anvumetostat (AMG 193) / Amgen - LARVOL DELTA

Phase 1 expansion results of IDE397, a first-in-class, oral, MAT2A inhibitor (MAT2Ai) in MTAP deleted(del) non-small cell lung cancer (NSCLC) and urothelial cancer (UC) (EORTC-NCI-AACR 2024) - P1, P1/2 | "IDE397 provides preliminary clinical proof of concept for MAT2A inhibition in MTAPdel tumors with manageable safety & antitumor activity in pre-treated NSCLC & UC. Expansion of IDE397 monotherapy is ongoing, as well as in combination with sacituzumab-govitecan (Trodelvy®) (NCT04794699), and AMG 193 (NCT05975073)."

Late-breaking abstract • P1 data • Genito-urinary Cancer • Lung Adenocarcinoma • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Urothelial Cancer • MAT2A • MTAP

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."

Journal • Preclinical • Oncology • Solid Tumor • KRAS • MTAP

Phase I dose escalation and initial dose expansion results of AMG 193: A MTA-cooperative PRMT5 inhibitor, in patients (pts) with MTAP-deleted solid tumors (ESMO 2024) - P1/2 | "AMG 193 demonstrated a favorable safety profile, no evidence of clinically significant myelosuppression as observed with first generation PRMT5 inhibitors, and encouraging antitumor activity in solid tumors, including NSCLC, PDAC and BTC. Table: 604O Antitumor activity CI, confidence interval; CR, complete response; DCR, disease control rate; NE, not estimable; ORR, objective response rate; PD, progressive disease; c/u PR, confirmed/unconfirmed partial response; QD, once daily; SD, stable disease."

Clinical • P1 data • Biliary Cancer • Biliary Tract Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • MTAP

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."

Journal • P1 data • Biliary Cancer • Biliary Tract Cancer • Fatigue • Gastrointestinal Cancer • Hepatology • Immunology • Lung Adenocarcinoma • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CDKN2A • MTAP

Phase 1/2, Dose-expansion Study of AMG 193, an MTA-cooperative PRMT5 Inhibitor, In MTAP-deleted NSCLC (IASLC-WCLC 2024) - "Key eligibility criteria for patients with NSCLC (Part 1c) include adult patients (≥ 18 years of age) with MTAP -deleted advanced tumors (determined by NGS or evidence of MTAP depletion determined by IHC); treatment with 1-3 prior lines of systemic therapy in the advanced/metastatic setting including platinum-based chemotherapy. Additionally, patients without actionable mutations must have received treatment with a PD(L)-1 inhibitor (unless contraindicated or PD-L1 < 1%), and patients whose tumors harbor actionable genomic aberrations (i.e. EGFR, ALK, MET, RET, ROS1, KRAS G12C ) should have disease progression on approved systemic therapies for these aberrations."

IO biomarker • P1/2 data • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • KRAS • MTAP • ROS1

A Study Evaluating Anvumetostat in Combination With Other Therapies in Participants With Advanced Gastrointestinal, Biliary Tract, or Pancreatic Cancers With Homozygous Methylthioadenosine Phosphorylase (MTAP)-Deletion (MTAPESTRY 103) (clinicaltrials.gov) - P1 | N=120 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting | N=350 ➔ 120 | Trial completion date: Feb 2029 ➔ Nov 2026 | Trial primary completion date: Feb 2027 ➔ Oct 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • MTAP

A Phase 2 Study of Anvumetostat in Participants With MTAP-deleted Advanced NSCLC (MTAPESTRY 201) (clinicaltrials.gov) - P2 | N=61 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting | N=200 ➔ 61 | Trial completion date: Nov 2030 ➔ Nov 2026 | Trial primary completion date: Nov 2028 ➔ Oct 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

