Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial

Tatsunori Shimoi; Kuniko Sunami; Makoto Tahara; Satoshi Nishiwaki; Shota Tanaka; Eishi Baba; Masashi Kanai; Ichiro Kinoshita; Hidekazu Shirota; Hideyuki Hayashi; Naohiro Nishida; Toshio Kubo; Nobuaki Mamesaya; Yayoi Ando; Natsuko Okita; Taro Shibata; Kenichi Nakamura; Noboru Yamamoto

doi:10.1016/j.eclinm.2024.102447

Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial

EClinicalMedicine. 2024 Feb 2:69:102447. doi: 10.1016/j.eclinm.2024.102447. eCollection 2024 Mar.

Authors

Tatsunori Shimoi^{1

2}, Kuniko Sunami³, Makoto Tahara⁴, Satoshi Nishiwaki⁵, Shota Tanaka⁶, Eishi Baba⁷, Masashi Kanai⁸, Ichiro Kinoshita⁹, Hidekazu Shirota¹⁰, Hideyuki Hayashi¹¹, Naohiro Nishida¹², Toshio Kubo¹³, Nobuaki Mamesaya¹⁴, Yayoi Ando¹⁵, Natsuko Okita¹⁵, Taro Shibata¹⁶, Kenichi Nakamura^{2

15}, Noboru Yamamoto¹⁷

Affiliations

¹ Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
² Department of International Clinical Development, National Cancer Center Hospital, Tokyo, Japan.
³ Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan.
⁴ Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
⁵ Department of Advanced Medicine, Nagoya University Hospital, Aichi, Japan.
⁶ Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
⁷ Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
⁸ Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
⁹ Department of Medical Oncology, Hokkaido University Hospital, Hokkaido, Japan.
¹⁰ Department of Medical Oncology, Tohoku University Hospital, Sendai, Miyagi, Japan.
¹¹ Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan.
¹² Center for Cancer Genomics and Personalized Medicine, Osaka University Hospital, Osaka, Japan.
¹³ Center for Clinical Oncology, Okayama University Hospital, Japan.
¹⁴ Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
¹⁵ Research Management Division, Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan.
¹⁶ Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Tokyo, Japan.
¹⁷ Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.

Abstract

Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations.

Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)].

Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2-7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5-12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs.

Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer.

Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

Keywords: BRAF inhibitors; Bayesian statistics; MEK inhibitors; Platform clinical trials; Rare cancers.