Tumor-Type Agnostic, Targeted Therapies: BRAF Inhibitors Join the Group

Abstract

<p>In the present review, we briefly discuss the breakthrough advances in precision medicine using a tumor-agnostic approach and focus on BRAF treatment modalities, the mechanisms of resistance and the diagnostic approach in cancers with BRAF mutations. Tumor-type agnostic drug therapies work across cancer types and present a significant novel shift in precision cancer medicine. They are the consequence of carefully designed clinical trials that showed the value of tumor biomarkers, not just in diagnosis but in therapy guidance. Six tumor-agnostic drugs (with seven indications) have been approved through October 2022 by FDA. The first tumor-agnostic treatment modality was pembrolizumab for MSI-H/dMMR solid tumors, approved in 2017. This was followed by approvals of larotrectinib and entrectinib for cancers with NTRK fusions without a known acquired resistance mutation. In 2020, pembrolizumab was approved for all TMB-high solid cancers, while a PD-L1 inhibitor dostarlimab-gxly was approved for dMMR solid cancers in 2021. A combination of BRAF/MEK inhibitors (dabrafenib/trametinib) was approved as a tumor-agnostic therapy in June 2022 for all histologic types of solid metastatic cancers harboring BRAFV600E mutations. In September 2022, RET inhibitor selpercatinib was approved for solid cancers with RET gene fusions.</p><p><strong>Conclusion</strong>. Precision cancer medicine has substantially improved cancer diagnostics and treatment. Tissue type-agnostic drug therapies present a novel shift in precision cancer medicine. This approach rapidly expands to provide treatments for patients with different cancers harboring the same molecular alteration.</p>

Borderline ovarian tumors: a review of its biology, molecular profile, and management

“…[57] Finally, considering the frequency of BRAF mutations in BOTs/LGOC, it is interesting to mention the agnostic approval of the combination of dabrafenib (BRAF inhibitor) plus trametinib for patients with metastatic cancers harboring a BRAF V600E mutation. [58] Some impressive responses to this combination have been described in case reports of patients with LGOC with a BRAF V600E mutation. [59,60] In face of these results, further studies directed to this pathway, including studies for patients with BOTs, are warranted.…”

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

“…Several agnostic targets and their matched drugs have been approved by the Food and Drug Administration (FDA) in the past few years [21][22][23]. This list includes microsatellite instability (MSI) and/or deficient mismatch DNA repair (MMR-D) coupled with immune therapy; high TMB (tumor mutation burden), which includes both MSI and some other instances of accumulation of multiple somatic genetic alterations, and is also associated with a response to immune checkpoint inhibitors (ICIs); NTRK1-3 rearrangements rendering tumor sensitivity to NTRK tyrosine kinase inhibitors (TKIs); RET rearrangements calling for the therapeutic use of RET TKI; and BRAF V600E mutations associated with tumor responsiveness to combined BRAF and MEK inhibition (Figure 1; Table 1).…”

Tumor-type agnostic, targeted therapies make a new step forward: The first tumor-agnostic approval of a HER2-targeted therapy

“…Tumor-type agnostic, targeted therapies make a new step forward: The first tumor-agnostic approval of a HER2-targeted therapy Semir Vranic 1 * and Zoran Gatalica 2 Oncologic treatment has recently undergone substantial therapeutic paradigm shifts, from classical tumor-specific and biomarker-agnostic approaches to more molecular, biomarkerspecific, and tumor-agnostic. Tumor-type (histology) agnostic drugs work across cancer types and present a novel shift in precision oncology [1]. Compared with traditional cancer therapies, this novel approach implies molecularly informed treatment strategies and enables targeted treatment regardless of tumor histology (type).…”