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Background: Evaluating multiple biomarkers including human epidermal growth factor receptor 2 (HER2), mismatch repair (MMR) status, programed death-ligand 1 (PD-L1), and claudin 18.2 (CLDN18.2) is essential for selecting appropriate first-line therapy of metastatic gastroesophageal adenocarcinoma (mGEA). However, this can be challenging if tumor tissue amount is limited and may cause delays in the initiation of chemotherapy. Therefore, we assessed the feasibility of multiple biomarkers testing in routine clinical practice. Materials and methods: We reviewed the medical records of treatment-naïve patients with mGEA who underwent prospective multiple biomarkers testing between April 2022 and October 2023 in our institution. Eight biomarker status including HER2, MMR, PD-L1, CLDN18.2, Epstein–Barr virus, fibroblast growth factor receptor 2, epidermal growth factor receptor and mesenchymal epithelial transition expressions were simultaneously examined using biopsy or surgical specimens. Results: A total of 203 patients with mGEA were analyzed. Most patients underwent gastroendoscopy and tumor biopsy shortly after referral to our institution. Biomarkers testing was successfully completed on the first attempt in 198 patients (97.5%). With additional steps including additional biopsy or asking remaining tumor samples from the referring hospital, the biomarker results were eventually available in all cases. The median turnaround time from sample collection to reporting results was 7 days. Consequently, 178 patients (87.7%) could receive first-line treatment after obtaining the biomarker status. Conclusions: Multiple biomarkers testing for patients with mGEA was feasible in clinical practice. Establishment of a testing infrastructure based on the collaboration with multiple departments is essential for implementing biomarker-driven precision treatment.

Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting HER2-positive gastric cancer or gastroesophageal junction cancer (GC/GEJC). Although effective, T-DXd has notable toxicities, including interstitial lung disease (ILD). This study evaluated the efficacy, safety, and prognostic factors associated with T-DXd for GC/GEJC., Methods: A retrospective observational study was conducted at our institution by reviewing medical records of patients treated with T-DXd until September 2023. Eligible patients had unresectable advanced or recurrent GC/GEJC, HER2 status of IHC 3 + or IHC 2 + /ISH-positive, and prior treatment with trastuzumab-containing regimen., Results: Among the 101 patients analyzed, the initial T-DXd dose was 6.4 mg/kg in 77 patients and 5.4 mg/kg in 24 patients. The objective response rate was 54.3%, with a median PFS of 5.4 months and a median OS of 11.4 months. The significant prognostic factors for shorter PFS and OS included ECOG PS ≥ 1, presence of primary lesion, and peritoneal metastasis but not the initial T-DXd dose. ILD occurred in 14.9% of patients. Notably, higher T-DXd dose and smaller tumor burden were associated with a higher incidence of ILD., Conclusions: Several factors were associated with prognosis after T-DXd treatment in patients with GC/GEJC. Tumor burden is a potential risk factor for T-DXd-related ILD. Further studies are needed to optimize dosing based on tumor burden and to improve the therapeutic index., Competing Interests: Declarations. Conflict of interest: A. Jubashi have no conflict of interest. I. Nakayama has received research funding from Ono, MSD, and CHUGAI PHARMACEUTICAL CO., LTD. outside the submitted work. S. Koganemaru has received research funding from Eisai Inc., Amgen, Bristol-Myers Squibb, MSD, Daiichi Sankyo, AbbVie and Incyte outside the submitted work. Y. Matsubara has received honoraria from Taiho, Takeda, Elli Lilly Japan, MSD, and Bristol-Myers Squibb outside the submitted work. S. Mishima has received honoraria from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Eli Lilly Co., Ltd. outside the submitted work. D. Kotani has received honoraria from Takeda, Chugai, Lilly, MSD, Ono, Taiho, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Eisai, and Merck biopharma and research funding from Ono, MSD, Novartis, Servier, Janssen, IQVIA, Syneos Health, Cimic, and Cimicshiftzero outside the submitted work. A. Kawazoe has received honoraria from Daiichi Sankyo, Lilly, Ono, Taiho, Bristol-Myers Squibb, and Merck Serono biopharma and research funding from Ono, MSD, Taiho, Bayer, Sumitomo Dainippon and AstraZeneca outside the submitted work. T. Hashimoto has received honoraria from CytoGen, Inc. and Takata Pharmaceutical outside the submitted work. Y. Nakamura plays an advisory role at Guardant Health Pte Ltd., Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Exact Sciences Corporation, and Gilead Sciences, Inc.; is included in the speakers’ bureau from Guardant Health Pte Ltd., MSD K.K., Eisai Co., Ltd., Zeria Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., CareNet, Inc., Hisamitsu Pharmaceutical Co., Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Becton, Dickinson and Company, and Guardant Health Japan Corp; and has received research funding from Seagen, Inc., Genomedia Inc., Guardant Health AMEA, Inc., Guardant Health, Inc., Tempus Labs, Inc., Roche Diagnostics K.K., Daiichi Sankyo Co., Ltd., and Chugai Pharmaceutical Co., Ltd. outside the submitted work. Y. Kuboki has received personal fees for advisory roles from Taiho, Takeda, and Boehringer Ingelheim; honoraria from Taiho, Ono, Bayer, and Sanofi; and institutional grants or contracts with Taiho, Takeda, Ono, AbbVie, AstraZeneca, Boehringer Ingelheim, Incyte, Amgen, Chugai, GlaxoSmithKline, Genmab, Astellas, and Daiichi Sankyo outside the submitted work. H. Bando has received research fund from Ono Pharmaceutical and honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly Japan outside the submitted work. T. Kojima has received honoraria as an invited speaker and for manuscript writing from Bristol-Myers Squibb, Ono Pharmaceutical Co., Ltd., Covidien Japan, Inc., MSD K.K., TAIHO PHARMACEUTICAL CO., LTD., and Oncolys BioPharma Inc.; research funding from Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb, BeiGene Ltd., EPS Corporation., MSD K.K., Amgen Inc., SHIONOGI & Co., Ltd., and CHUGAI PHARMACEUTICAL CO., LTD. outside the submitted work. T. Yoshino has received honoraria from Chugai Pharmaceutical, Takeda Pharmaceutical, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, and MSD K.K; consulting fee from Sumitomo Corp.; and research funding from Amgen, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, FALCO biosystems, Genomedia, Medical & Biological Laboratories, Merus N.V., Molecular Health GmbH, MSD, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer Japan, Roche Diagnostics, Sanofi, Sysmex, Taiho Pharmaceutical, and Takeda Pharmaceutical outside the submitted work. K. Nakao has received honoraria from AstraZeneca outside the submitted work. K. Shitara has received personal fees for advisory roles from Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Merck Pharmaceutical, Taiho Pharmaceutical, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, Boehringer Ingelheim, and Janssen; honoraria (lecture fee) from Takeda and Bristol-Myers Squibb; and research funding from Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai, Merck Pharmaceutical, Medi Science, Eisai, and Amgen outside the submitted work. All remaining authors have no competing interest. Informed consent: All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later versions. Informed consent to be included in the study or the equivalent was obtained from all patients., (© 2024. The Author(s).)

