lifirafenib (BGB-283) / BeOne Medicines - LARVOL DELTA

Identification of molecular targets from the interactome of primary sclerosing cholangitis and their therapeutic modulation (FFS-AIH 2025) - "In silico screening identified their ligands BGB-283 and RAF-265, which downregulated NF-kB signature expression in PSC organoids. GW-493838 combined with BMS270394 notably downregulated both TGF-beta and Notch signatures. We discovered perspective molecular targets in PSC and showed the impact of their predicted small molecule ligands on transcriptomes of primary PSC cholangiocyte organoids. OP and CF share first authorship MT and TR share senior authorship"

Cholestasis • Fibrosis • Gastroenterology • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Primary Biliary Cholangitis • ABCB4 • CD1C • CD36 • ITGAX • KRT19 • NFKB1 • NRP1 • SCARB1 • SLIT2 • TGFB1 • VEGFA

Using Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia (ASH 2024) - "Mice were then treated with vehicle, lifirafenib (LIF; 10 mg/kg, p.o.), encorafenib (ENCO; 20 mg/kg, p.o.), SB590885 (SB; 25 mg/kg, IP), or either drug combination (LIF + ENCO or LIF + SB). 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."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Solid Tumor • AFDN • KMT2A • KRAS • NRAS • PTPRC • RAS

A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia. (PubMed, bioRxiv) - "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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KRAS • NRAS • RAS

Defining lung adenocarcinoma subtypes with glucocorticoid-related genes and constructing a prognostic index for immunotherapy guidance. (PubMed, J Thorac Dis) - "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."

IO biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CYP17A1 • IGF2BP1 • IGFBP1

Identification of different lung adenocarcinoma subtypes in combination with antidiuretic hormone-related genes and creation of an associated index to predict prognosis and guide immunotherapy. (PubMed, Comput Biol Chem) - "This study provided potential prognostic biomarkers for LUAD and might facilitate the development of effective immunotherapy strategies for LUAD patients."

IO biomarker • Journal • Tumor mutational burden • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • DKK1 • IGFBP1 • TMB

In silico drug repurposing of potential antiviral inhibitors targeting methyltransferase (2'-O-MTase) domain of Marburg virus. (PubMed, In Silico Pharmacol) - "We then screened 62 known inhibitors against this domain and identified four promising candidates: Lifirafenib (- 9.5 kcal/mol), Dolutegravir (- 8.5 kcal/mol), BRD3969 (- 8.3 kcal/mol), and JFD00244 (- 8.2 kcal/mol). While these findings highlight promising candidates for MARV, experimental validation through in vitro and in vivo assays is essential to assess their safety and efficacy. The online version contains supplementary material available at 10.1007/s40203-025-00355-z."

Journal • BRD3

Study of the Safety and Pharmacokinetics of BGB-283 (Lifirafenib) and PD-0325901 (Mirdametinib) in Participants With Advanced or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=93 | Active, not recruiting | Sponsor: BeiGene | Recruiting ➔ Active, not recruiting

Enrollment closed • Endometrial Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thyroid Gland Carcinoma • NRAS

Identification of potent TMPRSS4 inhibitors through structural modeling and molecular dynamics simulations. (PubMed, Sci Rep) - "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."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • TMPRSS4

Study of the Safety and Pharmacokinetics of BGB-283 (Lifirafenib) and PD-0325901 (Mirdametinib) in Participants With Advanced or Refractory Solid Tumors (clinicaltrials.gov) - P1 | N=105 | Recruiting | Sponsor: BeiGene | Phase classification: P1b ➔ P1

Phase classification • Endometrial Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thyroid Gland Carcinoma • NRAS

BGB-283-AU-001: Study of the Safety and Pharmacokinetics of BGB-283 in Patients With Solid Tumors (clinicaltrials.gov) - P1 | N=131 | Completed | Sponsor: BeiGene | Phase classification: P1a/1b ➔ P1

Phase classification • Oncology • Solid Tumor • KRAS • RAS

T cell-mediated tumor killing sensitivity gene signature-based prognostic score for acute myeloid leukemia. (PubMed, Discov Oncol) - "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."

Gene Signature • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD4

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 (AACR 2024) - "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."