Anvumetostat Alone or in Combination With Other Therapies in Subjects With Advanced Thoracic Tumors With Homozygous MTAP-deletion (Master Protocol) (MTAPESTRY 104). (clinicaltrials.gov) - P1 | N=49 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting | N=500 ➔ 49 | Trial completion date: Oct 2031 ➔ Nov 2026 | Trial primary completion date: Oct 2028 ➔ Oct 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer • KRAS • MTAP • PD-L1

A Study of Anvumetostat in Participants With Advanced MTAP-null Solid Tumors (MTAPESTRY 101) (clinicaltrials.gov) - P1/2 | N=329 | Active, not recruiting | Sponsor: Amgen | Trial completion date: May 2028 ➔ Nov 2026 | Trial primary completion date: May 2026 ➔ Nov 2026

Trial completion date • Trial primary completion date • Brain Cancer • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CDKN2A • MTAP

OncoKBTM, MSK's precision oncology knowledge base: 2024 updates (AACR 2025) - "OncoKB promoted BRAF fusions to Level 1 following inclusion as patient eligibility criteria in the FDA drug label for tovorafenib (low-grade glioma). Additionally, OncoKB included KRAS G12C in colorectal cancer and IDH1 mutations in myelodysplastic syndromes as Level 1 following FDA approval of adagrasib + cetuximab and ivosidenib, respectively...Lastly, novel biomarkers including FBXW7 and PPP2R1A alterations (endometrial and ovarian cancer), SMARCA4 mutations (non-small cell lung cancer and esophageal adenocarcinoma) and MTAP deletions (all solid tumors) were included in OncoKB based on compelling preclinical and emerging clinical evidence in association with lunresertib + camonsertib, PRT3789, and AMG193 and MRTX1719, respectively...OncoKB also implemented major software updates to support data integration into the EPIC platform. Future OncoKB efforts are focused on whole genome/exome curation, inclusion of biomarkers for non-NGS-based precision oncology therapies,..."

Tumor mutational burden • Brain Cancer • CNS Tumor • Colorectal Cancer • Endometrial Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Glioma • Hematological Malignancies • Lung Cancer • Microsatellite Instability • Myelodysplastic Syndrome • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Small Intestinal Carcinoma • Solid Tumor • BRAF • FBXW7 • IDH1 • KRAS • MSI • MTAP • POLD1 • PPP2R1A • SMARCA4 • TMB

Autophagy alterations in KRAS-mutant colorectal cancer following PRMT5 inhibition (AACR 2026) - "This study evaluates the mechanism of autophagy induction under PRMT5 inhibition and the possible apoptotic transition.Methodology: Four CRC cell lines, HCT116, SW640 (KRAS mutant), HKE3, and LIM2405 (KRAS wild type), were treated with three inhibitors, EPZ015666 (EPZ), GSK3326595 (GSK), and AMG-193 (AMG), each at 0.5 µM, 1 µM, and 10 µM, and assessed at 24 h and 48 h. Western blot analysis was conducted for ATG5, BECLIN1, BRG1, LC3B, ULK1, and ACTIN (housekeeping) to quantify autophagy regulation. Across four CRC lines, PRMT5 inhibition enhanced autophagy signaling, significantly in KRAS-mutant backgrounds. AMG consistently caused the strongest activation across early and late autophagy markers, indicating potent disruption of PRMT5-regulated stress-response circuits. We are currently investigating the onset of apoptosis under these treatment conditions by western blotting and gene expression by transcriptomics."

Colorectal Cancer • Oncology • Solid Tumor • ATG5 • BECN1 • KRAS • PRMT5 • SMARCA4

Following a comprehensive review of the oncology portfolio and emerging AMG 193 clinical data, the Company will discontinue further development of AMG 193. (Amgen Press Release) - "As such, the following studies will be discontinued: a Phase 2 study of AMG 193 in patients with methylthioadenosine phosphorylase (MTAP)-null previously treated advanced non-small cell lung cancer (NSCLC). a Phase 1/1b/2 study of AMG 193 in patients with advanced MTAP-null solid tumors in the dose-expansion portion of the study. a Phase 1b study of AMG 193 alone or in combination with other therapies in patients with advanced MTAP-null thoracic malignancies. a Phase 1b study of AMG 193 in combination with other therapies in patients with advanced MTAP-null gastrointestinal, biliary tract or pancreatic cancers."

