Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).

Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.

Clinical utility of BRCA and ATM mutation status in circulating tumour DNA for treatment selection in advanced pancreatic cancer.

BACKGROUND: Identification of homologous recombination deficiency (HRD) remains a challenge in advanced pancreatic cancer (APC). We investigated the utility of circulating tumour DNA (ctDNA) profiling in the assessment of BRCA1/2 and ATM mutation status and treatment selection in APC. METHODS: We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360. RESULTS: Inactivating BRCA1/2 and ATM mutations were detected in 4.8% (putative germline, 3.7%) and 4.4% (putative germline, 0.9%) of patients, respectively. Objective response (63.2% vs. 16.2%) and PFS (HR 0.55, 95% CI 0.32-0.93) on platinum-containing chemotherapy were significantly better in patients with putative germline BRCA1/2 (gBRCA) mutation than those without. In contrast, putative gBRCA mutation had no impact on the efficacy of gemcitabine plus nab-paclitaxel. In 2 patients treated with platinum-containing therapy, putative BRCA2 reversion mutations were detected. Three of seven patients with somatic BRCA mutations responded to platinum-containing therapy, while only one of four with putative germline ATM mutations did. One-third of somatic ATM mutations were in genomic loci associated with clonal haematopoiesis. CONCLUSION: Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.

Early Tumor Shrinkage and Depth of Response as Predictors of Survival for Advanced Biliary Tract Cancer: An Exploratory Analysis of JCOG1113.

BACKGROUND: Recent studies suggest that early tumor shrinkage (ETS) and depth of response (DpR) reflect outcomes of chemotherapy in various cancers. This study evaluated the association of ETS and DpR with clinical outcomes using data from JCOG1113, which demonstrated the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for chemotherapy-naïve advanced biliary tract cancer. MATERIAL AND METHODS: In total, 354 (289 with measurable target lesions) patients enrolled in JCOG1113 were divided into ETS-unachieved and ETS-achieved groups (≥20% tumor reduction at week 6) and DpR-low and DpR-high groups (≥40% maximum shrinkage) until 12 weeks after enrollment. The impact of ETS and DpR on survival outcome was evaluated using the multivariable Cox proportional hazard model. RESULTS: The proportions of patients in the ETS-achieved and DpR-high groups were similar between the 2 treatment arms. The hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for the ETS-achieved group were 0.70 (95% confidence interval (CI), 0.52-0.93) and 0.60 (95%CI, 0.44-0.81), respectively. The HRs of PFS and OS for the DpR-high group were 0.67 (95%CI, 0.48-0.94) and 0.64 (95%CI, 0.46-0.90), respectively. In the subpopulation treatment effect pattern plot analysis, most patients in the ETS-achieved group in the GC arm did not experience disease progression after 12 weeks from the landmark. CONCLUSION: As on-treatment markers, ETS and DpR were effective tools. ETS was clinically useful, because it can be used to evaluate the outcomes of treatment early at a specific time.

Early tumor shrinkage as a prognostic predictor in chemotherapy-naïve patients with locally advanced pancreatic cancer treated with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel combination therapy: An exploratory analysis of JCOG1407.

BACKGROUND: Early tumor shrinkage (ETS) is a prognostic predictor for patients treated with chemotherapy in colorectal cancer, although scarce studies evaluated its potential in locally advanced pancreatic cancer (LAPC). In this exploratory analysis of JCOG1407, a randomized phase II study comparing modified 5-fluorouracil, levofolinate, irinotecan, and oxaliplatin (mFOLFIRINOX) and gemcitabine plus nab-paclitaxel (GnP), we evaluated whether ETS can predict prognosis of patients with LAPC. METHODS: Of the 126 patients enrolled in JCOG1407, 112 with measurable lesions were included in this study. ETS was defined as a ≥20 % reduction in tumor diameter compared with baseline at the initial imaging assessment 6-10 weeks after initiating chemotherapy. Patients were divided into the ETS (achieved ETS) and non-ETS (failed to achieve ETS) groups based on their ETS status. The impact of ETS on overall survival (OS) was compared using multivariable Cox regression analysis. RESULTS: Fourteen of 55 (25.5 %) and 24 of 57 (42.1 %) patients in the mFOLFIRINOX and GnP arms, respectively, achieved ETS. In the overall population, mFOLFIRINOX arm, and GnP arm, the median OS in the ETS and non-ETS groups was 27.1 and 20.4, 29.8 and 20.6, and 24.1 and 20.4, months, respectively. The adjusted hazard ratios of OS for the ETS group in the overall population, mFOLFIRINOX arm, and GnP arm were 0.451 (95 % confidence interval [CI]: 0.270-0.754), 0.371 (95 % CI: 0.149-0.926), and 0.508 (95 % CI: 0.255-1.004), respectively. CONCLUSIONS: ETS may be a prognostic predictor in chemotherapy-naïve patients with LAPC treated with mFOLFIRINOX or GnP.

