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BIOMARKER:

MTAP deletion

i
Other names: MTAP, Methylthioadenosine Phosphorylase, S-Methyl-5'-Thioadenosine Phosphorylase, MSAP, 5’-Methylthioadenosine Phosphorylase, MTA Phosphorylase, MTAPase, C86fus, Epididymis Secretory Sperm Binding Protein, Epididymis Luminal Protein 249, MeSAdo Phosphorylase, HEL-249, DMSMFH, DMSFH, LGMBF, BDMF
Entrez ID:
Related biomarkers:
6d
Discovery of TNG462: A Highly Potent and Selective MTA-Cooperative PRMT5 Inhibitor to Target Cancers with MTAP Deletion. (PubMed, J Med Chem)
We have previously described the discovery of TNG908, a brain-penetrant clinical-stage compound that selectively targets MTAP-deleted cancer cells by binding to and inhibiting PRMT5 cooperatively with MTA, which is present in elevated concentrations in MTAP-deleted cells. Herein we describe the discovery of TNG462, a more potent and selective MTA-cooperative PRMT5 inhibitor with improved DMPK properties that is selective for MTAP-deleted cancers and is currently in Phase I/II clinical trials.
Journal
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MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
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TNG908 • TNG462
12d
A Phase 1/2 Study of AMG 193 in Combination With IDE397 in Participants With Advanced Methylthioadenosine Phosphorylase (MTAP)-Null Solid Tumors (clinicaltrials.gov)
P1/2, N=53, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=184 --> 53 | Trial completion date: Feb 2027 --> Aug 2025
Enrollment closed • Enrollment change • Trial completion date
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MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
IDE397 • AMG 193
17d
Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma. (PubMed, Cell Rep Med)
Methionine intervention also activates the immune-related signaling pathways in MTAP-deleted OS cells and attracts CD8+ T cells, thereby enhancing the efficacy of ICT. Combining methionine intervention with ICT provides a significant survival benefit in MTAP-deleted OS murine models, suggesting a rationale for combination regimens in OS ICT.
Journal • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8) • MTAP (Methylthioadenosine Phosphorylase) • IKZF1 (IKAROS Family Zinc Finger 1) • MAT2A (Methionine Adenosyltransferase 2A)
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PD-L1 expression • MTAP deletion
1m
MTA-Cooperative PRMT5 Inhibitors: Mechanism Switching Through Structure-Based Design. (PubMed, J Med Chem)
MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5•MTA complex relative to the PRMT5•SAM complex can lead to selective killing of cancer cells with MTAP deletion. Herein, we describe the discovery of novel compounds using structure-based drug design to switch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitors to an MTA-cooperative binding mechanism by occupying the portion of the SAM binding pocket in PRMT5 that is unoccupied when MTA is bound and hydrogen bonding to Arg368, thereby allowing them to selectively target MTAP-deleted cancer cells.
Journal
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MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
2ms
Biomedical Effects of Protein Arginine Methyltransferase Inhibitors. (PubMed, J Biol Chem)
The promising effects of PRMT5 inhibitors in targeted therapy of MTAP-deleted cancers is particularly highlighted. At last, we provide a perspective on the challenges and further opportunities of developing and applying novel PRMT inhibitors for clinical advancement.
Review • Journal
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MTAP (Methylthioadenosine Phosphorylase)
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MTAP deletion
2ms
Discovery of Potent, Highly Selective, and Orally Bioavailable MTA Cooperative PRMT5 Inhibitors with Robust In Vivo Antitumor Activity. (PubMed, J Med Chem)
Compound 20 exhibited strong antiproliferation activity in multiple MTAP-deleted cancer cell lines, excellent selectivity over MTAP wild-type cell lines, as well as satisfactory oral pharmacokinetic properties over various preclinical species. Notably, compound 20 demonstrated a dose-dependent reduction of symmetric dimethylarginine (SDMA) expression in the LU99 cell line and robust in vivo antitumor activity in the LU99 subcutaneous model.