Background: Aberrant Wnt pathway signaling has been implicated in the development of many cancers. Targeting of low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptors inhibits Wnt signaling and may be a novel therapy. BI 905677 is an LRP5/6 antagonist that has demonstrated preclinical antitumor activity., Patients and Methods: This (NCT03604445) was a phase I, dose-escalation study evaluating BI 905677 for patients with advanced solid tumors over two dosing schedules (A: i.v. infusion every 3 weeks, 3-week cycles; B: i.v. infusion every 2 weeks, 4-week cycles). Adult patients were eligible if they had exhausted treatment options and had an Eastern Cooperative Oncology Group performance status of 0-1. The primary endpoints were the maximum tolerated dose (MTD) and safety. Other endpoints were pharmacokinetics, pharmacodynamics, and efficacy., Results: In total, 37 patients received BI 905677 over nine dose cohorts (0.05-3.6 mg/kg/every 3 weeks). Dose-limiting toxicities were only reported during cycle 1 in the 3.6 mg/kg cohort and the MTD was established at 2.8 mg/kg every 3 weeks. Enrollment for schedule B was not pursued. The most frequently reported adverse events were diarrhea (35.1%), vomiting (21.6%), and C-telopeptide increase (18.9%). All patients in the 3.6 mg/kg cohort experienced a dose-limiting toxicity, suggesting a narrow therapeutic index. Paired pre-treatment and on-treatment biopsies, where available, showed decreased Axin2 expression by reverse transcriptase polymerase chain reaction with treatment, suggesting target inhibition. Best response observed was stable disease in 14 (38%) patients., Conclusion: The MTD of BI 905677 was set at 2.8 mg/kg every 3 weeks. BI 905677 was well tolerated but a narrow therapeutic range and minimal efficacy led to early termination of the trial., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immunosuppressive conditions within the tumor microenvironment (TME) can allow tumors to evade the immune system, including by hampering programmed death ligand 1 (PD-L1) inhibitor activity. Interleukin (IL)-8 contributes to immunosuppression and fibrosis in the TME. AMY109, a humanized anti-IL-8 monoclonal antibody, reduced fibrosis and decreased immunosuppressive cells in tumor tissue in animals. Combining AMY109 with atezolizumab (anti-PD-L1 antibody) may enhance its antitumor effects by making the TME more favorable to PD-L1 inhibition., Methods: This multicenter, open-label, dose-escalation study evaluated the safety, pharmacokinetics, and clinical activity of AMY109 plus atezolizumab in patients with previously treated advanced solid tumors and Eastern Cooperative Oncology Group performance status 0 or 1. Patients received AMY109 (2-45 mg/kg) plus atezolizumab (1200 mg) intravenously every 3 weeks in part 1, and AMY109 (15-45 mg/kg) plus atezolizumab (1200 mg) in part 2. Primary endpoints were the dose-limiting toxicity (DLT), safety, and pharmacokinetics of AMY109 and atezolizumab in Part 1, and safety and antitumor activity per investigator-assessed Response Evaluation Criteria in Solid Tumors 1.1 in part 2. Exploratory analyses of peripheral and tumor biomarker were conducted., Results: Overall, 38 patients (18 in part 1 and 20 in part 2) were enrolled. Part 1 showed no DLTs and a dose-proportional increase in AMY109 exposure over 2-45 mg/kg, with no apparent change in mean atezolizumab serum concentrations across AMY109 dosing. Plasma IL-8 concentration accumulation was seen in all dose cohorts after AMY109 initiation. Grade 1-3 treatment-related adverse events (AEs) occurred in 21 of 38 patients (55%). Treatment-related serious AEs occurred in two patients (5%). No AEs led to treatment withdrawal. Partial responses (PRs) occurred in 2 of 38 patients; the confirmed objective response rate was 5%. These patients had uterocervical and pancreatic cancer, respectively, and had been treated for >500 days at the cut-off date: one had received 45 mg/kg of AMY109 throughout, and the other received 30 mg/kg of AMY109 until cycle 5, then 45 mg/kg thereafter., Conclusions: With no DLTs, AMY109 plus atezolizumab was well tolerated in patients with advanced solid tumors, with no new safety signals. AMY109 showed a dose-proportional increase in exposure. The PRs in two patients were durable., Competing Interests: Competing interests: NY has received research grants from Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, Ono Pharmaceutical, Janssen Pharma, MSD, Merck, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, Toray, KAKEN, AstraZeneca, CMIC, and Rakuten Medical; participates in advisory boards for Eisai, Takeda, Boehringer Ingelheim, CMIC, Chugai, Merck, and Healios; participates in speakers bureaus for Ono Pharmaceutical, Chugai, Daiichi-Sankyo, and Eisai. SK has received research support from AstraZeneca, Pfizer, Boehringer Ingelheim, MSD, Eisai, Astellas, Ono Pharmaceutical, Takara Bio, GSK, Daiichi-Sankyo, Chugai, Incyte, Takeda, Eli Lilly Japan KK, AbbVie, LOXO Oncology, Japan Society for the Promotion of Science, and Japan Agency for Medical Research and Development; has received lecture fees from AstraZeneca, Pfizer, Boehringer Ingelheim, Taiho, Novartis, MSD, Eisai, BMS, GSK, Daiichi-Sankyo, Chugai, Merck KGaA, Eli Lilly Japan KK, Novartis, and Janssen; participates in advisory boards for Boehringer Ingelheim, Novartis, MSD, Sumitomo Pharma, Eisai, Astellas, Ono Pharmaceutical, NMS, Rakuten Medical, GSK, Chugai, ImmuniT Research, United Immunity; and has received comment fees from Pharmaceuticals and Medical Devices Agency (PMDA). TK has participated in speakers bureaus for Chugai and Sysmex and has received research grants from Chugai, Daiichi-Sankyo, Novartis, Lilly, Takeda, and Zymworks. MI has received honoraria to self from Bayer, Chugai Pharmaceutical, Eisai, Eli Lilly, and Takeda; advisory/consulting fees to self from Chugai Pharmaceutical, Eisai, Eli Lilly, MSD, and Takeda; and research funding to institution from Bayer, BMS, Chugai Pharmaceutical, Eisai, Eli Lilly, F. Hoffmann-La Roche, MSD, and Takeda. HM has nothing to disclose. TN, YY, TI, RT, CO, MS and YN are employees of Chugai Pharmaceutical. YK has received grants from Taiho, Astellas, Lilly, Takeda, Daiichi-Sankyo, AstraZeneca, Boehringer Ingelheim, Chugai, Genmab, Incyte, AbbVie, Amgen, and Merck; consulting fees from Incyte, Takeda, Boehringer Ingelheim, and Amgen; and honoraria from Taiho, Lilly, and Takeda., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Advanced gastric and gastroesophageal junction cancers (GC/GEJCs) harbor diverse molecular signatures, highlighting the need for intricate evaluations to identify potential therapeutic targets. Although whole-transcriptome sequencing (WTS) has emerged as a useful tool for understanding these molecular intricacies, its clinical implications have yet to be fully elucidated. This study evaluated the correlation between immunohistochemistry (IHC) and WTS, compared their clinical significance, and identified potential therapeutic targets undetectable through IHC alone. We enrolled 140 patients with advanced GC/GEJC and assessed them using IHC for six pivotal biomarkers: claudin-18 (CLDN18), human epidermal growth factor receptor 2 (HER2), multiple receptor tyrosine kinases (RTKs), and programmed death ligand 1 (PD-L1). Concurrently, WTS was employed as part of the analyses in MONSTAR-SCREEN-2, a multicenter multiomics study. IHC analysis revealed 16.4% HER2, 39.3% CLDN18 (2+/3 + ≥75%), and 15.8% PD-L1 (combined positive score ≥ 10) positivity, among other molecular markers. Significant correlations were observed between IHC and WTS for all six pivotal biomarkers. Among nineteen HER2 IHC-positive patients treated with anti-HER2 therapeutics, ERBB2 status in WTS was significantly associated with progression-free survival (ERBB2-high vs. -low: median 9.0 vs. 5.6 months, log-rank p = 0.046). IHC-based molecular profiling revealed significantly high expression of CLDN18 in RTK-negative patients, with 78.4% positive for either CLDN18 or PD-L1. Additionally, WTS revealed elevated expression of pivotal biomarkers in patients displaying negative targetable biomarkers via IHC. Our findings highlighted the significant correlation between IHC and WTS, reinforcing the clinical utility of WTS. A subset with IHC-negative but WTS-positive status may benefit from specific biomarker-targeted therapies., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Retifanlimab is a humanized monoclonal antibody targeting programmed death protein-1, and INCB001158 is an oral arginase inhibitor. This phase Ib study investigated retifanlimab, INCB001158, and their combination in Japanese patients with advanced solid tumors., Methods: Patients received retifanlimab (500 mg every 4 weeks [Q4W] i.v.) or escalating doses of INCB001158 (75 or 100 mg twice daily [BID]) monotherapy in Part 1 and combination of retifanlimab (500 mg Q4W) and INCB001158 (100 mg BID) in Part 2. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and determination of recommended phase II doses in Japanese patients., Results: Eighteen patients (retifanlimab or INCB001158 monotherapy and combination; n = 6 each) were enrolled at 2 sites in Japan. There were no DLTs, fatal adverse events (AEs), or discontinuations due to AEs. Rash (all grade 1) was the most common treatment-emergent AE with retifanlimab (n = 6). Treatment-related AEs were reported with retifanlimab (n = 4) or INCB001158 (n = 2) monotherapy and with combination (n = 4); an immune-related AE (thyroid disorder, grade 2) was reported with combination. Two responses were observed with retifanlimab monotherapy (1 complete, 1 partial) and 1 stable disease (SD), for an overall response rate of 33.3% (95% confidence interval [CI], 4.3-77.7) and disease control rate (DCR) of 50% (95% CI, 11.8-88.2). Three patients had SD with INCB001158 monotherapy (DCR 50%; 95% CI, 11.8-88.2). No responses or SD were observed with combination therapy., Conclusion: Retifanlimab, INCB001158, and their combination had acceptable safety profiles. Promising retifanlimab antitumor activity warrants further investigation in Japanese patients., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Immune checkpoint inhibitor (ICI) combinations represent an emerging treatment strategies in cancer. However, their efficacy in microsatellite stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer (CRC) is variable. Here, a multiomic characterization was performed to identify predictive biomarkers associated with patient response to ICI combinations in MSS/pMMR CRC for the further development of ICI combinations., Methods: Whole-exome sequencing, RNA sequencing, and multiplex fluorescence immunohistochemistry of tumors from patients with MSS/pMMR CRC, who received regorafenib plus nivolumab (REGONIVO) or TAS-116 plus nivolumab (TASNIVO) in clinical trials were conducted. Twenty-two and 23 patients without prior ICI from the REGONIVO and TASNIVO trials were included in this study. A biomarker analysis was performed using samples from each of these studies., Results: The epithelial-mesenchymal transition pathway and genes related to cancer-associated fibroblasts were upregulated in the REGONIVO responder group, and the G2M checkpoint pathway was upregulated in the TASNIVO responder group. The MYC pathway was upregulated in the REGONIVO non-responder group. Consensus molecular subtype 4 was significantly associated with response (p=0.035) and longer progression-free survival (p=0.006) in the REGONIVO