PMID- 38343359 OWN - NLM STAT- MEDLINE DCOM- 20240410 LR - 20240411 IS - 1557-9077 (Electronic) IS - 1050-7256 (Linking) VI - 34 IP - 4 DP - 2024 Apr TI - A Phase 2 Study of Encorafenib in Combination with Binimetinib in Patients with Metastatic BRAF-Mutated Thyroid Cancer in Japan. PG - 467-476 LID - 10.1089/thy.2023.0547 [doi] AB - Background: Driver mutations at BRAF V600 are frequently identified in papillary thyroid cancer and anaplastic thyroid cancer (ATC), in which BRAF inhibitors have shown clinical effectiveness. This Japanese phase 2 study evaluated the efficacy and safety of a BRAF inhibitor, encorafenib, combined with an MEK inhibitor, binimetinib, in patients with BRAF V600-mutated thyroid cancer. Methods: This phase 2, open-label, uncontrolled study was conducted at 10 institutions targeted patients with BRAF V600-mutated locally advanced or distant metastatic thyroid cancer not amenable to curative treatment who became refractory/intolerant to >/=1 previous vascular endothelial growth factor receptor-targeted regimen(s) or were considered ineligible for those. The primary endpoint was centrally assessed objective response rate (ORR). The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: We enrolled 22 patients with BRAF(V600E)-mutated thyroid cancer: 17 had differentiated thyroid cancer (DTC), and 5 had ATC. At data cutoff (October 26, 2022), the median follow-up was 11.5 (range = 3.4-19.0) months. The primary endpoint of centrally assessed ORR was 54.5% (95% confidence interval [CI] 32.2-75.6; partial response in 12 patients and stable disease in 10). The ORRs in patients with DTC and ATC were 47.1% (8 of 17) and 80.0% (4 of 5), respectively. The medians for DOR and PFS by central assessment and for OS were not reached in the overall population, the DTC subgroup, or the ATC subgroup. At 12 months, the rate of ongoing response was 90.9%, and the PFS and OS rates were 78.8% and 81.8%, respectively. All patients developed >/=1 adverse events (AEs): grade 3 AEs in 6 patients (27.3%). No patients developed grade 4-5 AEs. The most common grade 3 AE was lipase increased (4 patients [18.2%]). Those toxicities were mostly manageable with appropriate monitoring and dose adjustment. Conclusions: Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAF(V600E)-mutated thyroid cancer regardless of its histological type, such as DTC or ATC, with no new safety concerns identified. Encorafenib plus binimetinib could thus be a new treatment option for BRAF V600-mutated thyroid cancer. Clinical Trial Registration number: Japan Registry of Clinical Trials: jRCT2011200018. FAU - Tahara, Makoto AU - Tahara M AD - Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. FAU - Kiyota, Naomi AU - Kiyota N AD - Department of Medical Oncology and Hematology, Cancer Center, Kobe University Hospital, Kobe, Hyogo, Japan. FAU - Imai, Hiroo AU - Imai H AD - Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan. FAU - Takahashi, Shunji AU - Takahashi S AD - Department of Medical Oncology, The Cancer Institute Hospital of JFCR, Koto-ku, Tokyo, Japan. FAU - Nishiyama, Akihiro AU - Nishiyama A AD - Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan. FAU - Tamura, Shingo AU - Tamura S AD - Department of Medical Oncology, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Fukuoka, Japan. FAU - Shimizu, Yasushi AU - Shimizu Y AD - Department of Medical Oncology, Hokkaido University Hospital, Sapporo, Hokkaido, Japan. FAU - Kadowaki, Shigenori AU - Kadowaki S AD - Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan. FAU - Ito, Ken-Ichi AU - Ito KI AD - Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan. FAU - Toyoshima, Masahiro AU - Toyoshima M AD - ONO Pharmaceutical Co., Ltd., Osaka, Japan. FAU - Hirashima, Yoshinori AU - Hirashima Y AD - ONO Pharmaceutical Co., Ltd., Osaka, Japan. FAU - Ueno, Shinji AU - Ueno S AD - ONO Pharmaceutical Co., Ltd., Osaka, Japan. FAU - Sugitani, Iwao AU - Sugitani I AD - Department of Endocrinology, Nippon Medical School Hospital, Bunkyo-ku, Tokyo, Japan. LA - eng PT - Clinical Trial, Phase II PT - Journal Article DEP - 20240314 PL - United States TA - Thyroid JT - Thyroid : official journal of the American Thyroid Association JID - 9104317 RN - 0 (Benzimidazoles) RN - 181R97MR71 (binimetinib) RN - EC 2.7.11.1 (BRAF protein, human) RN - 0 (Carbamates) RN - 8L7891MRB6 (encorafenib) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) RN - 0 (Sulfonamides) RN - 0 (Vascular Endothelial Growth Factor A) SB - IM MH - Humans MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects MH - *Benzimidazoles MH - *Carbamates MH - Japan MH - Mutation MH - Protein Kinase Inhibitors MH - Proto-Oncogene Proteins B-raf/genetics MH - *Sulfonamides MH - *Thyroid Carcinoma, Anaplastic/chemically induced/drug therapy/genetics MH - *Thyroid Neoplasms/drug therapy/genetics/chemically induced MH - Vascular Endothelial Growth Factor A/genetics OTO - NOTNLM OT - BRAF OT - anaplastic thyroid cancer OT - differentiated thyroid cancer OT - molecular targeted therapy OT - papillary thyroid cancer EDAT- 2024/02/12 15:42 MHDA- 2024/04/10 06:42 CRDT- 2024/02/12 03:53 PHST- 2024/04/10 06:42 [medline] PHST- 2024/02/12 15:42 [pubmed] PHST- 2024/02/12 03:53 [entrez] AID - 10.1089/thy.2023.0547 [doi] PST - ppublish SO - Thyroid. 2024 Apr;34(4):467-476. doi: 10.1089/thy.2023.0547. Epub 2024 Mar 14.