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Purpose: Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC., Methods: In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment., Results: Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm., Conclusion: In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

Background: The randomized, open-label, phase III LYNK-003 study assessed the efficacy of first-line maintenance olaparib, alone or in combination with bevacizumab, versus bevacizumab plus a fluoropyrimidine in participants with unresectable or metastatic colorectal cancer (mCRC). We present results of the prespecified interim futility analysis., Methods: Eligible participants were ≥18 years of age with unresectable or mCRC that had not progressed after induction with first-line bevacizumab plus 5-fluorouracil plus oxaliplatin plus leucovorin (FOLFOX) or capecitabine plus oxaliplatin (CAPOX). Participants were randomly assigned 1:1:1 to olaparib plus bevacizumab, olaparib alone, or bevacizumab plus a fluoropyrimidine (5-fluorouracil or capecitabine). The primary end point was progression-free survival (PFS) per RECIST v1.1 by central review., Results: Between August 2020 and May 2022, 309 participants were assigned to olaparib plus bevacizumab (n = 104), olaparib (n = 107), or bevacizumab plus fluoropyrimidine (n = 98). At interim analysis, with a median follow-up of 7.6 months (range 0.1-19.7 months), the median PFS was 3.7 months (95% CI 2.8-5.3) with olaparib plus bevacizumab (HR 1.52; 95% CI 1.02-2.27; P = 0.982) and 3.5 months (95% CI 2.0-3.7) with olaparib (HR 2.11; 95% CI 1.39-3.18; P = 0.999) versus 5.6 months (95% CI 3.8-5.9) with bevacizumab plus fluoropyrimidine. Treatment-related adverse events occurred in 64 (62%), 52 (50%), and 57 (59%) participants, respectively. There were no treatment-related deaths., Conclusion: The LYNK-003 study was stopped prematurely as criteria for futility were met. Maintenance olaparib with or without bevacizumab did not demonstrate clinical efficacy compared with bevacizumab plus a fluoropyrimidine., Gov Registration: NCT04456699., Competing Interests: Declaration of Competing Interest Atsuo Takashima reports grants and payment or honoraria from Lilly, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharma, Takeda, and Merck Serono. Pilar García Alfonso reports honoraria for speakers’ bureau from, travel support from, and advisory board participation for Amgen, Roche, Merck Serono, MSD, Sanofi-Aventis, Pierre Fabre, and Servier. Matthew Burge reports consulting fees from Servier; payment or honoraria and travel support from MSD; and advisory board participation for BMS, MSD, and AstraZeneca. Takayuki Yoshino reports honoraria from Bayer, Chugai, Merck Biopharma, MSD, Ono, and Takeda; consulting fees from Sumitomo Corporation; and institutional research funding from Amgen, Chugai, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia Inc., Molecular Health, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer, Roche Diagnostics, Sanofi, Sysmex, and Taiho. Tae Won Kim reports institutional research funding from Genentech. Karen Cui reports stock or stock options with AstraZeneca. Chenxiang Li reports employment with Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD). Rishi Jain reports employment with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stock or stock options with Merck & Co., Inc., Rahway, NJ, USA. David Adelberg reports employment with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and stock or stock options with Merck & Co., Inc., Rahway, NJ, USA. Julien Taieb reports consulting fees and honoraria for speakers’ bureau from Amgen, BMS, AstraZeneca, MSD, Pierre Fabre, Roche, Sanofi, and Servier. Raimundo Manneh, Ali Ayberk Beşen, Yong Sang Hong, Pieter-Jan Cuyle, and Patricio Yanez report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a)., Materials and Methods: Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study., Results: RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0)., Conclusion: GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874., (© 2023. Crown.)

Background: KRAS G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy., Methods: In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator's choice of trifluridine-tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response., Results: After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib-panitumumab and 240-mg sotorasib-panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib-panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P = 0.006), and the hazard ratio in the 240-mg sotorasib-panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P = 0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab., Conclusions: In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.)., (Copyright © 2023 Massachusetts Medical Society.)

Robust clinical activity has been observed with the immune checkpoint inhibitor pembrolizumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). However, given the response rate of 45% and a median progression-free survival of 16.5 months with first-line pembrolizumab demonstrated in KEYNOTE-177, there is room for improvement. Targeting a second immune receptor, such as CTLA-4, LAG-3, TIGIT, or ILT-4 may improve efficacy of PD-1 inhibition. Here we describe the design and rationale for the open-label, randomized, phase II KEYSTEP-008 trial, which will evaluate the efficacy and safety of pembrolizumab-based combination therapy compared with pembrolizumab monotherapy in chemotherapy-refractory (cohort A) or previously untreated (cohort B) MSI-H/dMMR mCRC. Clinical Trial Registration: NCT04895722 (ClinicalTrials.gov).

Aim: The OPTIM1SE study observed long-term real-world outcomes of cetuximab-based infusional 5-fluorouracil (5-FU) regimens for first-line treatment of metastatic colorectal cancer (mCRC) across Asia-Pacific and Middle East regions, aiming to characterize their use, effectiveness, and safety in routine practice., Methods: OPTIM1SE was a prospective, open-label, observational study. Patients with untreated KRAS wild-type mCRC and distant metastases were treated per locally approved labels and monitored for 3 years via electronic medical records. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS)., Results: From November 19, 2013, to June 30, 2016, 520 patients were enrolled in 51 sites. Patients were mostly male (61.2%), with a mean age of 58.5 (±12.0) years; 420 patients received leucovorin, 5-FU, and irinotecan-based regimens and 94 received leucovorin, 5-FU, and oxaliplatin. The most common primary tumor site was the rectum (38.8%), with liver metastases (65.0%). ORR was 45.4% (95% CI, 41.1%-49.7%), including 26 patients (5.0%) with a complete response. Median PFS was 9.9 months (95% CI, 8.2-11.0); median OS (mOS) was 30.8 months (95% CI, 27.9-33.6). Higher mOS was associated with tumors of left compared with right-sided origin (hazard ratio, 0.69 [95% CI, 0.49-0.99]); higher ORR was also associated with liver metastases compared with all other metastases (55.4% vs. 40.2%). Adverse events were consistent with the known safety profile of cetuximab., Conclusion: Cetuximab-based 5-FU regimens were effective first-line treatments for mCRC in routine practice, particularly in patients with left-sided disease and liver metastases only., (© 2023 The Authors. Asia-Pacific Journal of Clinical Oncology published by John Wiley & Sons Australia, Ltd.)

Microsatellite-stable colorectal cancer (MSS-CRC) is highly refractory to immunotherapy. Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve MSS-CRC patient outcomes. Here, we demonstrate that high tumor expression of the core autophagy gene ATG16L1 is associated with poor clinical response to anti-PD-L1 therapy in KRAS-mutant tumors from IMblaze370 (NCT02788279), a large phase III clinical trial of atezolizumab (anti-PD-L1) in advanced metastatic MSS-CRC. Deletion of Atg16l1 in engineered murine colon cancer organoids inhibits tumor growth in primary (colon) and metastatic (liver and lung) niches in syngeneic female hosts, primarily due to increased sensitivity to IFN-γ-mediated immune pressure. ATG16L1 deficiency enhances programmed cell death of colon cancer organoids induced by IFN-γ and TNF, thus increasing their sensitivity to host immunity. In parallel, ATG16L1 deficiency reduces tumor stem-like populations in vivo independently of adaptive immune pressure. This work reveals autophagy as a clinically relevant mechanism of immune evasion and tumor fitness in MSS-CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic., (© 2023. Springer Nature Limited.)

