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    DRUG:

    naporafenib (ERAS-254)

    i
    Other names: ERAS-254, LXH254, LXH 254, LXH-254
    Company:
    Erasca, Novartis
    Drug class:
    BRAF inhibitor, pan-RAF inhibitor, cRAF inhibitor
    Related drugs:
    4d
    A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov)
    P1, N=122, Terminated, Novartis Pharmaceuticals | Trial completion date: Jan 2025 --> Sep 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Sep 2024; The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations.
    Trial completion date • Trial termination • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Tevimbra (tislelizumab-jsgr) • spartalizumab (PDR001) • naporafenib (ERAS-254) • batoprotafib (TNO155) • rineterkib (LTT462)
    1m
    A phase Ib study of the combination of naporafenib with rineterkib or trametinib in patients with advanced and metastatic KRAS- or BRAF-mutant non-small cell lung cancer. (PubMed, Lung Cancer)
    Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect.
    P1 data • Journal • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • BRAF mutation • NRAS mutation
    |
    Mekinist (trametinib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    1m
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Aug 2024 --> Nov 2024
    Trial primary completion date • Metastases
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    2ms
    Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov)
    P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2024 --> Apr 2025 | Trial primary completion date: Dec 2024 --> Apr 2025
    Trial completion date • Trial primary completion date • Combination therapy
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR exon 20 insertion • EGFR exon 20 mutation
    |
    Mekinist (trametinib) • gefitinib • Kisqali (ribociclib) • Tabrecta (capmatinib) • naporafenib (ERAS-254) • nazartinib (EGF816)
    2ms
    A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov)
    P1, N=122, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2024 --> Jan 2025 | Trial primary completion date: Oct 2024 --> Jan 2025
    Trial completion date • Trial primary completion date • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Tevimbra (tislelizumab-jsgr) • spartalizumab (PDR001) • naporafenib (ERAS-254) • batoprotafib (TNO155) • rineterkib (LTT462)
    3ms
    The mTOR pathway controls phosphorylation of BRAF at T401. (PubMed, Cell Commun Signal)
    Importantly, the BRAF/RAF1 inhibitor naporafenib, the MEK inhibitor trametinib and the ERK inhibitor ulixertinib failed to reduce pT401 levels in these settings, supporting an alternative ERK-independent pathway to T401 phosphorylation...Conversely, genetic mTOR pathway activation by oncogenic RHEB (Q64L) and mTOR (S2215Y and R2505P) mutants substantially increased pT401, an effect that was reverted by dactolisib and torin1 but not by trametinib...Using mass spectrometry, we provide further evidence that torin1 suppresses the phosphorylation of T401, S405 and S409 but not of other important regulatory phosphorylation sites such as S446, S729 and S750. In summary, our data identify the mTOR axis and its inhibitors of (pre)clinical relevance as novel modulators of BRAF phosphorylation at T401.
    Journal
    |
    BRAF (B-raf proto-oncogene) • RHEB (Ras Homolog, MTORC1 Binding)
    |
    Mekinist (trametinib) • dactolisib (RTB101) • ulixertinib (BVD-523) • naporafenib (ERAS-254) • Torin1
    6ms
    A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma (clinicaltrials.gov)
    P1, N=241, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business reasons
    Trial termination • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    KRAS mutation • BRAF mutation • NRAS mutation
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    6ms
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2024 --> Jul 2024
    Trial completion date • Metastases
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    7ms
    A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2) (clinicaltrials.gov)
    P3, N=470, Recruiting, Erasca, Inc. | Not yet recruiting --> Recruiting
    Enrollment open • Metastases
    |
    Mekinist (trametinib) • temozolomide • dacarbazine • naporafenib (ERAS-254)
    8ms
    A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2) (clinicaltrials.gov)
    P3, N=470, Not yet recruiting, Erasca, Inc.