trial. CD8 + T cells, regulatory T cells, and M2 macrophages density was significantly higher in the REGONIVO trial responders than in non-responders. Mutations in the POLE gene and patient response were significantly associated in the TASNIVO trial; however, the frequencies of other mutations or tumor mutational burden were not significantly different between responders and non-responders in either trial., Conclusions: We identified molecular features associated with the response to the REGONIVO and TASNIVO, particularly those related to tumor microenvironmental factors. These findings are likely to contribute to the development of biomarkers to predict treatment efficacy for MSS/pMMR CRC and future immunotherapy combinations for treatment., Competing Interests: Competing interests: ST, YT, and Y-TL have nothing to disclose. SKoy has received research funding from Otsuka Pharmaceutical, Shionogi Pharmaceutical and Chugai Pharmaceutical outside the submitted work. SF has nothing to disclose. HH has received honoraria from Bayer, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD, Ono, Taiho, Takeda, and Yakult; fees for consulting or advisory roles for Bristol-Myers Squibb, Boehringer Ingelheim and Daiichi-Sankyo; and research grants from ALX Oncology, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Janssen, Merck Biopharma, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. YN has received honoraria from Chugai, Merck, and Guardant Health AMEA and research grants from Taiho, Chugai, Guardant Health, Genomedia, Daiichi-Sankyo, Seagen, and Roche Diagnostics outside the submitted work. YK has nothing to disclose. DK has received personal fees for advisory roles from Takeda and Eisai; honoraria from MSD, Pfizer, Chugai, Merck biopharma, Lilly, Sysmex, Nipponkayaku, Bristol-Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Eisai, and Daiichi-Sankyo; and research funding from Ono Pharmaceutical, MSD, Novartis, Sanofi, Janssen, Pierre Fabre Medicament, Isofol Medical AB, Hutchison MediPharma Limited, and Nippon Servier outside the submitted work. TKo has received honoraria from MSD, Bristol-Myers Squibb and Ono Pharmaceutical; personal fees for advisory roles from Boehringer Ingelheim, Kyowa Kirin and Taiho Pharmaceutical; and research funding from AstraZeneca, BeiGene, MSD, Amgen, Chugai Pharmaceutical, Taiho Pharmaceutical, Shionogi Pharma, and Amgen Astellas BioPharma outside the submitted work. HB has received honoraria from Ono Pharmaceutical, Taiho Pharmaceutical, and Eli Lilly Japan and research funding from Ono Pharmaceutical outside the submitted work. SM, TU, SKoj, MW, NS, and MK have nothing to disclose. TKu has received honoraria from AstraZeneca, Astellas Pharma, Ono Pharmaceutical, Bristol-Myers Squibb Japan, Daiichi-Sankyo, and Roche Diagnostics; personal fees for consulting or advisory roles from Astellas Pharma; and research funding from Daiichi-Sankyo and Roche Diagnostics outside the submitted work. TY has received research grants from Taiho, Ono, Chugai, Amgen, MSD, Daiichi-Sankyo, Eisai, FALCO biosystems, Genomedia, Molecular Health, Nippon Boehringer Ingelheim, Pfizer, Roche Diagnostics, Sysmex, and Sanofi outside the submitted work and honoraria from Bayer, Chugai, Merck Biopharma, MSD, Ono, and Takeda. HN has received research funding and honoraria from Ono Pharmaceutical, MSD, Bristol-Myers Squibb, and Chugai Pharmaceutical and research funding from Taiho Pharmaceutical, Daiichi-Sankyo, Kyowa Kirin, Zenyaku Kogyo, Oncolys BioPharma, Debiopharma, Asahi-Kasei, Sysmex, Fujifilm, SRL, Astellas Pharmaceutical, Sumitomo Dainippon Pharma, and BD Japan outside the submitted work. HM has nothing to disclose. IE has received research grants from Taiho Pharmaceutical and Ono Pharmaceutical outside the submitted work. AK has received personal fees for advisory roles from Roche and Lilly; honoraria from Roche, Merck Biopharma, Lilly, Bristol-Myers Squibb, Ono Pharmaceutical, Taiho Pharmaceutical, and Daiichi-Sankyo; and research funding from Ono Pharmaceutical, MSD, Sanofi, AstraZeneca, and Eisai outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We have developed a series of 2-monoaryl-5-diarylmethylene analogs of the green fluorescent protein chromophore to study their viscosity-induced emission (VIE) properties. The analogs were synthesized by a condensation with methyl imidate and N-(diarylmethylene)glycinate. Among the analogs, the N-methylpyrrol-2-yl-substituted analog 1h induced the most remarkable VIE behavior in triglyceride and lipid bilayers probably due to the high π-electron-rich property of the pyrrole ring. The pyrrole substituent in imidazolone analogs can be expected to become a common template for introducing VIE behavior.

The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRAS G12C -mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg -1 , once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRAS G12C -mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

(1) Background: Inflammatory responses induce the formation of both anti-tumor and pro-tumor neutrophils known as myeloid-derived suppressor cells (MDSCs). Intermittent intravesical infusion of Bacillus Calmette-Guérin (BCG) is an established cancer immunotherapy for non-muscle-invasive bladder cancer (NMIBC). However, the types of neutrophils induced via the inflammatory response to both tumor-bearing and BCG remain unclear. (2) Methods: We therefore analyzed neutrophil dynamics in the peripheral blood and urine of patients with NMIBC who received BCG therapy. Further, we analyzed the effects of BCG in a mouse intraperitoneal tumor model. (3) Results: BCG therapy induced the formation of CXCL10 and MHC class II-positive neutrophils in the urine of patients with NMIBC but did not induce MDSC formation. CXCL10- and MHC class II-expressing neutrophils were detected in peritoneal exudate cells formed after BCG administration. Partial neutrophil depletion using an anti-Ly6G antibody suppressed the upregulation of CXCL10 and MHC class II in neutrophils and reversed the anti-tumor activity of BCG in mouse models. (4) Conclusions: These results indicated that intracellular MHC class II- and CXCL10-expressing neutrophils indicate the state of anti-tumor activity induced via BCG. The status of neutrophils in mixed inflammation of immunosuppressive and anti-tumor responses may therefore be useful for evaluating immunological systemic conditions.

Background: Trifluridine/tipiracil plus VEGF inhibition with ramucirumab (RAM) for advanced gastric cancer (AGC) demonstrated clinical activity with an acceptable toxicity profile in previous phase II trial. However, little is known about its efficacy and safety in clinical practice in comparison with trifluridine/tipiracil monotherapy., Methods: We retrospectively investigated efficacy and safety of trifluridine/tipiracil plus RAM and trifluridine/tipiracil monotherapy as third or later line treatment for AGC patients., Results: Forty-one patients receiving trifluridine/tipiracil plus RAM and 60 patients receiving trifluridine/tipiracil monotherapy were analyzed. The objective response rate (ORR) and the disease control rate (DCR) were 13.5% and 64.9% in the trifluridine/tipiracil plus RAM group, and 3.8% and 42.3% in the trifluridine/tipiracil monotherapy group, respectively (ORR; P = 0.122, DCR; P = 0.052). The median progression-free survival (PFS) and the median overall survival (OS) were 3.0 months and 7.2 months in the trifluridine/tipiracil plus RAM group, and 1.8 months and 3.8 months in the trifluridine/tipiracil monotherapy group, respectively (HR for PFS = 0.66; P = 0.059, HR for OS = 0.50; P = 0.007). Multivariate analysis showed significantly longer PFS (HR = 0.52; P = 0.011) and OS (HR = 0.51; P = 0.031) in the trifluridine/tipiracil plus RAM group compared to the trifluridine/tipiracil monotherapy group. No unexpected adverse events were observed in both groups., Conclusions: Trifluridine/tipiracil plus RAM might show favorable anti-tumor activity with an acceptable toxicity profile in comparison with trifluridine/tipiracil monotherapy, suggesting one treatment option for AGC patients in salvage line. The combination needs further evaluation in ongoing randomized trials., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: Advanced or metastatic esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis; new first-line systemic treatment options are needed. Combining immuno-oncology therapies with standard chemotherapy may represent a promising approach for the treatment of solid tumors. Results from a Phase Ib study evaluating durvalumab with tremelimumab and chemotherapy in patients with advanced or metastatic ESCC are reported., Methods: Adults with advanced or metastatic ESCC who were candidates for first-line platinum-based chemotherapy received durvalumab 1500 mg (Day 1), tremelimumab 75 mg (Day 1), cisplatin 80 mg/m 2 (Day 1) and 5-fluorouracil (5-FU) 800 mg/m 2 (Days 1-5) in 28-day cycles until disease progression or discontinuation due to toxicity. The study consisted of safety run-in (Part A) and expansion (Part B) periods. The primary endpoint was safety. Antitumor activity was an exploratory endpoint., Results: Sixteen patients were enrolled, 6 in Part A and 10 in Part B, and received a median of 4.0 treatment cycles. All patients were Asian; median age was 65.0 years. All patients experienced adverse events (AEs) related to cisplatin and 5-FU, and 8 (50.0%) patients experienced AEs related to durvalumab and tremelimumab. Grade ≥3 treatment-related AEs occurred in 7 (43.8%) patients. There were no deaths associated with AEs. Six (37.5%) patients achieved an objective response. Median progression-free survival was 3.75 months, and median overall survival was 9.69 months., Conclusions: Durvalumab with tremelimumab and chemotherapy demonstrated manageable safety and antitumor activity in patients with advanced or metastatic ESCC, warranting further investigation in randomized trials. Registered with ClinicalTrials.gov: NCT02658214., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: This open-label, multicentre, phase II/III trial assessed the noninferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab vs. fluoropyrimidine and irinotecan plus bevacizumab (control) as second-line treatment for metastatic colorectal cancer (mCRC)., Methods: Patients were randomised (1:1) to receive FTD/TPI (35 mg/m 2 twice daily, days 1-5 and days 8-12, 28-day cycle) plus bevacizumab (5 mg/kg, days 1 and 15) or control. The primary endpoint was overall survival (OS). The noninferiority margin of the hazard ratio (HR) was set to 1.33., Results: Overall, 397 patients were enrolled. Baseline characteristics were similar between the groups. Median OS was 14.8 vs. 18.1 months (FTD/TPI plus bevacizumab vs. control; HR 1.38; 95% confidence interval [CI] 0.99-1.93; P noninferiority  = 0.5920). In patients with a baseline sum of the diameter of target lesions of <60 mm (n = 216, post hoc analyses), the adjusted median OS was similar between groups (FTD/TPI plus bevacizumab vs. control, 21.4 vs. 20.7 months; HR 0.92; 95% CI 0.55-1.55). Grade ≥3 adverse events (FTD/TPI plus bevacizumab vs. control) included neutropenia (65.8% vs. 41.6%) and diarrhoea (1.5% vs. 7.1%)., Conclusions: FTD/TPI plus bevacizumab did not demonstrate noninferiority to fluoropyrimidine and irinotecan plus bevacizumab as second-line treatment for mCRC., Clinical Trial Registration: JapicCTI-173618, jRCTs031180122., (© 2023. The Author(s).)

Background: FIGHT-102 was a phase 1, dose-escalation, dose-expansion study of pemigatinib in Japanese patients with advanced solid tumors. Here, we report safety, tolerability, and preliminary efficacy of pemigatinib from FIGHT-102., Methods: Patients (≥20 years old) self-administered oral pemigatinib 9, 13.5, or 18 mg QD on intermittent dosing (Part 1) or 13.5 mg QD intermittent or continuous dosing (Part 2). A dosing cycle was 21 days (2 weeks on/1 week off or 21 continuous days). Primary endpoint was safety. Secondary endpoints were pharmacokinetics, pharmacodynamics, and preliminary efficacy., Results: Forty-four patients (Part 1, n = 14; Part 2, n = 30) were enrolled; most common tumors, cholangiocarcinoma, n = 8; esophageal, n = 6; 26 patients had confirmed FGF/FGFR alterations (Part 1, n = 3; Part 2, n = 23); 70.5% had ≥3 prior systemic therapies. Maximum tolerated dose was not identified. The recommended phase 2 dosage was determined to be 13.5 mg QD. Most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (81.8%), dysgeusia (45.5%), stomatitis (43.2%), and alopecia (38.6%); most frequent Grade ≥3 TEAEs were anemia and decreased appetite (9.1% each). In Part 1, no patient achieved partial response (PR) or complete response, and 7 (50.0%) patients had stable disease (SD). In Part 2, 5 (16.7%) patients achieved PR (one each with cholangiocarcinoma, gall bladder cancer, breast cancer, urothelial tract/bladder cancer, and sweat gland carcinoma) and 6 (20%) had SD. Median duration of response was 9.56 months (95% CI: 4.17, 14.95)., Conclusions: Pemigatinib demonstrated manageable adverse events, consistent pharmacokinetics and pharmacodynamics profiles, and preliminary efficacy in Japanese patients with advanced solid tumors., (© 2023 Incyte Corporation and The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background and Purpose: Intratumour heterogeneity frequently leads to drug resistance, which is a major issue in drug discovery. Drug distribution is one of the key factors for elucidating the resistance mechanism; however, quantitative and regional drug measurement is challenging. Here, we developed a novel ultra-sensitive analytical method and applied it to HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd), aiming to explore its payload (DXd) distribution within heterogeneous tissues., Experimental Approach: The developed analytical method is named LDMS-CE-MS, a capillary electrophoresis-mass spectrometry (CE-MS) coupled with a novel sample preconcentration/separation method called "large-volume dual-sample stacking by micelle collapse and sweeping (LDMS)". First, the analytical performance of LDMS-CE-MS for DXd detection was evaluated. Subsequently, we evaluated the bystander effect of HER3-DXd, where tumour tissues were excised from xenograft models and clinical specimens after administration of HER3-DXd. HER3-high expression, adjacent, and HER3-low expression regions were then sampled by laser microdissection to quantify the released DXd., Key Results: LDMS concentrated DXd by 1000-fold and separated it from the hydrophilic bio-matrix through continuous capture and release by the charged micelles, allowing quantification at sub-attomole-level. DXd concentrations decreased in the order of antigen-high expression > adjacent > antigen-low expression regions in the tumour xenograft model, whereas in clinical specimens, adjacent and antigen-high expression regions had approximately the same concentration. These distributions represent a bystander effect., Conclusions and Implications: Our LDMS-CE-MS successfully visualized the attomole-level drug distributions in heterogeneous clinical specimens. This new platform opens a new era of quantitative pharmacokinetic analysis, facilitating drug discovery and development., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

This phase I study was designed to: (1) determine the maximum tolerated dose (MTD) and recommended dose (RD) of the fibroblast growth factor receptor (FGFR) inhibitor futibatinib in Japanese patients with advanced solid tumors, and (2) examine the antitumor activity of the RD in patients with gastric cancer (GC) or other advanced solid tumors who have FGFR or FGF/FGFR abnormalities, respectively. In the dose-escalation phase, patients were assigned to 21-day cycles of oral futibatinib 8-160 mg three times a week (TIW) or 16 or 20 mg once daily (QD). In the expansion phase, patients received oral futibatinib 56, 80, or 120 mg TIW, or 16 or 20 mg QD. Eighty-three patients received futibatinib TIW (n = 40) or QD (n = 43). No dose-limiting toxicities were observed according to the final study protocol definition, and the MTD was not reached. The most common adverse events with both regimens were hyperphosphatemia (TIW, 82.5%; QD, 100.0%) and decreased appetite (TIW, 40.0%; QD, 58.1%). Hyperphosphatemia was asymptomatic, not leading to futibatinib discontinuation. The overall response rate (ORR) was 11.5% in patients with FGF/FGFR abnormalities. Notably, in GC patients harboring FGFR2 copy number (CN) ≥10, the ORR was 36.4% versus 0 in patients with CN <10. Therefore, futibatinib had a generally predictable and manageable safety profile in patients with advanced solid tumors. Antitumor activity was seen in patients with FGF/FGFR abnormalities, particularly those with GC and high FGFR2 CNs. Thus, futibatinib 20 mg QD was chosen as the RD for phase II studies., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: We conducted comprehensive clinical and molecular characterization of claudin 18.2 expression (CLDN18.2) in advanced gastric or gastroesophageal junction cancer (GC/GEJC)., Patients and Methods: Patients with advanced GC/GEJC who received systemic chemotherapy from October 2015 to December 2019 with available tumor specimens were analyzed. We evaluated clinicopathological features of CLDN18.2 expression with four molecular subtypes: mismatch repair deficient, Epstein-Barr virus-positive, human epidermal growth factor receptor 2-positive, and others. In addition, programmed death-ligand 1 (PD-L1) combined positive score (CPS), genomic alterations, and the expression of immune cell markers were assessed. Clinical outcomes of standard first- or second-line chemotherapy and subsequent anti-programmed cell death protein 1 (anti-PD-1) therapy were also investigated according to CLDN18.2 expression., Results: Among 408 patients, CLDN18.2-positive (moderate-to-strong expression in ≥75%) was identified in 98 patients (24.0%) with almost equal distribution in the four molecular subtypes or CPS subgroups. CLDN18.2-positive was associated with Borrmann type 4, KRAS amplification, low CD16, and high CD68 expression. Overall survival with first-line chemotherapy was not significantly different between CLDN18.2-positive and -negative groups [median 18.4 versus 20.1 months; hazard ratio 1.26 (95% confidence interval 0.89-1.78); P = 0.191] regardless of stratification by PD-L1 CPS ≥5. Progression-free survival and objective response rates of first- and second-line chemotherapy, and anti-PD-1 therapy also showed no significant differences according to CLDN18.2 status., Conclusions: CLDN18.2 expression in advanced GC/GEJC was associated with some clinical and molecular features but had no impact on treatment outcomes with chemotherapy or checkpoint inhibition. CLDN18.2-positive also had no impact on overall survival. This information could be useful to interpret the results from currently ongoing clinical trials of CLDN18.2-targeted therapies for advanced GC/GEJC and to consider a treatment strategy for CLDN18.2-positive GC/GEJC., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Trifluridine/tipiracil plus bevacizumab (FTD/TPI + BEV) has shown efficacy and tolerability in refractory metastatic colorectal cancer (mCRC). Because randomized controlled trial (RCT) data comparing FTD/TPI + BEV with FTD/TPI are lacking, this meta-analysis evaluated outcomes with both regimens., Data Sources and Methods: Electronic databases, congress proceedings (past 3 years), trial registries, systematic review bibliographies, gray literature, and guidelines through June 2021 were searched for RCTs, non-RCTs, and prospective observational studies involving >20 previously treated patients with mCRC receiving FTD/TPI + BEV or FTD/TPI. Absolute and relative disease control rate (DCR), progression-free survival (PFS), overall survival (OS), adverse event (AE) rates, and discontinuation rates due to AEs were evaluated using fixed-effects and random-effects models. Study quality, heterogeneity, and publication bias were assessed., Results: In all, 29 of 875 screened publications were selected (26 studies: 5 RCTs, 11 non-RCTs, and 10 prospective observational studies). One RCT compared FTD/TPI + BEV with FTD/TPI. FTD/TPI + BEV versus FTD/TPI had a higher absolute DCR [64% (6 studies; n  = 289) versus 43% (10 studies; n  = 2809)], median PFS [4.2 (5 studies; n  = 244) versus 2.6 (6 studies; n  = 1781) months], 12-month PFS [9% (5 studies; n  = 244) versus 3% (6 studies; n  = 1781)], median OS [9.8 (5 studies; n  = 244) versus 8.1 (6 studies; n  = 1814) months], and 12-month OS [38% (5 studies; n  = 244) versus 32% (6 studies; n  = 1814)]. Grade ⩾3 febrile neutropenia, asthenia/fatigue, diarrhea, nausea, and vomiting rates were similar (1%-7%). Grade ⩾3 neutropenia rate was higher with FTD/TPI + BEV than with FTD/TPI [43% (6 studies; n  = 294) versus 29% (12 studies; n  = 7139)]. Discontinuation rates due to AEs were similar [8% (5 studies; n  = 244) and 7% (10 studies; n  = 3724)]. Low study quality, heterogeneity, and/or publication bias were detected in certain instances., Conclusion: Despite fewer patients treated with the combination, this meta-analysis consistently suggested that FTD/TPI + BEV provides benefits over FTD/TPI in refractory mCRC and has similar safety, except for more frequent grade ⩾3 neutropenia., Competing Interests: Takayuki Yoshino reports medical writing support for the submitted work from Taiho Oncology; lecture fees and/or honoraria from Bayer Yakuhin, MSD K.K., Chugai Pharmaceutical, Eli Lilly Japan K.K, Merck Biopharma, Ono Pharmaceutical, and Taiho Pharmaceutical; research funds to his institution from Amgen K.K., Pfizer Japan, Chugai Pharmaceutical, Genomedia, MSD K.K., Nippon Boehringer Ingelheim, Ono Pharmaceutical, Parexel International, Sanofi K.K, Daiichi Sankyo, Sysmex Corporation, and Taiho Pharmaceutical. Julien Taieb reports medical writing support for the submitted work from Taiho Oncology; consulting fees, payment or honoraria, and support for attending meetings and/or travel from Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Merck, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Servier. Yasutoshi Kuboki reports medical writing support for the submitted work from Taiho Oncology; grants or contracts Abbie, Astelas, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Genmab, GlaxoSmithKline, Incyte, Lilly, Taiho Oncology, and Takeda; consulting fees from Amgen, Boehringer Ingelheim, Taiho, and Takeda; payment or honoraria from Bristol Myers Squibb, Lilly, Ono, and Taiho Oncology. Per Pfeiffer reports medical writing support for the submitted work from Taiho Oncology and grants to his institution from Servier. Amit Kumar reports medical writing support for the submitted work from Taiho Oncology and is an employee of SmartAnalyst, the consulting firm contracted by Taiho Oncology to conduct the analysis for the submitted work and by Bristol Myers Squibb, Janssen, Pfizer, and Merck for unrelated work. Howard S. Hochster reports medical writing support for the submitted work and payment for expert testimony from Taiho Oncology, Inc., (© The Author(s), 2023.)

Migratory cycloisomerization using transition metal catalyst is useful for synthesizing substituted heterocyclic compounds. We achieved palladium-catalyzed migratory cycloisomerization of 3-o-alkynylphenoxy acrylic acid ester derivatives to give 2,3-disubstituted benzofurans. Although there are several reports of benzofuran synthesis with palladium-catalyzed migratory cycloisomerization, migratory groups are limited to allyl and propargyl groups. This report is the first example of benzofuran synthesis with palladium-catalyzed cycloisomerization of C(sp 2 )-O bond cleavage.

Purpose: We conducted a first-in-human, dose-escalation study, to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and activity of TAK-931, a cell division cycle 7 inhibitor, in Japanese patients with advanced solid tumors., Experimental Design: Patients ages ≥20 years received oral TAK-931: once daily for 14 days in 21-day cycles (schedule A; from 30 mg); once daily or twice daily for 7 days on, 7 days off in 28-day cycles (schedule B; from 60 mg); continuous once daily (schedule D; from 20 mg); or once daily for 2 days on, 5 days off (schedule E; from 100 mg) in 21-day cycles., Results: Of the 80 patients enrolled, all had prior systemic treatment and 86% had stage IV disease. In schedule A, 2 patients experienced dose-limiting toxicities (DLTs) of grade 4 neutropenia and the maximum tolerated dose (MTD) was 50 mg. In schedule B, 4 patients experienced DLTs of grade 3 febrile neutropenia ( n = 3) or grade 4 neutropenia ( n = 1); the MTD was 100 mg. Schedules D and E were discontinued before MTD determination. The most common adverse events were nausea (60%) and neutropenia (56%). Time to maximum plasma concentration of TAK-931 was approximately 1-4 hours postdose; systemic exposure was approximately dose proportional. Posttreatment pharmacodynamic effects correlating to drug exposure were observed. Overall, 5 patients achieved a partial response., Conclusions: TAK-931 was tolerable with a manageable safety profile. TAK-931 50 mg once daily days 1-14 in 21-day cycles was selected as a recommended phase II dose and achieved proof of mechanism., Trial Registration Id: NCT02699749., Significance: This was the first-in-human study of the CDC7 inhibitor, TAK-931, in patients with solid tumors. TAK-931 was generally tolerable with a manageable safety profile. The recommend phase II dose was determined to be TAK-931 50 mg administered once daily on days 1-14 of each 21-day cycle. A phase II study is ongoing to confirm the safety, tolerability, and antitumor activity of TAK-931 in patients with metastatic solid tumors., Competing Interests: Y. Kuboki reports grants and personal fees from Takeda during the conduct of the study; grants and personal fees from Taiho, Lilly, Boehringer Ingelheim, Bristol-Myers-Squibb; grants from Astelas, Daiichi-Sankyo, AstraZeneca, Chugai, Genmab, GlaxoSmithkline, Incyte, Abbie; grants, personal fees, and non-financial support from Amgen outside the submitted work. T. Shimizu reports grants and personal fees from Takeda during the conduct of the study; grants from AbbVie, Eli Lilly, LOXO Oncology, Novartis, Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Eisai, AstraZeneca, Astellas, Incyte, Chordia Therapeutics, 3D-Medicine, Symbio Pharmaceuticals, PharmaMar; personal fees from Chugai, MSD, Eli Lilly, and Chordia Therapeutics outside the submitted work. K. Yonemori reports personal fees from Pfizer, Eisai, Takeda, AstraZeneca, Eli Lilly, Daiichi Sankyo, Chugai, Fuji Film, MSD, Ono, Bayel, Boeringer Ingelheim, OncoXerna, Genmab; grants from MSD, Takeda, Sanofi, Chugai, Daiichi Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Ono, Seagen, genmab, Eli Lilly, Haihe, Boeringer Ingelheim, Nihon Kayaku, and Bayel outside the submitted work. T. Kojima reports personal fees from Merck Biopharma Co., Ltd, Oncolys BioPharma Inc, Astellas Pharma Inc, Bristol Myers Squibb, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd, Covidien Japan, Inc, MSD K.K, Taiho Pharmaceutical Co., Ltd., Oncolys BioPharma Inc; grants from Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, BeiGene Ltd., EPS Corporation, MSD K.K, Amgen Inc, Shionogi & Co., Ltd, Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd., Parexel International, and Merck Biopharma Co., Ltd. outside the submitted work. S. Koganemaru reports other from Eisai Inc. outside the submitted work. S. Iwasa reports grants from Takeda during the conduct of the study; grants and personal fees from Daiichi Sankyo, Taiho, BMS, Ono; personal fees from Lilly, Chugai, Agilent; grants from Pfizer, Zymeworks, Segen, Bayer, and Amgen outside the submitted work. K. Harano reports personal fees from AstraZeneca, Takeda, Chugai, and Nihon Kayaku; grants and personal fees from MSD; grants from Diichi-Sankyo during the conduct of the study; personal fees from AstraZeneca, Takeda, Chugai, and Nihon Kayaku; grants and personal fees from MSD; grants from Daiichi-Sankyo outside the submitted work. T. Koyama reports personal fees from Sysmex; grants from Chugai, Lilly, Takeda, Daiichi Sankyo, and Novartis outside the submitted work. X. Zhou reports other from Takeda Development Center Americas outside the submitted work. T. Yanai reports personal fees from Takeda Pharmaceutical company outside the submitted work; and is an employee of Takeda Pharmaceutical Company. I. Garcia-Ribas reports personal fees from Takeda during the conduct of the study. T. Doi reports grants from Lilly, MSD, Novartis, Merck Biopharma, Janssen Pharma, Boehringer Ingelheim, Pfizer, Eisai, IQVIA; grants and personal fees from Daiichi Sankyo, Sumitomo Dainippon, Taiho, BMS, Abbvie, Chugai Pharma; personal fees from Takeda, Bayer, Rakuten Medical, Otsuka Pharma, Kaken Pharma, Kyowa Kirin, Shionogi, PRA Health Science, Ono Pharma, and AstraZeneca outside the submitted work. N. Yamamoto reports grants from Chugai, Taiho, Eisai, Eli Lilly, Astellas, BMS, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical Co., Ltd, Takeda, Janssen Pharma, MSD, Merck, GSK, Sumitomo Dainippon, Chiome Bioscience Inc., Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY; personal fees from Ono Pharmaceutical Co., Ltd, Chugai, BMS, Sysmex, Eisai, Eisai, Otsuka, Takeda, Boehringer Ingelheim, and Cimic outside the submitted work. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Objectives: We assessed the safety, tolerability, pharmacokinetics, preliminary antitumour activity and pharmacodynamics of danvatirsen, an antisense oligonucleotide targeting signal transducer and activator of transcription 3 (STAT3), monotherapy and danvatirsen plus durvalumab, an antiprogrammed cell death ligand 1 monoclonal antibody, in patients with advanced solid malignancies., Design: Phase 1, open-label study with two cohorts., Setting: Two centres in Japan., Participants: Japanese individuals aged ≥20 years, with histologically confirmed solid malignancies, except for hepatocellular carcinoma, refractory to standard therapy., Interventions: In cohort 1, patients received danvatirsen monotherapy; in cohort 2, patients received danvatirsen plus durvalumab combination therapy., Primary and Secondary Outcome Measures: The primary endpoint was safety and tolerability based on adverse events (AEs). Secondary endpoints were pharmacokinetics, immunogenicity, antitumour activity and pharmacodynamics., Results: Eleven patients were assigned to treatment and included in the analysis. Danvatirsen dose reductions were only required in cohort 2 for hepatic function abnormal (alanine aminotransferase (ALT)/ aspartate aminotransferase (AST)/gamma-glutamyl transferase (γGT) increased), neutrophil count decreased and platelet count decreased. One patient experienced grade 3 ALT/AST increased and new appearance of eosinophilia as a dose-limiting toxicity. AEs were reported in 90.9% (10/11) patients. Commonly reported AEs causally related to the danvatirsen were platelet count decreased (60% (3/5)) and ALT/AST/γGT increased (50% (3/6)) in cohorts 1 and 2, respectively; none was causally related to durvalumab. One serious AE occurred in cohort 1 (pancreatitis; unrelated to study treatment). One case of ALT/AST/γGT increased occurred in cohort 2, leading to discontinuation. No AEs led to death. Danvatirsen did not accumulate in plasma after multiple dosing. In cohort 2, three patients had disease control at 12 weeks and one had unconfirmed partial response. STAT3 expression tended to decrease regardless of monotherapy or combination therapy., Conclusions: Danvatirsen was well tolerated by Japanese patients with advanced solid tumours as monotherapy and combined with durvalumab. No new safety signals arose., Trial Registration Number: NCT03394144; ClinicalTrials.gov., Competing Interests: Competing interests: TN has received grants from AstraZeneca K.K., during the conduct of the study; grants from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., MSD K.K., Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K., Eli Lilly Japan K.K., and Sumitomo Dainippon Pharma Co., Ltd., outside the submitted work. TF is an employee of, and reports stock ownership in, AstraZeneca K.K. NY is an employee of AstraZeneca K.K. KS is an employee of, and reports stock ownership in, AstraZeneca K.K. KM is an employee of, and reports stock ownership in, AstraZeneca K.K. YK has received grants and honoraria from Taiho Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd.; honoraria from Bayer Yakuhin, Ltd., Sanofi K.K., Eli Lilly Japan K.K., and Bristol-Myers Squibb K.K.; and grants from Takeda Pharmaceutical Co., Ltd., AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Amgen K.K., Chugai Pharmaceutical Co., Ltd., AbbVie GK, and GlaxoSmithKline K.K., outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: We previously reported preliminary activity of regorafenib plus nivolumab (REGONIVO) or lenvatinib plus pembrolizumab (LENPEM) in advanced gastric cancer (AGC). Meanwhile, several studies demonstrated liver metastases are less responsive to immunotherapy., Patients and Methods: Combined efficacy outcomes with a longer follow-up in a phase Ib trial of REGONIVO and a phase II trial of LENPEM were examined in AGC with or without liver metastases (REGONIVO plus LENPEM cohort). We also investigated the efficacy of anti-PD-1 monotherapies (anti-PD-1 monotherapy cohort). A comparison of the immune microenvironment between gastric primary tumors and liver metastases was also conducted by multiplex IHC., Results: In the REGONIVO plus LENPEM cohort, with a median follow-up of 14.0 months, objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were 46%, 7.8 months, and 15.6 months in patients with liver metastases, while 69%, 6.9 months, and 15.5 months in those without. In the anti-PD-1 monotherapy cohort, with a median follow-up of 27.6 months, ORR, mPFS, and mOS were 9%, 1.4 months, and 6.4 months in patients with liver metastases, while 22%, 2.3 months, and 9.0 months in those without. Multiplex IHC revealed liver metastases were associated with an abundance of immune-suppressive cells, such as tumor-associated macrophages and regulatory T cells, with fewer CD8+ T cells compared with gastric primary tumors., Conclusions: Anti-PD-1 antibodies plus regorafenib or lenvatinib for AGC showed promising antitumor activity with a longer follow-up, irrespective of liver metastases status, despite a more immune-suppressive tumor microenvironment in liver metastases., (©2022 The Authors; Published by the American Association for Cancer Research.)

Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 monotherapy.

New treatments, particularly second-line options, are needed to improve outcomes for patients with recurrent/metastatic cervical cancer (r/mCC). Tisotumab vedotin (TV) is an antibody-drug conjugate directed to tissue factor, a transmembrane protein commonly expressed in cancer cells, to deliver cytotoxic monomethyl auristatin E. This single-arm, open-label phase 1/2 trial evaluated the consistency of safety and efficacy outcomes of TV in Japanese patients with r/mCC to bridge the current findings with those reported in previous trials in non-Japanese patients in the United States and Europe. In part 1 (dose escalation; N = 6), patients with advanced solid tumors received TV 1.5 or 2.0 mg/kg once every 3 weeks to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Part 2 (dose expansion; N = 17) evaluated the RP2D in r/mCC patients with 1-2 prior lines of therapy. In part 1, no dose-limiting toxicities were observed, the MTD was not reached, and TV 2.0 mg/kg was established as the RP2D. In part 2, the most common treatment-emergent adverse events were anemia (58.8%), nausea (58.8%), alopecia (47.1%), epistaxis (47.1%), and diarrhea (35.3%); adverse events of special interest were bleeding (76.5%), ocular events (35.3%), and peripheral neuropathy (17.6%), and were mostly grade 1/2. In part 2, confirmed objective response rate was 29.4%, median duration of response was 7.1 months, and median time to response was 1.2 months. In Japanese patients with r/mCC, TV demonstrated a manageable and tolerable safety, pharmacokinetics, and efficacy profile consistent with that observed in non-Japanese patients., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: Transcriptomic profiling was performed for microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal tumors to determine the predictors of response to PD-1 blockade., Experimental Design: Thirty-six patients with MSI-H/dMMR gastrointestinal tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, and pancreatic cancer, being treated with PD-1 blockade were analyzed. We conducted the transcriptomic analysis of gastrointestinal tumors using RNA sequencing data, including the consensus molecular subtypes (CMS) of colorectal cancer., Results: Gene set enrichment analysis (GSEA) demonstrated that non-responders had upregulations of epithelial-mesenchymal transition, angiogenesis, hypoxia, mTORC1, TNF-α, KRAS, Wnt/β-catenin, TGF-β, and various metabolism-related signaling pathways. Meanwhile, the IFNγ pathway was enriched in responders. On the basis of the leading-edge analysis of GSEA, VEGF-A was significantly correlated with enriched pathways in non-responders. Patients with high VEGF-A expression, compared with those with low expression, had significantly shorter progression-free survival [PFS; median 4.8 months vs. not reached (NR), P = 0.032] and overall survival (median 11.1 months vs. NR, P = 0.045). Among 13 patients with colorectal cancer evaluable for CMS classification, the objective response rate was 100%, 0%, 0%, and 16.7% in CMS1, CMS2, CMS3, and CMS4, respectively. Patients with CMS1 had significantly longer PFS (NR vs. 4.8 months, P = 0.017) than those with CMS2, CMS3, or CMS4., Conclusions: Several transcriptomic features, including CMS classification and related genes, were associated with response to PD-1 blockade in MSI-H/dMMR gastrointestinal tumors. These findings can help develop predictive biomarkers or combination immunotherapies., (©2022 The Authors; Published by the American Association for Cancer Research.)

Xentuzumab is an insulin-like growth factor (IGF) ligand-neutralizing antibody. This phase 1 trial assessed xentuzumab in Japanese patients with solid tumors. Patients aged ≥20 y old with solid tumors that were refractory or not amenable to standard therapy were enrolled. Patients received xentuzumab intravenously at a starting dose of 750 mg/wk. Dose escalation used a 3 + 3 design with dose de-escalation. The primary endpoint was to determine the maximum tolerated dose (MTD) of xentuzumab. Safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity were also assessed. Fifteen patients received xentuzumab in the dose escalation part (750 mg/wk [n = 6]; 1000 mg/wk [n = 3]; 1400 mg/wk [n = 6]). There were no dose-limiting toxicities at any dose; the MTD of xentuzumab was not reached. Xentuzumab 1000 mg/wk was recommended as the relevant biological dose. Six further patients received xentuzumab 1000 mg/wk in an expansion cohort. Of 21 patients, 13 (61.9%) experienced a drug-related adverse event, most commonly fatigue (23.8%), neutropenia (19.0%), diarrhea, nausea, white blood cell count decrease, and muscle spasms (14.3% each). No relevant deviations from dose linearity of xentuzumab exposure were observed during dose escalation. Total IGF-1 and IGF-2 levels increased and bioactive IGF levels decreased from baseline to 24 h after the first infusion in cycle 1. Partial response was observed in 2 (9.5%) patients with desmoid-type fibromatosis. Disease control was achieved in 6 (28.6%) patients (median duration 42.4 mo). Xentuzumab monotherapy was well tolerated in Japanese patients and showed evidence of anti-tumor activity. This study was registered with www.clinicaltrials.gov (NCT02145741)., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background and study aims  Patients with head and neck squamous cell carcinoma (HNSCC) are at risk of a second primary tumor in the gastrointestinal tract, most commonly in the esophagus. Screening these patients for esophageal carcinoma may help detect asymptomatic dysplasia and early cancer, thus allowing curative treatment and more prolonged survival, but the impact of endoscopic screening remains uncertain. Here we aimed to describe the long-term results of an esophageal SCC screening program in patients with head and neck cancer in terms of prevalence, associated risk factors, and survival. Patients and methods  We performed an observational study of a prospectively collected database including patients with HNSCC who had undergone high-definition endoscopy with chromoscopy between 2010 and 2018 at a Brazilian tertiary academic center. Results  The study included 1,888 patients. The esophageal SCC prevalence was 7.9 %, with the majority (77.8 %) being superficial lesions. Significant risk factors for esophageal high-grade dysplasia (HGD) and invasive cancer included tumors of the oral cavity and oropharynx and the presence of low-grade dysplasia (LGD). Overall survival (OS) was significantly shorter among patients in whom esophageal cancer was diagnosed at an advanced stage ( P  < .001). OS did not significantly differ between patients with HGD and early esophageal cancer versus those without esophageal cancer ( P  = .210) Conclusions  Endoscopic screening for superficial esophageal neoplasia in patients with HNSCC improves esophageal cancer detection. Screening could potentially benefit patients with primary cancer located at the oropharynx or oral cavity. In addition, the detection of esophageal LGD indicates a need for endoscopic surveillance., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Purpose: This is a phase Ib trial of TAS-116, an oral HSP90 inhibitor, plus nivolumab for colorectal cancer and other solid tumors., Patients and Methods: Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the recommended dose. Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80-160 mg) was administered for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLT). We also conducted biomarker research using paired samples from repeated blood collections and tumor biopsies., Results: A total of 44 patients with colorectal cancer ( n = 29), gastric cancer ( n = 8), sarcoma ( n = 5), non-small cell lung cancer ( n = 1), and melanoma ( n = 1) were enrolled. Eleven patients had previously received immune-checkpoint inhibitors. No DLTs were observed at all dose levels, and TAS-116 160 mg was determined as recommended dose. The common grade 3 or worse treatment-related adverse events included liver transaminase increased (7%), creatinine increased (5%), and platelet count decreased (5%). Objective tumor response was observed in 6 patients, including 4 microsatellite stable (MSS) colorectal cancers, 1 microsatellite instability-high colorectal cancer, and 1 leiomyosarcoma, resulting in an objective response rate of 16% in MSS colorectal cancer without prior immune-checkpoint inhibitors. Biomarker analysis showed that TAS-116 inhibited the activity of regulatory T cells in peripheral blood mononuclear cells and tumor-infiltrating lymphocytes., Conclusions: TAS-116 160 mg plus nivolumab had manageable safety profiles and antitumor activity, especially for MSS colorectal cancer patients., (©2021 American Association for Cancer Research.)

Comprehensive genomic profiling has been approved for use in patients with advanced solid tumours; however, it is only indicated in advanced solid tumour patients without available standard chemotherapeutic treatment or those who have completed standard treatments in Japan, and there are no available data on the clinical feasibility and utility of comprehensive genomic profiling in treatment-naive patients. This multicentre, single-arm, prospective study aims to evaluate the feasibility and utility of the OncoGuide NCC Oncopanel System in treatment-naive patients with six advanced major malignancies: non-small cell lung cancer, breast cancer, gastric cancer, colon cancer, pancreatic cancer and biliary tract cancer (NCCH1908). This study (study cohort) will be compared with the other prospective observational study (control cohort), which enrols patients not receiving comprehensive genomic profiling prior to initial systemic treatment. A total of 200 patients will be enrolled in the study over 21 months. This study has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (UMIN000040743)., Clinical Trial Registration: This study, initiated in June 2020, has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (registration number: UMIN000040743). We plan to enrol a total of 200 patients over a period of 21 months., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This phase 1, multi-center, nonrandomized, open-label, dose-escalation study consisted of Part A wherein merestinib 80 or 120 mg (40-mg tablets) was administered orally QD during a 28-day cycle to patients diagnosed with solid tumors and Part B wherein merestinib 80 mg (40-mg tablets) was administered orally QD, and cisplatin 25 mg/m 2  + gemcitabine 1000 mg/m 2 administered IV on Day 1 and Day 8 of a 21-day cycle (for a maximum of eight cycles) to patients diagnosed with biliary tract carcinoma (BTC). Nineteen patients were screened and 18 patients were (Part A, n = 10; Part B, n = 8) enrolled in the trial and received treatment. All patients in Parts A and B were from Japan and were within an age range of 43-73 years, with an ECOG PS of 0.1. No dose-limiting toxicity or deaths were experienced in the study. Dose-limiting toxicity equivalent toxicity of Grade 4 platelet count decreased (n = 1) and was observed in Part B. In Part A, treatment-related Grade ≥3 TEAEs were reported in one patient (PT: ALT increased and AST increased), while in Part B, five patients reported treatment-related Grade ≥3 TEAEs with four of the five patients reporting an event of neutrophil count decreased. No complete response was reported in either Part. One patient in Part B reported partial response while four patients in each part reported stable disease. Merestinib monotherapy was concluded to be tolerable in Japanese patients, and its combination with cisplatin and gemcitabine is a tolerable regimen for Japanese patients with BTC. Trial registration: NCT03027284 (ClinicalTrials.gov) registered on 23 January 2017., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: This study performed a comprehensive molecular characterization of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) gastrointestinal (GI) tumors to elucidate predictors of response to PD-1 blockade., Experimental Design: Forty-five patients with MSI-H/dMMR GI tumors, including gastric cancer, colorectal cancer, cholangiocarcinoma, small intestine cancer, pancreatic cancer, and duodenal cancer, receiving PD-1 blockade were analyzed. We conducted the genomic profiling of GI tumors by whole-exome sequencing or targeted next-generation sequencing. The tumor microenvironment was evaluated by transcriptomic analysis and multiplex fluorescence IHC., Results: Patients with low tumor mutational burdens (TMBs) had lower objective response rates (ORRs; 0% vs. 48.8%) and a significantly shorter progression-free survival (PFS; 2.3 vs. 15.6 months; HR, 6.20; P = 0.002) than those with high TMBs. Among common gene alterations in GI tumors, only PTEN mutations, which were mutually exclusive with a low TMB, were significantly associated with a lower ORRs than wild-type PTEN (21.4 vs. 54.8%; odds, 4.45; P = 0.045). Compared with wild-type PTEN, PTEN mutations in the phosphatase domain were associated with significantly lower ORRs (12.5 vs. 54.8%; P = 0.049), shorter PFS (2.6 vs. 15.6 months; HR, 5.04; P < 0.001), lower intratumoral CD8 + T-cell levels, higher intratumoral CD204 + macrophage levels, and PI3K/AKT/mTOR pathway enrichment, whereas PTEN mutations in the C2 domain were not., Conclusions: Low TMBs and PTEN mutations, especially mutations in the phosphatase domain associated with an immunosuppressive environment, were mutually exclusive and might be negative predictors of PD-1 blockade responses in patients with MSI-H/dMMR GI tumors., (©2021 American Association for Cancer Research.)