Background: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity., Methods: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed., Results: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib., Conclusions: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Pembrolizumab demonstrated durable clinical benefit and manageable safety in previously treated advanced or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer (CRC) in the phase 2 KEYNOTE-164 study. Results from the final analysis are presented., Methods: Eligible patients had unresectable or metastatic MSI-H/dMMR CRC and ≥2 prior systemic therapies (cohort A) or ≥1 prior systemic therapy (cohort B). Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles. The primary end-point was objective response rate (ORR) assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 by blinded independent central review. Secondary end-points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability., Results: Sixty-one patients in cohort A and 63 patients in cohort B were enroled; median follow-up was 62.2 months and 54.4 months, respectively. ORR was 32.8% (95% CI, 21.3%-46.0%) in cohort A and 34.9% (95% CI, 23.3%-48.0%) in cohort B. Median DOR was not reached (NR) in either cohort. Median PFS was 2.3 months (95% CI, 2.1-8.1) in cohort A and 4.1 months (95% CI, 2.1-18.9) in cohort B. Median OS was 31.4 months (95% CI, 21.4-58.0) in cohort A and 47.0 months (95% CI, 19.2-NR) in cohort B. No new safety signals were observed. Nine patients who initially responded experienced disease progression off therapy and received second-course pembrolizumab. Six patients (66.7%) completed an additional 17 cycles of pembrolizumab, and 2 patients achieved a partial response., Conclusions: Pembrolizumab continued to show durable antitumor activity, prolonged OS, and manageable safety in patients with previously treated MSI-H/dMMR CRC., Clinical Trial Registry Information: ClinicalTrials.gov, NCT02460198., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: DTL reports honoraria from MSD; consulting or advisory roles for MSD, Bristol Myers Squibb, Nouscom, Janssen, G1 Therapeutics, and Merus; research funding from MSD, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, and Nouscom; and being listed as an inventor for a patent related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1). LAD reports consulting or advisory roles for PetDx, Innovatus Capital Partners, Se’er, Delfi, Kinnate, and NeoPhore; equity interests in Epitope, Jounce Therapeutics, Thrive Detect, Se’er, Delfi, Kinnate, NeoPhore and PetDx; positions on the board of directors of Jounce Therapeutics and Epitope; intellectual property interests in multiple licensed patents related to technology for circulating tumour DNA analyses and mismatch repair deficiency for diagnosis and therapy; and a spouse with an equity interest in Amgen. TWK reports research funding from Roche/Genentech paid to his institution. EVC reports consulting or advisory roles for AbbVie, Array Pharma, Astellas, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Halozyme, GlaxoSmithKline, Incyte, Ipsen, Janssen Research, Lilly, MSD, Merck KGaA, Mirati, Novartis, Pierre Fabre, Roche, Seattle Genetics, Servier, Sirtex, Terumo, Taiho, TRIGR, and Zymeworks; and research funding from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ipsen, Lilly, MSD, Merck KGaA, Novartis, Roche, and Servier paid to his institution. RGe reports honoraria from Medison, Roche, Janssen, MSD, and Pfizer; consulting or advisory roles for Eisai, AstraZeneca, Bayer, MSD, BOL Pharma, Ranium, JNJ, and Roche; travel and accommodation expenses from Takeda; a leadership role at Pyxis (Medical Lead); and equity interests in BOL Pharma and Pyxis Oncology. DJ reports honoraria from SKK Kliniken Heilbronn GmbH, Georg Thieme Verlag, Terrapinn, Touch Medical Media, BMS GmbH & Co, KGaA, MSD, Guppe 5 Fileproduktion GmbH, AstraZeneca GmbH, Department of Radiation Medicine, University of Kentucky, and The Norwegian Cancer Society Oslo; consulting or advisory roles for CureVac AG, Definiens, F. Hoffmann-La Roche, Genmab A-S, Life Science Inkubator GmbH, VAXIMM AG, OncoOne Research & Development GmbH, Oncolytics Biotech Inc., Zelluna, HDIT GmbH, AYOXXA, Seattle Genetics, BreakBio Corp., and Roche Pharma AG; expert testimony for courts, Wilhelm-Sander-Stiftung, Else Kröner-Fresenius-Stiftung, Schering Stiftung, and Nordforsk; a leadership role at BMS Stiftung Immunonkologie; and travel accommodation expenses from Amgen Inc, Oryx GmbH, Roche Glycart AG, Parexel.com, IKTZ HD GmbH, BMS. HH reports honoraria from Asahi Kasei, Bayer, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, MSD Biopharma, MSD, Ono, Sanofi, Taiho, Takeda, and Yakult; consulting or advisory roles for Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Dainippon Sumitomo Pharma, MSD, and Ono; and research grants from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Incyte, Janssen, MSD Biopharma, MSD, Ono, and Taiho. MB reports honoraria, consulting or advisory roles, and travel and accommodation expenses for MSD. PK reports consulting or advisory roles for MSD and BMS; expert testimony for BMS; and research grant from MSD and BMS paid to his institution. TY reports honoraria from Taiho, Chugai, Eli Lilly, MSD Biopharma, Bayer, MSD, and Ono; and research grants from Taiho, Ono, Chugai, Amgen, Parexel International, Sanofi, Pfizer Japan, MSD, Genomedia Inc., Sysmex, Nippon Boehringer Ingelheim, and Daiichi Sankyo paid to his institution. RGu reports honoraria from Amgen, Servier, Roche, Ipsen, MSD and BMS; and advisory or consultancy for AAA Pharmaceutical, MSD, BMS, Servier, and P Fabre. HT reports honoraria from Taiho, Takeda, Chugai, Eli Lilly, and MSD Biopharma; and research funding from Taiho, Takeda, Chugai, and Daiichi-Sankyo paid to his institution. EE reports consulting or advisory roles for Amgen, Pierre Fabre, Bayer, MSD, F. Hoffmann-La Roche, Merck Serono, Organon, Sanofi, and Servier; and research grants from Amgen, Array Pharma, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm, Genentech, HalioDx SAS, F. Hoffmann-La Roche, Hutchison, Janssen-Cilag, MedImmune, Menarini, Merck KGaA, MSD, Merus, Mirati, Novartis, Pfizer, PharmaMar, Sanofi Aventis, and Taiho; travel and accommodation expenses from Amgen, Bayer, F. Hoffman-La Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, and Servier; and non-remunerated activities with ASCO, ESMO, and SEOM. SEAB reports consulting or advisory roles for AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Immutep, Lilly, and MSD; speaker bureau for Bristol Myers Squibb, Lilly, and MCI Deutschland GmbH; a leadership role at Institut für Klinische Krebsforschung IKF GmbH; equity interests in Institut für Klinische Krebsforschung IKF GmbH; and research funding from AstraZeneca, Bristol Myers Squibb, Celgene, Eurozyto, Hospira, Immutep, Lilly, Medac, Roche, and Vifor. PMB reports advisory and consulting roles for MSD, Pfizer, Bayer, Guardant Health, and Merrimack; and research grants from AbbVie, Boehringer Ingelheim, Ipsen, Processa, Taiho, MacroGenics, and Merck. YC and PL report employment by MSD, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. PM reports employment by and equity interests in MSD, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. TA reports honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, MSD, Pierre Fabre, Roche/Ventana, Sanofi, and Servier; consulting or advisory roles for Amgen, Aptitude Health, Astellas Pharma, Bristol Myers Squibb, GamaMabs Pharma, Gilead, Gritstone Oncology, MSD, Kaleido Biosciences, Pierre Fabre, Seagen, Servier, and Transgène; speaker’s bureaus for Bristol Myers Squibb, MSD, Seagen, and Servier; research funding from Bristol Myers Squibb and MSD; travel and accommodation expenses from MSD and Bristol Myers Squibb; and non-remunerated activities for the ARCAD Foundation and GERCOR Group. BON has declared no conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Carcinoembryonic antigen (CEA) is the most widely used tumor marker in metastatic colorectal cancer (mCRC). However, its potential as a predictive marker of progression in mCRC during systemic chemotherapy, particularly in patients receiving monoclonal antibodies as a combination therapy, has remained of interest. Herein, we investigated whether CEA changes could predict disease progression and clinical outcomes in patients with mCRC cotreated with systemic chemotherapy and/or biologic agents. A total of 1261 patients with mCRC undergoing a first-line systemic treatment were included in this retrospective study. We analyzed the optimal cut-off value for CEA changes to predict progression at the first response evaluation by the treatment arm (chemotherapy alone, chemotherapy plus anti-vascular endothelial growth factor (VEGF) monoclonal antibody [mAb], and chemotherapy plus anti-epidermal growth factor receptor [EGFR] mAb). These cut-off values were then used to predict overall survival (OS) and progression-free survival (PFS). When stratified by their treatment arm, 891 (70.6%), 266 (21.0%), and 104 (8.2%) of the study patients were included in the chemotherapy alone-, anti-VEGF mAb, and anti-EGFR mAb groups, respectively. The optimal CEA cut-off values were 16.5% and 38.9% increase in the whole cohort and anti-EGFR mAb group, respectively, and these values showed high sensitivity and specificity for predicting disease progression. The patients in the entire population and anti-EGFR mAb group with CEA changes below these cut-off values showed significantly better OS and PFS outcomes compared those whose changes were above cut-off values. Among the patients with mCRC treated with anti-VEGF mAb, no associations were found between OS or PFS outcomes and CEA changes. CEA is potentially a good surrogate marker for predicting disease progression and survival outcomes in patients with mCRC receiving first-line systemic chemotherapy alone or chemotherapy with anti-EGFR mAb, whereas it is less effective in those treated with anti-VEGF mAb., (© 2023. The Author(s).)

Objective: This study aimed to develop and validate post- and preoperative models for predicting recurrence after curative-intent surgery using an FDG PET-CT metabolic parameter to improve the prognosis of patients with synchronous colorectal cancer liver metastasis (SCLM)., Methods: In this retrospective multicenter study, consecutive patients with resectable SCLM underwent upfront surgery between 2006 and 2015 (development cohort) and between 2006 and 2017 (validation cohort). In the development cohort, we developed and internally validated the post- and preoperative models using multivariable Cox regression with an FDG metabolic parameter (metastasis-to-primary-tumor uptake ratio [M/P ratio]) and clinicopathological variables as predictors. In the validation cohort, the models were externally validated for discrimination, calibration, and clinical usefulness. Model performance was compared with that of Fong's clinical risk score (FCRS)., Results: A total of 374 patients (59.1 ± 10.5 years, 254 men) belonged in the development cohort and 151 (60.3 ± 12.0 years, 94 men) in the validation cohort. The M/P ratio and nine clinicopathological predictors were included in the models. Both postoperative and preoperative models showed significantly higher discrimination than FCRS (p < .05) in the external validation (time-dependent AUC = 0.76 [95% CI 0.68-0.84] and 0.76 [0.68-0.84] vs. 0.65 [0.57-0.74], respectively). Calibration plots and decision curve analysis demonstrated that both models were well calibrated and clinically useful. The developed models are presented as a web-based calculator ( https://cpmodel.shinyapps.io/SCLM/ ) and nomograms., Conclusions: FDG metabolic parameter-based prognostic models are well-calibrated recurrence prediction models with good discriminative power. They can be used for accurate risk stratification in patients with SCLM., Key Points: • In this multicenter study, we developed and validated prediction models for recurrence in patients with resectable synchronous colorectal cancer liver metastasis using a metabolic parameter from FDG PET-CT. • The developed models showed good predictive performance on external validation, significantly exceeding that of a pre-existing model. • The models may be utilized for accurate patient risk stratification, thereby aiding in therapeutic decision-making., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1-57.8) months with pembrolizumab and 43.9 (range 36.6-55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months-NR) with pembrolizumab versus 10.4 (95% CI 6.3-22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26-1.20). Median OS was NR (range 13.8 months-NR) versus 30.0 (14.7-NR) months (HR 0.65, 95% CI 0.27-1.55) and ORR was 50% (95% CI 28-72) versus 46% (95% CI 27-67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002., (© 2022 Merck Sharp & Dohme LLC and The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: Colorectal cancer with peritoneal metastasis (PM) has been considered a non-curative disease. PM is associated with reduced overall survival (OS) and worse prognosis compared with metastasis at other sites. We aimed to investigate the treatment outcome and recurrence after curative resection of colorectal PM during a long-term follow-up., Methods: Patients who were diagnosed with colorectal PM and underwent surgery between December 2001 and December 2019 were included (n = 309). Curative resection was defined as PM resection without residual disease after surgery (complete macroscopic resection)., Results: Of 309 patients, 208 (67.8%) had PM as an initially metastatic disease. Curative (R0/1) resection was achieved in 155 (50.2%) patients, while non-curative operation (R2 resection or palliative operation including colostomy) was performed in 154 (49.8%) patients. Compared with patients who underwent non-curative operation, those with curative resection more often had a single PM on preoperative imaging (34.2% vs. 20.8%, p = 0.011) and postoperative results (59.4% vs. 22.7%, p < 0.001) and less often had concurrent metastasis (distant lymph node, liver, or lung) at the time of surgery (p < 0.001). During a median follow-up of 90.4 months, 80.6% (125/155) patients had recurrence in the curative resection group; the peritoneum was the most common site (56.0%). The median OS was 47.7 months (95% CI, 39.2-56.2) in the curative resection group and 24.8 months (95% CI, 20.8-28.9) in the non-curative resection group, respectively (p < 0.001). In particular, twenty-six patients without recurrence showed long-term survival after curative resection (median OS, 87.1 months; range, 40.1-127.5)., Conclusion: Surgical resection can be considered for selected patients with colorectal PM because a significant number of them could seize the cure changes during their treatment continuum., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Circular RNAs (circRNAs) play a critical role in colorectal cancer (CRC) progression, including metastasis. However, the detailed molecular mechanism is not fully understood., Methods: Differentially expressed circRNAs between primary KM12C and liver metastatic KM12L4 colon cancer cells were identified by microarray. The expression of circRNAs was measured by semi-quantitative (semi-qPCR) and real time-quantitative PCR (RT-qPCR). Metastatic potential including invasive and migratory abilities, and liver metastasis were examined by transwell assays and intrasplenic injection, respectively. CircPPFIA1-associated microRNA (miRNA) and RNA-binding protein (RBP) were screened by an antisense oligonucleotide (ASO) pulldown experiment. The effects of circPPFIA1 on target gene expression were evaluated by RT-qPCR and western blot analyses., Results: By analyzing circRNA microarray data, we identified two anti-metastatic circRNAs generated from PPFIA1 with different length, which named circPPFIA1-L (long) and -S (short). They were significantly downregulated in liver metastatic KM12L4 cells compared to primary KM12C cells. The knockdown of circPPFIA1s in KM12C enhanced metastatic potential and increased liver metastasis. Conversely, overexpression of circPPFIA1s weakened metastatic potential and inhibited liver metastasis. circPPFIA1s were found to function as sponges of oncogenic miR-155-5p and Hu antigen R (HuR) by an ASO pulldown experiment. circPPFIA1s upregulated tumor-suppressing CDX1 expression and conversely downregulated oncogenic RAB36 by decoying miR-155-5p and by sequestering HuR, respectively., Conclusion: Our findings demonstrate that circPPFIA1s inhibit the liver metastasis of CRC via the miR-155-5p/CDX1 and HuR/RAB36 pathways., (© 2022. The Author(s).)

