- |||||||||| SB-590885 / GSK, Zunyi Medical University, Braftovi (encorafenib) / Pfizer, lifirafenib (BGB-283) / BeiGene
Using Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_5324;
Conclusions We used a structural biology and in silico computational modelling approach to identify novel, non-obvious kinase inhibitor combinations. Computational approaches were notably validated by the high efficacy of well-tolerated treatments in a pre-clinical mouse model, suggesting potential translatability for treating RAS-mutant AML.
- |||||||||| Tabrecta (capmatinib) / Incyte, Novartis, GSK1521498 / GSK, lifirafenib (BGB-283) / BeiGene
Journal, Gene Signature: T cell-mediated tumor killing sensitivity gene signature-based prognostic score for acute myeloid leukemia. (Pubmed Central) - Apr 15, 2024
A T-cell mediated killing sensitivity gene-based prognostic score TTKPI showed good accuracy in predicting survival in AML. TTKPI corresponded to functional and immunological features of the tumor microenvironment including checkpoint expression patterns and should be investigated for precision medicine approaches.
- |||||||||| plixorafenib (FORE-8394) / Fore Biotherap
Plixorafenib (plixo) synergizes with MEK inhibitors (MEKi) in MAPK pathway inhibition in BRAF V600 and non V600 alterations, with higher potency compared to early generation BRAFi and pan-RAFi (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_6687;
Using ForeSight assay, a unique platform for testing MAPK signaling, we tested the efficacy of plixo and 4 MEKi (trametinib, cobimetinib, binimetinib and mirdametinib) across a cohort 18 BRAF alterations (V600E, 2 class II and 15 fusions) as single agents and in combinations...Furthermore, we compared the potency of a combination of plixo with binimetinib (bini) to that of another BRAFi (vemurafenib) or pan-RAFi's (tovorafenib and lifirafenib) with bini in 2 class I, 3 class II and 7 BRAF fusions using the foresight assay...These results indicate the improved efficacy of plixo + bini combination in inhibiting MAPK signaling and cancer cell proliferation. Overall results support that maximal suppression of the MAPK pathway with plixo is more potent in combination with a MEK inhibitor in BRAF V600 and non-V600 nonclinical models compared to BRAF or pan-RAF combinations.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, lifirafenib (BGB-283) / BeiGene
Safety, pharmacokinetics, and antitumor activity findings from a phase 1b, open-label, dose-escalation and expansion study investigating RAF dimer inhibitor lifirafenib in combination with MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors (Chapin Theater - Convention Center) - Mar 14, 2023 - Abstract #AACR2023AACR_5503;
The combination warrants further clinical investigation.Table 1Demographics (N=56)Age (y), median (range)59.5 (29-78)ECOG PS 0/1, n (%)56 (100.0)Prior lines of therapy, median (range)1 (1-6)Efficacy Set (N=54), n (%)LGSOC (n=17)Other than LGSOC (n=37)All malignancies (n=54)ORR (CR+PR)10 (58.8)5 (13.5)15 (27.8)CR1 (5.9)01 (1.9)PR9 (52.9)5 (13.5)14 (25.9)SD6 (35.3)18 (48.6)24 (44.4)DCR (CR+PR+SD)16 (94.1)23 (62.2)39 (72.2)Safety Set (N=56), n (%)TEAEa55 (98.2)SAE23 (41.1)Grade 3 TEAE24 (42.9)TEAE leading to treatment discontinuation3 (5.4)DLT6 (10.7)CR, complete response; DCR, disease control rate; DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; LGSOC, low-grade serous ovarian cancer; ORR, objective response rate; PR, partial response; SAE, serious adverse event; SD, stable disease; TEAE, treatment-emergent adverse event. a Commonly reported (>40%): fatigue (55.4%), dermatitis acneiform (46.4%), and diarrhea (44.6%).
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, lifirafenib (BGB-283) / BeiGene, BGB-3245 / MapKure, SpringWorks Therap
Vertical inhibition of the MAPK pathway as potential treatment strategy in NRAS-mutant melanoma (Exhibition Hall) - Sep 3, 2022 - Abstract #AACRNCIEORTC2022AACR_NCI_EORTC_284;
These data support the evaluation of MAPK pathway vertical inhibition through combination of MEK and panRAF inhibitors for treatment of patients with RAS mutations. Lastly, NRAS Q61 may serve as a prospective biomarker for patient stratification in trials assessing the combination of MEK and pan-RAF inhibitors in mutant melanoma.
- |||||||||| Journal: RAF dimer inhibition enhances the antitumor activity of MEK inhibitors in K-RAS mutant tumors. (Pubmed Central) - Jul 2, 2021
This synergistic effect was not observed with the B-RAF selective inhibitor vemurafenib...A pharmacodynamic analysis supported a role for the synergistic phospho-ERK blockade in enhancing the antitumor activity observed in the K-RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEK inhibitors are combined to target K-RAS-mutated cancers, and has led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K-RAS mutations and other MAPK pathway aberrations.
