AMG 193 / Amgen - LARVOL DELTA

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

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

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

A Phase 1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 193 Alone or in Combination With Other Therapies in Subjects With Homozygous MTAP-Deletion Advanced Thoracic Tumors (Master Protocol) (ChiCTR) - P=N/A | N=312 | Not yet recruiting | Sponsor: Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences); Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sci

New trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Thoracic Cancer • MTAP • PD-L1

Discovery of AMG 193, an MTA-Cooperative PRMT5 Inhibitor for the Treatment of MTAP-Deleted Cancers. (PubMed, J Med Chem) - "Preclinical data indicate that AMG 193 is brain-penetrant. AMG 193 is currently in Phase I/II clinical trials for the treatment of advanced MTAP-deleted solid tumors."

Journal • Oncology • Solid Tumor • CDKN2A • MTAP

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 | Sponsor: Amgen | Recruiting ➔ Active, not recruiting | N=184 ➔ 53 | Trial completion date: Feb 2027 ➔ Aug 2025

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

A Phase 2 Study of AMG 193 in Participants With MTAP-deleted Advanced NSCLC (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Amgen | Trial completion date: Feb 2029 ➔ Sep 2029 | Trial primary completion date: Feb 2027 ➔ Sep 2027

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

A Study of AMG 193 in Subjects With Advanced MTAP-null Solid Tumors (clinicaltrials.gov) - P1/2 | N=649 | Recruiting | Sponsor: Amgen | Trial completion date: Jan 2028 ➔ Jun 2028

Trial 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

A Study of AMG 193 in Subjects With Advanced MTAP-null Solid Tumors (clinicaltrials.gov) - P1/2 | N=649 | Recruiting | Sponsor: Amgen | Trial completion date: Oct 2027 ➔ Jan 2028 | Trial primary completion date: Apr 2026 ➔ Aug 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

A Phase 2 Study of AMG 193 in Participants With MTAP-deleted Advanced NSCLC (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Amgen | Not yet recruiting ➔ Recruiting

Enrollment open • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

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 | Sponsor: Amgen | Trial completion date: Sep 2027 ➔ Feb 2027 | Trial primary completion date: Mar 2026 ➔ Aug 2025

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

AMG 193 Alone or in Combination With Other Therapies in Subjects With Advanced Thoracic Tumors With Homozygous MTAP-deletion (Master Protocol) (clinicaltrials.gov) - P1 | N=500 | Recruiting | Sponsor: Amgen | Trial completion date: Jun 2032 ➔ Oct 2031 | Trial primary completion date: Jun 2029 ➔ Oct 2028

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thoracic Cancer

A Study Evaluating AMG 193 in Combination With Other Therapies in Participants With Advanced Gastrointestinal, Biliary Tract, or Pancreatic Cancers With Homozygous Methylthioadenosine Phosphorylase (MTAP)-Deletion (clinicaltrials.gov) - P1 | N=188 | Recruiting | Sponsor: Amgen | Trial completion date: Apr 2028 ➔ Feb 2029 | Trial primary completion date: May 2026 ➔ Feb 2027

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

Exploring the Clinical Translation of Synthetic Lethality, PRMT5 Inhibitors in MTAP-Deleted Cancers: A Scoping Review (ISPOR-EU 2024) - P1/2 | "Notably, six oral PRMT5 inhibitors—MRTX1719, AG-270, AMI, LLY-238, HLCL-61, and EPZ015666 demonstrated significant antitumor activity in MTAP-deleted tumours in mouse xenograft models...Among the 25 clinical trials, two PRMT5 inhibitors, AMG193 (NCT05975073) and TNG908 (NCT05275478) are currently in Phase 1/2 trials targeting MTAP-null solid tumours. There is compelling evidence supporting the initial stages of drug development aimed at PRMT5 in MTAP-deleted cancers. Additional research is required to clarify molecular mechanisms and improve the clinical viability of this SL combination."

Clinical • Review • Synthetic lethality • Oncology • Solid Tumor • BRCA • MTAP

A Phase 2 Study of AMG 193 in Participants With MTAP-deleted Advanced NSCLC (clinicaltrials.gov) - P2 | N=200 | Not yet recruiting | Sponsor: Amgen | Trial completion date: Sep 2029 ➔ Feb 2029 | Trial primary completion date: Sep 2027 ➔ Feb 2027

Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

IDE397 demonstrated deep and durable regressions in combination with PRMT5 inhibitors BMS-986504 and AMG 193 in preclinical models (PRNewswire) - "...IDEAYA had additional poster presentations at ENA 2024 highlighting preclinical data for the MAT2A and PARG programs. In the ENA 2024 concomitant publication, IDE397 demonstrated deep and durable regressions in combination with clinical stage PRMT5 inhibitors BMS-986504 and AMG 193 in multiple MTAP-deletion preclinical models."

