Published papers

Fruquintinib, a novel, highly selective, small-molecule tyrosine kinase inhibitor of VEGF receptors (VEGFRs)-1, -2 and -3, is approved in China for the treatment of metastatic colorectal cancer. FRESCO-2, a global, randomized, double-blind, placebo-controlled, Phase III study, is investigating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Key inclusion criteria include: progression on or intolerance to TAS-102 and/or regorafenib; and prior treatment with approved chemotherapy, anti-VEGF therapy, and, if RAS wild-type, anti-EGFR therapy. Approximately 687 patients will be randomized 2:1 to fruquintinib plus best supportive care or placebo plus best supportive care. Primary and key secondary end points are overall survival and progression-free survival, respectively. FRESCO-2 is enrolling in the USA, Europe, Australia and Japan.

BACKGROUND: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer. METHODS: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting. FINDINGS: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group). INTERPRETATION: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population. FUNDING: HUTCHMED.

Background: Fruquintinib is a highly selective, oral inhibitor of all 3 VEGF receptors. The global, randomized, double-blind phase 3 FRESCO-2 trial (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival in patients with refractory metastatic colorectal cancer (mCRC) who received fruquintinib plus best supportive care (BSC) versus placebo plus BSC. Here we report detailed safety data from FRESCO-2 including an analysis of treatment-related adverse events of special interest (AESIs). Patients and methods: Patients with mCRC eligible for FRESCO-2 had received all standard chemotherapies and prior anti-VEGF and anti-EGFR therapies if indicated, and displayed progression on, or intolerance to, TAS-102 and/or regorafenib. Prespecified AESIs based on VEGFR tyrosine kinase inhibitor drug classes were evaluated. Results: Incidences of treatment-related AESIs were 64.9% with fruquintinib + BSC versus 23.0% with placebo + BSC. The most frequent all-grade treatment-related AESIs for fruquintinib were hypertension (28.9%; grade ≥3 10.7%), palmar-plantar erythrodysesthesia syndrome/hand-foot skin reaction (PPE 18.6%; grade ≥3 6.1%), and hypothyroidism (15.6%; grade ≥3 0.4%). Dose reductions due to treatment-related AESIs were reported in 10.3% of patients who received fruquintinib + BSC versus 0.4% with placebo + BSC. The most common treatment-related AESIs resulting in dose reduction for fruquintinib were PPE syndrome (5.0%), hypertension (2.9%), and proteinuria (1.3%). Overall, 5.9% versus 0.9% had treatment-related AESIs resulting in study drug discontinuation. Conclusion: Fruquintinib + BSC demonstrated a predictable and manageable safety profile in pretreated patients with mCRC and is a novel oral treatment option that prolongs survival and enriches the continuum of care in this population.

The present study proposes a novel full-field extensional rheo-optical technique to investigate the relationship between the rheological properties and internal structural deformation of complex fluids under uniaxial extensional flow. Macroscopic viscoelasticity from rheological measurements and microscopic birefringence from optical measurements are integrated to evaluate the microstructural deformation and orientation of the fluids under extensional stress. The proposed technique integrates a liquid dripping method with a high-speed polarization camera to measure the extensional stress and flow birefringence simultaneously. In the liquid dripping method, temporal evolution images of the liquid filament diameter for fluids dripping from a nozzle are measured to obtain the extensional stress loading on the filament. These images are acquired using the high-speed polarization camera that captures full-field two-dimensional (2D) birefringence with high spatiotemporal resolution. Wormlike and networked micellar solutions of cetyltrimethylammonium bromide (CTAB) and sodium salicylate (NaSal) with varying concentrations of CTAB and NaSal are employed as the measurement targets. Consequently, we successfully visualized temporally developing images of the flow birefringence field of uniaxially extending micellar solutions induced by the orientation of micelles. Furthermore, the proposed technique supports investigating the conditions for establishing the stress-optical rule, which is the linear relationship between stress and birefringence. The stress-optical coefficient, which is a proportionality constant indicating the sensitivity of birefringence to stress, is analyzed from these measurements. The stress-optical coefficient under uniaxial extensional flow, obtained using the proposed technique, is confirmed to be comparable to that under shear flow.

Despite therapeutic advancements, disease-free survival and overall survival of patients with locally advanced rectal cancer have not improved in most trials as a result of distant metastases. For treatment decision-making, both long-term oncologic outcomes and impact on quality-of-life indices should be considered (for example, bowel function). Total neoadjuvant therapy (TNT), comprised of chemotherapy and radiotherapy or chemoradiotherapy, is now a standard treatment approach in patients with features of high-risk disease to prevent local recurrence and distant metastases. In selected patients who have a clinical complete response, subsequent surgery might be avoided through non-operative management, but patients who do not respond to TNT have a poor prognosis. Refined molecular characterization might help to predict which patients would benefit from TNT and non-operative management. Specifically, integrated analysis of spatiotemporal multi-omics using artificial intelligence and machine learning is promising. Three prospective trials of TNT and non-operative management in Japan, the USA and Germany are collaborating to better understand drivers of response to TNT. Here, we address the future direction for TNT.

