BRAF T599

EGFR gene mutations were found in 16 (29%) and KRAS or NRAS alterations in 8 (14%) of the 54 tumors analyzed. We described herein seven non-hotspot/novel variants in the BRAF gene, highlighting their potential role in expanding our understanding of FCDTC genetics.

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

However, the efficacy of dabrafenib + trametinib on non-V600E mutant NSCLC in clinical practice only exists in some case reports. Here, we report a case of NSCLC patient carrying BRAF ex15 p.T599dup, who showed a clinical response to the combined therapy of dabrafenib + trametinib.

Conclusion  This constitutes one of the few reports on comprehensive analysis of molecular alterations underlying melanomas in Indian patients. A larger sample size, with more extensive molecular markers, would yield additional information on the disease manifestation.

Cobimetinib plus vemurafenib showed antitumor activity in patients with advanced solid tumors with BRAF V600E mutations; additional study is warranted to confirm the antitumor activity in tumors with non-V600E BRAF mutations.

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

He was addressed to Dabrafenib/Trametinib targeted therapy, showing an initial dramatic response. In parallel, in-silico ligand-based homology modeling was set up and performed on this and an additional B-RAF rare variant (p.A598_T599insV) to unveil and justify the success of the B-RAF inhibitory activity of Dabrafenib, showing that it could adeptly bind both these variants in a similar manner to how it binds and inhibits the V600E mutant. These findings open up the possibility of broadening the spectrum of BRAF inhibitor-sensitive mutations beyond mutations at codon V600, suggesting that B-RAF V600 WT melanomas should undergo more specific investigations before ruling out the possibility of targeted therapy.

Molecular profiling of liquid biopsies at baseline identified alterations that could impact on patient outcomes. Our data suggest that the presence of BRAF pathogenic variants may be a good prognostic factor in stage IV NSCLC patients treated with immunotherapy or chemo-immunotherapy, while pathogenic mutations in ERBB3 could be a biomarker of high risk of disease progression. Additional studies analyzing larger cohorts of patients are needed to clarify these hypotheses.

P1/2, N=37, Terminated, Haihe Biopharma Co., Ltd. | N=150 --> 37 | Trial completion date: Dec 2024 --> Mar 2023 | Recruiting --> Terminated | Trial primary completion date: Dec 2023 --> Mar 2023; Sponsor business decision

P1/2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2023 --> Feb 2024 | Trial primary completion date: Feb 2023 --> Feb 2024

Novel BRAF mutations and V600E were frequently detected in thyroid cancer of Libyan patients; this suggests a potential role of these novel mutations in carcinogenesis and in anti-EGFR therapy resistance.

P1/2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=38 --> 17

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.

C+Vdemonstrated evidence of anti-tumor activity in pts with advanced solid tumors with BRAF V600E and other muts.

Activating BRAF mutation, HER2 amplification, HER2 mutation and KRAS mutation were not mutually exclusive. However, they may even have a synergistic effect in tumorigenesis. BRAF mutation is not uncommon in primary MOC of Taiwanese. The BRAF mutant (T599I) stands the majority. We suggested that there was a lower potential response to the existing V600 BRAF inhibitors, but may be responsive to dual BRAF plus MEK inhibitors or single MEK inhibitor. Further studies are warranted to investigate the clinical benefits of newly targeted therapy in recurrent or advanced stage primary MOC patients carrying different classes of BRAF mutation.

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

Vemurafenib and dabrafenib have already been approved for the treatment of melanoma, NSCLC and colorectal carcinoma. BRAF gene mutations, especially BRAF non-V600, was extensively mutated in Chinese multiple cancer types. Our revealed the potential targeted therapeutic strategies among non-V600 population with solid tumors should be considered in further study.

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

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