lifirafenib (BGB-283)

Lifirafenib (Type II) + encorafenib (Type I½) was highly synergistic against both NRAS - and KRAS -mutant lines, while synergy of lifirafenib + SB590885 (Type I) was specific to NRAS -mutants. Assessment of leukemia burden in bone marrow and spleen during treatment further showed site-specific efficacy against circulating and spleen-resident blasts for both combinations. In summary, we report that our structure based-modelling approach can effectively identify novel, non-obvious, and well-tolerated RAFi combinations that are highly effective against in vitro and in vivo models, thereby suggesting alternative potential therapeutic strategies for high-risk RAS -mutant AML.

This study provided potential prognostic biomarkers for LUAD and might facilitate the development of effective immunotherapy strategies for LUAD patients.

BGB-283 was a candidate for LUAD targeting VGF. Our study elucidates the impact of GCGs on LUAD prognosis and immune responses, offering insights for prognostic forecasting and immunotherapeutic strategies for LUAD patients.

P1, N=93, Active, not recruiting, BeiGene | Recruiting --> Active, not recruiting

Therefore, this study aims to disover potential TMPRSS4 inhibitors that have better binding affinity than the approved inhibitors: 2-hydroxydiarylamide and tyroserleutide...Moreover, through a systematic analysis, MD simulations and MM-GBSA binding free energy calculations revealed that the best candidates Ergotamine, S55746, NPC478048, Lifirafenib, and NPC77101 are highly stable drug candidates in complex with TMPRSS4, displaying low RMSD and RMSF values with strong binding stability. Among these compounds, Ergotamine showed the most favorable binding energy (-33.73 kcal/mol). Overall, our in silico results revealed that these compounds could act as potent TMPRSS4 inhibitors and need to be validated by future experimental studies.

P1, N=105, Recruiting, BeiGene | Phase classification: P1b --> P1

P1, N=131, Completed, BeiGene | Phase classification: P1a/1b --> P1

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.

P1b, N=105, Recruiting, BeiGene | Trial completion date: Apr 2024 --> Feb 2026 | Trial primary completion date: Mar 2024 --> Sep 2025

This led to the development of sotorasib as a second-line treatment of KRAS mutant non-small cell lung cancer. Considerable effort also has been expended to develop MAP kinase and PI3-kinase pathway inhibitors as indirect RAS antagonists.

"In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of VUS more likely to be oncogenic drivers. Our data indicate certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide treatment for BRAF-mutant NSCLC."

Here, we report that the RAF dimer inhibitors, lifirafenib (BGB-283) and Compound C, show a strong synergistic effect with MEK inhibitors (MEKi), including mirdametinib (PD-0325901) and selumetinib, in suppressing the proliferation of K-RAS-mutated non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cell lines. 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.