Scintillators have long been known as radiation detectors and are still used in various applications. Recently, scintillators containing $^6$Li have been developed as neutron detectors and have attracted attention. $^6$Li absorbs thermal neutrons and emits $α$+$^3$H, which is promising as a neutron detector if it can be separated from background gamma rays. We have been developing Eu:LiI-CaI$_2$-based scintillators (Eu:LiCaI) for this purpose. In scintillator detectors, waveform information is generally used to distinguish particles such as neutrons and gamma rays. We propose a new particle identification method using emission wavelengths information. In this study, experiments were conducted using Eu:LiCaI crystals, multi-pixel photon counter optical sensors, and long-wavelength cut filters to verify the proposed method. The results of irradiating a $^{252}$Cf neutron source and a $^{60}$Co gamma-ray source indicate that there is a particle dependence of the output signal ratio between with and without filters. This means that different types of radiation particles have different emission wavelengths. This is the first demonstration of a wavelength-based particle identification method.

This prospective study evaluated the clinical significance of circulating tumor DNA (ctDNA) profiling in patients with advanced urothelial carcinoma (aUC) using FoundationOne®Liquid CDx. A total of 133 Japanese patients (SCRUM-Japan cohort) were analyzed, including serial ctDNA sampling before and after platinum-based chemotherapy or pembrolizumab. Cross-sectional comparison was made with 1059 patients from the U.S.-based Foundation Medicine cohort (FMI cohort). The most frequent genomic alterations in the SCRUM-Japan cohort were TP53 (43%), MLL2 (26%), and TERT (19%). Compared to the FMI cohort, the prevalence of TP53 and TERT alterations was lower, while KRAS alterations were more frequent in upper tract urothelial carcinoma (UTUC) than in bladder cancer (BC) across both cohorts. High ctDNA tumor fraction (≥10%) was associated with significantly worse overall survival, and alterations in TERT, and TP53 were also linked to significantly worse prognosis. The concordance rate of gene alterations before and after chemotherapy was 61%, and 66% for pembrolizumab. In contrast, concordance between tissue and ctDNA profiling was only 46%, with ctDNA identifying additional actionable mutations not detected in tissue. These findings underscore the potential of ctDNA as a non-invasive tool for dynamic molecular monitoring and prognostication in aUC, supporting its integration into clinical practice.

PURPOSE: Genomic characterization of the predisposition of tumors to metastasize to specific sites has been performed in a few studies using mainly tissue-derived genomes. This nationwide prospective observational study investigated the association between genomic characteristics using circulating tumor DNA (ctDNA), and the synchronous and metachronous metastasis of tumors to specific target organs in advanced prostate cancer. METHODS: Patients with advanced prostate cancer undergoing systemic treatment were included. ctDNA was analyzed using the FoundationOne®Liquid CDx assay at enrollment. Associations between genomic characteristics and metastatic status were examined. RESULTS: Alterations in the genes MYC, APC, and BRCA2 and the DNA repair, MYC, and WNT pathways were associated with lung and liver metastasis. PTEN gene alterations and PI3K pathway alteration were associated with synchronous lung metastasis. RB1 gene alteration and RAS/RAF/MAPK pathway alteration were associated with synchronous liver metastasis. RB1 and BRCA2 gene alterations predicted metachronous lung metastasis, while TP53 and MYC gene alterations predicted metachronous liver metastasis. CONCLUSIONS: This study identifies genomic alterations in ctDNA associated with synchronous and metachronous metastases. These findings may be clinically helpful for treating, managing, and monitoring cancer.