    New P3 trial
    |
    Mekinist (trametinib) • temozolomide • dacarbazine • naporafenib (ERAS-254)
    9ms
    A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov)
    P1, N=122, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: May 2024 --> Sep 2024 | Trial primary completion date: May 2024 --> Sep 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Tevimbra (tislelizumab-jsgr) • spartalizumab (PDR001) • naporafenib (ERAS-254) • batoprotafib (TNO155) • rineterkib (LTT462)
    12ms
    First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations. (PubMed, Eur J Cancer)
    Naporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation.
    P1 data • Journal • PD(L)-1 Biomarker • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • NRAS mutation • DUSP6 expression
    |
    spartalizumab (PDR001) • naporafenib (ERAS-254)
    12ms
    Protomer selectivity of type II RAF inhibitors within the RAS/RAF complex. (PubMed, Cell Chem Biol)
    The intracellular protomer selectivity of clinical-stage type II RAF inhibitors revealed that ARAF protomer engagement, but not engagement of BRAF or CRAF, is commensurate with inhibition of MAPK signaling in various mutant RAS cell lines. Our results support a fundamental role for ARAF in mutant RAS signaling and reveal poor ARAF protomer vulnerability for a cohort of RAF inhibitors undergoing clinical evaluation.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ARAF (A-Raf Proto-Oncogene)
    |
    BRAF mutation • RAS mutation
    |
    naporafenib (ERAS-254)
    1year
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2024 --> Apr 2024 | Trial primary completion date: Jan 2024 --> Apr 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    1year
    A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma (clinicaltrials.gov)
    P1, N=242, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2023 --> Apr 2024 | Trial primary completion date: Dec 2023 --> Apr 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • BRAF mutation • NRAS mutation
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    over1year
    Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov)
    P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2024 --> Sep 2024 | Trial primary completion date: Mar 2024 --> Sep 2024
    Trial completion date • Trial primary completion date • Combination therapy
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR exon 20 insertion • EGFR exon 20 mutation
    |
    Mekinist (trametinib) • gefitinib • Kisqali (ribociclib) • Tabrecta (capmatinib) • naporafenib (ERAS-254) • nazartinib (EGF816)
    over1year
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Oct 2023 --> Jan 2024
    Trial primary completion date • Metastases
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    over1year
    SEACRAFT-1: A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With RAS Q61X Mutations (clinicaltrials.gov)
    P1, N=115, Not yet recruiting, Erasca, Inc.
    New P1 trial • Metastases
    |
    RAS mutation
    |
    Mekinist (trametinib) • naporafenib (ERAS-254)
    over1year
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2023 --> Oct 2023 | Trial primary completion date: May 2023 --> Oct 2023
    Trial completion date • Trial primary completion date • Metastases
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    over1year
    Structure and RAF-family kinase isoform selectivity of Type II RAF inhibitors tovorafenib and naporafenib. (PubMed, J Biol Chem)
    Selective inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) are used clinically for these indications, but they are not effective inhibitors in the context of oncogenic RAS, which drives dimerization and activation of RAF, nor for malignancies driven by aberrantly dimerized truncation/fusion variants of BRAF. Our findings have important clinical ramifications. Type II RAF inhibitors are generally regarded as Pan-RAF inhibitors, but our studies of these two agents, together with recent work with type II inhibitors belvarafenib and naporafenib, indicate that relative sparing of ARAF may be a property of multiple drugs of this class.
    Journal
    |
    BRAF (B-raf proto-oncogene) • ARAF (A-Raf Proto-Oncogene)
    |
    BRAF mutation
    |
    Zelboraf (vemurafenib) • Tafinlar (dabrafenib) • Braftovi (encorafenib) • belvarafenib (RG6185) • Ojemda (tovorafenib) • naporafenib (ERAS-254)
    over1year
    A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov)
    P1, N=122, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=350 --> 122
    Enrollment closed • Enrollment change • Metastases
    |
    BRAF (B-raf proto-oncogene) • DUSP6 (Dual specificity phosphatase 6)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Tevimbra (tislelizumab-jsgr) • spartalizumab (PDR001) • naporafenib (ERAS-254) • batoprotafib (TNO155) • rineterkib (LTT462)
    over1year
    Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study. (PubMed, J Clin Oncol)
    Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.
