plixorafenib (FORE-8394)

P1, N=15, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

P2, N=250, Recruiting, Fore Biotherapeutics | N=135 --> 250

P1/2, N=113, Completed, Fore Biotherapeutics | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jul 2024

P1, N=12, Recruiting, Fore Biotherapeutics | Not yet recruiting --> Recruiting

P1, N=12, Not yet recruiting, Fore Biotherapeutics

P1/2, N=113, Active, not recruiting, Fore Biotherapeutics | Trial completion date: Apr 2024 --> Dec 2024 | Trial primary completion date: Feb 2024 --> May 2024

In conclusion, our data indicate that PLX8394 inhibits several serine-threonine kinases in malignantly transformed human keratinocytes and cSCC cells and inhibits cSCC invasion and tumor growth in vitro and in vivo. We identify PLX8394 as a potential therapeutic compound for advanced human cSCC.

An approved BRAFi, when used with MEKi, has ORR 33% with mDOR 13.6=months and ORR=50% with DOR of 6-29 months in V600+ HGG and LGG, respectively (dabrafenib US Prescribing Information, 2023). Phase 1/2a is a single-arm study (NCT02428712) in patients (n=113) with BRAF-altered advanced tumors to assess safety, PK, and efficacy of oral plixorafenib 900-3600 mg/day alone or with cobicistat (CYP3A4/P-gp inhibitor)...Prior anti-cancer treatments included surgery (8/10), radiotherapy (8/10), and systemic therapy (8/10, including temozolomide [n=8], bevacizumab [n=2], carboplatin [n=1], dendritic cell vaccine [n=1])...Plixorafenib has a benign safety profile and leads to a high ORR and durable response in MAPKi-naïve BRAFV600+ PCNST. A phase 2 study is ongoing to confirm these findings (NCT05503797).

P1/2, N=113, Active, not recruiting, Fore Biotherapeutics | Recruiting --> Active, not recruiting | Trial completion date: Sep 2023 --> Apr 2024 | Trial primary completion date: Sep 2022 --> Feb 2024

Therefore, our central hypothesis is that inhibition of lipid metabolism will sensitize CRC cells to BRAF inhibitors and overcome acquired resistance. We established HT29 cells and primary PT130 and PT2449pt cells resistant to PLX8394, a novel BRAF inhibitor... Our study demonstrates that resistance to BRAF inhibitors is associated with a significant increase in proliferation, metastasis, and upregulation of lipid metabolism. We show that combination of FASN and BRAF inhibitors has a combinational effect on inhibiting cell viability in parental but not resistant cells, suggesting that the addition of FASN inhibitor to the standard regimen for BRAFV600E mutation positive patients can improve efficacy of these therapies. Additional screening of lipid metabolism-targeted therapies in combination with standard BRAF regimens are needed to develop novel and more efficacious strategies for CRC patients with BRAF mutations.

SB202190 was a more effective inhibitor of BRAF-mutated organoid growth in the long term than the specific BRAF inhibitors Dabrafenib and PLX8394. Overall, SB202190 can predict BRAF-activating mutations in patient-derived organoids, as well as allowing for the identification of new BRAF variants, preceding and enforcing NGS data.

P2, N=135, Recruiting, Fore Biotherapeutics | Not yet recruiting --> Recruiting | Initiation date: Nov 2022 --> Mar 2023

Resistor correctly identified eight clinically significant EGFR resistance mutations, including the erlotinib and gefitinib "gatekeeper" T790M mutation and five known osimertinib resistance mutations. Furthermore, Resistor predictions are consistent with BRAF inhibitor sensitivity data from both retrospective and prospective experiments using KinCon biosensors. Resistor is available in the open-source protein design software OSPREY.

All the uncommon mutants displayed higher sensitivity than both the wild type and BRAF-V600E towards PLX 8394 and LSN3074753...Notably, molecular dynamic (MD) simulation revealed that increased number of interactions caused enhanced sensitivity of G469R and N581S towards sorafenib. RAF kinase inhibitors were further classified into two groups as per their selectivity (Group I: BRAF-V600E-selective and Group II: CRAF-selective) based on which potential mutation-wise combinations of RAF kinase inhibitors were proposed to overcome resistance. Based on computational inhibitor sensitivity profiles, appropriate treatment strategies may be devised to prevent or overcome secondary drug resistance in lung cancer patients with uncommon mutations.

P2, N=135, Not yet recruiting, Fore Biotherapeutics

Biochemical analysis revealed that CRBN(BRAF)-24 showed more potent and sustained suppression of MAPK signaling than a BRAF inhibitor, PLX-8394, in BRAF -driven cancer cells. Targeted degradation of BRAF by CRBN(BRAF)-24 could be a promising strategy to evade paradoxical activation of the RAF-MAPK pathway.

