values in the absence of encorafenib. In EC + mFOLFOX6, oxaliplatin PK was not significantly altered by steady-state encorafenib. Conclusions: Based on these data, BREAKWATER phase 3 will compare EC ± mFOLFOX6 with mFOLFOX6/FOLFOXIRI/CAPOX ± bevacizumab. Clinical trial information: NCT04607421. [Table: see text]
A pilot study to reliably measure the tissue concentration of mitomycin C after hyperthermic intraperitoneal chemotherapy in patients with gastrointestinal malignancies.
Authors: Kriley Isaac , Rozich Noah , Bellini Geoffrey , Papenfuss Wesley Allan , Anshus Emily , Schwind Analeah , Hribar Austin , Rehrauer Kyle , Castillo Uvidelio , Weese James L. , FACS Aaron Chevinsky
Published: January 2022

138

Background: HIPEC with MMC is a treatment for gastrointestinal cancers metastatic to the peritoneal cavity. The pharmacokinetics of MMC in plasma, peritoneal fluid, and urine are described. The amount of MMC in intraabdominal tissues after HIPEC are not well described. The aim of this study is to evaluate if MMC concentrated in tissue samples after HIPEC by high performance liquid chromatography (HPLC) from patients with gastrointestinal neoplasms. Methods: HIPEC was performed at 40°C with 40mg of MMC for 90 minutes, after which the peritoneal cavity was flushed, anastomoses created as needed, and the wound closed. Eligible patients were treated at a single institution, ≥18 years old, and underwent HIPEC with MMC. Samples were taken of the omentum, peritoneum, liver core biopsy, tumor, and mesenteric fat before and after HIPEC. All patients signed informed consent. Samples were frozen in liquid nitrogen, minced, and sonicated in 500µL of phosphate buffered saline. The homogenized samples were centrifuged, and the supernatant was analyzed by HPLC for MMC. The HPLC was performed using a Dionex Ultimate 3000. Analysis was performed with a Kinetex - 5µm Biphenyl 100A  150 x 4.6mm column. MMC was detected with a Diode Array Detector 3000 with fixed UV at 365nm, 280nm, 254nm, and 210nm. The mobile phase used isocratic 40% acetonitrile and 60% water at 0.5 ml/min. The analysis volume was 10µL. Samples were blinded prior to analysis and analyzed in triplicate. Results: Thirteen patients were enrolled, 11 were female, the average age was 57 years (range: 30  85). Diagnoses were low-grade appendiceal mucinous neoplasm (7), high-grade appendiceal mucinous neoplasm (1), appendiceal adenocarcinoma (1), colon adenocarcinoma (1), colon mucinous adenocarcinoma (1), peritoneal mesothelioma (1), and small bowel mucinous adenocarcinoma (1). Complete tissue samples were available for 10 patients. Two patients had complete cytoreduction and did not have tumor for analysis after HIPEC. One patient refused liver biopsy. MMC was not detected in any sample prior to HIPEC. After HIPEC, MMC was most often detected in peritoneum (12 of 13 cases) and tumor (9 of 11). MMC was less often detected in omentum (5 of 13), mesenteric fat (2 of 13), or liver (1 of 12). Conclusions: MMC concentrated in 92% of peritoneal samples, 82% of tumor samples, and less often in liver tissue. MMC is hydrophilic which may contribute to the low detection rates in omentum and mesenteric fat. A reliable method to measure MMC concentration in normal and malignant tissues is novel and may have clinical implications. Our next steps are to expand the cohort of patients and evaluate whether tissue concentration is associated with clinical outcomes.
The immune impact of PI3K-AKT pathway inhibition in colorectal cancer.
Authors: Nusrat Maliha , Syed Muddassir Ali , Katkhuda Riham , Parra Edwin R. , Wistuba Ignacio Ivan , Kong Paul , Koehne Amanda , Dasari Arvind , Overman Michael J. , Menter David , Kopetz Scott
Published: January 2022