Preclinical • Oncology • Solid Tumor

IDEAYA Biosciences, Inc. Reports Third Quarter 2024 Financial Results and Provides Business Update (PRNewswire) - "Darovasertib in 1L MUM and Neoadjuvant Uveal Melanoma (UM): Enrollment in darovasertib + crizotinib 1L HLA-A2+ MUM potential Ph2/3 registration-enabling trial is ahead of schedule and has exceeded 150 patients....Following a successful Type C meeting with the U.S. Food and Drug Administration (FDA), IDEAYA is finalizing the Phase 3 registrational trial protocol and is targeting to initiate its potential registration-enabling trial in the first half of 2025. IDE397 in MTAP-Deletion Solid Tumors: Enrollment is ongoing in the IDE397 and AMG 193 Phase 1 dose escalation, and targeting expansion in NSCLC in late 2024 to early 2025. Ongoing Phase 1 trial evaluating IDE397 in combination with Trodelvy in MTAP-deletion UC; targeting combination expansion in the fourth quarter of 2024."

Trial status • Non Small Cell Lung Cancer • Urothelial Cancer • Uveal Melanoma

Discovery of novel MTA-cooperative PRMT5 inhibitors as targeted therapeutics for MTAP-deleted cancers (EORTC-NCI-AACR 2024) - "Ryvu PRMT5 inhibitors have a robust antiproliferative effect on MTAP-deleted cell lines and provide a good safety window for MTAP WT cells, as shown in a wide cell line panel 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

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 | Sponsor: Amgen | Trial completion date: Dec 2026 ➔ Sep 2027

Combination therapy • Metastases • Trial completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MTAP

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

The mechanistic basis of both deep and durable antitumor activity by combinatorial inhibition of MAT2A and PRMT5 in MTAP-deleted tumors (EORTC-NCI-AACR 2024) - P1/2 | "Finally, broad combination profiling in MTAPdel PDX models demonstrated robust and consistent combination benefit in multiple indications. These findings strongly support clinical evaluation of the IDE397/AMG 193 combination (NCT05975073)."

Oncology • Solid Tumor • MAT2A • MTAP

A Study Evaluating AMG 193 in Combination With Other Therapies in Participants With Advanced Gastrointestinal, Biliary Tract, or Pancreatic Cancers With Homozygous Methylthioadenosine Phosphorylase (MTAP)-Deletion (clinicaltrials.gov) - P1 | N=188 | Recruiting | Sponsor: Amgen | Trial completion date: Nov 2027 ➔ Apr 2028 | Trial primary completion date: Nov 2025 ➔ May 2026

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

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 | Sponsor: Amgen | Trial completion date: Aug 2026 ➔ Dec 2026 | Trial primary completion date: Nov 2025 ➔ Mar 2026

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • 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

AMG 193 Shows Preliminary Clinical Activity in MTAP-Deleted Solid Tumors (OncLive) - P1b/2 | N=649 | NCT05094336 | Sponsor: Amgen | "AMG 193, an MTA-cooperative PRMT5 inhibitor, demonstrated responses across patients with MTAP-deleted solid tumors, as well as an acceptable safety profile, according to first-in-human results of a dose-exploration/dose-expansion phase 1 trial (NCT05094336) that were presented at the 2024 ESMO Congress....Non–small cell lung cancer (NSCLC; n = 17): 2 confirmed partial responses (PRs), 3 unconfirmed PRs, 6 with stable disease (SD), 3 with progressive disease (PD), and 3 who were not evaluable (NE); Pancreatic ductal adenocarcinoma (n = 23): 2 confirmed PRs, 3 unconfirmed PRs, 4 with SD, 8 with PD, and 6 who were NE; Biliary tract cancer (n = 19): 2 confirmed PRs, 8 with SD, 3 with PD, and 6 who were NE; Esophageal/gastric cancer (n = 6): 1 confirmed PR, 1 unconfirmed PR, 2 with SD, and 2 with PD."

P1 data • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor