Published papers

BACKGROUND: The novel oral nucleoside antineoplastic agent trifluridine/tipiracil was approved for metastatic colorectal cancer in Japan in March 2014. In this post-marketing surveillance study, we investigated the safety and efficacy of trifluridine/tipiracil in a real-world setting, particularly haematological drug reactions classified according to the baseline renal and hepatic functions. METHODS: We investigated patients with metastatic colorectal cancer who received trifluridine/tipiracil during the first four treatment cycles prospectively. The patients typically received 35 mg/m2 trifluridine/tipiracil twice daily on days 1-5 and 8-12 every 28 days. The primary objective was to assess the safety of trifluridine/tipiracil, but its efficacy was also evaluated. RESULTS: Between July 2014 and June 2016, 860 patients were enrolled in the study, and the safety and efficacy of trifluridine/tipiracil were evaluated in 823 patients. Adverse drug reactions occurred in 89.7% of the patients. The most common adverse drug reactions were decreased white blood cell count (67.0%) and neutrophil count (63.9%). Haematological drug reactions of grade ≥3 were observed in 41.7% of the patients with normal renal function; 50.3, 65.6 and 78.9% of the patients had mild, moderate and severe renal impairments, respectively. Hepatic impairment was not associated with a higher incidence of haematological drug reactions. The median overall survival was 8.4 months, with a 1-year survival rate of 33.7%. CONCLUSION: This post-marketing surveillance study further confirmed the safety and tolerability profile of trifluridine/tipiracil observed in a clinical study setting.

PURPOSE: Anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) is the key drug for RAS/BRAF V600E wild-type metastatic colorectal cancer (mCRC). However, anti-EGFR mAb-induced skin fissures often affect a patient's quality of life. Shiunko, a traditional Japanese topical herbal medicine, is used for burns and dermatitis and may potentially have wound-healing effects. Herein, we report cases of patients with mCRC who were treated with Shiunko for anti-EGFR mAb-induced skin fissure. METHODS: We retrospectively reviewed consecutive patients with mCRC who received an anti-EGFR mAb-containing regimen and were treated with Shiunko twice a day for skin fissures at the National Cancer Center Hospital East between March 2022 and December 2022. Skin fissures were assessed at baseline and at every visit until 28 days after Shiunko initiation according to CTCAE v5.0. RESULTS: Among the 11 patients, 5 patients were female; the median age was 61 (range, 43-79) years. The median treatment duration with anti-EGFR mAb before Shiunko initiation was 13.1 (range, 6-52) weeks. Skin moisturizer and topical steroids were applied for skin fissures in 11 and 5 patients, respectively. All patients had grade 2 skin fissures at baseline of Shiunko initiation. Two weeks after Shiunko initiation, complete recovery was noted in 4 patients and improvement to grade 1 was noted in 6 patients. There were no Shiunko-related adverse events. Ten patients continued anti-EGFR mAb treatment until disease progression, while 1 patient discontinued anti-EGFR mAb treatment due to severe eruptions. CONCLUSION: Shiunko could be a treatment option for anti-EGFR mAb-induced skin fissure. Further studies are warranted to investigate the efficacy and safety of Shiunko for anti-EGFR mAb-induced skin fissure.

IMPORTANCE: Personalized medicine based on tumor profiling and identification of actionable genomic alterations is pivotal in cancer management. Although tissue biopsy is still preferred for diagnosis, liquid biopsy of blood-based tumor analytes, such as circulating tumor DNA, is a rapidly emerging technology for tumor profiling. OBSERVATIONS: This review presents a practical overview for clinicians and allied health care professionals for selection of the most appropriate liquid biopsy assay, specifically focusing on circulating tumor DNA and how it may affect patient treatment and case management across multiple tumor types. Multiple factors influence the analytical validity, clinical validity, and clinical utility of testing. This review provides recommendations and practical guidance for best practice. Current methodologies include polymerase chain reaction-based approaches and those that use next-generation sequencing (eg, capture-based profiling, whole exome, or genome sequencing). Factors that may influence utility include sensitivity and specificity, quantity of circulating tumor DNA, detection of a small vs a large panel of genes, and clonal hematopoiesis of indeterminate potential. Currently, liquid biopsy appears useful in patients unable to undergo biopsy or where mutations detected may be more representative of the predominant tumor burden than for tissue-based assays. Other potential applications may include screening, primary diagnosis, residual disease, local recurrence, therapy selection, or early therapy response and resistance monitoring. CONCLUSIONS AND RELEVANCE: This review found that liquid biopsy is increasingly being used clinically in advanced lung cancer, and ongoing research is identifying applications of circulating tumor DNA-based testing that complement tissue analysis across a broad range of clinical settings. Circulating tumor DNA technologies are advancing quickly and are demonstrating potential benefits for patients, health care practitioners, health care systems, and researchers, at many stages of the patient oncologic journey.