154

Background: Our prior work has shown that PI3K-altered colorectal cancer (CRC), with PIK3CA mutation or PTEN loss, has increased expression of key immune checkpoints (including PD-L1) resulting in immune evasion, despite increased immune engagement. Here, we investigated the impact of PI3K-AKT inhibition on the immune repertoire of CRC. Methods: Multiplex immunofluorescence was performed using two Vectra panels [1: AE1/AE3, CD3, CD8, PD-1, PD-L1, CD68; and 2: AE1/AE3, CD3, CD8, Granzyme B (GzB), CD45RO, FoxP3] on paired biopsies (baseline and cycle 1 day 15) from 6 patients with PI3K-altered metastatic CRC (mCRC) treated with AKT inhibitor, MK2206 (200 mg oral weekly), on a phase 2 clinical trial. Separately, one million CT26 CRC cells were implanted in BALB/C-e mice. After 48 hours, 10 mice/group were randomized for treatment with pan-PI3K inhibitor copanlisib (C, 10 mg/Kg IV 2x/week), anti-PD-1 (P, 200 µg IP 2x/week), copanlisib + anti-PD-1 (C+P), or control (Ct), for 21 days. Mouse tumors were stained with 6-plex immunohistochemistry (CD3, CD8, PD-L1, Ki67, GzB, AE1/AE3). Data were analyzed using related-samples Wilcoxon Signed-Rank test, Mann-Whitney U test, Kruskal-Wallis test, and Student’s t-test, as appropriate. Results: In PI3K-altered mCRC patients, AKT inhibition resulted in a trend towards increased median densities of intratumoral CD8+ T cells (0.8 vs 4.8 density/mm2, P = 0.14) and memory T cells (0 vs 10.3, P = 0.07), and decreased density of macrophages (12.4 vs 0, P = 0.07). No antigen experienced T cells were seen and activated CD8+ T cells were present in 1 patient only. In CT26 mice, PI3K and PD-1 co-inhibition resulted in the smallest mean tumor volumes (C+P 12% of Ct vs C 40% and P 42% of Ct, P < 0.05 for both), and the highest median % of intratumoral CD8+Ki67+ T cells as compared to all other treatment arms (C+P 1.6% vs C 0.5%, P 0.4%, Ct 0.6%, P < 0.05 for each pairwise comparison). C+P also increased the % of total CD3+ and CD8+ cells as compared to Ct and C (P < 0.05 for all). C alone did not increase immune infiltration in this non-PI3K activated model. Conclusions: PI3K-AKT pathway inhibition has the potential to improve effector T cell infiltration in PI3K-altered CRC. PI3K inhibitor synergizes with anti-PD-1 to improve treatment efficacy and CD8+ T cell proliferation. The mechanisms behind this immune repertoire shift are yet to be elucidated, such as via cytokine modulation. Therapeutic approaches to activate the proliferating CD8+ cells would be useful, and may require PI3Kα/β specific inhibitors to allow early T cell activation through PI3Kδ/γ isoforms.
Association of circulating nucleosomes levels with FIT performance for advanced adenomas in a symptomatic population.
Authors: Chang Li-Chun , Herzog Marielle , Hardat Nathalie , Pamart Dorian , Chiu Han Mo
Published: January 2022

