BRAF V600R

P2, N=26, Active, not recruiting, University Health Network, Toronto | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Oct 2023 --> Apr 2025

P2, N=26, Active, not recruiting, University Health Network, Toronto | Trial completion date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2023 --> Mar 2024 | Recruiting --> Active, not recruiting

The Idylla BRAF Mutation Assay is a highly reliable and sensitive platform for detecting BRAF pathogenic variants in codon 600 in malignant melanoma. The test can be performed in less than two hours, significantly improving turnaround time, thus allowing faster time to treatment.

P=N/A, N=3, Terminated, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Oct 2024 --> Jul 2023 | Recruiting --> Terminated | Trial primary completion date: Oct 2023 --> Jul 2023; low accrual and lack of funds

P=N/A, N=8, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: May 2024 --> Oct 2024 | Trial primary completion date: May 2023 --> Oct 2023

A complex of methods for determination of the nucleotide sequence of the BRAF codons 592-601 and the algorithm for testing samples and analyzing mutations in the BRAF codons 600-601 was developed. The method provides sufficient sensitivity to detect frequent mutations in codons 600 and 601 and allows them to be precisely differentiated.

P2/3, N=8, Terminated, The Christie NHS Foundation Trust | N=1050 --> 8 | Trial completion date: Oct 2030 --> Jan 2023 | Recruiting --> Terminated | Trial primary completion date: Oct 2030 --> Jan 2023; Closed earlier than expected due to the need for a redesign to reflect the recent change in standard of care guidelines. New design will include these treatments.

Rare BRAF mutations are not anecdotal in the metastatic melanoma population. Although data interpretation must remain careful owing to the limited size of some subsets of patients, non-E/K V600 BRAF mutations seem to confer a high sensitivity to targeted therapy, whereas MAPKis seem less effective in patients with non-V600 BRAF mutations. However, this strategy may be used as an alternative option in the case of immunotherapy failure in the latter population.

Four patients received combined BRAF/MEK inhibitors, two patients BRAF inhibitor monotherapy, and six patients were treated with ICI for advanced melanoma; four patients received adjuvant treatment with nivolumab. Given the few cases and the absence of randomized clinical trials, it is important to report clinical experiences, which can guide physicians in the treatment of melanomas harboring rare BRAF mutations.

P1/2, N=50, Completed, Abramson Cancer Center of the University of Pennsylvania | Active, not recruiting --> Completed | Trial completion date: Oct 2026 --> Oct 2021 | Trial primary completion date: Oct 2024 --> Oct 2021

P2/3, N=1050, Recruiting, The Christie NHS Foundation Trust | Not yet recruiting --> Recruiting

Our results demonstrate that the Idylla BRAF Mutation Assay produces accurate, precise results in less than 3 hours, with faster TAT compared to NGS. Single-use cartridges eliminate the need for manual sample preprocessing and the risk of PCR contamination. In addition, this sensitive assay correctly identifies BRAF V600 alterations in samples with necrosis and low tumor cell content.

Conclusion Our results - on a small number of patients - suggest that patients with rare BRAF mutations may have inferior survival outcomes with first line targeted treatment, compared with patients with classical BRAF mutations. Impact statement Our findings add to the limited clinical knowledge on rare BRAF mutations in melanoma and may help guide treatment decisions on this small subset of patients.

P2, N=26, Recruiting, University Health Network, Toronto | Trial completion date: Sep 2021 --> Dec 2023 | Trial primary completion date: Sep 2021 --> Dec 2023

P2/3, N=1050, Not yet recruiting, The Christie NHS Foundation Trust | Initiation date: Jun 2021 --> Sep 2021

P2/3, N=1050, Not yet recruiting, The Christie NHS Foundation Trust

The successful use of the IL-6 receptor antagonist tocilizumab has also been described...The patient had been receiving dabrafenib and trametinib for one month after being treated with pembrolizumab as adjuvant...The administration of paracetamol and an imputed antibiotic therapy with piperacillin / tazobactam did not lead to defever, but to further increasing lymphocytopenia and increasing CRP up to 311.5 mg / L (norm: <3 mg / l)...The intravenous administration of 150 mg prednisolone daily for 4 days led to a prompt defever, normalization of weight and resolution of all other symptoms. The patient tolerated the subsequent change in therapy to vemurafenib / cobimetinib without complications. Due to the increasing combination of therapies in patients with metastatic melanoma, the frequency of CRS can increase and should be included in differential diagnostic considerations for the symptoms mentioned above.

P2, N=26, Recruiting, University Health Network, Toronto | Active, not recruiting --> Recruiting

Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.

P2, N=26, Active, not recruiting, University Health Network, Toronto | Recruiting --> Active, not recruiting

BRAF inhibitors dabrafenib and vemurafenib and ROCK inhibitor Y27632 were used in the 2-D in vitro cultures. Our data suggest that BRAF inhibition treatment can induce PD-L1 expression in BRAF-mutated PTC via mTOR pathway activation. In vivo immunocompetent models are ongoing and results will be presented at the meeting.

Regressed melanocytic nevi are an emerging dermatologic effect from pembrolizumab therapy.

P=N/A, N=658, Completed, Genentech | N=1000 --> 658