Clinical studies intended for regulatory approval must demonstrate the clinical benefits of the drug in a target population. Clinical development of a drug proceeds by stepwise clinical studies; after safety and pharmacokinetics are evaluated and the recommended dosage and administration are determined, efficacy and safety are evaluated in an exploratory manner, and finally clinical benefits are compared with conventional standard therapies. Guidelines for the clinical evaluation of anti-cancer drugs in Japan were established in 1991 and amended in 2006 after molecular-targeted drugs were introduced. Recent progress in the development of drugs acting on the immune system and cancer genomic medicine targeting rare but important molecular subtypes have altered the strategy for development of anti-cancer drugs. It is often difficult to conduct a confirmatory randomized controlled study using overall survival as the primary endpoint in rare molecular subtypes, and the primary evaluation of the efficacy of some drugs and subsequent approval is based on the tumor response. As conducting clinical studies for rare subtypes solely within Japan is difficult, drug development needs to be conducted within a global study. However, this requires robust monitoring to detect possible ethnic differences in pharmacokinetics and drug efficacy. Development using the conditional approval system for drugs enforced in 2020 may be considered, when clinical utility is evaluated based on surrogate endpoints. Because of these changes, we have revised the guidelines for the clinical evaluation of anti-cancer drugs in Japan. To promote global development of anti-cancer drugs involving Japan, the guidelines have been translated into English., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Recent advances in adjuvant chemotherapy for early colon cancer have widened physicians' recommendations on the regimen and duration (3 or 6 months) of the treatment. We conducted this prospective study to evaluate whether the 12-gene recurrence score (12-RS) assay affected physicians' recommendations on adjuvant treatment selection., Patients and Methods: Patients with stage IIIA/IIIB or stage II colon cancer were enrolled. After the patients discussed adjuvant treatment with their treating physicians, the physicians filled in the questionnaire before assay indicating the treatment recommendation. When the 12-RS assay results were available, the physicians again filled in the questionnaire after assay. The primary endpoint was the rate of change in treatment recommendations from before to after the assay, with a threshold rate of change being 20%. Patients with stage IIIA/B to II were enrolled in a ratio of 2 : 1., Results: Overall, the treatment recommendations changed in 40% of cases after obtaining 12-RS assay results. Recommendations were changed in 45% (80/178; 95% confidence interval, 37% to 53%; P < 0.001) and 30% (29/97; 95% confidence interval, 21% to 40%; P < 0.001) of patients with stage IIIA/B and II colon cancer, respectively. Patients with stage IIIA/B cancer had significantly more change than those with stage II cancer (P = 0.0148). From before to after the 12-RS assay, the percentage of patients whose physicians reported being confident in their treatment recommendations significantly increased from 54% to 81% in stage IIIA/B (P < 0.001) and from 65% to 83% in stage II (P < 0.001)., Conclusion: Our study confirmed the usefulness of the 12-RS assay in aiding the physician-patient decision-making process for tailoring adjuvant chemotherapy for stage IIIA/B colon cancer., Competing Interests: Disclosure EO reports receiving honoraria for lecturing from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Bayer Yakuhin Japan, Eli Lilly, Yakult Honsha Co., Ltd, Takeda Pharmaceutical Co., Ltd, ONO Pharmaceutical Co., Ltd, and Merck Biopharma Co., Ltd, outside the submitted work. JW reports receiving honoraria for lecturing from Johnson and Johnson and Medtronic Co., Ltd, outside the submitted work. YK reports receiving honoraria for lecturing from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Bayer Yakuhin Japan, Eli Lilly, Yakult Honsha Co., Ltd, Takeda Pharmaceutical Co., Ltd, ONO Pharmaceutical Co., Ltd, and Merck Biopharma Co., Ltd, outside the submitted work. YK reports receiving honoraria from Taiho Pharmaceutical Co., Ltd, ONO Pharmaceutical Co., Ltd, Bayer Yakuhin Japan, Sanofi, and Eli Lilly, and receiving honoraria for consultancy/advisory roles from Takeda and Boehringer Ingelheim, receiving research funding from Taiho Pharmaceutical Co., Ltd, Takeda Pharmaceutical Co., Ltd, ONO Pharmaceutical Co., Ltd, AstraZeneca, Daiichi-Sankyo, Boehringer Ingelheim, Incyte, Amgen, Chugai Pharmaceutical Co., Ltd, and GlaxoSmithKline, outside the submitted work. MI reports receiving honoraria for consultancy/advisory roles from Daiichi-Sankyo, Pfizer Inc, Bayer Yakuhin, Taiho Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd, Eli Lilly and Merck Biopharma Co., Ltd, outside the submitted work. TK reports receiving research funding from ONO Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd, Takeda Pharmaceutical Co., Ltd, Eli Lilly, and Bayer Yakuhin, outside the submitted work. TM reports receiving honoraria from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Bayer Yakuhin Japan, Eli Lilly, Yakult Honsha Co., Ltd, Takeda Pharmaceutical Co., Ltd, Sanofi, and Merck Biopharma Co., Ltd, receiving research funding from Merck Sharp & Dohme (MSD), Daiichi-Sankyo, and ONO Pharmaceutical Co., Ltd, outside the submitted work. KY reports receiving honoraria for lecturing from Sanofi, Taiho Pharmaceutical Co., Ltd, Yakult Honsha Co., Ltd, and ONO Pharmaceutical Co., Ltd, receiving research funding from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Eli Lilly, and Takeda Pharmaceutical Co., outside the submitted work. TN reports receiving honoraria from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, ONO Pharmaceutical Co., Ltd, Bristol-Myers Squibb, and Eli Lilly, receiving research funding from Taiho Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd, Daiichi-Sankyo, MSD, ONO Pharmaceutical Co., Ltd, Bristol-Myers Squibb, Eli Lilly, and Sumitomo Dainippon Pharmaceutical Co., Ltd, outside the submitted work. TY reports receiving honoraria from Chugai Pharmaceutical Co., Takeda Pharmaceutical Co., Ltd, Bayer Yakuhin Japan, and Boehringer-Ingelheim, receiving research funding from Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Takeda Pharmaceutical Co., and Daiichi-Sankyo, outside the submitted work. TY reports receiving research funding from ONO Pharmaceutical Co., Daiichi-Sankyo, Parexel, Sumitomo Dainippon Pharmaceutical Co., Ltd, Chugai Pharmaceutical Co., Ltd, Sanofi, MSD, and GlaxoSmithKline, outside the submitted work. All authors have declared no conflicts of interest. Data sharing Data are available upon reasonable request., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The C-TASK-FORCE phase I/II and Danish randomized phase II trials reported the promising efficacy of trifluridine/tipiracil (TAS102) plus bevacizumab (BEV) in patients with chemorefractory metastatic colorectal cancer (mCRC). However, there had been no direct comparative phase III trial to compare the efficacy between TAS102 plus BEV and standard therapy with either TAS102 or regorafenib monotherapy., Methods: We retrospectively reviewed the medical records of patients with mCRC who received TAS102 plus BEV, TAS102 monotherapy, or regorafenib monotherapy after standard chemotherapies during 2013-2019., Results: Patients received TAS102 plus BEV ( n  = 139), TAS102 monotherapy ( n  = 153), or regorafenib monotherapy ( n  = 133). With a median follow-up of 25.3 months, median overall survival (OS) was 11.5 months [95% confidence interval (CI), 9.9-13.9] for TAS102 plus BEV, 8.1 months (95% CI, 6.8-9.2) for TAS102 monotherapy, and 6.8 months (95% CI, 5.7-8.5) for regorafenib monotherapy. The hazard ratios were 0.67 (95% CI, 0.51-0.88) for TAS102 plus BEV versus TAS102 monotherapy and 0.71 (95% CI, 0.54-0.94) for TAS102 plus BEV versus regorafenib monotherapy. Median progression-free survival (PFS) was 4.4 months (95% CI, 3.7-5.4) for TAS102 plus BEV, 2.5 months (95% CI, 1.6-2.3) for TAS102 monotherapy, and 2.1 months (95% CI, 1.6-2.3) for regorafenib monotherapy. The hazard ratios were 0.57 (95% CI, 0.45-0.73) for TAS102 plus BEV versus TAS102 monotherapy and 0.44 (95% CI, 0.34-0.58) for TAS102 plus BEV versus regorafenib monotherapy. On multivariate analysis, TAS102 plus BEV was independently correlated with better OS and PFS. No unexpected adverse events were observed in any group., Conclusion: Our study shows that OS and PFS are longer in patients treated with TAS102 plus BEV than in those treated with TAS102 or regorafenib monotherapy., Competing Interests: Conflict of interest statement: Daisuke Kotani received honoraria from Takeda, Chugai, Lilly, Merck Serono, Taiho, Ono, and Sysmex. Yoshiaki Nakamura received research grants from Taiho, Chugai, and Genomedia Inc. Akihito Kawazoe received honoraria from Taiho and research grants from Ono, Sumitomo Dainippon, and MSD. Yasutoshi Kuboki received honoraria from Taiho, Sanofi, Bayer, and Ono and research grants from Taiho, Boehringer, AbbVie, GlaxoSmithKline, Chugai, Daiichi Sankyo, and Genmab K.K. Kohei Shitara received honoraria from Novartis, AbbVie, and Yakult and research grants from Astellas, Lilly, Ono, Sumoitomo Dainippon, Daiichi Sankyo, Taiho, Chugai, MSD, and Medi Science. Takashi Kojima received research grants from Ono, MSD, Astellas, BMS, and Merck (H), Ono, MSD, Astellas Amgen, Taiho, and Shionogi. Hiroya Taniguchi received honoraria from Bayer, Sanofi, Takeda, Chugai, Taiho, Lilly, Merck, Yakult Honsha, MBL, Bristol-Myers Squibb, MSD, Novartis, Daiichi Sankyo, Mitsubishi Tanabe, and Nippon Kayaku and research grants from Dainippon Sumitomo, Array BioPharma, MSD, Ono, Daiichi Sankyo, Sysmex, Novartis, and Takeda. Takayuki Yoshino received honoraria from Taiho, Chugai, Lilly, Bayer, and Merck Biopharma and research grants from Taiho, Ono, Amgen, Parexel International, MSD, Chugai, Daiichi Sankyo, Sumitomo Dainippon, and Sanofi. All other authors declare no potential conflicts of interest., (© The Author(s), 2021.)