News - MAP2K1 K57N - LARVOL VERI

7ms

A Study of Mirdametinib on Its Own or in Combination With Fulvestrant in People With Solid Tumor Cancer (clinicaltrials.gov)

P1b, N=6, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Sep 2027 --> Oct 2023 | Trial primary completion date: Sep 2027 --> Oct 2023

7 months ago

Trial completion • Trial completion date • Trial primary completion date • Combination therapy • Metastases

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1) • MAP2K2 (Mitogen-activated protein kinase kinase 2)

ER positive • HR positive • HER-2 negative • MAP2K1 mutation • MAP2K1 P124L • MAP2K1 P124S • MAP2K2 mutation • MAP2K1 C121S • MAP2K1 F53L • MAP2K1 K57N • MAP2K1 P124

fulvestrant • mirdametinib (PD-0325901)

11ms

A Study of Mirdametinib on Its Own or in Combination With Fulvestrant in People With Solid Tumor Cancer (clinicaltrials.gov)

P1b, N=6, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=150 --> 6

11 months ago

Enrollment closed • Enrollment change • Combination therapy • Metastases

ER positive • HR positive • HER-2 negative • MAP2K1 mutation • MAP2K1 P124L • MAP2K1 P124S • MAP2K2 mutation • MAP2K1 C121S • MAP2K1 F53L • MAP2K1 K57N • MAP2K1 P124

fulvestrant • mirdametinib (PD-0325901)

12ms

A Study of Mirdametinib on Its Own or in Combination With Fulvestrant in People With Solid Tumor Cancer (clinicaltrials.gov)

P1b, N=150, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2024 --> Sep 2027

12 months ago

Trial completion date • Trial primary completion date • Combination therapy • Metastases

ER positive • HR positive • HER-2 negative • MAP2K1 mutation • MAP2K1 P124L • MAP2K1 P124S • MAP2K2 mutation • MAP2K1 C121S • MAP2K1 F53L • MAP2K1 K57N • MAP2K1 P124

fulvestrant • mirdametinib (PD-0325901)

2years

Evaluation of somatic and germline variants in patients with small bowel adenocarcinoma reveals clinically actionable targets. (ASCO 2022)

Of the entire cohort, we observed five activating PIK3CA mutations (R108H; G364R; E542K; E545K, n = 2) which may be sensitive to FDA-approved PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 2), STK11 (n = 1) and PTEN (n = 1) can be targeted with MEK inhibitor selumetinib and mTOR inhibitor everolimus, respectively. Except for one V600E mutation, all mutations in BRAF are either type 2 (L597R, n = 1) or type 3 (N581S, n = 1; D594N, n = 4) which were sensitive to MEK inhibitor trametinib...Interestingly, one IDH1 mutation (R132C) carrier in our cohort might benefit from ivosidenib... Through comprehensive genomic characterization of Chinese SBA patients, we identified actionable variants of multiple signaling pathways in plenty. NGS profiling results can guide physicians to enroll a significant portion of SBA patients in genomically-matched clinical trials.

2 years ago

Clinical • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • STK11 (Serine/threonine kinase 11) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1) • MDM2 (E3 ubiquitin protein ligase) • MLH1 (MutL homolog 1) • SMAD4 (SMAD family member 4) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • KMT2C (Lysine Methyltransferase 2C) • FGF3 (Fibroblast growth factor 3) • ARID2 (AT-Rich Interaction Domain 2) • FAT3 (FAT Atypical Cadherin 3) • ERCC5 (ERCC Excision Repair 5 Endonuclease 2) • SOX9 (SRY-Box Transcription Factor 9) • SPTA1 (Spectrin Alpha)

TP53 mutation • BRAF V600E • KRAS mutation • HER-2 amplification • PIK3CA mutation • BRAF V600 • IDH1 mutation • PTEN mutation • STK11 mutation • PIK3CA E545K • NF1 mutation • HER-2 S310F • HER-2 V777L • PIK3CA E542K • IDH1 R132C • PIK3CA E545 • BRAF L597R • HER-2 V842I • IDH1 R132 • PIK3CA E542 • BRAF D594N • MAP2K1 F53L • MAP2K1 K57E • MAP2K1 K57N • BRAF L597 • HER-2-H