Discontinued • Trial termination • Biliary Tract Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer • Solid Tumor • Thoracic Cancer

Targeting MTAP-deleted/KRAS mutant cancers using RAS inhibitors in combination with AMG 193, an MTA-cooperative PRMT5 inhibitor (AACR 2026) - P1 | "Overall, AMG 193 displays synergy with RAS targeted agents in vitro, and combination treatment with sotorasib in vivo substantially inhibits tumor growth. A clinical study evaluating AMG 193 in combination with RMC-6236 in MTAP-deleted PDAC is ongoing (NCT06360354)."

Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • MTAP

Developing drug combinations with AMG 193, a novel MTA-cooperative PRMT5 inhibitor, using patient-derived xenograft models of MTAP-deleted non-small cell lung cancer and mesothelioma (AACR 2026) - "A spectrum of AMG 193 activity was demonstrated across MTAP-del LUAD, LUSC, MESO PDX models, recapitulating the range of response & resistance seen clinically. Combination therapy with AMG 193 overcame sotorasib resistance in KRAS G12C LUAD models. Other drug combinations will be evaluated in primary or acquired resistance models."

Preclinical • Lung Adenocarcinoma • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • KRAS • MTAP

A Phase 1/2 Study of Anvumetostat in Combination With IDE397 in Participants With Advanced Methylthioadenosine Phosphorylase (MTAP)-Null Solid Tumors (clinicaltrials.gov) - P1/2 | N=53 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers (AACR 2024) - "The antitumor activities were compared in vitro and in vivo to MRTX1719 and AMG193 in MTAP null tumors such as HCT116 MTAP KO, DoHH-2 and Lu99. The correlation between compound exposure and on-target effect was confirmed in PK/PD and efficacy studies. Taken together, these studies confirm that MTA cooperative PRMT5 inhibitors exert strong synthetic lethal phenotype in MTAP deleted cancers and offer an exciting therapeutic opportunity for a large patient population."

Brain Cancer • CNS Tumor • Gastrointestinal Cancer • Glioblastoma • Lung Adenocarcinoma • Lung Cancer • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CDKN2A • MTAP

MTAP loss alters the epigenetic landscape and demonstrates superior therapeutic sensitivity to concomitant PRMT5 and PARP inhibition in cholangiocarcinoma (AACR 2024) - P1 | "This renders selective targeting of MTAP null tumors with agents (MRTX1719, AMG193, TNG462, TNG908) targeting MTA bound PRMT5 (PRMT5:MTA), while sparing surrounding normal MTAP wild-type (WT) tissue...To address this pressing need, we co-treated CCA cell lines with MRTX1719 and PARP inhibitor olaparib...Similar differences in proportion of splicing events were also observed in MTAP loss CCA patient derived xenografts as compared to WT models. Collectively, these data implicate MTAP to be a crucial player in modulation of the chromatin and splicing events that may drive therapeutic response to PRMT5 inhibition."

Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • MTAP

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors with MTAP loss (AACR 2025) - "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 are clinical-stage MTA-cooperative PRMT5 inhibitors for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant. Oral administration of TNG456 drives dose-dependent antitumor activity including durable tumor regressions and complete responses in multiple cell line- and patient-derived xenograft models. With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including gliomas and CNS metastases."

Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

Targeting RNA splicing sensitizes MTAP-deleted cancers to MTA-cooperative PRMT5 inhibitors (AACR 2025) - "AMG 193, currently in Phase 1/2 trials, is an MTA-cooperative PRMT5 inhibitor that is showing promise as a targeted therapy in MTAP-deleted tumors...Additional resistance and sensitization pathways identified from the CRISPR screens are currently being evaluated using in vitro and in vivo assays. Furthermore, clinical biomarker datasets from the ongoing early phase trials will be utilized to validate these preclinical findings."

Oncology • MTAP

Correlation of MTAP Immunohistochemistry and Next-Generation Sequencing in Cytology and Small Biopsy Specimens of Pancreatobiliary Adenocarcinomas: A Single Institutional Retrospective Study (USCAP 2026) - "AMG 193 is a methylthioadenosine-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor, and it selectively induces synthetic lethality in MTAP-deleted tumor cells... Given the high sensitivity of MTAP IHC and NGS limitations (e.g., tumor purity, turnaround time, cost, and coverage), MTAP IHC may serve as a screening method to identify MTAP loss. However, larger studies are needed to validate these findings. Presentation (PDF): Click to View"

Biomarker • Biopsy • Cytology • Next-generation sequencing • Retrospective data • Biliary Cancer • Oncology • CDKN2A • MTAP

A Study of AMG 193 in Participants With Advanced MTAP-null Solid Tumors (MTAPESTRY 101) (clinicaltrials.gov) - P1/2 | N=329 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting | N=649 ➔ 329

Enrollment change • Enrollment closed • Brain Cancer • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CDKN2A • MTAP

MTAP Deletion in Oncogenesis: A Synthetic Lethality Scenario. (PubMed, Cancer Res) - "MTA-cooperative PRMT5 inhibitors such as BMS-986504/MRTX1719 and AMG 193 target the PRMT5-MTA complex, while inhibitors of the SAM synthetase methionine adenosyl transferase 2A (MAT2A), such as IDE397, deprive PRMT5 of its methyl donor SAM. In this review article, we summarize the mechanisms of action, preclinical data, and clinical data available thus far for these novel classes of oncology precision medicine and discuss potential future directions relevant to MTAP deletion as a promising synthetic lethal vulnerability for cancer therapy."

Journal • Hematological Disorders • Oncology • MAT2A • MTAP

A Study of AMG 193 in Participants With Advanced MTAP-null Solid Tumors (MTAPESTRY 101) (clinicaltrials.gov) - P1/2 | N=649 | Recruiting | Sponsor: Amgen | Trial completion date: Nov 2028 ➔ Jun 2028 | Trial primary completion date: Dec 2026 ➔ Jul 2026

Trial completion date • Trial primary completion date • Brain Cancer • Head and Neck Cancer • Hematological Malignancies • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CDKN2A • MTAP

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors, including glioblastoma, with MTAP loss (SNO 2025) - P1/2 | "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 were the first MTA-cooperative PRMT5 inhibitors entered in clinical trials for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant in preclinical species. TNG456 is currently enrolling patients with MTAP-null solid tumors, including glioblastoma, in a Phase 1/2 clinical study (NCT06810544). With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including glioblastoma and CNS metastases."

Brain Cancer • Glioblastoma • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

TNG456 is a next-generation, brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of solid tumors, including glioblastoma, with MTAP loss (WFNOS 2025) - P1/2 | "TNG908, TNG462, AMG 193, BMS-986504, and AZD3470 were the first MTA-cooperative PRMT5 inhibitors entered in clinical trials for the treatment of solid tumors with MTAP loss, though only TNG908 and AMG 193 are reported to be brain-penetrant in preclinical species. TNG456 is currently enrolling patients with MTAP-null solid tumors, including glioblastoma, in a Phase 1/2 clinical study (NCT06810544). With enhanced potency and selectivity for MTAP-null cancer cells, and strong preclinical evidence of brain-penetrance, TNG456 has the potential for broad clinical activity in MTAP-null solid tumors including glioblastoma and CNS metastases."

Brain Cancer • Glioblastoma • Glioma • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • MTAP