    Journal • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    KRAS mutation • BRAF mutation • NRAS mutation
    |
    Mekinist (trametinib) • naporafenib (ERAS-254)
    over1year
    A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma (clinicaltrials.gov)
    P1, N=242, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2023 --> Dec 2023 | Trial primary completion date: Jun 2023 --> Dec 2023
    Trial completion date • Trial primary completion date • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • BRAF mutation • NRAS mutation
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    over1year
    A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov)
    P1, N=350, Recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2024 --> Apr 2024 | Trial primary completion date: Oct 2024 --> Apr 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    BRAF (B-raf proto-oncogene) • DUSP6 (Dual specificity phosphatase 6)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Tevimbra (tislelizumab-jsgr) • spartalizumab (PDR001) • naporafenib (ERAS-254) • batoprotafib (TNO155) • rineterkib (LTT462)
    over1year
    Transcriptomic analysis in a renal cancer PDX model enables the deconvolution of additive and synergistic effects of six different standard of care compounds with anti-PD-1 treatment (AACR 2023)
    Several agents showed a significant increase in apoptosis induction when aPD1 was added: The largest increase was observed for the panRAF inhibitor LXH254, Sorafenib, Oxaliplatin and Doxorubicin...A more focused analysis using a subset of 19 genes described to be predictive for ICD in solid cancer confirmed the activity of LXH254 but identified Sunitinib in combination with anti PD1 as another potential inducer of ICD...Our results demonstrate that local tumor response signatures of ICD can be used to systemically identify synergistic combinations of a range of drugs with immunotherapy on a tumor specific basis. A deeper dive into the transcriptomic data will help to identify other predictive biomarker for efficacy beyond ICD.
    PD(L)-1 Biomarker • IO biomarker • Omic analysis
    |
    ICAM1 (Intercellular adhesion molecule 1) • ITGAM (Integrin, alpha M)
    |
    MHC-II expression
    |
    sorafenib • sunitinib • doxorubicin hydrochloride • oxaliplatin • naporafenib (ERAS-254)
    almost2years
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2023 --> Jul 2023
    Trial completion date • Metastases
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    almost2years
    Phase I Study of LXH254 in Patients With Advanced Solid Tumors Haboring MAPK Pathway Alterations (clinicaltrials.gov)
    P1, N=142, Terminated, Novartis Pharmaceuticals | Completed --> Terminated
    Trial termination • IO biomarker • Metastases
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • NRAS mutation
    |
    spartalizumab (PDR001) • naporafenib (ERAS-254)
    almost2years
    Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov)
    P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2023 --> Mar 2024 | Trial primary completion date: Sep 2023 --> Mar 2024
    Trial completion date • Trial primary completion date • Combination therapy
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR exon 20 insertion • EGFR exon 20 mutation
    |
    Mekinist (trametinib) • gefitinib • Kisqali (ribociclib) • Tabrecta (capmatinib) • naporafenib (ERAS-254) • nazartinib (EGF816)
    2years
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial primary completion date: Aug 2022 --> Feb 2023
    Trial primary completion date
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    over2years
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2022 --> Mar 2023
    Trial completion date
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    over2years
    A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma (clinicaltrials.gov)
    P1, N=241, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2022 --> Apr 2023 | Trial primary completion date: Nov 2022 --> Apr 2023
    Trial completion date • Trial primary completion date
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • BRAF mutation • NRAS mutation
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    over2years
    Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC (clinicaltrials.gov)
    P1, N=105, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2022 --> Sep 2023 | Trial primary completion date: Nov 2022 --> Sep 2023
    Trial completion date • Trial primary completion date • Combination therapy
    |
    EGFR (Epidermal growth factor receptor)
    |
    EGFR mutation • EGFR L858R • EGFR exon 19 deletion • EGFR T790M • EGFR exon 20 insertion • EGFR exon 20 mutation
    |
    Mekinist (trametinib) • gefitinib • Kisqali (ribociclib) • Tabrecta (capmatinib) • naporafenib (ERAS-254) • nazartinib (EGF816)