Onco PanScan™

Mekinist (trametinib) • everolimus • Koselugo (selumetinib) • Piqray (alpelisib) • Tibsovo (ivosidenib)

over2years

A Study of Mirdametinib on Its Own or in Combination With Fulvestrant in People With Solid Tumor Cancer (clinicaltrials.gov)

P1b, N=150, Recruiting, Memorial Sloan Kettering Cancer Center

over 2 years ago

Clinical • New P1 trial • Combination therapy

ER positive • HR positive • HER-2 negative • MAP2K1 mutation • MAP2K1 P124L • MAP2K1 P124S • MAP2K2 mutation • MAP2K1 C121S • MAP2K1 F53L • MAP2K1 K57N • MAP2K1 P124

fulvestrant • mirdametinib (PD-0325901)

3years

[VIRTUAL] Genomic profiling of small bowl adenocarcinoma reveals targetable mutations in multiple signaling pathways (AACR 2021)

We also found two MAP2K1 activating mutations (K57E and K57N) which can be targeted by trametinib...We also observed two activating PIK3CA mutations (R108H and G364R) which may be sensitive to PIK3CA inhibitor alpelisib... The mutational landscape of our SBA cohort provided compelling evidence that multiple signaling pathways play a role in the pathogenesis of SBA and many driver mutations in these pathways are targetable. Our findings indicated that SBA patients should participate in matched clinical trials for better management of this disease.

3 years ago

Tumor Mutational Burden

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • MLH1 (MutL homolog 1) • SMAD4 (SMAD family member 4) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • KMT2C (Lysine Methyltransferase 2C) • FGF3 (Fibroblast growth factor 3) • ARID2 (AT-Rich Interaction Domain 2) • FAT3 (FAT Atypical Cadherin 3) • ERCC5 (ERCC Excision Repair 5 Endonuclease 2) • ZKSCAN1 (Zinc Finger With KRAB And SCAN Domains 1)

TP53 mutation • BRAF V600E • KRAS mutation • HER-2 amplification • PIK3CA mutation • BRAF V600 • HER-2 V777L • BRAF L597R • HER-2 V842I • MET fusion • MAP2K1 K57E • MAP2K1 K57N • BRAF L597

Mekinist (trametinib) • Piqray (alpelisib)

3years

[VIRTUAL] Mechanisms of acquired resistance to KRAS G12C inhibition in cancer (AACR 2021)

In early phase clinical trials of patients with KRASG12C-mutant cancers, promising antitumor activity has been reported with drugs such as adagrasib (MRTX849) and sotorasib (AMG510) which are direct inhibitors of KRASG12C. Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors in patients with cancer. Acquired genomic mutations, amplifications, and rearrangements may be potentially targetable by combining KRASG12C inhibition with available kinase inhibitors or SHP2 inhibitors.

3 years ago

Preclinical • Late-breaking abstract

EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • MET (MET proto-oncogene, receptor tyrosine kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • FGFR (Fibroblast Growth Factor Receptor)

BRAF V600E • KRAS mutation • EGFR mutation • NRAS mutation • BRAF V600 • MET amplification • EGFR amplification • KRAS G13D • NRAS Q61K • RET M918T • NRAS Q61 • KRAS G13 • KRAS amplification • NRAS G13 • BRAF amplification • KRAS Q61K • MAP2K1 K57N

Lumakras (sotorasib) • Krazati (adagrasib)

over3years

Molecular mechanisms of resistance to BRAF and MEK inhibitors in BRAF non-small cell lung cancer. (PubMed, Eur J Cancer)

Novel resistance mechanisms to BRAF/MEK inhibitors in BRAF NSCLC were identified, pointing out the recurring involvement of the MAPK pathway and guiding the development of new treatment strategies.

over 3 years ago

Journal • Tumor Mutational Burden

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • MAP2K1 (Mitogen-activated protein kinase kinase 1)

BRAF V600E • KRAS mutation • BRAF V600 • PTEN mutation • NRAS Q61 • NRAS Q61R • MAP2K1 K57N

Mekinist (trametinib) • Zelboraf (vemurafenib) • Tafinlar (dabrafenib)