Statistics of Visceral Sarcoma in Japan: Report From the Population-Based National Cancer Registry (NCR) in Japan.

BACKGROUND AND OBJECTIVES: Sarcomas developing in the visceral organs are extremely rare, with no previous reports to describe their national epidemiology. We analyzed Japanese domestic statistics for visceral sarcoma, using the National Cancer Registry (NCR) in Japan, a population-based database launched in 2016. METHODS: We identified 3245 cases of visceral sarcomas in the NCR dated 2016-2019 to analyze demographic and disease information, initial diagnostic process, volume and type of the hospitals, treatment, and prognosis. RESULTS: Visceral sarcoma shows a higher prevalence in the older generation (60+ years), with a significant male predominance (p = 0.006). Leiomyosarcomas occurred frequently in the gastrointestinal tract (N = 240; 39.5%), and angiosarcomas in the liver, gall bladder, pancreas, and spleen (N = 244; 43.9%). Visceral sarcomas were often treated in facilities of lower volume without specific adjuvant treatments (p < 0.001). The cumulative 3-year overall survival was 44.8%, and several factors such as surgery or absence of chemotherapy positively affected survival. CONCLUSIONS: This is the first nationwide study in Japan to analyze the inclusive epidemiology of visceral sarcomas. Visceral sarcomas are characterized by senior and male predominance with relatively poor prognosis, often managed in nonspecialized facilities and rarely with adjuvant therapies. Several histologic subtypes had the propensity to develop in specific organs.

Efficacy of endoscopic ultrasound-guided gastroenterostomy using self-expandable metallic stent for afferent loop syndrome: A single-center retrospective study.

BACKGROUND AND AIM: Endoscopic ultrasound-guided gastroenterostomy is a procedure used to connect the stomach and dilated afferent loop using a stent under endoscopic ultrasound for afferent loop syndrome. However, the actual efficacy and safety of this procedure remain unclear. Therefore, this retrospective study aimed to evaluate the efficacy and safety of endoscopic ultrasound-guided gastroenterostomy using a laser-cut-type fully covered self-expandable metallic stent and an anchoring plastic stent for afferent loop syndrome. METHODS: Technical and clinical success rates, adverse events, recurrent intestinal obstruction rates, time to recurrent intestinal obstruction, and technical and clinical success rates of re-intervention were evaluated in intended patients who underwent endoscopic ultrasound-guided gastroenterostomy for afferent loop syndrome from October 2018 to August 2022. RESULTS: In 25 intended patients with afferent loop syndrome who intended endoscopic ultrasound-guided gastroenterostomy, the technical success rate was 100% (25/25), whereas the clinical success rate was 96% (24/25). Two patients experienced grade ≥ 3 early adverse events, including one with intra-abdominal abscess and one with hypotension. Both events were attributed to intestinal fluid leakage. No late adverse events were observed. The recurrent intestinal obstruction rate was 32% (8/25), and the median time to recurrent intestinal obstruction was 6.5 months (95% confidence interval: 2.8-not available). The technical and clinical success rates of re-intervention were both 100% (8/8). CONCLUSIONS: Endoscopic ultrasound-guided gastroenterostomy using a fully covered self-expandable metallic stent and an anchoring plastic stent is effective and safe as a treatment procedure for afferent loop syndrome.

Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced biliary tract cancer, pancreatic ductal adenocarcinoma or other solid tumors.

Mouse double minute 2 homolog (MDM2) is a key negative regulator of the tumor suppressor p53. Blocking the MDM2-p53 interaction, and restoring p53 function, is therefore a potential therapeutic strategy in MDM2-amplified, TP53 wild-type tumors. MDM2 is amplified in several tumor types, including biliary tract cancer (BTC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinoma and bladder cancer, all of which have limited treatment options and poor patient outcomes. Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown promising activity in preclinical and early-phase clinical studies. This manuscript describes the rationale and design of an ongoing phase IIa/IIb Brightline-2 trial evaluating brigimadlin as second-line treatment for patients with advanced/metastatic BTC, PDAC, lung adenocarcinoma, or bladder cancer.

Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced BTC, PDAC, or other solid tumorsIn some types of cancer, including cancers of the bile duct, pancreas, bladder and lung, the number of copies of a gene called MDM2 is abnormally increased (MDM2 amplification). MDM2 usually regulates p53, a protein that stops cancer cells from growing uncontrollably. When MDM2 is amplified, the cell makes too much of the MDM2 protein, which prevents p53 from stopping cancer growth. Blocking the interaction between MDM2 and p53 may allow p53 to do its job again and stop cancer cells from growing.Brightline-2 is a clinical trial that is currently in progress. This trial is assessing the efficacy and safety of an investigational drug, brigimadlin (or BI 907828), in patients with selected advanced or metastatic cancers. To be included, patients must have advanced biliary tract cancer, pancreatic ductal adenocarcinoma, bladder cancer, or lung adenocarcinoma. The tumor must show amplification of MDM2 when tested by a laboratory. Patients will take a 45 mg tablet of brigimadlin by mouth, once every 3 weeks. In this trial, researchers are investigating the ability of the drug to shrink tumors, the side effects of the drug, and the impact of the drug on a patients' quality of life.The goal of this trial is to assess the potential of brigimadlin as a new treatment option for patients with advanced biliary tract cancer, pancreatic ductal adenocarcinoma, bladder cancer, or lung adenocarcinoma.Clinical Trial Registration: NCT05512377 (ClinicalTrials.gov).

Phase II trial of niraparib for BRCA-mutated biliary tract, pancreatic and other gastrointestinal cancers: NIR-B.

Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort.Clinical Trial Registration: jRCT2011200023 (ClinicalTrials.gov).

A clinical study to confirm the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with the BRCA genetic mutation: the NIR-B trial.BRCA gene is involved in repairing DNA injury and plays an important role in cancer growth. Cells with a mutation in the BRCA gene cannot repair DNA using a method called homologous recombination repair. Niraparib is part of a class of drugs called 'PARP inhibitors' that inhibit enzymes called 'PARP' involved in repairing DNA injury, and has shown efficacy against cancers with BRCA gene mutations. BRCA gene mutations are infrequent but have been found in a variety of cancers. The NIR-B trial is a clinical trial to evaluate the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with BRCA gene mutations.

Plain language summary of the FOENIX-CCA2 study: futibatinib for people with advanced bile duct cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life. WHAT WERE THE RESULTS?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib. WHAT DO THE RESULTS MEAN?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).

Immune-related adverse event-associated sclerosing cholangitis due to immune checkpoint inhibitors: imaging findings and treatments.