Purpose: Recent clinical trials have reported response rates < 50% among patients treated with programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for microsatellite instability‒high (MSI-H) colorectal cancer (CRC), and factors predicting treatment response have not been fully identified. This study aimed to identify potential biomarkers of PD-1/PD-L1 inhibitor treatment response among patients with MSI-H CRC., Materials and Methods: MSI-H CRC patients enrolled in three clinical trials of PD-1/PD-L1 blockade at Asan Medical Center (Seoul, Republic of Korea) were screened and classified into two groups according to treatment response. Their histopathologic features and expression of 730 immune-related genes from the NanoString platform were evaluated, and a machine learning-based classification model was built to predict treatment response among MSI-H CRCs patients., Results: A total of 27 patients (15 responders, 12 non-responders) were included. A high degree of lymphocytic/neutrophilic infiltration and an expansile tumor border were associated with treatment response and prolonged progression-free survival (PFS), while mucinous/signet-ring cell carcinoma was associated with a lack of treatment response and short PFS. Gene expression profiles revealed that the interferon-γ response pathway was enriched in the responder group. Of the top eight differentially expressed immune-related genes, PRAME had the highest fold change in the responder group. Higher expression of PRAME was independently associated with better PFS along with histologic subtypes in the multivariate analysis. The classification model using these genes showed good performance for predicting treatment response., Conclusion: We identified histologic and immune-related gene expression characteristics associated with treatment response in MSI-H CRC, which may contribute to optimal patient stratification.

Purpose: This study aimed to compare the treatment outcomes of radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) for colorectal cancer liver metastases (CRLM) and to determine the favorable treatment modality according to tumor characteristics., Materials and Methods: We retrospectively analyzed the records of 222 colorectal cancer patients with 330 CRLM who underwent RFA (268 tumors in 178 patients) or SBRT (62 tumors in 44 patients) between 2007 and 2014. Kaplan-Meier method and Cox models were used by adjusting with inverse probability of treatment weighting (IPTW)., Results: The median follow-up duration was 30.5 months. The median tumor size was significantly smaller in the RFA group than in the SBRT group (1.5 cm vs 2.3 cm, p<0.001). In IPTW-adjusted analysis, difference in treatment modality was not associated with significant differences in 1-year and 3-year recurrence-free survival (35% vs 43%, 22% vs 23%; p=0.198), overall survival (96% vs 91%, 58% vs 56%; p=0.508), and freedom from local progression (FFLP; 90% vs 72%, 78% vs 60%; p=0.106). Significant interaction effect between the treatment modality and tumor size was observed for FFLP (p=0.001). In IPTW-adjusted subgroup analysis of patients with tumor size >2 cm, the SBRT group had a higher FFLP compared with the RFA group (HR, 0.153; p<0.001)., Conclusion: SBRT and RFA showed similar local control in the treatment of patients with CRLM. Tumor size was an independent prognostic factor for local control and SBRT may be preferred for larger tumors.

The aim of our study is to evaluate the clinical efficacy of durvalumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) or polymerase epsilon (POLE)-mutated metastatic or unresectable colorectal cancer (mCRC) who had disease progression after standard chemotherapy. This prospective, open-label, multicenter, phase II study enrolled patients with mCRC harboring MSI-H/dMMR or POLE mutations treated with at least one prior line of therapy. The participants received durvalumab (1500 mg) every 4 weeks intravenously. The primary endpoint was the objective response rate (ORR). Of the 33 patients, 30 had MSI-H/dMMR and 3 had POLE-mutated microsatellite stable (MSS) CRC. With a median follow-up duration of 11.2 months (95% confidence interval [CI]: 7.3-15.0), the ORR was 42.4% (95% CI: 25.5-60.8). Among three patients with POLE-mutated CRC, one patient who had an exonuclease domain mutation (EDM) achieved an objective response, but the others with mutations in the non-exonuclease domain had progressive disease. Overall, the median duration of response was not reached and 85.7% of the responses were ongoing at data cutoff. The progression-free survival rate of 12 months was 58.2% (95% CI: 39.0-73.1) and the 12-month overall survival rate was 68.3% (95% CI: 48.8-81.7). Grade 3 treatment-related adverse events occurred in 36.4% of the patients and were manageable. In conclusion, durvalumab showed promising clinical activity with encouraging response rates and satisfactory survival outcomes in mCRC patients with MSI-H/dMMR or POLE EDM. In patients with POLE-mutated mCRC, clinical response to durvalumab may be restricted to those with EDM., (© 2022 UICC.)

