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Kan Yonemori,Keiichi Fujiwara,Kosei Hasegawa,Mayu Yunokawa,Kimio Ushijima,Shiro Suzuki,Ayumi Shikama,Shinichiro Minobe,Tomoka Usami,김재원,김병기,Peng-Hui Wang,Ting-Chang Chang,Keiko Yamamoto,Shirong Han,Jo 대한부인종양학회 2024 Journal of Gynecologic Oncology Vol.35 No.2
Objective: In the global phase 3 Study 309/KEYNOTE-775 (NCT03517449) at the first interimanalysis, lenvatinib+pembrolizumab significantly improved progression-free sur vival (PFS),overall sur vival (OS), and objective response rate (ORR) versus treatment of physician’schoice chemotherapy (TPC) in patients with previously treated advanced/recurrentendometrial cancer (EC). This explorator y analysis evaluated outcomes in patients enrolledin East Asia at the time of prespecified final analysis. Methods: Women ≥18 years with histologically confirmed advanced, recurrent, or metastaticEC with progressive disease after 1 platinum-based chemotherapy (2 if 1 given in neoadjuvant/adjuvant setting) were enrolled. Patients were randomized 1:1 to lenvatinib 20 mg orallyonce daily plus pembrolizumab 200 mg intravenously ever y 3 weeks (≤35 cycles) or TPC(doxorubicin or paclitaxel). Primar y endpoints were PFS per RECIST v1.1 by blindedindependent central review and OS. No alpha was assigned for this subgroup analysis. Results: Among 155 East Asian patients (lenvatinib+pembrolizumab, n=77; TPC, n=78),median follow-up time (data cutoff: March 1, 2022) was 34.3 (range, 25.1–43.0) months. Hazard ratios (HRs) with 95% confidence inter vals (CIs) for PFS (lenvatinib+pembrolizumabvs. TPC) were 0.74 (0.49–1.10) and 0.64 (0.44–0.94) in the mismatch repair proficient(pMMR) and all-comer populations, respectively. HRs (95% CI) for OS were 0.68 (0.45–1.02)and 0.61 (0.41–0.90), respectively. ORRs were 36% with lenvatinib+pembrolizumab and 22%with TPC (pMMR) and 39% and 21%, respectively (all-comers). Treatment-related adverseevents occurred in 97% and 96% (grade 3–5, 74% and 72%), respectively. Conclusion: Lenvatinib+pembrolizumab provided clinically meaningful benefit withmanageable safety compared with TPC, supporting its use in East Asian patients withpreviously treated advanced/recurrent EC. Trial Registration: ClinicalTrials.gov Identifier: NCT03517449
Kazuhiro Takehara,Takashi Matsumoto,Junzo Hamanishi,Kosei Hasegawa,Motoki Matsuura,Kiyonori Miura,Shoji Nagao,Hidekatsu Nakai,Naotake Tanaka,Hideki Tokunaga,Kimio Ushijima,Hidemichi Watari,Yoshihito Y 대한부인종양학회 2021 Journal of Gynecologic Oncology Vol.32 No.2
Objective: The primary objective of this study was to evaluate the safety of niraparib 300 mg/dayin Japanese patients with platinum-sensitive, relapsed ovarian cancer in a maintenance setting. Methods: Phase 2, multicenter, open-label, single-arm study enrolled Japanese patients withplatinum-sensitive, relapsed ovarian cancer who had received ≥2 platinum-based regimens. The primary endpoint (incidence of grade 3 or 4 thrombocytopenia-related events within 30days after initial niraparib administration) was justified by the incidences of a global pivotalphase 3 study and its post-hoc safety analysis on thrombocytopenia, the major hematologicaladverse event of niraparib. The overall safety analysis examined other treatment-emergentadverse events (TEAEs). Results: Enrolled patients (n=19) had a median (min, max) body weight of 53.9 (40.8–79.1)kg; all but one patient weighed <77 kg. Most (94.7%) patients initially received niraparib300 mg/day but this decreased in subsequent cycles (mean±standard deviation doseintensity, 191.6±65.7 mg/day). In total, 6/19 (31.6%) patients experienced grade 3 or 4 thrombocytopenia-related events within 30 days of initial niraparib administration. Other common TEAEs included nausea, and decreased platelet or neutrophil counts. Noprogression-free or overall survival events occurred; only 1 of 4 response-evaluable patientshad a post-baseline tumor assessment (stable disease). Conclusion: The incidence of grade 3 or 4 thrombocytopenia-related events in Japaneseovarian cancer patients was similar to that in the corresponding non-Japanese study. Overall,the safety profile was acceptable and consistent with the known safety profile and previousexperience with niraparib. Trial Registration: ClinicalTrials.gov Identifier: NCT03759587
Aikou Okamoto,Eiji Kondo,Toshiaki Nakamura,Satoshi Yanagida,Junzo Hamanishi,Kenichi Harano,Kosei Hasegawa,Takeshi Hirasawa,Kensuke Hori,Shinichi Komiyama,Motoki Matsuura,Hidekatsu Nakai,Hiroko Nakamur 대한부인종양학회 2021 Journal of Gynecologic Oncology Vol.32 No.2
Objective: To evaluate the efficacy and safety of niraparib in Japanese women with heavilypretreated ovarian cancer. Methods: This Phase 2 open-label, single-arm study enrolled Japanese women withhomologous recombination deficiency-positive relapsed, high-grade serous ovarian,fallopian tube, or primary peritoneal cancer who had completed 3–4 lines of therapy. The starting dose of niraparib was 300 mg administered once daily in continuous 28-daycycles until objective progressive disease, unacceptable toxicity, consent withdrawal ordiscontinuation. The primary endpoint, objective response rate (ORR), was assessed bythe investigator using RECIST version 1.1. Safety evaluations included the incidence oftreatment-emergent adverse events (TEAEs), including serious TEAEs. Results: Twenty women were enrolled and the confirmed ORR in the full analysis set (FAS)was 35.0% (7/20), consisting of 1 complete response and 6 partial responses. Diseasecontrol rate in the FAS was 90.0%. The most frequently reported TEAEs (>50%) wereanemia, nausea, and platelet count decreased. One patient (5.0%) had TEAEs leadingto discontinuation of niraparib whereas reductions or interruptions were reported in 14(70.0%) and 15 (75.0%) patients, respectively. The median dose intensity (202.9 mg daily)corresponded to a relative dose intensity of 67.6%. Conclusion: Efficacy and safety of niraparib in heavily pretreated Japanese women wascomparable to that seen in an equivalent population of non-Japanese women. No new safetysignals were identified.Trial Registration: ClinicalTrials.gov Identifier: NCT03759600
Aiko Ogasawara,Taro Hihara,Daisuke Shintani,Akira Yabuno,Yuji Ikeda,Kenji Tai,Keiichi Fujiwara,Keisuke Watanabe,Kosei Hasegawa 대한암학회 2020 Cancer Research and Treatment Vol.52 No.4
Purpose Circulating tumor DNA (ctDNA) is an attractive source for liquid biopsy to understand molecular phenotypes of a tumor non-invasively, which is also expected to be both a diagnostic and prognostic marker. PIK3CA and KRAS are among the most frequently mutated genes in epithelial ovarian cancer (EOC). In addition, their hotspot mutations have already been identified and are ready for a highly sensitive analysis. Our aim is to clarify the significance of PIK3CA and KRAS mutations in the plasma of EOC patients as tumor-informed ctDNA. Materials and Methods We screened 306 patients with ovarian tumors for somatic PIK3CA or KRAS mutations. A total of 85 EOC patients had somatic PIK3CA and/or KRAS mutations, and the correspon-ding mutations were subsequently analyzed using a droplet digital polymerase chain reaction in their plasma. Results The detection rates for ctDNA were 27% in EOC patients. Advanced stage and positive peritoneal cytology were associated with higher frequency of ctDNA detection. Preoperative ctDNA detection was found to be an indicator of outcomes, and multivariate analysis revealed that ctDNA remained an independent risk factor for recurrence (p=0.010). Moreover, we assessed the mutation frequency in matched plasma before surgery and at recurrence from 17 patients, and found six patients had higher mutation rates in cell-free DNA at recurrence compared to that at primary diagnosis. Conclusion The presence of ctDNA at diagnosis was an indicator for recurrence, which suggests potential tumor spread even when tumors were localized at the time of diagnosis.
Yuji Ikeda,Sho Sato,Akira Yabuno,Daisuke Shintani,Aiko Ogasawara,Maiko Miwa,Makda Zewde,Takashi Miyamoto,Keiichi Fujiwara,Yusuke Nakamura,Kosei Hasegawa 대한부인종양학회 2020 Journal of Gynecologic Oncology Vol.31 No.6
Objective: Maternal embryonic leucine zipper kinase (MELK) is receiving an attentionas a therapeutic target in various types of cancers. In this study, we aimed to evaluate theprognostic significance of MELK expression in ovarian cancer using clinical samples, andassessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derivedovarian cancer cells as well as cell lines. Methods: Expression levels of MELK in 11 ovarian cancer cell lines were confirmed bywestern blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay. MELK messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients byquantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluatedusing freshly-isolated primary ovarian cancer cells including spheroid formation condition. Results: MELK mRNA expression was significantly higher in ovarian cancer than in normalovaries (p<0.001), and high MELK mRNA expression was observed in patients with advancedstage, positive ascites cytology and residual tumor size. Patients with high MELK mRNAexpression showed shorter progression-free survival (p=0.001). Expression of MELK wasalso confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitoryconcentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167showed significant growth inhibitory effect against patient-derived ovarian cancer cells,regardless of their tumor locations, histologic subtypes and stages. Conclusions: We demonstrated MELK as both a prognostic marker and a therapeutic targetfor ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may bean effective approach to treat ovarian cancer patients.
Clinical utility of CA-125 in the management of uterine carcinosarcoma
Koji Matsuo,Malcolm S. Ross,Mayu Yunokawa,Marian S. Johnson,Hiroko Machida,Kohei Omatsu,Merieme M. Klobocista,Dwight D. Im,Shinya Satoh,Tsukasa Baba,Yuji Ikeda,Stephen H. Bush,Kosei Hasegawa,Erin A. B 대한부인종양학회 2018 Journal of Gynecologic Oncology Vol.29 No.6
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