OBJECTIVES: Immune-related adverse event-sclerosing cholangitis caused by treatment with immune checkpoint inhibitors is rare, and the diagnostic criteria and treatment strategy remain unclear. In this study, we confirmed the clinicopathological features of immune-related adverse event-sclerosing cholangitis and clarified its diagnosis and appropriate management. METHODS: We retrospectively evaluated 10 patients diagnosed with immune-related adverse event-sclerosing cholangitis and identified by electronic database searches. RESULTS: Blood tests revealed liver dysfunction with a predominance of biliary tract enzymes in all patients; however, jaundice was present in only one patient. Contrast-enhanced computed tomography revealed diffuse hypertrophy of the extrahepatic bile duct wall as the most frequent finding; however, endoscopic retrograde cholangiopancreatography showed various imaging features, such as the pruned-tree appearance of intrahepatic bile ducts, in all patients. Transpapillary bile duct biopsy showed inflammatory cell infiltration using immunostaining, with a predominance of cluster of differentiation 8-positive T cells in 63% of the cases. Initial steroid therapy was effective in two cases. Mycophenolate mofetil and tacrolimus were used in steroid-refractory cases. Although six patients showed improvements, all of the remaining patients died owing to immune-related adverse event-sclerosing cholangitis. CONCLUSIONS: Various bile duct imaging findings of immune-related adverse event-sclerosing cholangitis were revealed; transpapillary bile duct biopsy may be useful in the diagnosis of immune-related adverse event-sclerosing cholangitis. Despite the combination of multiple immunosuppressive agents, prognosis of immune-related adverse event-sclerosing cholangitis remains poor. Longer follow-up and larger clinical studies are necessary to establish its treatment strategy.

Protocol digest of a randomized phase III trial comparing S-1-based chemoradiotherapy with/without nivolumab for unresectable locally advanced or borderline resectable pancreatic cancer: JCOG1908E (PENETRATE).

Pancreatic cancer remains a highly lethal disease with a 5-year survival proportion of <10%. Chemoradiotherapy is a treatment option for unresectable locally advanced (UR-LA) or borderline resectable (BR) pancreatic cancer, but its efficacy is not sufficient. Induction of the synergistic effect of irradiation and immune checkpoint inhibitors can be an attractive strategy. An open-label randomized phase III trial has been conducted since October 2020 to confirm the superiority of nivolumab plus S-1-based chemoradiotherapy over S-1-based chemoradiotherapy alone in patients with UR-LA or BR pancreatic cancer. A total of 216 patients will be enrolled in 14 institutions within 3.5 years. The primary endpoint of the safety run-in part is dose-limiting toxicity, and that of the phase III part is overall survival. This trial was registered at the Japan Registry of Clinical Trials as jRCT2080225361 (https://jrct.niph.go.jp/latest-detail/jRCT2080225361).

Soft-tissue sarcoma in Japan: National Cancer Registry-based analysis from 2016 to 2019.

BACKGROUND: No previous reports have characterized national profiles of soft-tissue sarcoma overall. We examined the nationwide statistics for soft-tissue sarcoma in Japan using data from the population-based National Cancer Registry. METHODS: We identified 23 522 soft-tissue-sarcoma patients who were entered in the National Cancer Registry during 2016-19 using International Classification of Diseases-Oncology, Third Edition codes for cancer topography and morphology. We extracted data on patient demographics, tumor details (reason for diagnosis, tumor location, histology, extent of disease), hospital volume/type, treatment, and prognosis for each patient. RESULTS: Soft-tissue sarcoma showed a slight male preponderance. Approximately 5500-6000 new cases were diagnosed as soft-tissue sarcoma per year, with the age-adjusted incidence of soft-tissue sarcoma being 3.22/100000/year. The age distribution showed a single peak in the 70-79 age range, and sex-stratified data showed it was higher in men. The most common histologic subtype was liposarcoma. The most frequent tumor locations were the soft tissue and skin, followed by the retroperitoneum. Extent of disease was categorized as: "localized" (31.3%), "regional" (38.9%), or "distant" (10.5%). We found significant associations between overall survival and sex, age, tumor location, facility type, hospital volume, reason for diagnosis, extent of disease, and surgical treatment. CONCLUSIONS: This is the first study to outline the epidemiology, clinical features, treatment, prognosis, and significant factors affecting prognosis of soft-tissue sarcoma in Japan using the National Cancer Registry. Documenting our data regarding elderly patients' outcomes is essential so other countries showing similar population-aging trends can learn from our experiences. LEVEL OF EVIDENCE: Prognostic studies, Level III.

Clear cell sarcoma in Japan: an analysis of the population-based cancer registry in Japan.