- |||||||||| lifirafenib (BGB-283) / BeiGene, EMD Serono
Clinical, Journal: Phase I, Open-Label, Dose-Escalation/Dose-Expansion Study of Lifirafenib (BGB-283), an RAF Family Kinase Inhibitor, in Patients With Solid Tumors. (Pubmed Central) - Feb 3, 2021
Lifirafenib is a novel inhibitor of key RAF family kinases and EGFR, with an acceptable risk-benefit profile and antitumor activity in patients with B-RAF-mutated solid tumors, including melanoma, PTC, and LGSOC, as well as K-RAS-mutated NSCLC and endometrial carcinoma. Future comparisons with first-generation B-RAF inhibitors and exploration of lifirafenib alone or as combination therapy in patients with selected RAS mutations who are resistant/refractory to first-generation B-RAF inhibitors are warranted.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, lifirafenib (BGB-283) / BeiGene, EMD Serono
RAF dimer inhibitor lifirafenib enhances the antitumor activity of MEK inhibitor mirdametinib in RAS mutant tumors (Virtual Meeting II: E-Posters) - May 16, 2020 - Abstract #AACRII2020AACR-II_510;
P1b
Pharmacodynamic analysis supported the role of synergistic phospho-ERK blockade in enhancing the antitumor activity in the K-RAS mutant models. These findings support the rationale to combine a RAF dimer inhibitor and a MEK inhibitor to treat K-RAS-mutated cancers and led to the ongoing a Phase Ib/II clinical trial of lifirafenib and mirdametinib in patients with K-RAS mutations or other MAPK pathway aberrations (Clinical Trial ID: NCT03905148).
- |||||||||| lifirafenib (BGB-283) / BeiGene, EMD Serono
Journal: Pathway-Centric Structure-Based Multi-Target Compound Screening for Anti-Virulence Drug Repurposing. (Pubmed Central) - Dec 23, 2019
In principle, inhibiting multiple targets in a pathway will be more effective and have less chance of the emergence of drug resistance than targeting a single protein. Our multi-target structure-based drug design strategy can be applied to other pathways, as well as provide a systematic approach to polypharmacological drug repositioning.
- |||||||||| lifirafenib (BGB-283) / BeiGene
Trial completion, Enrollment change, Trial completion date, Metastases: BGB-283-CN-001: The Study of BGB-283 in Chinese Subjects With Local Advanced or Metastatic Malignant Solid Tumor (clinicaltrials.gov) - May 28, 2019
P1, N=42, Completed,
The method showed robust and sensitive, it successfully fulfilled the requirement of clinical pharmacokinetic study of lifirafenib in Chinese patients with locally advanced or metastatic solid tumors. Active, not recruiting --> Completed | N=68 --> 42 | Trial completion date: Dec 2018 --> Mar 2019
- |||||||||| Opdivo (nivolumab) / Ono Pharma, BMS, Yervoy (ipilimumab) / Ono Pharma, BMS
Review, Journal, PD(L)-1 Biomarker, IO Biomarker: Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. (Pubmed Central) - Apr 11, 2019
Besides targeting B-Raf and MEK protein kinases, immunotherapies that include ipilimumab, pembrolizumab, and nivolumab have been FDA-approved for the treatment of melanomas. Current clinical trials are underway to determine the optimal usage of targeted and immunotherapies.
- |||||||||| lifirafenib (BGB-283) / BeiGene, EMD Serono
Clinical, Journal: An In silico Investigation of Potential EGFR Inhibitors for the clinical treatment of Colorectal Cancer. (Pubmed Central) - Apr 9, 2019
...Molecular docking of existing inhibitors resulted in the compound titled as BGB-283 (PubChem CID-89670174) having the highest score, which was subjected to similarity search to retrieve the drugs with similar structure...Comparative study and ADMET study ahead of both the compounds resulted properties some place equivalent, whereas interestingly the established compound BGB-283 shows the high rerank score. These drugs identified as high potential in EGFR inhibitors and probably can be held for further studies.
- |||||||||| lifirafenib (BGB-283) / BeiGene
Trial completion, Trial completion date, Trial primary completion date: BGB-283-AU-001: Study of the Safety and Pharmacokinetics of BGB-283 in Patients With Solid Tumors (clinicaltrials.gov) - Jul 24, 2018
P1a/1b, N=131, Completed,
Our findings provide evidence of critical survival signals in BRAF non-V600E mutant cancers, which could pave the way for effective treatment of these cancers. Active, not recruiting --> Completed | Trial completion date: Jun 2017 --> Oct 2017 | Trial primary completion date: Jun 2017 --> Oct 2017
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