Background: Pembrolizumab has shown improved progression-free survival versus chemotherapy in patients with newly diagnosed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. However, the treatment's effect on overall survival in this cohort of patients was unknown. Here, we present the final overall survival analysis of the KEYNOTE-177 study., Methods: This randomised, open-label, phase 3 study was done in 193 academic medical centres and hospitals in 23 countries. We recruited patients aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. Patients were randomly assigned (1:1) in blocks of four using an interactive voice response system or integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to the investigator's choice of intravenous mFOLFOX6 (oxaliplatin 85 mg/m 2 on day 1, leucovorin 400 mg/m 2 on day 1, and fluorouracil 400 mg/m 2 bolus on day 1 followed by a continuous infusion of 1200 mg/m 2 per day for 2 days on days 1-2) or intravenous FOLFIRI (irinotecan 180 mg/m 2 on day 1, leucovorin 400 mg/m 2 on day 1, and fluorouracil 400 mg/m 2 bolus on day 1 followed by a continuous infusion of 1200 mg/m 2 per day for 2 days on days 1-2), every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous weekly cetuximab (first dose 400 mg/m 2 , then 250 mg/m 2 for every subsequent dose). Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 treatment cycles after progression. The co-primary endpoints were overall survival and progression-free survival in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov, NCT02563002, and is no longer enrolling patients., Findings: Between Feb 11, 2016, and Feb 19, 2018, 852 patients were screened, of whom 307 (36%) were randomly assigned to pembrolizumab (n=153) or chemotherapy (n=154). 93 (60%) patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy (56 patients to on-study pembrolizumab and 37 patients to off-study therapy). At final analysis (median follow-up of 44·5 months [IQR 39·7-49·8]), median overall survival was not reached (NR; 95% CI 49·2-NR) with pembrolizumab vs 36·7 months (27·6-NR) with chemotherapy (hazard ratio [HR] 0·74; 95% CI 0·53-1·03; p=0·036). Superiority of pembrolizumab versus chemotherapy for overall survival was not demonstrated because the prespecified α of 0·025 needed for statistical significance was not achieved. At this updated analysis, median progression-free survival was 16·5 months (95% CI 5·4-38·1) with pembrolizumab versus 8·2 months (6·1-10·2) with chemotherapy (HR 0·59, 95% CI 0·45-0·79). Treatment-related adverse events of grade 3 or worse occurred in 33 (22%) of 153 patients in the pembrolizumab group versus 95 (66%) of 143 patients in the chemotherapy group. Common adverse events of grade 3 or worse that were attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhoea, and fatigue in three (2%) patients each, and those attributed to chemotherapy were decreased neutrophil count (in 24 [17%] patients), neutropenia (22 [15%]), diarrhoea (14 [10%]), and fatigue (13 [9%]). Serious adverse events attributed to study treatment occurred in 25 (16%) patients in the pembrolizumab group and in 41 (29%) patients in the chemotherapy group. No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy., Interpretation: In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in overall survival between the two treatment groups. These findings support pembrolizumab as an efficacious first-line therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer., Funding: MSD., Competing Interests: Declaration of Interests LAD Jr reports membership on the board of directors of Personal Genome Diagnostics and Jounce Therapeutics; honoraria for consulting and advisory role to Personal Genome Diagnostics, 4Paws, and Neophore; uncompensated advisory and consulting role for Merck Sharp & Dohme; clinical trial funding paid to institution from Merck Sharp & Dohme; and patents for circulating tumour DNA analyses and mismatch repair deficiency for diagnosis and therapy with checkpoint blockade from Johns Hopkins University, the latter licensed to Personal Genome Diagnostics and Qiagen (some licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and LAD Jr); and equity in 4Paws, Personal Genome Diagnostics, Jounce Therapeutics, Thrive Earlier Detection and Neophore; his spouse holds equity in Amgen. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. K-KS reports honoraria including compensation for travel, accommodation, and expenses from Bayer, Bristol Myers Squibb, Guardant Health, Daiichi-Sankyo, Innovent Biologics, Merck KGaA, Merck Sharp & Dohme, Mirati Therapeutics, Roche, and Servier; and Institutional Funding for Research from Adaptimmune Therapeutics, AstraZeneca, Merck KGaA, Merck Sharp & Dohme, and Roche. T-WK reports clinical trial funding paid to institution from Merck Sharp & Dohme and Merck Serono. BVJ, DS, MB, and PG report clinical trial funding paid to institution funding paid to institution from Merck Sharp & Dohme. LHJ reports research funding to the institution from Merck Sharp & Dohme, 2cureX, Incyte, and Bristol Myers Squibb. CP reports research funding to the institution from Merck Sharp & Dohme; and a consulting and advisory role to Bayer, Nordic Pharma, and Servier. RG-C reports clinical trial funding paid to institution from Merck Sharp & Dohme, Bristol Myers Squibb, Ipsen, Roche, Servier, Novartis, Pfizer, Merck, Bayer, and Pharma Mar; and honoraria from Roche, Sanofi Aventis, Servier, Novartis, Pfizer, Merck, Bayer, Pharma Mar, AAA, Advandz Pharma, Midatech Pharma, and Pierre Fabre. CdlF reports clinical trial funding paid to institution funding paid to institution from Merck Sharp & Dohme; a consulting and advisory role for Merck Sharp & Dohme (ESMO 2019). FR reports clinical trial funding paid to institution funding paid to institution from Merck Sharp & Dohme, Roche, Merck-Serono, Amgen, Pierre-Fabre, Sanofi-Aventis, Bayer, Servier, and Lilly; a consulting and advisory role for Roche, Merck-Serono, Amgen, Pierre Fabre, Sanofi-Aventis, Bayer, Servier, Lilly, AstraZeneca, and Bristol Myers Squibb; honoraria from Merck Sharp & Dohme, Roche, Merck-Serono, Amgen, Pierre-Fabre, Sanofi-Aventis, Bayer, Servier, Lilly, AstraZeneca, Pfizer, and Bristol Myers Squibb; and non-financial support from Merck Sharp & Dohme, Roche, Merck-Serono, Amgen, Pierre-Fabre, Sanofi-Aventis, Bayer, and Servier. Exrts clinical trial funding paid to institution from Merck Sharp & Dohme and Sanofi; honoraria from Amgen, Sanofi, Servier, Merck Sharp & Dohme, Pierre Fabre, and Hoffman La Roche; and non-financial support from Amgen, Sanofi, Merck Sharp & Dohme, and Hoffman La Roche. DTL serves on advisory boards for Merck, Bristol Myers Squibb, and Janssen; has received research funding from Merck, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, Nouscom, and AbbVie; has received speaking honoraria from Merck; and is an inventor of licensed intellectual property related to technology for mismatch repair deficiency for diagnosis and therapy (WO2016077553A1) from Johns Hopkins University. The terms of these arrangements are being managed by Johns Hopkins. TY reports grants from Merck Sharp & Dohme for the submitted work; and grants from Ono, Sanofi, Daiichi Sankyo, Chugai, Parexel International, Taiho, Amgen, and Sumitomo Dainippon, outside the submitted work; WYZ, DF, and PM are employees of Merck Sharp & Dohme, a subsidiary of Merck, and hold stock in Merck. TA reports honoraria from Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Chugai, Clovis, Gritstone Oncology, GSK, Haliodx, Kaleido Biosciences, Merck, Pierre Fabre, Roche/Ventana, Sanofi, Transgene, Seagen, and Servier; and compensation for travel, accommodation, and expenses from Roche/Genentech, Merck Sharp & Dohme, and Bristol Myers Squibb., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background/aim: Colorectal cancer is reported to have the highest mortality rate among human malignancies. Although many research results for the treatment of colorectal cancer have been reported, there is no suitable treatment when resistance has developed. Therefore, it is necessary to develop new therapeutic agents. Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling plays an essential role in cell differentiation, proliferation, and survival. Abnormal activation of the JAK/STAT signaling pathway, by gene mutation or amplification, may induce cancer development, and sustained JAK/STAT activation is involved in chemoresistance. While many therapeutic agents have been developed to treat colon cancer, there remains no drug to overcome resistance to chemotherapies. The purpose of this study was to determine the potential of CJ14939 as a novel JAK inhibitor for the treatment of colorectal cancer., Materials and Methods: In this study, cell culture, cell death assay, 3- (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, colony formation assay, immunoblot analysis and tumor xenograft were applied., Results: CJ14939 induced cell death, and inhibited phosphorylation of JAK1 and STAT3 in colorectal cancer cells. Furthermore, CJ14939 also promoted oxaliplatin-induced cell death, up-regulated expression of cleaved caspase-3, and down-regulated expression of phospho-JAK1 and phospho-STAT3. In vivo, co-treatment with CJ14939 and oxaliplatin notably reduced tumor growth when compared with CJ14939 or oxaliplatin treatment alone., Conclusion: This study identifies the important potential of CJ14939 in colorectal cancer treatment and suggests that combining CJ14939 with oxaliplatin might be a novel therapeutic strategy for patients with colorectal cancer., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

We aimed to investigate the dynamic changes of gene expression profiles and immune microenvironment linked to resistance to cetuximab-based treatments in patients with metastatic colorectal cancer (mCRC). A total of 106 patients with RAS-wild type mCRC who were treated with cetuximab-based treatments were included as the study population. RNA-sequencing and multiplexed immunohistochemistry were performed using paired or unpaired pre-treatment and post-treatment tumor tissues. Differentially expressed gene analysis of paired pre-treatment and post-treatment tumor tissues that develop acquired resistance (AR) identified the AR signature. Gene ontology analysis of the AR signature indicated enrichment of immune-related pathway genes. Among the immune subsets whose abundance was estimated by CIBERSORT, M2 macrophages showed the most prominent positive correlation with the expression of the AR signature. Among the post-treatment samples, progressive disease (PD) tumors showed a significantly higher abundance of M2 macrophages compared to non-PD tumors. These findings were validated by multiplexed immunohistochemistry analysis: the density of CD68 + CD206 + M2 macrophages significantly increased at the time of PD following cetuximab-based treatment, whereas it did not consistently change in the tumor pairs of non-PD. In conclusion, a dynamic increase of M2 macrophages is associated with disease progression during cetuximab-based treatment of mCRCs. Targeting M2 macrophages is a promising immunotherapeutic strategy in this clinical context., (© 2022. The Author(s).)