Melanoma • Oncology • Solid Tumor • BRAF

Using structure-based modelling to identify effective drug combinations in high-risk acute leukaemia (EACR-AACR 2024) - "Combined lifirafenib (Type 2) and encorafenib (Type 1.5) was highly synergistic against both NRAS- and KRAS-mutant lines (Loewe additivity scores = 7.9-31.1), while synergy observed for combined lifirafenib and SB-590885 (Type 1) was specific to NRAS-mutant lines (Loewe additivity scores = 21.4-27.9). Conclusion We have utilized a systems biology approach to identify novel, non-obvious kinase inhibitor combinations, providing a promising therapeutic avenue for treating RAS-mutant AML. Efficacy of these combinations in vivo will provide rationale for promoting these combinations into clinical use."

Hematological Malignancies • Leukemia • Oncology • Pediatrics • Solid Tumor • KRAS • NRAS • PTPRC

Study of the Safety and Pharmacokinetics of BGB-283 (Lifirafenib) and PD-0325901 (Mirdametinib) in Participants With Advanced or Refractory Solid Tumors (clinicaltrials.gov) - P1b | N=105 | Recruiting | Sponsor: BeiGene | Trial completion date: Apr 2024 ➔ Feb 2026 | Trial primary completion date: Mar 2024 ➔ Sep 2025

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Endometrial Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thyroid Gland Carcinoma • NRAS

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 (AACR 2023) - "L+M demonstrated a favorable safety profile and showed antitumor activity in pts with various KRAS, NRAS, and BRAF mutations across several solid tumor types, including LGSOC, NSCLC, and endometrial cancer. 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..."

Clinical • Combination therapy • Metastases • P1 data • PK/PD data • Endometrial Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRAF • KRAS • NRAS

BeiGene and SpringWorks Present Clinical Data on Lifirafenib, in Combination with Mirdametinib, in Patients with Advanced or Refractory Solid Tumors with MAPK Pathway Aberrations at the American Association for Cancer Research Annual Meeting 2023 (Businesswire) - P1 | N=105 | NCT03905148 | Sponsor: BeiGene | "BeiGene...announced that they will present updated clinical data from the Phase 1b trial of BeiGene’s RAF dimer inhibitor, lifirafenib, in combination with SpringWorks’ MEK inhibitor, mirdametinib, in patients with advanced or refractory solid tumors with RAS mutations, RAF mutations and other MAPK pathway aberrations....Of 17 patients with LGSOC treated, 10 patients (59%) had objective responses, with median duration of treatment of approximately 26 months. Of the 4 endometrial cancer patients treated, 2 (50%) had objective responses in tumors that harbor BRAF fusion mutation or KRAS mutation, respectively."

P1 data • PK/PD data • Oncology • Solid Tumor

SpringWorks and BeiGene Present Clinical Data on Lifirafenib, in combination with Mirdametinib, in Patients with Advanced or Refractory Solid Tumors with MAPK Pathway Aberrations at the American Association for Cancer Research Annual Meeting 2023 (GlobeNewswire) - P1b/2 | N=105 | NCT03905148 | Sponsor: BeiGene | "SpringWorks Therapeutics...announced that they will present updated clinical data from the Phase 1b trial of BeiGene’s RAF dimer inhibitor, lifirafenib, in combination with SpringWorks’ MEK inhibitor, mirdametinib, in patients with advanced or refractory solid tumors with RAS mutations, RAF mutations and other MAPK pathway aberrations.....Results from the Part A dose-escalation and dose-finding study are being presented at AACR....As of the data cut-off of January 20, 2023, 71 patients were treated across 9 dose levels evaluating different dosing regimens.....The combination showed antitumor activity in patients with various KRAS, NRAS, and BRAF mutations across several solid tumor types, including low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC), and endometrial cancer....The expansion is expected to start in the second half of 2023."

P1 data • Trial status • Endometrial Cancer • Gynecologic Cancers • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor • Thoracic Cancer • Uterine Cancer • BRAF • KRAS • NRAS

[VIRTUAL] RAF dimer inhibitor lifirafenib enhances the antitumor activity of MEK inhibitor mirdametinib in RAS mutant tumors (AACR-II 2020) - P1b | "This synergistic effect was not observed using vemurafenib, a first-generation B-RAFV600E selective inhibitor. 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)."