    over2years
    A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov)
    P1, N=350, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2024 --> Oct 2024 | Trial primary completion date: Jun 2024 --> Oct 2024
    Trial completion date • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene) • DUSP6 (Dual specificity phosphatase 6)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Tevimbra (tislelizumab-jsgr) • spartalizumab (PDR001) • naporafenib (ERAS-254) • batoprotafib (TNO155) • rineterkib (LTT462)
    over2years
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=320, Recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2023 --> Oct 2022 | Trial primary completion date: Nov 2022 --> Aug 2022
    Trial completion date • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    over2years
    A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov)
    P1, N=350, Recruiting, Novartis Pharmaceuticals | Trial completion date: Aug 2023 --> Jun 2024 | Trial primary completion date: Aug 2023 --> Jun 2024
    Trial completion date • Trial primary completion date
    |
    BRAF (B-raf proto-oncogene) • DUSP6 (Dual specificity phosphatase 6)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Tevimbra (tislelizumab-jsgr) • spartalizumab (PDR001) • naporafenib (ERAS-254) • batoprotafib (TNO155) • rineterkib (LTT462)
    over2years
    A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma (clinicaltrials.gov)
    P1, N=241, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • BRAF mutation • NRAS mutation
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    over2years
    Phase I Study of LXH254 in Patients With Advanced Solid Tumors Haboring MAPK Pathway Alterations (clinicaltrials.gov)
    P1, N=142, Completed, Novartis Pharmaceuticals | Active, not recruiting --> Completed
    Trial completion • IO biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • NRAS mutation
    |
    spartalizumab (PDR001) • naporafenib (ERAS-254)
    over2years
    A controlled drug release device facilitates the identification of favorable combinations of immune-oncology drugs with targeted or cytotoxic drugs in a patient-derived humanized mouse model of renal cancer (AACR 2022)
    Several agents showed a significant increase in apoptosis induction when nivolumab was added: The largest increase was observed for the panRAF inhibitor LXH254, Sorafenib, Oxaliplatin and Doxorubicin. Our results demonstrate that local tumor response signatures of ICD can be used to systemically identify synergistic combinations of a range of drugs with immunotherapy on a tumor specific basis. The approach may represent a new paradigm for efficient in vivo screening of novel combinations, particularly with combinations involving immunotherapies.
    Preclinical • PD(L)-1 Biomarker • IO biomarker
    |
    PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • ICAM1 (Intercellular adhesion molecule 1) • ITGAM (Integrin, alpha M)
    |
    MHC-II expression
    |
    Opdivo (nivolumab) • sorafenib • doxorubicin hydrochloride • oxaliplatin • naporafenib (ERAS-254)
    almost3years
    A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma (clinicaltrials.gov)
    P1, N=331, Recruiting, Novartis Pharmaceuticals | Trial primary completion date: Jan 2022 --> Nov 2022
    Trial primary completion date
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • BRAF mutation • NRAS mutation
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    3years
    Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma (clinicaltrials.gov)
    P2, N=320, Recruiting, Novartis Pharmaceuticals | Trial completion date: Apr 2023 --> Sep 2023
    Trial completion date
    |
    BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    NRAS mutation • BRAF V600
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)
    3years
    Phase I Study of LXH254 in Patients With Advanced Solid Tumors Haboring MAPK Pathway Alterations (clinicaltrials.gov)
    P1, N=142, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2021 --> Feb 2022 | Trial primary completion date: Nov 2021 --> Feb 2022
    Trial completion date • Trial primary completion date • IO biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • NRAS mutation
    |
    spartalizumab (PDR001) • naporafenib (ERAS-254)
    3years
    A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma (clinicaltrials.gov)
    P1, N=331, Recruiting, Novartis Pharmaceuticals | Trial completion date: May 2022 --> Nov 2022
    Clinical • Trial completion date
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DUSP6 (Dual specificity phosphatase 6)
    |
    KRAS mutation • BRAF mutation • NRAS mutation
    |
    Mekinist (trametinib) • Kisqali (ribociclib) • naporafenib (ERAS-254) • rineterkib (LTT462)