Preclinical • Journal
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MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
2ms
A Phase 1/2 Study of AMG 193 in Combination With IDE397 in Participants With Advanced Methylthioadenosine Phosphorylase (MTAP)-Null Solid Tumors (clinicaltrials.gov)
P1/2, N=184, Recruiting, Amgen | Trial completion date: Sep 2027 --> Feb 2027 | Trial primary completion date: Mar 2026 --> Aug 2025
Trial completion date • Trial primary completion date
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MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
IDE397 • AMG 193
2ms
Cholangiocarcinoma Targeted Therapies: Mechanisms of Action and Resistance. (PubMed, Am J Pathol)
In this review, we examine the clinical efficacy and mechanisms of resistance associated with these treatments, as well as insights into the molecular and biological effects of pathway activation and inhibition, based on study of patient samples and preclinical models. We also explore strategies to overcome resistance and possible precision medicine approaches for additional patient subsets.
Review • Journal • IO biomarker
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • FGFR2 (Fibroblast growth factor receptor 2) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • MTAP (Methylthioadenosine Phosphorylase)
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BRAF V600E • KRAS mutation • HER-2 amplification • BRAF V600 • IDH1 mutation • FGFR2 fusion • MTAP deletion • IDH mutation + BRAF V600E
3ms
Inhibitory Effect of PRMT5/MTA Inhibitor on MTAP-Deficient Glioma May Be Influenced by Surrounding Normal Cells. (PubMed, Cancer Med)
Due to the complexity of the tumor environment in vivo, the anti-tumor effects of PRMT5/MTA-specific inhibitors may be somewhat attenuated, and their ability to achieve suitable therapeutic effects in the clinic might require more in-depth studies.
Journal
|
MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
BMS‐986504
3ms
Loss of MTAP expression is strongly linked to homozygous 9p21 deletion, unfavorable tumor phenotype, and noninflamed microenvironment in urothelial bladder cancer. (PubMed, J Pathol Clin Res)
Drugs targeting MTAP-deficiency may be useful in urothelial bladder carcinoma. MTAP IHC is a near perfect surrogate for MTAP deficiency in this tumor type.
Journal • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • MTAP (Methylthioadenosine Phosphorylase)
|
PD-L1 expression • MTAP deletion • MTAP negative
3ms
Enrollment change • Metastases
|
MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
Keytruda (pembrolizumab) • TNG462
3ms
Journal • Synthetic lethality
|
MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
4ms
TNG908-C101: Safety and Tolerability of TNG908 in Patients With MTAP-deleted Solid Tumors (clinicaltrials.gov)
P1/2, N=192, Active, not recruiting, Tango Therapeutics, Inc. | Recruiting --> Active, not recruiting
Enrollment closed • Metastases
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MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
TNG908
4ms
Detection of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) in patients with glioblastoma treated in phase I clinical trial. (SNO 2024)
Conclusion : We showed in this small cohort of patients that detection of CSF-ctDNA is technically feasible. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.
P1 data • Clinical • Circulating tumor DNA
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EGFR (Epidermal growth factor receptor) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • MTAP (Methylthioadenosine Phosphorylase)
|
EGFR mutation • EGFR amplification • MTAP deletion
|
FoundationOne® Liquid CDx
4ms
Prevalence and co-mutation status of MTAP deletions (COSA 2024)
MTAP deletions are common in the MoST/CaSP population, most frequently in CNS, pancreas, lung and melanoma patients. Detection of MTAP deletion was higher with the FM1&A paltform. MTAP deletions co-existed with CDKN2A deletions in >80% of the cohort.
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase) • MAT2A (Methionine Adenosyltransferase 2A)
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CDKN2A deletion • MTAP deletion • KRAS deletion
|
TruSight Oncology 500 Assay
4ms
Trial completion date • Combination therapy • Metastases
|
MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
IDE397 • AMG 193
5ms
A Phase 1/2 Study of AMG 193 in Combination With IDE397 in Participants With Advanced Methylthioadenosine Phosphorylase (MTAP)-Null Solid Tumors (clinicaltrials.gov)
P1/2, N=184, Recruiting, Amgen | Trial completion date: Aug 2026 --> Dec 2026 | Trial primary completion date: Nov 2025 --> Mar 2026
Trial completion date • Trial primary completion date • Combination therapy • Metastases
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MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
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IDE397 • AMG 193
6ms
SCR-7952, a highly selective MAT2A inhibitor, demonstrates synergistic antitumor activities in combination with the S-adenosylmethionine-competitive or the methylthioadenosine-cooperative protein arginine methyltransferase 5 inhibitors in methylthioadenosine phosphorylase-deleted tumors. (PubMed, MedComm (2020))
Different from AG-270, SCR-7952 exhibited little influence on metabolic enzymes and did not increase the plasma levels of bilirubin. The mechanism was via the aggravated inhibition of PRMT5 and FANCA splicing perturbations. These results indicated that SCR-7952 could be a potential therapeutic candidate for the treatment of MTAP-deleted cancers, both monotherapy and in combination with PRMT5 inhibitors.
Journal • Combination therapy
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MTAP (Methylthioadenosine Phosphorylase) • FANCA (FA Complementation Group A) • MAT2A (Methionine Adenosyltransferase 2A)
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MTAP deletion
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S095033
6ms
First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase 1 dose exploration. (PubMed, Ann Oncol)
AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on ORR and ctDNA clearance.
P1 data • Journal
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CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase)
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CDKN2A deletion • MTAP deletion
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AMG 193
6ms
AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers. (PubMed, Cancer Discov)
AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.
Preclinical • Journal
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KRAS (KRAS proto-oncogene GTPase) • MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
Lumakras (sotorasib) • AMG 193
8ms
Detection of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) in patients with glioblastoma treated in phase I clinical trial (ESMO 2024)
We showed in this small cohort of patients that detection of CSF-ctDNA is technically feasible in clinical practice. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.
P1 data • Clinical • Circulating tumor DNA
|
EGFR (Epidermal growth factor receptor) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • MTAP (Methylthioadenosine Phosphorylase)
|
EGFR amplification • MTAP deletion
|
FoundationOne® Liquid CDx
10ms
Mechanistic safety assessment via multi-omic characterisation of systemic pathway perturbations following in vivo MAT2A inhibition. (PubMed, Arch Toxicol)
We infer that these pathway-wide perturbations represent adaptive responses to SAM depletion and confer a risk of oxidative stress, hepatic steatosis and an associated disturbance in plasma and cellular lipid homeostasis. The alterations also explain the dramatic increase in plasma and tissue methionine, which could be used as a safety and PD biomarker going forward to the clinic.
Preclinical • Journal
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CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase) • MAT1A (Methionine Adenosyltransferase 1A) • MAT2A (Methionine Adenosyltransferase 2A)
|
MTAP deletion
10ms
Study of IDE397 in Participants With Solid Tumors Harboring MTAP Deletion (clinicaltrials.gov)
P1, N=180, Recruiting, IDEAYA Biosciences | N=130 --> 180 | Trial completion date: Jun 2024 --> Mar 2027 | Trial primary completion date: Dec 2023 --> Dec 2026
Enrollment change • Trial completion date • Trial primary completion date • Metastases
|
MTAP (Methylthioadenosine Phosphorylase)
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MTAP deletion
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paclitaxel • docetaxel • Trodelvy (sacituzumab govitecan-hziy) • IDE397
11ms
Loss of p16 Immunoexpression and Deletions of CDKN2A in the Progression of Extramammary Paget Disease: An Immunohistochemical and Genetic Study of 24 Invasive/Metastatic Cases. (PubMed, Am J Dermatopathol)
CDKN2A homozygous deletions were confirmed in all 5 tested cases by sequencing, whereas MTAP deletions were detected in only 2 cases. In conclusion, p16 expression loss and CDKN2A deletions can be frequently seen in invasive/metastatic cases of EMPD.
Journal • Metastases
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CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase)
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CDKN2A deletion • MTAP deletion
11ms
Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers. (PubMed, J Med Chem)
Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.
Journal • Synthetic lethality
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MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
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TNG908
1year
Comparison of immunohistochemistry, next generation sequencing and fluorescence in situ hybridization for detection of MTAP loss in pleural mesothelioma. (PubMed, Mod Pathol)
We show that MTAP IHC and molecular assays are complementary in detecting 9p21 homozygous deletion. MTAP IHC may be particularly useful for low tumor purity samples and in low-resource settings.
Journal • Next-generation sequencing
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CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase)
|
CDKN2A deletion • MTAP deletion
1year
SERS analysis of cancer cell-secreted purines reveals a unique paracrine crosstalk in MTAP-deficient tumors. (PubMed, Proc Natl Acad Sci U S A)
Fibroblasts exposed to MTA exhibit: i) molecular reprogramming compatible with cancer aggressiveness, ii) a significant production of purine derivatives that could be readily recycled by cancer cells, and iii) the capacity to secrete purine derivatives that induce macrophage polarization. Our study supports the potential of SERS for cancer metabolism research and reveals an unprecedented paracrine crosstalk that explains TME reprogramming in MTAP-deleted cancers.
Journal
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MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
1year
Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors. (PubMed, ACS Med Chem Lett)
The selected compound 30 exhibited high potency for MAT2A inhibition and a favorable pharmacokinetic profile. Furthermore, in an HCT-116 MTAP-deleted xenograft model, compound 30 showed better in vivo potency than current clinical compound AG-270.
Journal
|
MTAP (Methylthioadenosine Phosphorylase) • MAT2A (Methionine Adenosyltransferase 2A)
|
MTAP deletion
|
S095033
over1year
Enrollment change
|
MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
paclitaxel • docetaxel • IDE397
over1year
Optical Genome Mapping Provides New Molecular Insights in High-Risk Mantle Cell Lymphoma: A Lysa Study (ASH 2023)
Two patients had deletion of SMARCA4 at diagnosis, that confers resistance to the BCL-2 inhibitor venetoclax (Agarwal et al...Mutations in the NF-κB alternative pathway, responsible for resistance to ibrutinib, are found in both LR and HR patients. ConclusionIn this small cohort of MCL patients included in a trial, complex structural alterations were identified by OGM at the time of diagnosis. OGM is a very promising technology that demonstrated its potential in the cytogenetic prognostic staging of MCL.
IO biomarker
|
TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • UBR5 (Ubiquitin Protein Ligase E3 Component N-Recognin 5)
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TP53 deletion • CDKN2A deletion • MTAP deletion • SMARCA4 deletion
|
Venclexta (venetoclax) • Imbruvica (ibrutinib)
over1year
Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition. (PubMed, J Biol Chem)
Combination MTDIA and AG-270 treatment differs from direct inhibition of PRMT5 by GSK3326595 by avoiding toxicity caused by cell death in the normal gut epithelium induced by the PRMT5 inhibitor. The combination of MTAP and MAT2a inhibitors expands this synthetic lethal approach to include MTAP cancers, especially the remaining 98% of CRCs without the MTAP genotype.
Preclinical • Journal • Synthetic lethality
|
MTAP (Methylthioadenosine Phosphorylase) • MDM4 (The mouse double minute 4) • MAT2A (Methionine Adenosyltransferase 2A)
|
MTAP deletion
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pemrametostat (GSK3326595) • S095033
over1year
MTA-cooperative PRMT5 inhibitors are efficacious in MTAP-deleted malignant peripheral nerve sheath tumor models (SNO 2023)
The proliferation effects of MTA-cooperative PRMT5 inhibitors, TNG908 or TNG462, and a SAM-cooperative PRMT5 inhibitor, GSK3326595, on MTAP-deleted and MTAP-intact MPNST cell lines were determined using CellTiter-Glo (CTG) assays. The clinical stage MTA-cooperative PRMT5 inhibitors TNG908 (NCT05275478) and TNG462 (NCT05732831) are efficacious in MPNST models in vitro and in vivo and are therefore promising therapeutic agents for patients with MTAP-deleted MPNST.
Preclinical
|
CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
TNG908 • TNG462 • pemrametostat (GSK3326595)
over1year
TNG908, a brain-penetrant MTA-cooperative PRMT5 inhibitor, is efficacious in preclinical MTAP-deleted models including glioblastoma (SNO 2023)
In summary, TNG908 is a potent, brain-penetrant, MTA-cooperative PRMT5 inhibitor that drives strong antitumor activity in preclinical models of MTAP-deleted GBM. TNG908 is currently enrolling patients with MTAP-deleted tumors including glioblastoma in a Phase I/II clinical trial (NCT05275478).