P1/2, N=100, Recruiting, Fore Biotherapeutics | Trial completion date: Jun 2022 --> Sep 2023 | Trial primary completion date: Feb 2022 --> Sep 2022

Vemurafenib induces paradoxical changes in HDF, enabled by a permissive chromatin landscape. These changes might provide an advantage during combination therapies, by compensating for the toxicity induced in stromal cells by less specific MAPK/ERK inhibitors. Our results highlight the relevance of evaluating the effects of the drugs on non-transformed stromal components, carefully considering the implications of their administration either as mono- or combination therapies. Video Abstract.

Moreover, SIJ1777 substantially inhibits the activation of MEK, ERK, and AKT and remarkably induces apoptosis and significantly blocks migration, invasion, and anchorage-independent growth of melanoma cells harboring BRAF class I/II/II mutations while both vemurafenib and PLX8394 have little to no effects on melanoma cells expressing BRAF class II/III mutations. Taken together, our six GNF-7 derivatives exhibit highly potent activities against melanoma cells harboring class I/II/III BRAF mutations compared with vemurafenib as well as PLX8394.

The most common breast cancer drugs that regulate or inhibit the MAPK pathway may include Farnesyltransferase inhibitors (FTIs), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, and Teriflunomide. In this review, we will discuss the roles of the MAPK/RAS/RAF/MEK/ERK pathway in BC and summarize the FDA-approved prescription drugs that target the MAPK signaling pathway in women with BC.

Current FDA approved inhibitors (Vemurafenib, Dabrafenib, Encorafenib) although improved progression-free survival of mtBRAF melanoma patients suffer from this treatment related side effect. Combinatorial treatments of BRAFi with Mcl-1 and Notch modulators show a better effect than mono-treatments. Additional pathways could be further exploited in novel efficient combinatorial treatment protocols with BRAFi.

We illustrate that the patient mutation harboring KinCon reporters display differences in the effectiveness of the three clinically approved BRAFi vemurafenib, encorafenib, and dabrafenib and the preclinical paradox breaker PLX8394. Moreover, we illustrate that the presented kinase reporter concept can be extended to other kinases which harbor patient mutations. Overall, KinCon profiling provides additional mechanistic insights into full-length kinase functions by reporting protein-protein interaction (PPI)-dependent, mutation-specific, and drug-driven changes of kinase activity conformations.

P1/2, N=100, Recruiting, NovellusDx | Active, not recruiting --> Recruiting | N=75 --> 100

P1/2, N=75, Active, not recruiting, Plexxikon | Trial completion date: Dec 2020 --> Jun 2022 | Trial primary completion date: Aug 2020 --> Feb 2022

PLX8394 + cobi demonstrated favorable safety profile and encouraging activity in refractory solid tumors with BRAF mutations including BRAF fusion. Further studies to refine the RP2D with a modified tablet formulation to reduce dose burden and improve dose linearity are ongoing.

The BEACON CRC trial demonstrated a survival advantage over chemotherapy for a combination of targeted agents comprising the potent BRAF inhibitor encorafenib together with cetuximab and binimetinib...The potency of encorafenib and PLX8394 was greater than vemurafenib and the degree of pathway reactivation somewhat less...Whilst these results support further investigation of PLX8394, all three agents tested reactivated the pathway in melanoma cells, a disease in which monotherapy is effective. Strategies focused on restricting RAF dimerization fail to address the impact that specific context of BRAF mutation in CRC has on targeted therapy outcomes.

In addition, GNF-7 and SIJ1227 suppress more strongly migration/invasion of these cancer cells than vemurafenib and PLX8394. Taken together, both GNF-7 and SIJ1227 are much superior to vemurafenib and PLX8394 in terms of capability to inhibit all classes of BRAF mutants.

Funding: Plexxikon. Clinical trial identification: NCT02428712.

MEKi selumetinib and trametinib also suppressed fusion driven signaling and oncogenic phenotypes. We show that novel MTAP-BRAF and MS4A6A-BRAF fusions, found in histiocytic tumors, do not respond to RAFi PLX8394 but are targeted by LY3009120 or MEKi. We show that novel MTAP-BRAF and MS4A6A-BRAF fusions, found in histiocytic tumors, do not respond to RAFi PLX8394 but are targeted by LY3009120 or MEKi. Our finding that PLX8394 does not disrupt MTAP-BRAF or MS4A6A-BRAF dimerization due to contribution of N-terminal partners defines a novel paradigm for the distinct mechanisms sought by BRAF fusions in response to RAFi therapy. We show potent suppression of these mechanistically distinct BRAF fusions with MEKi or LY3009120 which function independent of vulnerability to fusion dimerization.

P1/2, N=75, Active, not recruiting, Plexxikon | Trial completion date: Apr 2020 --> Dec 2020 | Trial primary completion date: Jan 2020 --> Aug 2020