The ability to accurately interpret implied meanings plays a crucial role in human communication and language use, and language models are also expected to possess this capability. This study demonstrates that providing language models with pragmatic theories as prompts is an effective in-context learning approach for tasks to understand implied meanings. Specifically, we propose an approach in which an overview of pragmatic theories, such as Gricean pragmatics and Relevance Theory, is presented as a prompt to the language model, guiding it through a step-by-step reasoning process to derive a final interpretation. Experimental results showed that, compared to the baseline, which prompts intermediate reasoning without presenting pragmatic theories (0-shot Chain-of-Thought), our methods enabled language models to achieve up to 9.6\% higher scores on pragmatic reasoning tasks. Furthermore, we show that even without explaining the details of pragmatic theories, merely mentioning their names in the prompt leads to a certain performance improvement (around 1-3%) in larger models compared to the baseline.

Background: The presence of circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who are at risk of recurrence and aid with postsurgical risk stratification. ~80% of stage II and only 50% of stage III colorectal cancer (CRC) patients are cured by surgery alone. A tumor-uninformed plasma-only approach for MRD assessment accelerates the turnaround time, enabling rapid adjuvant chemotherapy (ACT) treatment decision making, optimizing the impact on patient outcomes. Methods: A subset of samples from GALAXY, an observational arm of the CIRCULATE-Japan study (UMIN000039205), were analyzed for postsurgical ctDNA detection at a landmark time point (LMT) defined as 4 weeks after curative surgery in pathological stage II or III CRC patients. In a prospective lead-in to clinical validation, 80 patients meeting pre-specified eligibility criteria were randomly selected with enrichment for recurrence to 50% while maintaining the stage II: III recurrent (R)/nonrecurrent (NR) ratio to that observed in GALAXY. Residual plasma samples were analyzed with the Tempus xM assay (xM), a tumor-uninformed ctDNA MRD assay that integrates methylation and genomic variant MRD classifiers to deliver a binary MRD call. All calls were blinded to clinical outcomes. The methylation-based classifier detects fragments with CRC methylation signatures in differentially methylated regions trained by sequencing CRC and presumed-healthy samples on a6Mbppanel. The variant-basedMRDclassifier detects highly prevalent CRC variants. Artifacts, CHIP, and germline variant filtering algorithms were also applied. Results: Of the 80 patients (pts), 70 [Stage II n= 29 (41%), Stage III n= 41 (59%)] were evaluable (36 R and 34 NR). At the LMT and with at least 1-year follow-up, 18/36 R pts had detectable ctDNA (xM MRD+) and 30/34 NR pts had undetectable ctDNA (xM MRD-), providing a sensitivity of 50% and specificity of 88%. Additionally, xM MRD+/- status strongly correlated with disease-free survival (DFS) with a hazard ratio (HR) of 5.09, adjusted to account for a24% recurrence rate in GALAXY. In an updated, ongoing longitudinal analysis of the 4 false positive pts, 2 were Stage III, MRD+ from both the methylation and genomic classifiers, received ACT, and have likely cleared their ctDNA without any sign of clinical recurrence. An adjusted sensitivity and specificity analysis resulted in xM clinical performance of 53% (20/38 R) and 94% (30/32 NR), respectively. Conclusions: xM is a novel tumor-uninformed assay that demonstrated remarkable performance to detect clinical recurrence at a LMT, and a clinically meaningful correlation with DFS. A larger clinical validation study including longitudinal analysis, correlation with ACT, and outcomes from the GALAXY study is currently underway. Research Sponsor: None.

Patients diagnosed with metastatic colorectal cancer (mCRC) have a poor prognosis with survival ranging 2-3 years. The prevalence of human epidermal growth factor receptor 2 (HER2) amplification is approximately 3-4% in mCRC and increases up to 8% in patients with KRAS/NRAS/BRAF wild-type (WT) CRC tumors. Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor that, in combination with trastuzumab, has demonstrated clinically meaningful activity in patients with chemotherapy-refractory, HER2-positive (HER2+), RAS WT mCRC in the MOUNTAINEER trial. The MOUNTAINEER-03 phase III trial is designed to investigate the efficacy and safety of first-line tucatinib in combination with trastuzumab and modified FOLFOX6 (mFOLFOX6) versus standard of care (mFOLFOX6 plus bevacizumab or cetuximab) in patients with untreated HER2+, RAS WT locally advanced unresectable or mCRC. MOUNTAINEER-03 will include two arms of approximately 400 patients randomized 1:1 to either treatment arm. The primary endpoint is progression-free survival per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate (according to RECIST v1.1 per BICR). Safety assessments will include surveillance and recording of adverse events, physical examination findings, vital signs, cardiac assessments, Eastern Cooperative Oncology Group performance status, concomitant medications, and laboratory tests.Clinical trial registration: NCT05253651 (ClinicalTrials.gov).

Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of a humanized monoclonal anti-HER2 antibody, a cleavable tetrapeptide-based linker and a potent topoisomerase I inhibitor. The drug's efficacy has been proven in HER2-positive breast and gastric cancers. The rate of HER2 positivity in biliary tract cancer (BTC) has been reported to be 5-20%, and case reports and clinical trials have suggested that HER2 inhibitors might be active in HER2-positive BTC. Here we describe the rationale and design of the phase II HERB trial that will evaluate the efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing unresectable or recurrent BTC. The primary end point will be the centrally assessed objective response rate in HER2-positive patients. Plain language summary Trastuzumab deruxtecan (DS-8201) is a new drug against HER2, a receptor on cell membranes that has sensitivity to targeted inhibitors. The drug's efficacy has been proven in HER2-positive breast and gastric cancers. Some studies have suggested that HER2 inhibitors might be active in HER2-positive biliary tract cancers. This article describes the design of a new clinical trial. The HERB trial is designed to evaluate the efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing biliary tract cancers. Clinical trial registration: JMA-IIA00423.

Background: With very low survival rates, pancreatic cancer (PC) remains a disease in need of diagnostic and therapeutic innovation and novel biomarkers to guide and optimize treatment decisions are urgently needed. Analysis of circulating tumor DNA (ctDNA) has been shown to be a highly accurate method for determining treatment efficacy and detecting molecular residual disease (MRD) in patients (pts) with various cancer types as compared to tumor markers and imaging modalities. However, it has been reported that the ctDNA detection rate in PC using existing tumor-agnostic ctDNA assays was lower than those in other cancer types because of the high stromal and low cellular features of PC, which prevents the shedding of ctDNA into blood circulation. Even in advanced cancers, the sensitivity of ctDNA utilizing tumor-agnostic mutation panels is much lower as compared to that in tumor tissue specimens. The Invitae Personalized Cancer MonitoringTM test is a novel and highly sensitive, tumor-informed MRD detection assay. MRD assessment as well as recurrence and treatment response monitoring using this novel assay could lead to the development of improved treatment algorithms for pts with PC. The ARTEMIS-PC study (UMIN000043561) aims to evaluate the clinical utility of the Invitae Personalized Cancer Monitoring test in pts with resectable and unresectable PC. Methods: This is a multi-site, prospective, observational trial in Japan of 150 pts with resectable (50) and unresectable (100) PC. The main eligibility criteria are histopathologically diagnosed as adenocarcinoma, no prior treatment for PC, scheduled to undergo surgery for resectable PC or receive systemic therapy for unresectable PC. In resectable PC cohort, blood samples will be collected before surgery and at 1, 3, 6, 9, 12, 18, and 24 months after surgery, and imaging study will be performed before surgery, and at 3, 6, 9, 12, 18, and 24 months after surgery. In the unresectable PC cohort, blood samples will be collected before treatment and at 4, 8, 12, 16, 24, 32, 40, and 48 weeks on treatment, and imaging study will be performed before treatment and every 8 weeks on treatment until 48 weeks. Primary endpoint in the resectable PC cohort is success rate of creating personalized panel using tumor tissue obtained by EUS-FNA/FNB, and that in unresectable PC cohort is rate of concordance of KRAS mutations between tumor tissue and blood samples. Key secondary endpoints in resectable PC cohort are rate of ctDNA positivity for each cancer stage before neoadjuvant chemotherapy and 4 weeks after surgery, and that in unresectable PC cohort is pretreatment ctDNA detection rate for each disease stage. Active enrollment started in December, 2022 and 21 pts with resectable PC and 64 pts with unresectable have been enrolled as of September 2023.