PURPOSE: To understand the mutational landscape of circulating tumor DNA (ctDNA) and tumor tissue of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer (MBC) treated with abemaciclib + endocrine therapy (ET). METHODS: Blood samples for ctDNA and/or tissue samples were collected from abemaciclib-treated patients with HR+/HER2- MBC enrolled in the SCRUM-Japan MONSTAR-SCREEN project. Blood samples were collected before abemaciclib initiation (baseline) and at disease progression/abemaciclib discontinuation (post abemaciclib treatment). Clinical and genomic characteristics including neoplastic burden (measured by shedding rate and maximum variant allele frequency [VAF]) were assessed at baseline. Genomic alterations in ctDNA were compared in paired baseline and post abemaciclib treatment samples. RESULTS: All patients (N = 97) were female (median age, 57 years [IQR, 50-67]). In baseline ctDNA (n = 77), PIK3CA (37%), TP53 (28%), ESR1 (16%), and GATA3 (11%) were the most frequently mutated genes. Baseline tissue samples (n = 79) showed similar alteration frequencies. Among patients with baseline ctDNA data, 30% had received previous ET. ESR1 alteration frequency (35% v 8%; P < .01), median shedding rate (3 v 2), and maximum somatic VAF (4 v 0.8; both P < .05) were significantly higher in ctDNA from patients with previous ET than those without previous ET. In paired ctDNA samples (n = 33), PIK3CA and ESR1 alteration frequencies were higher after abemaciclib treatment than at baseline, though not statistically significant. Among the post-treatment alterations, those newly acquired were detected most frequently in FGF3/4/19 (18%); PIK3CA, TP53, CCND1, and RB1 (all 15%); and ESR1 (12%). CONCLUSION: We summarized the ctDNA and cancer tissue mutational landscape, including overall neoplastic burden and PIK3CA and ESR1 hotspot mutations in abemaciclib-treated patients with HR+/HER2- MBC. The data provide insights that could help optimize treatment strategies in this population.

Hematological immune-related adverse events caused by immunotherapy are relatively uncommon. Aplastic anemia triggered by immune checkpoint inhibition is rare and its genomic characteristic remains largely unexplored. This case report describes a 42-year-old female with metastatic cervical cancer who experienced aplastic anemia caused by pembrolizumab. Through a nationwide genomic screening study, MONSTAR-SCREEN-2, we examined genomic landscape of biopsied tissue and circulating tumor DNA. The patient harbored human leukocyte antigen-A*0201 haplotype, which is known as a risk allele of idiopathic acquired aplastic anemia. Clonal hematopoiesis (CH) of myeloid cancer candidate gene DNMT3A c.1429 + 1G>A was newly detected in the buffy-coated white blood cell sample at the time of aplastic anemia diagnosis. This case report contributes to further progress of genomic research of immune-related aplastic anemia.

Background: Primary tumor site and genomic status are utilized for regimen selection in metastatic colorectal cancer; however, the impact on clinical practice is not well known. Objective: We aimed to clarify the impact of primary tumor site and genomic status on clinical practice in metastatic colorectal cancer. Methods: The relationship between primary tumor site, genomic alterations, and clinical outcomes was evaluated in patients with untreated metastatic colorectal cancer using real-world data of a prospective observational study, SCRUM-Japan GI-SCREEN with clinical and genomic data set in 1011 patients enrolled from February 2015 to March 2017. Results: Five hundred and sixty-one patients were eligible for this study. Patients with right-sided tumors had a significantly worse survival, left-sided tumors with wild-type RAS had favorable outcomes when treated with anti-epidermal growth factor receptor monoclonal antibodies, and cecum tumors had poor prognosis when treated with bevacizumab. The rate of gene alterations varied considerably depending on the primary site. In addition, gene alterations of KRAS, BRAF, SMAD4, or TP53 had individually different contributions to survival from site to site. KRAS, BRAF, PTEN, or SMAD4 mutations were associated with efficacy of bevacizumab or anti-epidermal growth factor receptor monoclonal antibodies. Conclusions: Primary tumor site is a clinically useful biomarker to predict survival in patients with metastatic colorectal cancer treated with first-line chemotherapy. Moreover, the prognostic or predictive value of several gene alterations by primary tumor site should be considered in clinical practice.

BACKGROUND: Circulating tumor DNA (ctDNA) testing has emerged as a novel tool for cancer precision medicine. This study investigated the genomic profiling and clinical utility of ctDNA in metastatic prostate cancer. METHODS: This is a nation-wide prospective observational study. Patients treated with systemic treatment for metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC) were included. ctDNA was analyzed using FoundationOne Liquid®CDx at enrollment. In a subset of patients, ctDNA after disease progression and tissue prior to the initiation of treatment were examined using FoundationOne Liquid®CDx and FoundationOne®CDx, respectively. RESULTS: The frequency of AR alterations and homologous recombination repair (HRR) defect was higher in mCRPC compared with mCSPC. Tumor mutational burden was correlated between tissue and ctDNA at pre-treatment, as well as ctDNA between at pre-treatment and at post-treatment. Patients with HRR defect were associated with shorter time to castration resistance in androgen deprivation therapy/combined androgen blockade, but not in androgen receptor pathway inhibitor, compared with patients without HRR defect in mCSPC. Time to treatment failure in patients with AR amplification or AR mutation was shorter compared with patients without AR alterations in mCRPC. CONCLUSIONS: This study revealed valuable findings for the clinical care of metastatic prostate cancer. Especially, predictive factors such as HRR defect in mCSPC should be validated in the future.