Background: Sotorasib, a specific, irreversible KRAS G12C protein inhibitor, has shown monotherapy clinical activity in KRAS G12C -mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial. We aimed to investigate the activity and safety of sotorasib in phase 2 of the trial., Methods: In this single-arm, phase 2 trial, adult patients with KRAS G12C -mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries, if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with colorectal cancer, enrolled at 33 medical centres in nine countries, are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of sotorasib. This analysis is a prespecified analysis triggered by the phase 2 colorectal cancer cohort. This study is registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting., Findings: On March 1, 2021, at data cutoff, 62 patients with KRAS G12C -mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020, and had received at least one dose of sotorasib monotherapy. Objective response was observed in six (9·7%, 95% CI 3·6-19·9) of 62 patients, all with partial response. Treatment-related adverse events at grade 3 occurred in six (10%) patients, the most common of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred in one (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded. Serious treatment-related adverse events occurred in two (3%) patients (back pain and acute kidney injury)., Interpretation: Although the 9·7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms., Funding: Amgen., Competing Interests: Declaration of interests MGF reports honoraria from Amgen; consulting or advisory roles for Taiho, Bayer, Array, Pfizer, Seattle Genetics, GlaxoSmithKline, Zhuhai Biotech, Mirati, and Incyte; speakers' bureau for Guardant; and research funding (to the institution) from Verastem, Bristol Myers Squibb, Novartis, Amgen, and AstraZeneca. SK reports stock or ownership interests in Navire and Lutris; consulting or advisory roles to EMD Serono, Merck, Holy Stone Healthcare, Novartis, Lilly, Boehringer Ingelheim, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, Ispen, Daiichi Sankyo, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, Jazz Pharmaceuticals, Roche, Navire, and Amgen; and research funding (to the institution) from Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, and Daiichi Sankyo; and research funding (to self) from Merck, Navire, Holy Stone Healthcare, Boehringer Ingelheim, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, Redx Pharma, Ispen, Natera, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, and Jazz Pharmaceuticals. YK reports speaker's bureau for Taiho, ONO, Bayer, and Sanofi; research grants (to the institution) from Daiichi-Sankyo; being the principal investigator for Taiho, Takeda, ONO, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GlaxoSmithKline, Genmab, and Astelas; and advisory roles for Takeda, Boehringer Ingelheim, and Taiho. TWK reports research funding (to the institution) from Roche, Sanofi, Aventis, AstraZeneca. JCK reports support to the University of Michigan from Roche, Boston Biomedical, Bristol-Myers Squibb, NSABP Foundation, AstraZeneca, Isofol Medical, Merck Sharp and Dohme, AbbVie, Hutchison Medipharma, Novartis, and Tempest. GSF reports royalties from Wolters Kluwer; advisory roles (payment to the institution) for Fujifilm, Silicon, Navire, and Turning Point; advisory roles (payment to GSF) for EMD Serono; travel expenses (for research related to the institution) for Bristol-Myers Squibb, EMD Serono, Fujifilm, Millennium, and Sarah Cannon Research Institute; speaker's honorarium, Total Health Conferencing, and Rocky Mountain Oncology Society (2020); research funding (to the institution) for 3-V Biosciences, Abbisko, AbbVie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, AstraZeneca, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MacroGenics, Incyte, Jacobio, Jounce, Kolltan, Loxo/Bayer, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Navire, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, RasCal, Regeneron, Rgenix, Ribon, Sapience, Silicon, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point Therapeutics, University of Texas MD Anderson Cancer Center, Vegenics, and Xencor. VH reports honoraria from Amgen, Baxalta, Boehringer Ingelheim, Celgene, Lilly, Merck, Roche, Sanofi, SERVIER, Sirtex Medical, and Taiho Pharmaceutical; consulting or advisory roles for Amgen, Baxalta, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Halozyme, Merck, Merck Sharpe and Dohme (MSD), Roche, Sanofi, SERVIER, and Sirtex Medical; research funding from Amgen (to the institution), Boehringer Ingelheim (to the institution), Celgene (to the institution), Merck (to the institution), Roche (to the institution), Shire (to the institution), and Sirtex Medical (to the institution); and travel and accommodation expenses from Amgen, Bristol Myers Squibb, Merck, MSD, Roche, SERVIER, Shire, and Sirtex Medical. KM reports grants from Solasia Pharma, Merck Serono, Daiichi Sankyo, Parexel International, Pfizer, and MSD; grants and consulting fees from Amgen; grants, consulting fees, and honorarium from ONO Pharmaceutical; grants and honorarium from Sanofi and Taiho; consulting fees from AstraZeneca; and honorarium from Chugai, Takeda, Eli Lilly, Bristol Myers Squibb, and Bayer, outside the submitted work. JHS reports consulting and advisory board membership for AbbVie, Amgen, AstraZeneca, Bayer, Genentech/Roche, Inivata, Mereo, SeaGen, Natera, Pfizer, and Viatris; and research funding from SeaGen, Sanofi, AstraZeneca, AStar D3, Daiichi-Sankyo, Genentech/Roche, Gossamer Bio, AbbVie, Exelixis, Amgen, and Nektar. DSH reports grants from Bayer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichii-Sanko, Eisai, Adaptimmune, AbbVie, AstraZeneca, Bristol Myers Squibb, Genmab, Infinity, Kite, Kyowa, Medimmune, Molecular Template, Novartis, and Takeda; personal fees from Mirna and LOXO; and honoraria or stock options from Bayer, Baxter, Guidepoint Global, Oncoresponse, Janssen, and Molecular Match, outside the submitted work. CSD reports grants (to the institution for research) from Amgen, AstraZeneca, Agios, Bristol Myers Squibb, BeiGene, Exelixis, Genmab, Macrogenics, Zymeworks, Sanofi Aventis, MedImmune, Array BioPharma, and Lycera; and honoraria (personal for scientific advising or data safety monitoring board) from Bristol Myers Squibb, Merck, Bayer, BeiGene, Astellas, Exelixis, Eli Lilly, Taiho Oncology, and Zymeworks. GG reports research funding from Amgen, BMS, MSD, Merck, and Roche. HH, QT, JKP, and GN report Amgen employment and stock. TJP reports Servier speaker honorarium and being on the MSD advisory board. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Young-onset colorectal cancer (YOCR) is increasing. This study aimed to determine the difference between advanced YOCR and non-YOCR patient outcomes., Methods: We retrospectively included patients with recurrent/metastatic colorectal cancer treated with palliative systemic therapy between 2016 and 2018. Diagnosis at < 50 years was defined as YOCR. Targeted sequencing was used to assess the mutational status., Results: Among the 969 patients included, 210 (21.7%) were YOCR. The median progression-free survival with first-line chemotherapy (PFS1) was 9.7 vs 9.4 months ( P = .755), and the median overall survival (OS) was 25.9 vs 22.3 months ( P = .581) in the YOCR and the non-YOCR group, respectively. However, the youngest patients diagnosed at < 30 years showed poorer survival outcomes (median PFS1, 3.9 months; median OS, 8.6 months) compared with other age groups. PFS1 did not differ between YOCR and non-YOCR by choice of treatment regimen. Among the 340 patients with targeted sequencing results, YOCR had fewer APC mutations (61% vs 80%), but had similar KRAS (53% vs 48%), NRAS (7% vs 3%), and BRAF class I mutations (4% vs 6%). The median tumor mutational burden (TMB) was 10.9 vs 12.5 mut/Mb in YOCR and non-YOCR patients, respectively ( P = .064). TMB increased with age in tumors with high microsatellite instability (Pearson's R = .69, P = .028), but not in microsatellite-stable tumors ( R = .02, P = .658)., Conclusions: Survival outcomes with palliative systemic therapy were similar between recurrent/metastatic YOCR and non-YOCR with an age cut-off of 50 years. However, patients diagnosed at < 30 years of age showed poorer outcomes compared with other age groups.

Neurofibromin 1 (NF1) is a tumor suppressor that has been previously reported to regulate RAS‑MAPK signaling. The present study investigated the possible relationship between NF1 expression and anti‑EGFR antibody (cetuximab) sensitivity in colorectal cancer cell lines. In addition, primary or metastatic colorectal cancer samples from patients treated with cetuximab were assessed for the association of cetuximab sensitivity. The quantities of the NF1 transcript, NF1‑related pathway enrichment and NF1 mutation profile were measured and investigated using RNA sequencing and targeted DNA sequencing. Based on growth inhibition and colony formation assay results, cell lines were designated to be cetuximab‑sensitive (NCI‑H508 and Caco2) or cetuximab‑resistant (KM12C and SM480). Western blotting revealed NF1 was highly expressed in cetuximab‑sensitive cell lines whilst there was little expression in their cetuximab‑resistant counterparts. Knocking down  NF1  expression using small interfering RNA in the cetuximab‑sensitive cell lines enhanced the phosphorylation of MEK and ERK according to western blotting. NF1 knockdown also reduced apoptosis, as observed by the decreased number of apoptotic bodies by DAPI nuclear staining and reduced cleavage of caspase and poly‑(ADP ribose) polymerase. NF1 overexpression by transfection with GTPase‑activating protein‑related domain subunit rendered the cetuximab‑resistant cell lines, KM12C and SW480, more susceptible to cetuximab‑induced apoptosis. RNA sequencing of 111 RAS and BRAF V600 wild‑type tumor samples collected from cetuximab‑treated patients with metastatic colorectal cancer revealed that the pre‑treatment NF1 expression levels were not associated with the cetuximab response. However, tumor samples obtained after cetuximab treatment displayed slightly lower NF1 transcript levels compared with those in the pre‑treatment samples, suggesting that exposure to the anti‑EGFR antibody may be associated with reduced NF1 expression levels. Next‑generation sequencing revealed that the frequency of inactivating mutations in NF1 were rare (1.8%) in patients with colorectal cancer and were not associated with the protein expression levels of NF1 except for in a small number of cases (0.5%), where the biallelic inactivation of NF1 was observed. To conclude, the present study showed that modification of NF1 expression can affect sensitivity to cetuximab in colorectal cancer cell lines, though a limitation exists in terms of its potential application as a biomarker for RAS and BRAF V600 wild‑type tumors.

Oxaliplatin-based chemotherapy with a regimen such as FOLFOX with or without targeted therapy is a standard of care option for advanced colorectal cancer; however, long-term exposure to oxaliplatin is associated with cumulative toxicity. Growing evidence suggests maintenance therapy with a less intensive regimen after platinum-based induction therapy can provide continuing benefit with reduced toxicity. We describe the rationale and design of the Phase III LYNK-003 trial, which will evaluate the efficacy and safety of olaparib with or without bevacizumab compared with 5-fluoruracil plus bevacizumab in patients with unresectable or metastatic colorectal cancer that has not progressed on an induction course of FOLFOX plus bevacizumab. The primary end point is progression-free survival by independent central review; secondary end points include overall survival, objective response, duration of response and safety. Clinical trial registration: NCT04456699.

Recurrent gene mutations and copy number alterations in cancer patients are presumably associated with resistance to targeted therapy. In the present study, we assessed the gene mutations and copy number alterations that recurrently occurred in cetuximab-treated patients with metastatic colorectal cancer (mCRC). Targeted next-generation sequencing was performed in the tumor samples obtained pre- and postcetuximab treatment to assess the variations that occurred during cetuximab treatment. Moreover, we identified the emergent gene mutations (CDK6, EPHA3, ERCC2, MYC, PCMTD1, PIK3CA, PRIM2, RICTOR, and ZNRF3) and copy number alterations (ARAF, BCL2, BRCA2, EGFR, MYC, and SMAD4) that were recurrently observed only in postprogression samples and not in pretreatment or posttreatment samples from patients revealing clinical response. Furthermore, to identify the feasible candidate variations implicated in treatment resistance, we examined the variants with clonal expansion during treatment and discovered PCBP1 as a variant associated with posttreatment progression. Various recurrent mutations were enriched in the TGF-beta signaling pathway. Collectively, we identified recurrent variations in mCRC samples exhibiting post-cetuximab progression. Additionally, future studies are required to evaluate the therapeutic potential of these variations., Competing Interests: Declaration of competing Interest All of the authors have no conflict of interest or potential conflict of interest that bias this work within the past five years and foreseeable future., (Copyright © 2021. Published by Elsevier Inc.)

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second-line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events-caused by irinotecan-and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression-free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12-2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62-1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79-1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39-1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second-line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear., Methods: We conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation., Results: Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = - 0.526). Moreover, PDGFRA showed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients., Conclusions: Our study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients., (© 2021. The Author(s).)

Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m 2 ) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m 2 . No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017)., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The intrinsic immuno-ge7nomic characteristics of colorectal cancer cells that affect tumor biology and shape the tumor immune microenvironment (TIM) are unclear., Methods: We developed a patient-derived colorectal cancer organoid (CCO) model and performed pairwise analysis of 87 CCOs and their matched primary tumors. The TIM type of the primary tumor was classified as immuno-active, immuno-exhausted, or immuno-desert., Results: The gene expression profiles, signaling pathways, major oncogenic mutations, and histology of the CCOs recapitulated those of the primary tumors, but not the TIM of primary tumors. Two distinct intrinsic molecular subgroups of highly proliferative and mesenchymal phenotypes with clinical significance were identified in CCOs with various cancer signaling pathways. CCOs showed variable expression of cancer-specific immune-related genes such as those encoding HLA-I and HLA-II, and molecules involved in immune checkpoint activation/inhibition. Among these genes, the expression of HLA-II in CCOs was associated with favorable patient survival. K-means clustering analysis based on HLA-II expression in CCOs revealed a subgroup of patients, in whom cancer cells exhibited Intrinsically Immunogenic Properties (Ca-IIP), and were characterized by high expression of signatures associated with HLA-I, HLA-II, antigen presentation, and immune stimulation. Patients with the Ca-IIP phenotype had an excellent prognosis, irrespective of age, disease stage, intrinsic molecular type, or TIM status. Ca-IIP was negatively correlated with intrinsic E2F/MYC signaling. Analysis of the correlation between CCO immuno-genotype and TIM phenotype revealed that the TIM phenotype was associated with microsatellite instability, Wnt/β-catenin signaling, APC/KRAS mutations, and the unfolded protein response pathway linked to the FBXW7 mutation in cancer cells. However, Ca-IIP was not associated with the TIM phenotype., Conclusions: We identified a Ca-IIP phenotype from a large set of CCOs. Our findings may provide an unprecedented opportunity to develop new strategies for optimal patient stratification in this era of immunotherapy., (© 2021. The Author(s).)

Background/aims: This nationwide study was undertaken to determine differences in clinicopathologic characteristics and survival of patients with colorectal cancer (CRC) according to age using big data from the Korean National Health Insurance Service (NHIS)., Methods: The NHIS data including quality assessment of CRC by the Health Insurance Review & Assessment Service in Korea between 2011 and 2014 were analyzed. Based on age, patients were divided into three groups: not-old patients (< 65), young-old patients (65 to 74 years old) and old-old patients (≥ 75 years old)., Results: We included 71,513 CRC patients. The median follow-up duration was 3.2 years (range, 0.003 to 5.5). Male patients constituted 60%. The median age of patients was 65 years (range, 18 to 102). Colon was the cancer site in 59.8% of not-old patients, 62.9% of young-old patients, and 66.1% of old-old patients. Compared to not-old patients, young-old and old-old patients were more likely to be diagnosed with colon adenocarcinoma and well/moderate differentiation or adequate differentiation (all p < 0.001). Old patients underwent more emergency operation (p < 0.001) and received less adjuvant therapy in stage I-III (p < 0.001). The probability of 3-year survival of young-old or old-old patients was worse than that for not-old patients (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.46 to 1.64) (HR, 3.19; 95% CI, 3.03 to 3.37)., Conclusion: Old patients with CRC show different histology from younger patients. They are more frequently to have colon as primary lesion. They undergo less adjuvant therapy. Further studies and evidence-based guidelines for older patients with CRC are warranted to improve their outcome.

Background: Concomitant use of proton pump inhibitors (PPIs) with capecitabine was suggested to be associated with poor outcomes in gastrointestinal cancers. We analyzed the differential impact of PPI use on capecitabine and fluorouracil using the data set from the AXEPT trial, a phase III randomized trial that demonstrated the noninferiority of mXELIRI (modified XELIRI: capecitabine plus irinotecan) to FOLFIRI (leucovorin, fluorouracil, and irinotecan), either with or without bevacizumab in patients with metastatic colorectal cancer., Patients and Methods: Out of the per-protocol set (n = 620), patients with information on concomitant medications (n = 482) were included in this post hoc analysis. PPI use was defined as concomitant exposure of capecitabine and the use of any PPI for 20% or more of the study period. The treatment-by-PPI-use interaction was examined after adjusting for stratification factors., Results: Of the 482 patients, 49 (10.1%) used PPI. Among the PPI users, the mXELIRI group tended to have poorer overall survival compared with the FOLFIRI group. In contrast, among the nonusers, the overall survival of the mXELIRI group was significantly better than that of the FOLFIRI group. Similarly, a trend of worse progression-free survival with mXELIRI compared with FOLFIRI was observed in PPI users but not in nonusers. Treatment-by-PPI-use interaction was significant for overall survival and progression-free survival., Conclusion: The significant interaction between PPI use and the type of fluoropyrimidine in terms of overall and progression-free survival suggests that fluorouracil could be a more favorable option than capecitabine for patients with metastatic colorectal cancer using PPIs., Implications for Practice: This study showed a significant interaction between the use of proton pump inhibitors (PPIs) and the type of fluoropyrimidines. This interaction mainly comes from the positive impact of PPIs in the survival outcomes in the fluorouracil arm rather than a negative impact of PPIs in the capecitabine arm. The possible drug-drug interaction shown in this study suggests that fluorouracil, rather than capecitabine, could be a more appropriate choice of fluoropyrimidine for patients who are taking PPIs in the treatment of metastatic colorectal cancer., (© 2021 AlphaMed Press.)