BACKGROUND: Clear cell sarcoma is rare, so no reports have previously characterized its national profiles. We examined the nationwide epidemiology and clinical outcomes of patients with clear cell sarcoma based on the National Cancer Registry in Japan. METHODS: Overall, 23 522 patients with soft tissue sarcoma-entered in the National Cancer Registry in 2016-2019 using the International Classification of Diseases for Oncology, Third Edition cancer topography and morphology codes-were enrolled in either the clear cell or the non-clear cell sarcoma group. Data extracted included: demographics (sex and age), tumor details (reason for diagnosis, tumor location, histology and stage), hospital volume and facility type, treatment and prognosis for each patient. RESULTS: Of 23 522 soft tissue sarcoma patients, 122 were enrolled in the clear cell sarcoma group and 23 400 in the non-clear cell sarcoma group. The incidence of clear cell sarcoma was 0.52% of all soft tissue sarcoma, with an age-adjusted incidence of 0.024/100 000/year. The age at diagnosis was significantly younger, and more tumors were at the localized stage in the clear cell than the non-clear cell sarcoma group. In addition, the overall survival in the clear cell group was worse than in the non-clear cell group (P < 0.001). Of 122 patients with clear cell sarcoma, the localized stage, surgical treatment and treatment without chemotherapy were associated with better overall survival in the univariate analyses. CONCLUSIONS: The present study is the first to have clarified the epidemiology, clinical features, treatment, prognosis and significant factors affecting the prognosis of patients with clear cell sarcoma in Japan.

Current status of head and neck sarcomas in Japan in 2016-2019: an analysis using the national cancer registry.

BACKGROUND: Head and neck sarcomas are especially rare in Asia, leading to limited clinical evidence. This study aimed to investigate the incidence, clinical features, treatment status, and outcome of these sarcomas using data from the National Cancer Registry in Japan. METHODS: All head and neck sarcomas diagnosed between 2016 and 2019 and recorded in the National Cancer Registry were analyzed. Data on sex, age, primary site, histological type, stage, treatment modality, and prognostic information were collected. Age-adjusted incidence and 3-year survival rates of patients with head and neck sarcomas were calculated. RESULTS: Overall, 635 head and neck sarcoma patients were identified. Head and neck sarcoma occurred more frequently in men and patients in their 70 s. The age-adjusted annual incidence rate was 0.125 per 100,000 patients in the 2015 Japanese model or 0.089 per 100,000 patients in the world population model. The nasal cavity and paranasal sinuses were the most frequent primary sites, with rhabdomyosarcoma as the most common histologic type. Treatment typically involved chemotherapy and/or radiation therapy for rhabdomyosarcoma and Ewing's sarcoma, whereas surgical approaches for other types. Three-year survival rate of head and neck sarcoma patients was 64.8%. CONCLUSIONS: Head and neck sarcomas occurred rarely, but most frequently in the nasal cavity and paranasal sinuses in Japan. Poor outcomes were observed for sarcoma patients than for non-sarcoma head and neck cancer patients.

Statistics of bone sarcoma in Japan: report from the population-based cancer registry in Japan.

BACKGROUND: No previous reports have characterized national bone sarcoma profiles overall. We examined the nationwide statistics for bone sarcoma in Japan using data from the National Cancer Registry (NCR), a population-based cancer registry. METHODS: We identified 3,755 patients with bone sarcomas entered in the NCR during 2016-2019 using International Classification of Diseases-Oncology, Third Edition codes for cancer topography and morphology. We extracted data on patient demographics, tumor details (reason for diagnosis, tumor location, histology, extent of disease), hospital volume/type, treatment, and prognosis for each patient. RESULTS: Bone sarcoma showed a slight male preponderance. The age distribution peaked at ages 10-20 and 60-80; approximately 44% of patients were aged over 60 years. Chordoma, chondrosarcoma, and malignant fibrous histiocytoma of bone peaked in the elderly, and Ewing's sarcoma peaked in children. Osteosarcoma had two peaks in Japan as well as in Western countries. The most frequent tumor locations were the limb (45%) and the pelvis (21%). Extent of disease was categorized as: "localized" (39%), "regional" (27%), and "distant" (11%). We found significant associations between overall survival and age, tumor location, facility type, hospital volume, histologic subtype, reason for diagnosis, and extent of disease. The latter had the poorest survival. CONCLUSIONS: This is the first study to outline the epidemiology, clinical features, treatment, prognosis, and significant factors affecting prognosis of bone sarcoma in Japan using the NCR. Documenting our data regarding elderly patients' outcomes is essential so other countries showing similar population-aging trends can learn from our experiences. LEVEL OF EVIDENCE: Prognostic studies, Level III.