170

Background: The effectiveness of screening using either fecal immunochemical testing (FIT) or colonoscopy in reducing colorectal cancer (CRC) mortality has been demonstrated in previous studies. Nevertheless, the single test sensitivity of FIT for relevant precursor lesions, especially high-risk neoplasms like invasive cancer or advanced adenomas (AA), is a concern. Improving the sensitivity for high-risk neoplasm is critical to improving the effectiveness of screening in reducing CRC incidence and mortality. Dysregulation of histone post-translational modifications (PTMs) has been linked with several cancers including CRC. We investigated the clinical performance of circulating nucleosome levels containing specific histone PTMs in blood, in combination with FIT from symptomatic subjects referred to colonoscopy to evaluate their discriminant power towards CRC and AA. Methods: 10mls whole blood was obtained prior to colonoscopy from 476 patients referred to colonoscopy in National Taiwan University Hospital for surveillance or secondary to bowel symptoms. Patients were classified into 5 groups based on their colonoscopy reports: (i) patient with CRC (n = 67), (ii) patients with AA (n = 60, including 22 with AA≥2cm); (iii) patients with non-AA (n = 123); (iv) patients with non-neoplastic polyps (n = 29); (vi) healthy controls with no endoscopic lesion (n = 197). Plasma samples were analyzed for nucleosome levels using 7 different quantitative immunoassays (Nu.Q assays; Belgian Volition SRL, Belgium) targeting H3.1-nucleosomes or different histone modifications (H3K27Me3-, H3K36Me3-, H3K9Me3-, H3K14Ac-, H3K27Ac- or H3R8Cit-nucleosomes). All study subjects were asked to collect a stool sample at home within 48-hours before the colonoscopy. The fecal samples were assayed with the OC-SENSOR FIT kit (Eiken Chemical Co., Ltd., Tokyo, Japan) for all subjects. Results: At a cut-off of 20µg/g feces, the FIT test showed a sensitivity of 83.5% at 82.1% specificity for CRC +AA vs. Controls. All the CRC patients were detected but 35% of AA were missed, and 7 of which were high-risk adenomas (AA≥2cm). A combination of 2 Nu.Q biomarkers: H3K36Me3 and H3K9Me3 with FIT in a decision tree model showed an improved sensitivity of 98.4% allowing the detection of all CRC patients and 97% of the patients with AA including all high-risk adenomas. The 2 missed AA were one AA below 1cm and one between 1 and 2cm. Unnecessary colonoscopies could be reduced by 28.9% of the control and 20.7% of the non-neoplastic polyps subgroups as both are found negative with this panel of assays. Conclusions: At present, all the symptomatic patients are sent to colonoscopy in clinical practice. Our results indicate that H3K36Me3- and H3K9Me3-nucleosome levels, in combination with FIT in a decision tree model, could detect all CRC patients and all high-risk adenomas and help reduce unnecessary colonoscopies.
Circulating microRNA: Searching for new players in assessment of therapy response in colorectal cancer patients.
Authors: Vymetalkova Veronika , Cervena Klara , Vodicka Pavel , Filip Stanislav
Published: January 2022

183

Background: The identification of clinicopathological and molecular predictive and/or prognostic factors represents currently one the most challenging tasks in oncology. Significant efforts are currently being dedicated to identify patients who will or will not benefit from chemotherapy. In fact, drug resistance is a limiting factor of the efficacy of chemotherapy in colorectal cancer (CRC) treatment. However, despite modern surgical techniques and adjuvant systemic therapy, only 20% of patients with distant metastasis achieve long-term remission, while 60–70% of patients develop local or distant recurrence. Methods: Recently, we have identified by high-throughput approach that circulating microRNAs (miRNAs), namely, miR-122-5p and miR-142-5p show a high potential for CRC screening and early detection as well as for the assessment of patients’ outcomes and the effectiveness of treatment schedule. Results: In detail, the expression levels of these miRNAs were significantly different between CRC patients and controls. A year after diagnosis, miRNA expression profiles were significantly modified in patients responding to treatment and were no longer different from those measured in controls. On the other hand, patients not responding to therapy maintained low expression levels in their second sampling. As selection during metastasizing may shift molecular patterns by which CRC liver metastases retain their unique molecular profile, we thus elaborated our results on CRC patients with liver metastasis and measured these circulating miRNAs repeatedly over two years. The first sampling was performed at the time of post therapy developed liver metastasis (i.e., recurrence), and every 3 months depending on patients` conditions (i.e., covering the liver resection, administration of chemotherapy etc). Detailed results of the study will be presented during the meeting. Conclusions: The present study aimed to explain why patients with the same cancer stage may differ in treatment susceptibility and long-term outcomes.
Evaluation of SN-38 PK profile in patients with RAS wild-type metastatic colorectal cancer treated with a combination of SCO-101 and FOLFIRI.
Authors: Schou Jakob Hagen Vasehus , Roest Nicklas , Ladekarl Morten , Hansen Jens Bo Rode , Hedtjaern Maj , Vestlev Peter Michael
Published: January 2022

