Taro Shibata’s research while affiliated with National Cancer Center, Japan and other places

Ensuring the high quality of colonoscopies in colorectal cancer (CRC) screening is essential to reducing CRC. Recently, computer-aided detection systems (CADe) that use artificial intelligence have attracted much attention as potentially useful tools for improving lesion detection in colonoscopy. However, evidence on the efficacy of CADe in CRC screening is lacking. We have planned a multi-national, multi-center, randomized controlled trial in the Asia-Pacific region to assess whether colonoscopy with CADe (test method) yields higher lesion detection (primary endpoint: adenoma detection rate) than colonoscopy without CADe (standard method) in CRC screening populations. The study will include 1400 participants aged 50–79 years who are due to undergo colonoscopy for CRC screening, whether as a primary screening colonoscopy or following a positive fecal immunochemical test. If the efficacy of CADe is proven from this study, the use of CADe in colonoscopy for CRC screening will become standard, leading to improved CRC screening.

Previously, we conducted the phase I study of 64Cu-ATSM, which is Cu-diacetyl-bis (N4-methylthiosemicarbazone) radiolabeled with Cu-64, for patients with brain tumors and determined the maximum tolerated dose. We started a subsequent multicenter, randomized, open-label phase III study to evaluate the efficacy of 64Cu-ATSM as an investigator-initiated registration-directed trial for recurrent or residual malignant glioma (protocol No. NCCH2301, STEP-64). Patients will be randomized to either the control or study arm (64Cu-ATSM). A large-scale randomized trial seems difficult to perform for patients with brain tumors because of small sample sizes. Therefore, we designed a small randomized trial with 56 patients. Furthermore, as a pragmatic approach in the control arm, physicians can choose treatments depending on the patient’s condition among the clinically available options, where the drugs used are not regarded as investigational. The trial was registered in the Japan Registry of Clinical Trials as jRCT2031240090.

Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib–tamoxifen in patients with HR+/HER2− advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib–tamoxifen or placebo–tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1–32.4) with palbociclib–tamoxifen and 11.1 months (95% CI, 7.4–14.6) with placebo–tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43–0.85; P = 0.002). Palbociclib–tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44–1.21) with palbociclib–tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib–tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo–tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2− advanced breast cancer, palbociclib–tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib–tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.

Background Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune‐checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS. Methods The number of patients expected to be enrolled was 15–25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression‐free survival (PFS), overall survival (OS), and safety. Results A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7–8.6 months) and the median OS was 15.8 months (95% CI, 8.2–not reached). Conclusions The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS.

7001 Background: Aggressive adult T-cell leukemia-lymphoma (ATL) (i.e., acute, lymphoma and unfavorable chronic types) has poor prognosis with around a 1-year median survival time (MST) with chemotherapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a durable response with 3-year overall survival (3-y OS) of around 40%. However, the results were mostly from retrospective studies. This single-arm, phase 3 trial by the Japan Clinical Oncology Group (JCOG) evaluated upfront allo-HSCT for aggressive ATL (jRCTs031180243). Methods: Patients (pts) with newly diagnosed aggressive ATL who wished to receive allo-HSCT were eligible. At trial initiation, JCOG0907 was restricted to myeloablative allo-HSCT (MAST) for pts aged ≤ 55 years. After protocol amendment in September 2014, reduced intensity allo-HSCT (RIST) for pts aged 56-65 years was allowed. The protocol treatment was VCAP-AMP-VECP as induction chemotherapy based on the phase 3 JCOG9801 trial (3-y OS 24%) followed by transplantation in pts upon first remission from an HLA-matched or 1-locus mismatched related donor, or HLA-matched unrelated (UR) donor. MAST regimens consisted of busulfan (BU)/cyclophosphamide (CPA) for related donors and total body irradiation (TBI)/CPA for UR donors. RIST regimens consisted of BU/fludarabine (FLU) for related donors and FLU/BU/TBI for UR donors. The primary endpoint was 3-y OS in all registered pts. This study evaluated whether the lower limit of the two-sided 90% CI of 3-y OS exceeded a threshold of 25%. Results: Between September 2010 and June 2020, 110 pts (72 acute, 27 lymphoma, 10 unfavorable chronic and 1 other) were enrolled. Of 92 pts who received allo-HSCT (all transplants), 41 pts (19 MAST and 22 RIST, 12 related and 29 UR) received per-protocol allo-HSCT (study transplant) and 51 pts (11 related, 15 UR and 25 cord blood) received allo-HSCT not specified in the protocol, 35 of whom received allo-HSCT during first remission and 16 pts after progression. The primary endpoint was met with 3-y OS of 44.0% (90% CI, 36.0-51.6). MST was 3.0 years (95% CI, 1.5-5.8) for study transplants and 2.5 years (95% CI, 1.4-4.8) for all transplants. Multivariable analysis with a time-dependent covariate for the presence or absence of transplant revealed the hazard ratio of OS for study transplants compared with non-study transplants was 0.92 (95% CI, 0.55-1.51). In 41 study transplants, treatment-related deaths (TRD) were 16.7% in related transplants and 20.7% in UR transplants. Among 70 pts who died, causes of death were disease progression in 34, TRD due to protocol treatment in 9, TRD due to post-protocol treatment in 21, and other disease in 6. Conclusions: Upfront allo-HSCT can be recommended for chemotherapy-sensitive pts with aggressive ATL, but its survival benefit is not clear considering immortal time bias suggested by multivariable analysis with a time-dependent covariate. Clinical trial information: jRCTs031180243 .

578 Background: The RAFAELO study is designed to evaluate the safety and efficacy of breast radiofrequency ablation, enabling women between 20 and 79 years of age with small breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. Methods: The RAFAELO study is a prospective, multi-center, single-arm, confirmatory trial including women between 20 and 79 years of age with unifocal, MRI and ultrasound-visible invasive ductal carcinoma or ductal carcinoma in situ size 1.5 cm or smaller diagnosed by preoperative core-needle biopsy, and classified as any grade, any hormone receptor (HR) status, and any human epidermal growth factor receptor 2 (HER2) status. The primary endpoint was Ipsilateral breast tumor recurrence (IBTR) -free survival at 5 years. e planned sample size was set at 372 considering patients lost to follow-up to achieve the power of 80% with the one-sided alpha of 5%, the expected 5-year IBTR-free survival of 93.7%, and the threshold of 90%. The IBTR-free survival time was estimated using the Kaplan-Meier method. Results: Between August 2013 and November 2017, 372 patients were enrolled in this study. A total of 370 patients received successful radiofrequency ablation per protocol and 353 patients were included for the efficacy analysis. The median age was 55 years (range, 32-78 years). With median follow-up period of 5 years, IBTR was observed in 2 patients among 353 patients. The 5-year IBTR-free survival was 98.6% (90% CI 97.1%-99.3%) and the primary endpoint was met as its lower limit of 90% CI exceeded the threshold (90%). As device-related adverse events during radiofrequency ablation, burns were observed in 4 (1.1%) for Grade 1 and 3 (0.8%) for Grade 2 among 370 patients. No severe device-related adverse events were reported. Conclusions: Breast radiofrequency ablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Breast cancer patients in Japan can now avail themselves of this minimally invasive treatment that’s subsidized by public insurance. Further analysis within this clinical trial or registry is needed to confirm radiofrequency ablation as a viable alternative to surgical excision for breast cancer patients in the point of cosmetic results and patient’s satisfaction. Clinical trial information: jRCTs032180229 .

TPS10079 Background: In Japan, there are no pediatric regulations that encourage drug development for pediatric cancer, such as Pediatric Investigation Plans (PIPs) which are mandated in Europe, or the RACE Act in the U.S. Therefore, there are fewer early-phase clinical trials and approved drugs for pediatric cancer than in Western countries. In addition, because there is no rapid compassionate use program, there are delays when using an unapproved drug. According to a report from the Japanese cancer genome profiling (CGP) testing data center, C-CAT, 51.3% of pediatric patients with solid tumors had targetable genetic abnormalities. However, only 5.8% of them had access to the recommended molecular targeted therapy (Tanimura K. et al., presented at the Japanese Society of Pediatric Hematology and Oncology annual meeting 2022). Thus, Japanese pediatric patients with relapsed or refractory solid tumors have limited access to novel drugs, even if they have druggable mutations. Therefore, we designed a platform study (NCCH2220, PARTNER trial) to rapidly deliver molecularly targeted drugs based on CGP testing. Methods: This study has two objectives: first, to administer some drugs to pediatric patients that are not approved for pediatric cancer in Japan. These drugs have been shown to be safe in pediatric patients in foreign countries and are expected to be effective. Second, to evaluate the safety and efficacy of the drug in Japanese pediatric patients and, if necessary, its pharmacokinetics. These data will be used for potential future regulatory filings. This is an open-label, multicenter, multicohort study. Eligible patients are aged 0–29 years with diseases having no standard therapy, which are refractory, or when there is intolerance to standard therapy. The study drug must be recommended for the patient by CGP testing or approved for pediatric use for their disease in the U.S. or Europe, or approved in Japan for use in adults only. The drugs are used as monotherapy in the study. The study schedules follow a master protocol. Up to 30 patients can be enrolled in each cohort. The primary endpoint is the incidence of dose-limiting toxicity in each cohort. The secondary endpoints are the incidence of adverse events, the overall response rate, and, if necessary, the pharmacokinetics in each cohort. As of January 2024, the study had five treatment cohorts with the following agents: imatinib, pazopanib, ruxolitinib, trametinib, and atezolizumab. Additional cohorts will be added. We started planning the study in November 2022, and enrollment began on January 18, 2024. This platform trial has enabled us to deliver drugs to patients more quickly and efficiently than by conducting individual early-phase trials for each drug. Clinical trial information: jRCTs031230544 .

11159 Background: The integration of Comprehensive Genomic Profiling (CGP) with real-world data (RWD) provides crucial insights for anticancer drug development to achieve precision oncology, therefore, the current global trend to construct as the national projects, yet its clinical impact remains underexplored. The therapeutic efficacy of each line of anti-cancer drug in various cancer types and the relationship between genetic alterations and the effect of anticancer drugs is needed to guide the direction of future drug development promptly and precisely. Methods: A comprehensive analysis was conducted on data from Japan's Center for Cancer Genomics and Advanced Therapeutics (C-CAT) repository between June 2019 and December 2023. Five genomic profiling assays for CGP testing were reimbursed by nation-wide insurance in Japan. Utilizing the clinicogenomic repository of C-CAT, registered data of therapeutic efficacy of anticancer drug including cytotoxic agents, molecular-targeted agents, and immune checkpoint inhibitors were evaluated in association with genetic alterations. Data on anticancer drug of patients (pts) with recurrent or metastatic disease were included in the analysis. Results: The C-CAT registry data encompassed 60,256 pts across 32 tumor organ sites, classified ontology by the OncoTree over 4.5 years. Of these patients, 30,234 were male, and 30,017 were female, with 5 classified as unknown. In terms of age, 31,919 pts were < 65. The most registered origins were colorectal (n=10,110), pancreas (n=8,069), biliary tract (n=5,030), breast (n=3,744), esophagus/stomach (n=3,734), prostate (n=3,701), ovarian/fallopian tube (n=3,521), lung (n=3,427), and soft tissue (n=2,568). TP53mutations (58.3%, n=35,102) were most prevalent, followed by KRAS (25.8%, n=15,521), APC (19.9%, n=11,919), NOTCH3 (14.1%, n=8,502), and PIK3CA (13.0%, n=7,861). The frequency of BRCA1/2mutation was 4.1% (n=2,479). Overall response rate (ORR) for the first-, second-, third-, and fourth-lines treatment were 35.7%, 23.3%, 19.4%, and 19.2%, respectively. Pts treated with cisplatin or carboplatin in the first-line treatment, who had TP53 mutations, showed a better ORR than those without (44.0% vs. 38.9%, p < 0.001). Similarly, pts with BRCA1/2mutation showed a better ORR than those without (53.9% vs. 41.4%, p < 0.001) in the first-line treatment. Conclusions: This study was the first to report the relationship between genetic alterations and the therapeutic effect of anticancer drugs in each line. This approach based on big data analysis potentially accelerates drug development in the appropriate patient population by identifying significant associations between specific genetic mutations and improved outcomes with certain chemotherapy regimens in various cancers.

Colonoscopy is the gold standard for detecting and resecting adenomas or early stage cancers to reduce the incidence and mortality rates of colorectal cancer. In a recent observational study, texture and color enhancement imaging (TXI) was reported to improve polyp detection during colonoscopy. This randomized controlled trial involving six Japanese institutions aims to confirm the superiority of TXI over standard white-light imaging (WLI) in detecting colorectal lesions during colonoscopy. During the 1-year study period, 960 patients will be enrolled, with 480 patients in the TXI and WLI groups. The primary endpoint is the mean number of adenomas detected per procedure. The secondary endpoints include adenoma detection rate, advanced adenoma detection rate, polyp detection rate, flat polyp detection rate, depressed lesion detection rate, mean polyps detected per procedure, sessile serrated lesion (SSL) detection rate, mean SSLs detected per procedure and adverse events.