Preclinical
|
CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
TNG908
over1year
Early Clinical Success of MTA-Cooperative PRMT5 Inhibitors for the Treatment of CDKN2A/MTAP-Deleted Cancers. (PubMed, Cancer Discov)
In this issue of Cancer Discovery, Engstrom and colleagues report an MTA-cooperative PRMT5 methyltransferase inhibitor MRTX1719 that selectively kills CDKN2A/MTAP-codeleted cancers and demonstrates early efficacy in clinical trials for solid tumors harboring the CDKN2A/MTAP codeletion. See related article by Engstrom et al., p. 2412 (1).
Journal
|
CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase)
|
CDKN2A deletion • MTAP deletion
|
BMS‐986504
over1year
MRTX1719 is an MTA-cooperative PRMT5 inhibitor that exhibits synthetic lethality in preclinical models and patients with MTAP deleted cancer. (PubMed, Cancer Discov)
MRTX1719 demonstrated marked anti-tumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and MPNST from the Phase 1/2 study.
Preclinical • Clinical Trial,Phase II • Journal • Synthetic lethality
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MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
BMS‐986504
over1year
Deletions of CDKN2A and MTAP Detected by Copy-Number Variation Array Are Associated with Loss of p16 and MTAP Protein in Pleural Mesothelioma. (PubMed, Cancers (Basel))
Both p16 and MTAP IHC showed high concordance with Oncoscan CNV arrays (kappa = 0.952, p < 0.0001, and kappa = 0.787, p < 0.0001 respectively). We recommend combined MTAP and p16 immunohistochemistry to confirm the diagnosis of PM.
Journal
|
CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase)
|
CDKN2A deletion • MTAP deletion • MTAP negative
|
OncoScan™ CNV Assay
over1year
AMG 193 Effective in Multiple Tumor Types. (PubMed, Cancer Discov)
In a phase I trial of the MTA-cooperative PRMT5 inhibitor AMG 193, five of 39 patients with advanced MTAP-deleted solid tumors who had scans following initial treatment experienced partial responses. The responses occurred in five tumor types-esophageal, pancreatic, renal cell, gallbladder, and ovarian Sertoli-Leydig cell cancer.
Journal
|
MTAP (Methylthioadenosine Phosphorylase) • PRMT5 (Protein Arginine Methyltransferase 5)
|
MTAP deletion
|
AMG 193
over1year
Enrollment open • Combination therapy • Metastases
|
MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
IDE397 • AMG 193
over1year
Preclinical
|
MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
over1year
New P1/2 trial • Combination therapy • Metastases
|
MTAP (Methylthioadenosine Phosphorylase)
|
MTAP deletion
|
IDE397 • AMG 193
over1year
Frequency and Outcomes of Leptomeningeal Metastases in Patients with Fusion-Positive Lung Cancers (IASLC-WCLC 2023)
The most common tyrosine kinase inhibitors used to treat LM were lorlatinib (n=7), alectinib (n=6), and selpercatinib (n=5). We found leptomeningeal metastases in 8% of patients with fusion+ lung cancers, of which the majority developed on treatment. Responses occurred with a switch to another targeted therapy and proton craniospinal irradiation. Median survivals from LM detections ranged from 8 months (ROS1) to 30 months (ALK).
Clinical
|
EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NRG1 (Neuregulin 1) • MTAP (Methylthioadenosine Phosphorylase) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • NTRK (Neurotrophic receptor tyrosine kinase)
|
TP53 mutation • ALK fusion • ALK mutation • CDKN2A deletion • MTAP deletion • RET mutation • CDKN2A mutation • NRG1 fusion • CTNNB1 mutation
|
MSK-IMPACT
|
Alecensa (alectinib) • Lorbrena (lorlatinib) • Retevmo (selpercatinib)
over1year
Study of AG-270 in Participants With Advanced Solid Tumors or Lymphoma With MTAP Loss (clinicaltrials.gov)
P1, N=123, Terminated, Institut de Recherches Internationales Servier | Completed --> Terminated; Strategic reasons
Trial termination • Metastases
|
CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MTAP (Methylthioadenosine Phosphorylase)
|
CDKN2A deletion • MTAP deletion
|
gemcitabine • docetaxel • albumin-bound paclitaxel • S095033