185

Background: The FOLFIRI regimen (5-fluorouracil, leucovorin and irinotecan) is a predominant treatment regimen for metastatic colorectal cancer. To optimize the benefit for the patients, it would be desirable to increase the efficacy of irinotecan by increasing the exposure of SN-38 (the active metabolite of irinotecan) to the cancer cells, while maintaining a good safety profile. The oral drug SCO-101, that is currently being developed by Scandion Oncology A/S, was tested in an early clinical trial (CORIST-trial, ClinicalTrials.gov identifier: NCT04247256). SCO-101 is an inhibitor of ABCG2, UGT1A1 and SRPK1. The CORIST trial was set up to address the safety, tolerability, and efficacy of SCO-101 given orally for 6 days followed by FOLFIRI at varying doses from day 5 to 7, in a biweekly schedule, in patients with metastatic colorectal cancer who have formerly been treated with FOLFIRI and afterwards progressed. The first part of the study was a dose-finding study, where the impact of SCO-101 on the pharmacokinetics (PK) of SN-38 was studied. Methods: 12 patients from the dose-finding part of the CORIST study received 150 mg SCO-101 for 6 days and 45 – 80% of the recommended dose of FOLFIRI. 6 of the patients had RAS wild-type tumors and these patients are the subject of the current analysis. Blood for PK analysis was sampled from the patients at 1, 2, 4, 8, 24, 48, and 96 hours after treatment with FOLFIRI and SCO-101. The blood samples were analyzed for Cmax, T½ and AUC (0-24h) of SCO-101, irinotecan and SN-38. Results: The PK of SN-38 from the patients in the study, normalized to a dose of irinotecan of 90 mg/m2 showed a T½ day 5 of 19 hours (SD 5,7) a Cmax of 60 ng/ml (SD 20,6) and an AUC_0-24h of 1415 hxng/ml (SD: 670). The results were compared to SN-38 data from treatment with irinotecan at 180 mg/m2, which is used in standard doses of FOLFIRI and the data is presented in the table. The data analysis showed an increased T½, increased Cmax and increased AUC of SN-38 when combining SCO-101 with 90 mg/m2 irinotecan, compared to SN-38 PK data from standard irinotecan treatment of 180 mg/m2. The toxicity profile of the patients treated with 90 mg irinotecan/m2 (50% FOLFIRI) showed only grade 1 and 2 adverse events. Conclusions: SCO-101 in combination with FOLFIRI has demonstrated the ability to modulate the PK profile of SN-38 in mCRC patients with RAS wild-type tumors, by significantly increasing the half-life, the peak plasma concentration, and area under the curve of SN-38. The combined treatment was well tolerated, and the drug is now being tested for efficacy in the CORIST trial.[Table: see text]
Comprehensive genomic profiling (CGP)-informed personalized molecular residual disease (MRD) detection: An exploratory analysis from the PREDATOR study of metastatic colorectal cancer (mCRC) patients undergoing surgical resection.
Authors: Nimeiri Halla , Young Amanda , Madison Russell , Fine Alexander D. , Gjoerup Ole , Loupakis Fotios , Fassan Matteo , Lonardi Sara , Sharma Shruti , Wu Hsin-Ta , Aleshin Alexey , Renkonen Elise , Hegde Priti
Published: January 2022

187

Background: Detection of MRD following metastatic liver resection in advanced CRC patients is associated with poor prognosis with high rate of relapse. Nevertheless, there is currently no standard of care to guide further therapy after curative intent surgery. MRD detection has the promise to be implemented into standard of care and guide treatment decision making. Here we establish feasibility of MRD detection using Foundation Medicine’s novel tissue-informed personalized monitoring assay, FoundationOne Tracker (F1T), in mCRC patients undergoing surgical resection with curative intent. Methods: Tissue-based CGP was performed retrospectively on a cohort of 72 patients from the PREDATOR trial. Trackable patient-specific single nucleotide variants were selected using a novel computational approach negating the need for buffy coat sequencing to filter germline variants. Personalized multiplex PCR was used to detect and evaluate prognostic value of ctDNA from plasma collected at MRD timepoint post-surgery (median 27 days, range 8-99.5). Median follow-up of patients in the overall population was 10.7 months (range: 0.9-53.8 months). Survival analyses were performed using the Kaplan-Meier Estimator and Cox regression. Results: Post-surgical F1T analysis was successful on 96% of cases (69/72). CGP analysis revealed at least one driver mutation in 57% of samples (41/72) including KRAS/NRAS (46%) and BRAF mutations (3%). MRD was detected in 45% (31/69) of patients, of which 94% (29/31) had progressed at the time of the data cut. Median progression -free survival (PFS) was 3.2 months (2.1-7.1) in ctDNA-positive vs 28 months (20.9-NA) in ctDNA-negative population (HR 5, CI 2.7-9.3, p<0.001). Median overall survival (OS) was 31.6 months in ctDNA-positive vs not reached in ctDNA-negative group (HR 27, CI 3.6-205, p<0.001). Conclusions: CGP-informed post-operative MRD detection is a strong prognostic biomarker and correlates with survival outcomes in patients with resected mCRC. F1T is a novel and convenient technological approach to MRD detection utilizing highly validated FMI testing to reveal potentially targetable mutations and inform personalized ctDNA monitoring. These results demonstrate the ability of F1T to accurately detect MRD in mCRC patients following surgical resection, without the need for germline sequencing.
Clinical performance of Immunoscore in stage III colorectal cancer patients in the SCOT and IDEA-HORG cohorts.
Authors: Church David , Sansom Owen , Maka Noori , Edwards Joanne , Oien Karin , Iveson Timothy , Saunders Mark P. , Boukovinas Ioannis , Messaritakis Ippokratis , Moustou Eleni , Chondrozoumaki Maria , Georgoulias Vassilis , Kassambara Alboukadel , Catteau Aurelie , Galon Jerome , Dempsey Laura , Hay Jennifer , Kelly Caroline , Sougklakos Ioannis , Harkin Andrea
Published: January 2022

196

Background: The ESMO clinical practice guidelines recommend consideration of Immunoscore (IS) for risk assessment of early colon cancer patients. IS clinical performance was assessed in the SCOT and IDEA-HORG trials evaluating 3 vs. 6 months (3m vs. 6m) of mFOLFOX6 adjuvant chemotherapy in stage III colorectal cancer (CRC). Methods: 1,002 formalin-fixed paraffin-embedded (FFPE) tumor samples (762 from SCOT;240 from HORG) were collected, of which 851 were eligible for biomarker analysis. Eligible samples were classified into 2 groups using pre-defined cut-offs (IS-Low, IS- High) and the performance of IS to predict 3 year disease-free survival (3y-DFS) was evaluated. Results: IS was successfully assessed in 846 cases (99%). 615 (72.7%) samples were classified as IS-High (311 and 304 in 3m and 6m arm, respectively). No significant association between IS and patients’ gender, age, PS, BMI or primary tumour location was observed. However, a significant difference between IS-High (43.7%) and IS Low (57.1%) was observed in the proportion of high risk (T4 and/or N2) tumours (p=0.001). Patients with IS-High tumors had significantly longer 3y-DFS (79.4%, 95%CI: 75.9%-82.4%) compared to those with IS-Low tumors (65.0%, 95%CI: 58.3%-70.9%); adjusted hazard ratio (HR) 1.9 (95%CI: 1.46-2.46; p<0.0001). Similarly, IS-High was significantly correlated with longer 3y-DFS in both treatment arms: 78.5% (95% CI 73.4%-82.7%) for IS-High and 65.8% (95% CI 56.1%-73.9%) for IS-Low in 3m arm; 80.3% (95% CI 75.3%-84.5%) for IS-High and 64.4% (95% CI 54.8%-72.6%) for IS-Low in 6m arm. The estimated HRs according to treatment duration and IS classification were 1.80 (95% CI 1.25-2.60) in 3m arm, 2.00 (95% CI 1.38-2.92) in 6m arm and 1.89 (95% CI 1.46-2.47) in the total study population; interaction p = 0.687. Conclusions: The results of this study confirm the prognostic value of IS observed in the IDEA-France trial (Pagès F et al 2020). However, this analysis was not powered to determine the predictive value of IS for treatment duration. Similar analysis of patients treated with CAPOX is warranted.