Oncology • KRAS

SpringWorks Therapeutics Highlights 2022 Accomplishments and Anticipated Milestones for 2023 at the 41st Annual J.P. Morgan Healthcare Conference (GlobeNewswire) - "Anticipated 2023 Key Milestones: Present additional data from BeiGene-sponsored Phase 1b/2 trial evaluating mirdametinib in combination with lifirafenib in adult patients with RAS/RAF mutant and other MAPK pathway aberrant solid tumors at a medical conference in the first half of 2023; Dose first patient in BGB-3245 + mirdametinib combination study in MAPK-mutant solid tumors in the first half of 2023; File Investigational New Drug Application for TEAD inhibitor SW-682."

IND • P1/2 data • Trial status • Oncology • Solid Tumor

SpringWorks Therapeutics Reports Third Quarter 2022 Financial Results and Recent Business Highlights (GlobeNewswire) - "Biomarker-Defined Metastatic Solid Tumors: The BeiGene-sponsored Phase 1b/2 trial evaluating mirdametinib with BeiGene’s RAF dimer inhibitor, lifirafenib, in adult patients with RAS/RAF mutant and other MAPK pathway aberrant solid tumors is ongoing. SpringWorks expects data from this trial to be presented at a medical conference in the first half of 2023. The Phase 1 trial evaluating BGB-3245...in adult patients with RAF mutant solid tumors is ongoing. SpringWorks expects data from this trial to be presented at a medical conference in the first half of 2023. BGB-3245 monotherapy is advancing into cohort expansion studies and SpringWorks expects to begin dosing a Phase 1/2a combination study of BGB-3245 and mirdametinib in the first half of 2023."

P1 data • P1/2 data • Trial status • Oncology • Solid Tumor

Vertical inhibition of the MAPK pathway as potential treatment strategy in NRAS-mutant melanoma (AACR-NCI-EORTC 2022) - "Material and The combinatorial effects of mirdametinib with the pan-RAF dimer inhibitor lifirafenib or BGB-3245 were evaluated in a cohort of 14 primary and patient-derived melanoma cell lines harboring NRAS Q61 mutations. 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."

Melanoma • Oncology • Solid Tumor • NRAS

SpringWorks Therapeutics Reports Second Quarter 2022 Financial Results and Recent Business Highlights (GlobeNewswire) - "BGB-3245 Monotherapy to Advance into Cohort Expansion Studies and Combination Study of BGB-3245 and Mirdametinib Planned to Initiate in 2H 2022....Initial clinical data from the BeiGene-sponsored Phase 1b/2 trial evaluating mirdametinib with BeiGene’s RAF dimer inhibitor, lifirafenib, in adult patients with RAS/RAF mutant and other MAPK pathway aberrant solid tumors...SpringWorks expects these data to be presented at a medical conference in the second half of 2022."

Enrollment status • P1/2 data • Oncology • Solid Tumor

Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study. (PubMed, Curr Res Struct Biol) - "In-depth analysis revealed that these compounds maintained the active conformation of wild-type BRAF protein by inducing αC-helix-In, DFG-In, extended activation segment and well-aligned R-spine residues similar to already known drugs Vemurafenib (VEM), BGB283 and Ponatinib. In terms of binding energy, among the natural compounds, CAPE showed better affinity towards both wild-type and V600E mutant proteins than the other two compounds. These data suggested that CAPE, Wi-A and Wi-N have potential to block constitutive autophosphorylation of BRAF and hence warrant in vitro and in vivo experimental validation."

Journal • Oncology • BRAF

Blockade of mutant RAS oncogenic signaling with a special emphasis on KRAS. (PubMed, Pharmacol Res) - "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."

Journal • Review • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HRAS • KRAS • NRAS

SpringWorks Therapeutics Reports First Quarter 2021 Financial Results and Recent Business Highlights (GlobeNewswire) - "Phase 1b trial sponsored by GSK evaluating nirogacestat in combination with BLENREP (belantamab mafodotin-blmf), a Phase 1 study sponsored by Allogene evaluating nirogacestat in combination with ALLO-715...Initial data from the GSK-sponsored study are expected in 2021....Enrollment is ongoing in a Phase 1b/2 trial evaluating mirdametinib with BeiGene’s RAF dimer inhibitor, lifirafenib, in adult patients with RAS/RAF mutant and other MAPK pathway aberrant solid tumors. BeiGene is sponsoring this trial and SpringWorks and BeiGene expect to report initial clinical data in 2021, as previously disclosed."

P1 data • P1/2 data • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor