BRAF V600K

Background/Objective: Dabrafenib and trametinib (D + T) have been approved for the treatment of stage III melanoma with BRAF V600E V600K mutations in an adjuvant setting, based on the results from the COMBI-AD trial. Similarly, the median OS was not reached, with OS rates of 96.4% at 12 months and 92.5% at 24 months. D + T achieved an RFS benefit, with effects sustained beyond the treatment period, indicating positive outcomes in this patient population.

P1/2, N=58, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Nov 2025

P2, N=175, Active, not recruiting, German Cancer Research Center | Recruiting --> Active, not recruiting

This study highlights distinct genetic abnormalities and actionable alterations in Japanese melanoma patients. This suggests a lower tumor mutational burden in East Asian cutaneous melanoma, which may affect the efficacy of immune checkpoint inhibitors. The heterogeneity of driver mutations across and within individuals highlights the need for personalized treatment approaches.

P1/2, N=75, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

This review confirms an association between CM and HM within the same patient. The link is primarily attributed to genetic factors involving BRAF-V600K, tyrosine kinase pathway genes, CDKN2A (P16), and BCL-2. Additionally, risk factors such as ultraviolet radiation and compromised immune function are associated with the incidence of these cancers.

P2, N=4, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; Study stopped due to slow enrollment

P3, N=921, Completed, Pfizer | Active, not recruiting --> Completed

Matched SXOs and cell lines demonstrated sensitivity to BRAF and MEK inhibitors. Further study using SXOs may improve the translational relevance of preclinical studies and enable the study of the metastatic melanoma tumor microenvironment.

The STARBOARD SLI showed that safety across the cohorts was generally comparable to the known safety profile of each agent. The standard dose regimen of COMBO450 plus pembrolizumab was chosen as the RP3D.

P1, N=22, Terminated, National Cancer Institute (NCI) | Active, not recruiting --> Terminated; Drug supply issues

Due to the relevance of the BRAFV600E mutation, inhibitors to this kinase have been developed, vemurafenib-OMe and dabrafenib. Ligand-protein interactions were evaluated using Schrödinger-Maestro program, LigPlot + , and PLIP (protein-ligand interaction profiler). Finally, all of the protein figures presented in this article were made in the PyMOL program.

P1, N=6, Recruiting, City of Hope Medical Center | Trial completion date: Apr 2025 --> Oct 2025 | Trial primary completion date: Apr 2025 --> Oct 2025

P1, N=56, Completed, Pfizer | Active, not recruiting --> Completed

No abstract available

P2, N=38, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=150 --> 38

The distinct genomic profiling in Japanese patients, including lower TMB, compared to Caucasians, is associated with poorer treatment outcomes. This result underscores the need for more effective therapeutic agents.

Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of recurrence-free survival, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

P=N/A, N=1, Completed, Pfizer | Active, not recruiting --> Completed | Trial completion date: May 2024 --> Dec 2023 | Trial primary completion date: May 2024 --> Dec 2023

This is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/).

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

P3, N=921, Active, not recruiting, Pfizer | Trial completion date: Mar 2024 --> Jul 2024

P1, N=60, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Aug 2024 --> Aug 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

P1, N=2, Active, not recruiting, Richard Wu | Recruiting --> Active, not recruiting | N=15 --> 2 | Trial completion date: Dec 2025 --> Dec 2024

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

P3, N=922, Active, not recruiting, Pfizer | Trial completion date: Nov 2023 --> Mar 2024

P1/2, N=33, Recruiting, University of Utah | Not yet recruiting --> Recruiting

P1; Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

P2, N=58, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

P1, N=71, Suspended, JS InnoPharm, LLC | N=124 --> 71 | Trial primary completion date: Dec 2023 --> Jun 2024

P2, N=68, Suspended, ImmVira Pharma Co. Ltd | Phase classification: P2a --> P2 | Trial completion date: Jan 2026 --> Jan 2027 | Not yet recruiting --> Suspended | Trial primary completion date: Dec 2025 --> Dec 2026

P3, N=176, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting

P1/2, N=33, Not yet recruiting, University of Utah

P1/2, N=78, Recruiting, Peter MacCallum Cancer Centre, Australia | Phase classification: P1b --> P1/2 | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=280, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P3, N=240, Recruiting, Pfizer | N=624 --> 240

P1/2; Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

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.

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

In in vitro and ex vivo settings, the combination therapy was observed to elicit a response; however, it did not amplify the efficacy observed with binimetinib alone, whereas in a patient, the combinational treatment remained ineffective. The preclinical in vivo data showed no increased combinatorial effect. However, the in vivo effect of binimetinib as monotherapy was unexpectedly high in the tested regimen. Nevertheless, binimetinib proved to be advantageous in the treatment of melanoma in vivo and led to high rates of apoptosis in vitro; hence, it still seems to be a good base for combination with other substances in the treatment of patients with NRAS-mutant melanoma.

P1; Trial completion date: Jul 2023 --> Dec 2024 | Trial primary completion date: Jul 2023 --> Dec 2024

R-ISS and RNA-sequencing identify partially overlapping patient populations, with R-ISS missing, e.g., 30% (22/72) of highly proliferative myeloma. RNA-sequencing based assessment of risk and targets for first choice treatment is possible in clinical routine.