Influence of major hepatectomy on gemcitabine-based chemotherapy for recurrent biliary tract cancer after surgery: a subgroup analysis of JCOG1113.

BACKGROUND: Major hepatectomy (MH) can increase the risk of adverse events (AEs) owing to impaired drug metabolism due to decreased liver volume and surgical injury. Thus, we performed this subgroup analysis using data from JCOG1113, a phase III trial comparing gemcitabine plus S-1 (GS) and gemcitabine plus cisplatin (GC) in patients with advanced and recurrent biliary tract cancer (BTC), to evaluate the effect of MH on the safety and efficacy of GC and GS regimens in patients with recurrent BTC. METHODS: Of the 354 patients with advanced BTC enrolled in JCOG1113, 76 patients with postoperative recurrence (30 in the MH group and 46 in the non-MH group) were analyzed. RESULTS: Grade ≥ 3 platelet count decreased in both arms was more frequent in the MH group than in non-MH group (GC, 0.0 vs. 17.6%; GS, 3.9 vs. 15.4%). However, in the MH group, the white blood cell decreased (GC, 55.0 vs. 38.5%; GS, 23.1 vs. 7.7%) and anemia (GC, 15.0 vs. 11.8%; GS, 23.1 vs. 7.7%) were less common than in the non-MH group. The MH and non-MH groups showed no significant difference in overall survival (OS) in both GC [median OS, 23.0 in MH vs. 16.9 months in non-MH (hazard ratio, 0.857; 95% CI 0.387-1.899)], and GS [median OS, 21.5 vs. 14.9 months (hazard ratio, 0.670; 95% CI 0.310-1.447)] arms. CONCLUSIONS: The safety and efficacy of gemcitabine-based chemotherapy were comparable between patients who underwent MH and those who underwent other surgeries.

Phase I study of the irreversible fibroblast growth factor receptor 1-4 inhibitor futibatinib in Japanese patients with advanced solid tumors.

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.

Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer.

BACKGROUND: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC. METHODS: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment. RESULTS: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively). CONCLUSION: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.

Clinical features of germline BRCA1/2 or ATM pathogenic variant positive pancreatic cancer in Japan.

BACKGROUND: There has been increasing interest into the role of germline BRCA1/2 pathogenic variants (gBRCA PV) and gATM PV and likely PV (PV and LPV; PV + LPV) in the carcinogenesis and treatment of pancreatic cancer (PC), but the clinical features have not been well described. METHODS: Patients with confirmed gBRCA PV and gATM PV + LPV PC treated at our hospital between April 2016 and December 2021, were retrospectively evaluated for clinical characteristics and outcomes. RESULTS: Twenty-two patients harbored gBRCA PV and three patients harbored gATM PV + LPV. Of the gBRCA PV patients, 81.8 % received platinum-based chemotherapy with favorable treatment outcomes with an objective response rate of 50.0 % (95 % CI: 23.0-77.0), median progression free survival (PFS) of 334 days, and median overall survival (OS) of 926 days from the initiation of first-line chemotherapy. The annual number of patients with gBRCA PV was two patients per year before January 2021 (when BRACAnalysis became available in Japan), and ten patients during the 10 months thereafter. Four patients (20 %) with gBRCA PV developed soft-tissue metastasis with progression. Two patients with gATM PV + LPV received platinum-based chemotherapy and the best response of those patients was partial response and stable disease and their OS from the initiation of first-line chemotherapy was 1192 and 989 days, and PFS was 579 and 140 days, respectively. CONCLUSION: The diagnosis of gBRCA PV-positive PC has increased revealed in recent years. These tumors appear to be sensitive to platinum-based chemotherapy, with long term survival observed in gATM PV + LPV-positive patients.