Background: Anti-vascular endothelial growth factor (VEGF) agents have shown clinical benefits against metastatic colorectal cancer (mCRC) when combined with cytotoxic chemotherapeutic drugs. Because randomized controlled trials have restrictive enrollment criteria, and because the participants typically do not resemble actual patients, we here investigated the efficacy of bevacizumab as part of a combination therapy for mCRC in a Korean real-world practice setting., Patients and Methods: We retrospectively evaluated 3748 patients with an initial diagnosis of mCRC or recurrent colorectal cancer with distant metastasis who received first-line chemotherapy in a tertiary cancer center. The primary study endpoint was overall survival. We used multivariate analysis using the Cox regression hazard model and propensity score matching (PSM) methods to adjust for any confounding clinicopathologic factors. Subgroup analysis was also performed for patients who did not receive local treatments for metastatic lesions before receipt of first-line chemotherapy., Results: In an initial crude analysis, patients who received first-line FOLFOX or FOLFIRI showed better survival outcomes if these regimens were combined with bevacizumab (median overall survival, 3.5 vs. 2.3 years; hazard ratio [HR] = 0.66; 95% confidence interval [CI], 0.59-0.73; P < .001). However, Cox regression hazard model adjusted analysis using PSM methods revealed no significant survival differences between these groups (3.0 vs. 2.6 years; HR = 0.92; 95% CI, 0.79-1.07; P = .2612). We performed further survival analysis of 2814 patients with unresectable disease without metastasectomy who received metastatic radiofrequency ablation before chemotherapy. Cox regression and PSM analysis indicated that bevacizumab group showed better survival (HR = 0.82; 95% CI, 0.71-0.94; P = .005; and HR = 0.84; 95% CI, 0.71-0.99; P = .018)., Conclusion: The addition of bevacizumab to a first-line chemotherapeutic regimen provides survival benefits in a real-world setting for mCRC patients who cannot undergo curative-intent local treatment for metastatic lesions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In the KEYNOTE-177 study, pembrolizumab monotherapy provided statistically significant and clinically meaningful improvements in progression-free survival versus chemotherapy as first-line treatment in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. To further support the efficacy and safety findings of the KEYNOTE-177 study, results of the health-related quality of life (HRQOL) analyses are reported here., Methods: KEYNOTE-177 is an open-label, randomised, phase 3 trial being done at 192 cancer centres in 23 countries, in patients aged 18 years and older with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had not received previous systemic therapy for metastatic disease. Eligible patients were randomly assigned (1:1) centrally by use of interactive voice response or integrated web response technology to receive pembrolizumab 200 mg intravenously every 3 weeks or investigator's choice chemotherapy (mFOLFOX6 [leucovorin, fluorouracil, and oxaliplatin] or FOLFIRI [leucovorin, fluorouracil, and irinotecan] intravenously every 2 weeks with or without intravenous bevacizumab or cetuximab). Patients and investigators were not masked to treatment assignment. The primary endpoints were progression-free survival (previously reported) and overall survival (data to be reported at the time of the final analysis). HRQOL outcomes were evaluated as prespecified exploratory endpoints. The analysis population comprised all randomly assigned patients who received at least one dose of study treatment and completed at least one HRQOL assessment. HRQOL outcomes were mean change from baseline to prespecified week 18 in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Quality of Life Questionnaire-Colorectal 29 (EORTC QLQ-CR29) scale and item scores, and in the EuroQoL 5 Dimensions 3 Levels (EQ-5D-3L) visual analogue scale and health utility scores; the proportion of patients with improved, stable, or deteriorated scores from baseline to prespecified week 18 in EORTC QLQ-C30 scales and items; and time to deterioration in EORTC QLQ-C30 global health status/quality of life (GHS/QOL), physical functioning, social functioning, and fatigue scores and EORTC QLQ-CR29 urinary incontinence scores. The threshold for a small and clinically meaningful mean difference in EORTC QLQ-C30 score was 5-8 points. This study is registered with ClinicalTrials.gov, NCT02563002 and is ongoing; recruitment is closed., Findings: Between Feb 11, 2016, and Feb 19, 2018, 307 patients were enrolled and randomly assigned to receive pembrolizumab (n=153) or chemotherapy (n=154). The HRQOL analysis population comprised 294 patients (152 receiving pembrolizumab and 142 receiving chemotherapy). As of Feb 19, 2020, median time from randomisation to data cutoff was 32·4 months (IQR 27·7-37·8). Least squares mean (LSM) change from baseline to prespecified week 18 showed a clinically meaningful improvement in EORTC QLQ-C30 GHS/QOL scores with pembrolizumab versus chemotherapy (between-group LSM difference 8·96 [95% CI 4·24-13·69]; two-sided nominal p=0·0002). Median time to deterioration was longer with pembrolizumab versus chemotherapy for GHS/QOL (hazard ratio 0·61 [95% CI 0·38-0·98]; one-sided nominal p=0·019), physical functioning (0·50 [95% CI 0·32-0·81]; one-sided nominal p=0·0016), social functioning (0·53 [95% CI 0·32-0·87]; one-sided nominal p=0·0050), and fatigue scores (0·48 [95% CI 0·33-0·69]; one-sided nominal p<0·0001)., Interpretation: Pembrolizumab monotherapy led to clinically meaningful improvements in HRQOL compared with chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These data, along with the previously reported clinical benefits, support pembrolizumab as a first-line treatment option for this population., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA., Competing Interests: Declaration of interests TA reports consulting or advisory roles, or both, and received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Chugai, Clovis Oncology, GlaxoSmithKline, Gritstone Oncology, HalioDx, Pierre Fabre, Roche/Ventana, Sanofi, Servier, Tesaro and Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA (MSD); travel, accommodations, and expenses from Roche/Ventana, Bristol Myers Squibb, and MSD; speaker bureau fees from Bristol Myers Squibb and Servier; and research funding from MSD. TA also reports participation in the scientific committee of the ARCAD foundation and GERCOR group as non-renumerated activities. MA is an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA, and is a shareholder in Merck & Co, Kenilworth, NJ, USA. JMN is an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ USA, and may own stock or hold stock options, or both, in the Company. K-KS reports honoraria from Bristol Myers Squibb, Guardant Health, Innovent Biologics, Merck KGaA, Roche, and Servier; consulting or advisory roles, or both, for Roche; research grants or funding, or both, from Amgen, Bristol Myers Squibb, Gilead, Merck KGaA, Roche, and MSD; and travel, accommodations, and expenses from Merck KGaA, Innovent Biologics, and MSD. TWK reports research grants or funding, or both, from Merck Serono, AstraZeneca, and Pfizer. BVJ reports research grants or funding, or both, from MSD. LHJ reports research grants or funding, or both, to his institution from 2cureX, Incyte, Bristol Myers Squibb, and MSD. CJAP reports advisory roles for Nordic Pharma. DS declares no competing interests. RG-C has provided scientific advice, attended speakers bureau, or received honoraria from AAA, Advanz Pharma, Bayer, Bristol Myers Squibb, HMP, Ipsen, Merck & Co, Midatech Pharma, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Sanofi, Servier, and MSD; and has received support to his institution for the conduct of clinical trials or for molecular diagnostic platforms from ARMO Biosciences, AstraZeneca, Pfizer, Novartis, Ipsen, Roche, Pharmacyclics, Boston Biomedicals, Merck & Co, Amgen, Sanofi, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Sysmex, Gilead Sciences, Servier, Adacap, VCN, Lilly, Pharmamar, and MSD. RG-C also reports financial support from Pfizer and Bristol Myers Squibb to an investigator-initiated trial evaluating axitinib in neuroendocrine tumours and nivolumab in neuroendocrine carcinomas. RG-C also reports being a member of the Executive Committee of the Spanish Neuroendocrine Tumor Cooperative Group (GETNE), the Executive Committee of the European Society of Neuroendocrine Tumors (ENETS), the Scientific Advisory Group for Oncology (SAG-O) of the European Medicines Agency (EMA; 2008–17), EORTC, ASCO, ESMO, SEOM, TTD, GEMCAD; and is a global PI of a clinical trial of Axitinib (Pfizer) in neuroendocrine tumours and a clinical trial of nivolumab (Bristol Myers Squibb) and chemotherapy in neuroendocrine carcinomas. IS reports advisory or consultancy, or both, roles for Ipsen, Pfizer, Syrtex, Amgen, and Pharmamar; and speaker bureau fees from AAA, Sanofi, and Novartis. CDLF reports advisory or consultancy, or both, roles for Roche, Pierre Fabre, Oncologie, Eisai, Bayer, and MSD; and travel, accommodations, and expenses from Amgen, Eisai, Bristol Myers Squibb, and Roche. FR reports honoraria; advisory or consultancy roles, or both; research grants or funding, or both; travel, accommodations, and expenses from Roche, Merck-Serono, Sanofi, Bristol Myers Squibb, Servier, Lilly, Amgen, Bayer, Celgene, and MSD. EE reports personal financial interests, honoraria, advisory roles, travel grants, and research grants from Hoffman-La Roche, Sanofi, Aventis, Amgen, Merck Serono, Servier, Array Pharmaceuticals, Bristol Myers Squibb, and MSD; and institutional financial interests and honoraria from Hoffman-La Roche, Sanofi Aventis, Amgen, Merck Serono, Boehringer Ingelheim, AbbVie, Array Pharmaceuticals, Pierre Fabre, Novartis, Bristol Myers Squibb, GlaxoSmithKline, MedImmune, and MSD. LAD is a member of the board of directors of Personal Genome Diagnostics and Jounce Therapeutics. LAD is a compensated consultant to PGDx, 4Paws (PetDx), Innovatus CP, Se'er, Kinnate, and Neophore. LAD is an uncompensated consultant to Merck & Co. LAD has received research support for clinical trials from Merck & Co. LAD is an inventor of multiple licensed patents related to technology for circulating tumour DNA analyses and mismatch repair deficiency for diagnosis and therapy from Johns Hopkins University. Some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and LAD. LAD holds equity in Personal Genome Diagnostics, Jounce Therapeutics, Thrive Earlier Detection, Se'er, Kinnate and Neophore. LAD's spouse holds equity in Amgen. The terms of all these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with their conflict of interest policies. TY reports research funding from Novartis Pharma, MSD, Sumitomo Dainippon Pharma, Chugai Pharmaceutical, Sanofi, Daichi Sankyo, Parexel International, Ono Pharmaceutical, and GlaxoSmithKline. EVC reports advisory board roles for Array, AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Halozyme, GlaxoSmithKline, Incyte, Ipsen, Lilly, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and MSD; and research funding from Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck KGaA, Novartis, Roche, Servier, and MSD. PY is an employee of MSD China Holding. MF is an employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ USA, who may own stock or hold stock options, or both in the Company. DTL reports advisory board roles for MSD and Bristol Myers Squibb; research funding from MSD, Bristol Myers Squibb, Aduro Biotech, Curegenix, Medivir, and Nouscom; honoraria from MSD; and is an inventor of licensed intellectual property from Johns Hopkins University., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There is an unmet medical need for later-line treatment options for patients with metastatic colorectal cancer (mCRC). Considering that, beyond progression, co-treatment with bevacizumab and cytotoxic chemotherapy showed less toxicity and a significant disease control rate, we aimed to evaluate the efficacy of capecitabine and bevacizumab. This single-center retrospective study included 157 patients between May 2011 and February 2018, who received bevacizumab plus capecitabine as later-line chemotherapy after progressing with irinotecan, oxaliplatin, and fluoropyrimidines. The study treatment consisted of bevacizumab 7.5 mg/kg on day 1 and capecitabine 1,250 mg/m 2 orally (PO) twice daily on day 1 to 14, repeated every 3 weeks. The primary endpoint was progression-free survival (PFS). The median PFS was 4.6 months (95% confidence interval [CI] 3.9-5.3). The median overall survival (OS) was 9.7 months (95% CI 8.3-11.1). The overall response rate was 14% (22/157). Patients who had not received prior targeted agents showed better survival outcomes in the multivariable analysis of OS (hazard ratio [HR] = 0.59, 95% CI 0.43-0.82, P = 0.002) and PFS (HR = 0.61, 95% CI 0.43-0.85, P = 0.004). Bevacizumab plus capecitabine could be a considerably efficacious option for patients with mCRC refractory to prior standard treatments.

The global incidence of early-onset colorectal cancer (EO-CRC) is rapidly rising. However, the reason for this rise in incidence as well as the genomic characteristics of EO-CRC remain largely unknown. We performed whole-exome sequencing in 47 cases of EO-CRC and targeted deep sequencing in 833 cases of CRC. Mutational profiles of EO-CRC were compared with previously published large-scale studies. EO-CRC and The Cancer Genome Atlas (TCGA) data were further investigated according to copy number profiles and mutation timing. We classified colorectal cancer into three subgroups: the hypermutated group consisted of mutations in POLE and mismatch repair genes; the whole-genome doubling group had early functional loss of TP53 that led to whole-genome doubling and focal oncogene amplification; the genome-stable group had mutations in APC and KRAS, similar to conventional colon cancer. Among non-hypermutated samples, whole-genome doubling was more prevalent in early-onset than in late-onset disease (54% vs 38%, Fisher's exact P = 0.04). More than half of non-hypermutated EO-CRC cases involved early TP53 mutation and whole-genome doubling, which led to notable differences in mutation frequencies between age groups. Alternative carcinogenesis involving genomic instability via loss of TP53 may be related to the rise in EO-CRC.

Background: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown., Methods: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival., Results: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group., Conclusions: Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Antibodies against epidermal growth factor receptor (EGFR), panitumumab, a fully human monoclonal antibody, and cetuximab, a human/mouse chimeric monoclonal antibody, have shown clinical efficacy in metastatic colorectal cancer (mCRC). In the phase 3 noninferiority ASPECCT (ClinicalTrials.gov, NCT01001377) study, panitumumab was demonstrated to be noninferior to cetuximab and provided a similar overall survival benefit for patients with chemotherapy-refractory wild-type KRAS exon 2 mCRC. However, some patients eventually develop resistance to anti-EGFR therapy. EGFR p.S492R mutation was previously identified as conferring resistance to cetuximab, but not to panitumumab., Methods: This biomarker study analyzed plasma samples from ASPECCT collected at both baseline and posttreatment., Results: No EGFR p.S492R mutations were identified at baseline; however, after treatment the EGFR p.S492R mutation was detected in 1% of patients treated with panitumumab versus 16% of those treated with cetuximab, supporting that, in a large population, this mutation is more likely to be induced by cetuximab than by panitumumab. There were, however, no significant differences in progression-free survival or overall survival between patients who were wild-type compared with those with the S492R mutation within the cetuximab arm or the overall population., Conclusions: These results may support targeting treatment to small patient subgroups based on the presence of emerging EGFR mutations and provide a molecular rationale for rechallenging with a different anti-EGFR agent in patients who develop resistance. Prospective studies are needed to evaluate the efficacy of panitumumab in the EGFR p.S492R mutant population.

Purpose: We evaluated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations., Materials and Methods: In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLE mutations after failure of ≥1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for microsatellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1., Results: The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSI-H and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment-related adverse events occurred in four and two patients, respectively, with no treatment-related deaths., Conclusion: Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy.

Wait time and scheduling for outpatient chemotherapy administration depends on various factors including infusion room hours of operation, availability of oncologists, nursing and pharmacy staffing, and physical space limitations. The aim of this study was to use the electronic event log of patients on health information system (HIS) to map and analyze patient flow in advanced metastatic colorectal patients at an academic cancer center. From January 2009 to December 2014, patients who were diagnosed with metastatic colorectal cancer and received outpatient chemotherapy confined to FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX (folinic acid, fluorouracil, and oxaliplatin) were identified. From the HIS, patient flow was mapped by collection of event records including blood collection and pretreatment laboratory test, arrival to outpatient clinics, outpatient session (interview, drug accountability and appointment scheduling), and initiation of chemotherapy. A total of 10,638 patients were analyzed for 136,281 outpatient visits. The total office stay time from outpatient registration to initiation of chemotherapy was 92.58 ± 87.96 (mean ± standard deviation) minutes. Each outpatient session lasted 23.75 ± 51.55 minutes. After completing the outpatient session, patients waited 1,657.23 ± 3,027.65 minutes before chemotherapy and 46.66 ± 75.94 minutes within infusion room. Compared to the prior first come first serve rule, the new reservation system showed an improvement in overall waiting time from 2,432.3 ± 4,822.9 to 2,386.7 ± 143.4 minutes; however, waiting time within infusion room slightly increased from 36.68 ± 49.33 to 48.13 ± 46.32 minutes. Our findings indicate that transaction data analytics from HIS can be used to evaluate patient flow within oncology outpatient practice based on real-world hospital data.

Background: No therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRAS G12C ., Methods: We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1., Results: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma., Conclusions: Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)., (Copyright © 2020 Massachusetts Medical Society.)

Colorectal cancer (CRC) is prevalent with high mortality, with liver metastasis contributing as a major factor that worsens the survival of patients. The roles of miRNAs in CRC have been elucidated, subsequent to recent studies that suggest the involvement of miRNAs in cancer biology. In this study, we compare the miRNA and gene expression profiles of primary tumors between two groups of patients (with and without liver metastasis) to identify the metastasis-initiating microRNA-target gene regulations. Analysis from 33 patients with metastasis and 14 patients without metastasis revealed that 17 miRNAs and their 198 predicted target genes are differentially expressed, where the target genes showed association with cancer progression and metastasis with statistical significance. In order to evaluate the clinical implications of the findings, we classified CRC patients of independent data into two groups based on the identified miRNA-target regulations, where one group was closer to primary tumors with metastasis than the other group. The comparison of survival showed statistically significant difference, thereby implying the roles of the identified miRNA-target regulations in cancer progression and metastasis. The identification of metastasis-initiating miRNA-target regulations in this study will lead to better understanding of the roles of miRNAs in CRC progression.

Introduction: Whether patients with resectable colorectal liver metastases (CRLM) gain a survival benefit from perioperative chemotherapy remains controversial. The benefit of including bevacizumab in chemotherapy also remains unclear., Material and Methods: Seventy-six patients with CRLM were randomly assigned to either 6 cycles of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin)/FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) with bevacizumab before and after surgery or 12 cycles after surgery. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and compared by the log-rank test., Results: The median PFS of all patients was 37.4 months at 5.4 years follow-up, and the median overall survival (OS) was not reached. The PFS between the perioperative group and the postoperative group did not reveal a statistical difference (P = .280). The OS was significantly better in the perioperative group (hazard ratio [HR], 0.60; 95% confidence interval [CI],) 0.35-1.02; P = .049). In subgroup patients with carcinoembryonic antigens (CEA) ≥ 5 ng/mL or those with over 2 liver metastases, perioperative group had longer OS than postoperative group (CEA: HR, 0.49; 95% CI, 0.25-0.93; P = .030; number of liver metastases: HR, 0.55; 95% CI, 0.30-0.99; P = .049). The largest liver metastases size, disease-free interval, and sidedness did not affect PFS or OS. There was no difference between the 2 groups in postoperative complications with bevacizumab or adverse events during chemotherapy., Conclusions: In patients with resectable CRLMs, perioperative chemotherapy had no effect on PFS, but improved OS. Patients with high CEA levels or over 2 liver metastases may benefit from perioperative chemotherapy., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Epithelial-mesenchymal transition (EMT) is the most common cause of death in colorectal cancer (CRC). In this study, we investigated the functional roles of miRNA-17-5p in EMT of CRC cells., Methods: In order to determine if miRNA-17-5p regulated EMT, the precursors and inhibitors of miR-17-5p were transduced into four CRC cells. To evaluate the regulatory mechanism, we performed argonaute 2 (Ago2) immunoprecipitation (IP) and luciferase assay. In addition, we used an intra-splenic injection mouse model of BALB/c nude mice to investigate the metastatic potential of miRNA-17-5p in vivo., Results: The miRNA-17-5p expression was lower in primary CRC tissues with metastasis than in primary CRC tissues without metastasis in our RNA sequencing data of patient tissue. Real-time quantitative PCR revealed that miRNA-17-5p was inversely correlated with that of vimentin in five CRC cell lines. Over-expression of miRNA-17-5p decreased vimentin expression and inhibited cell migration and invasion in both LoVo and HT29 cells. However, inhibition of miRNA-17-5p showed the opposite effect. Ago2 IP and luciferase assay revealed that miRNA-17-5p directly bound to the 3'UTR of VIM mRNA. Furthermore, miRNA-17-5p inhibited the metastasis of CRC into liver in vivo., Conclusions: Our results demonstrated that miRNA-17-5p regulates vimentin expression, thereby regulating metastasis of CRC.

Over the last few decades, molecularly targeted agents have been used for the treatment of metastatic colorectal cancer. They have made remarkable contributions to prolonging the lives of patients. The emergence of several biomarkers and their introduction to the clinic have also aided in guiding such treatment. Recently, next-generation sequencing (NGS) has enabled clinicians to identify these biomarkers more easily and reliably. However, there is considerable uncertainty in interpreting and implementing the vast amount of information from NGS. The clinical relevance of biomarkers other than NGS are also subjects of debate. This review covers controversial issues and recent findings on such therapeutics and their molecular targets, including VEGF , EGFR , BRAF , HER2 , RAS , actionable fusions, Wnt pathway and microsatellite instability for comprehensive understanding of obstacles on the road to precision oncology in metastatic colorectal cancer., Competing Interests: Competing interests: None declared., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Purpose: KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC)., Methods: This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti-vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability., Results: A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A., Conclusion: Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

Background: Tyrosine kinase inhibitor-induced hypothyroidism is associated with favorable survival in patients with various cancers., Objective: We aimed to investigate the incidence of regorafenib-induced hypothyroidism and assess its prognostic value in patients with metastatic or unresectable colorectal cancer (CRC) receiving regorafenib., Patients and Methods: This study included 68 patients treated at Asan Medical Center (Seoul, Republic of Korea) between 2014 and 2016 with metastatic or unresectable CRC refractory to standard therapies. Regorafenib (160 mg/day on days 1-21 followed by a 7-day break) was administered., Results: The median patient age was 58 (range 26-72) years; 61.8% of patients were male. Among the 68 patients, 50 (73.5%) showed hypothyroidism; 39 (57.4%) had subclinical and 11 (16.2%) had symptomatic hypothyroidism. Overall, the objective response rate (ORR) and disease control rate (DCR) were 7.4% and 70.6%, respectively; both were significantly higher in patients with symptomatic or subclinical hypothyroidism than in euthyroid patients (ORR 27.3% vs. 5.1% vs. 0.0%, P = 0.001; DCR 100% vs. 76.9% vs. 38.9%, P = 0.001). Median progression-free survival (PFS) and overall survival (OS) were longer in patients with symptomatic hypothyroidism than in those with subclinical hypothyroidism (median PFS 9.1 vs. 3.8 months, P = 0.018; median OS: 19.2 vs. 9.4 months, P = 0.012) or with euthyroid status (median PFS 9.1 vs. 1.8 months, P < 0.001; median OS 19.2 vs. 4.7 months, P = 0.001). Symptomatic hypothyroidism was a significant protective factor for PFS (hazard ratio (HR) = 0.37, P = 0.006) and OS (HR = 0.35, P = 0.007); no other adverse events were associated with survival., Conclusions: Regorafenib-induced hypothyroidism frequently occurs in patients with metastatic CRC receiving regorafenib and is associated with improved survival. Thyroid function status should be actively monitored in CRC patients receiving regorafenib.

In vitro culture of patient‑derived tumor cells offers many advantages in the development of novel therapies for colorectal cancer. Although various culture systems have been developed, the long‑term expansion of patient‑derived tumor cells remains challenging. The present results suggested that tumor cells isolated from colorectal cancer patient‑derived xenografts can be efficiently immortalized in conditioned medium from irradiated feeder cells containing Y‑27632, a rho‑associated coiled‑coil containing protein kinase (ROCK) inhibitor. Patient‑derived tumor cells proliferated rapidly, reaching 90‑95% confluence in ~6 days. Short tandem repeat analysis suggested that these tumor tissues and cultured cells presented 13 identical short tandem repeat loci, including Amelogenin, Penta E, Penta D, D2S1338 and D19S433. Their epithelial phenotype was confirmed by staining for epithelial cell adhesion molecule and cytokeratin 20, whereas vimentin was used as a mesenchymal marker. When cells were transferred to 3D cultures, they continued to proliferate, forming well‑defined tumor spheroids. Expression levels of human telomerase reverse transcriptase and C‑Myc mRNA were increased in cultured cells. Finally, immortalized cells were used for the screening of 65 anticancer drugs approved by the Food and Drug Administration, allowing the identification of gene‑drug associations. In the present study, primary culture models of colorectal cancer were efficiently established using a ROCK inhibitor and feeder cells, and this approach could be used for personalized treatment strategies for patients with colorectal cancer.

Background: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling., Methods: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis., Results: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group., Conclusions: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.)., (Copyright © 2019 Massachusetts Medical Society.)