180Background: A considerable number of patients with stage II-III colon cancer experience disease recurrence following definitive treatment while others may receive unnecessary toxicity from adjuvant chemotherapy. Minimal residual disease (MRD) detection through ctDNA analysis can be evaluated without reliance on tissue which comes with logistic advantages and may be the only option for patients with limited tumor specimens. Methods: COSMOS-CRC-01 is an ongoing biomarker study that enrolled patients with resectable stage 0-III colorectal cancer between January 2020 and April 2021. Plasma samples and clinical data were collected 28 days post-operatively and every 3-6 months for up to 5 years alongside radiographic imaging. Samples were tested on the Guardant Reveal Infinity Oncology Platform for MRD detection. This analytically validated multiomic NGS assay interrogates >700 genes and ~15Mb of methylated regions. A bioinformatics algorithm trained for CRC detection classifies each sample as ctDNA detectable or undetectable based on a predefined statistical likelihood threshold and returns quantitative tumor fraction. The primary endpoint was time to recurrence (TTR) based on ctDNA detection status. Results: This subgroup analysis evaluated 801 post-surgical plasma samples (4mL each, median input 19ng, 96% passed QC) from 136 patients with R0 resected stage II-III colon cancer with a median follow-up of 28 months. ctDNA detection at Day 28 post-surgery and following adjuvant chemotherapy were both associated with significantly shorter TTR (p<0.0001; Table). Sensitivity with serial measurement was 80% (95% CI, 56.3-94.3%), with a median lead time of 5.3 months. Sensitivity was highest for detection of locoregional (2/2), brain (1/1), liver (7/7), or multiple (3/3) metastasis compared to isolated lung (2/4) or peritoneal (1/3) metastasis. Tumor fraction increased as expected in samples collected closer to the time of radiographic detection. Three recurred patients had KRAS G12C variants detected in ctDNA prior to recurrence, suggesting the potential of early intervention with targeted agents. Among 553 post-treatment samples from 114 non-recurred patients, sample specificity was 97.3% (95% CI 95.6-98.5%). Conclusions: We show a plasma-only genomic- and methylation-based assay to have sensitive and specific detection of MRD in stage II-III colon cancer. Serial measurement provides superior performance versus one-time measurement at Day 28 post-surgery and detects targetable variants prior to recurrence. [Table presented]

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.

BACKGROUND: Although nivolumab has a high efficacy, reliable biomarkers are needed to predict the efficacy. We evaluated the nivolumab efficacy according to the TP53 mutation in advanced gastric cancer patients enrolled in the GI-SCREEN project. METHODS: Sequence data of tumour specimens and clinicopathological information of 913 patients with advanced gastric cancer who were enrolled between April 2015 and March 2017 were obtained from the GI-SCREEN database. The follow-up information of 266 patients treated with nivolumab was also provided. RESULTS: Among 266 patients treated with nivolumab, the objective response rate (ORR) of TP53 wild type (wt) patients (24.6%) was higher than that of TP53 mutant patients (14.8%). Among TP53 mutant patients, the ORR of the frameshift type tended to be higher than the transition and transversion type (23.1%, 13.6%, and 13.0%, respectively). The median progression-free survival (PFS) was statistically longer in TP53 wt patients than in mutant patients (3.3 vs 2.1 months, HR 1.4, 95% CI 1.1-1.9). Among TP53 mutant patients, PFS was statistically longer in the frameshift type than in the transversion type. CONCLUSION: Nivolumab showed better efficacy in TP53 wt patients than in mutant patients. Among TP53 mutant patients, the frameshift type may have efficacy from nivolumab treatment.

PURPOSE: Napabucasin is an investigational, orally administered reactive oxygen species generator bioactivated by intracellular antioxidant NAD(P)H:quinone oxidoreductase 1 that has been evaluated in various solid tumors, including metastatic colorectal cancer (mCRC). Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is hypothesized to predict response in napabucasin-treated patients with mCRC. PATIENT AND METHODS: In the multi-center, open-label, phase III CanStem303C (NCT02753127) study, adults with histologically confirmed mCRC that progressed on first-line fluoropyrimidine plus oxaliplatin ± bevacizumab were randomized to twice-daily napabucasin plus FOLFIRI (napabucasin) or FOLFIRI alone (control). The primary endpoint was overall survival (OS) in the general study population and in patients with pSTAT3-positive tumors (biomarker-positive). RESULTS: In the general study population (napabucasin, n = 624; control, n = 629), median OS was 14.3 months for napabucasin and 13.8 months for control (hazard ratio [HR], 0.976, one-sided P = .74). Overall, 44% of patients were biomarker-positive (napabucasin, n = 275; control, n = 272). In the biomarker-positive population, median OS was 13.2 months for napabucasin and 12.1 months for control (HR, 0.969; one-sided P > .99). In the control arm, median OS was shorter for biomarker-positive versus biomarker negative patients (12.1 vs. 18.5 months; HR, 1.518; nominal 2-sided P = .0002). The most common treatment-emergent adverse events (TEAEs) were diarrhea (napabucasin, 84.6%; control, 53.9%), nausea (60.5%, 50.5%), vomiting (41.2%, 29.3%), and abdominal pain (41.0%, 25.2%). Grade ≥3 TEAEs occurred in 73.8% of napabucasin-treated and 66.7% of control-treated patients, most commonly diarrhea (21.2%, 7.0%), neutrophil count decreased (13.7%, 19.2%), and neutropenia (13.3%, 15.2%). Safety was similar in biomarker-positive patients. CONCLUSION: In patients with previously treated mCRC, adding napabucasin to FOLFIRI did not improve OS. Results from the control arm indicate that pSTAT3 is an adverse prognostic factor in mCRC.