AMG 193, a first-in-class MTA-cooperative PRMT5 inhibitor, has shown early signs of clinical activity in patients with MTAP-deleted solid tumors, according to results from a phase 1 trial presented at the 2024 ESMO Congress. The study (NCT05094336) evaluated the safety, tolerability, and anti-tumor activity of AMG 193 in a heavily pre-treated patient population with advanced solid tumors harboring MTAP deletions.
Targeting MTAP-Deleted Tumors
MTAP deletions are present in approximately 10% to 15% of cancers, including glioblastoma, mesothelioma, bladder cancer, pancreatic cancer, esophageal cancer, squamous NSCLC, and melanoma. AMG 193 exploits this vulnerability by selectively targeting MTAP-deleted tumors while sparing normal cells. The drug works by binding to the MTA-bound state of PRMT5, leading to complete inhibition of its activity, which affects RNA splicing, gene expression, and DNA repair, ultimately causing cell cycle arrest, senescence, and cell death.
Phase 1 Trial Results
The phase 1 trial included a dose-exploration phase (n = 80) and an ongoing dose-expansion phase (n = 87). In the dose-exploration phase, patients received daily doses of AMG 193 ranging from 40 mg to 1600 mg. The 1600-mg dose was not tolerated, and the 1200-mg dose was also explored as a twice-daily 600-mg dose. The dose-expansion phase is evaluating the 1200-mg daily dose in patients with pancreatic ductal adenocarcinoma, NSCLC, biliary tract cancer, esophageal/gastric cancer, glioma, and tumor-agnostic disease.
At a median follow-up of 4.5 months in patients who received AMG 193 at active doses (800 mg daily, 1200 mg daily, and 600-mg twice daily; n = 76), the best overall responses were reported as follows:
- Non-small cell lung cancer (NSCLC; n = 17): 2 confirmed partial responses (PRs), 3 unconfirmed PRs, 6 with stable disease (SD).
- Pancreatic ductal adenocarcinoma (n = 23): 2 confirmed PRs, 3 unconfirmed PRs, 4 with SD.
- Biliary tract cancer (n = 19): 2 confirmed PRs, 8 with SD.
- Esophageal/gastric cancer (n = 6): 1 confirmed PR, 1 unconfirmed PR, 2 with SD.
"There are 6 patients with PRs that are ongoing treatment beyond 6 months, despite the short duration of follow-up, a further 13 patients with PRs continue on treatment at the time of data cut, and there are 6 patients with SD that have been treated for 6 months or longer, implying that there may be clinical benefit even amongst those who do not achieve a partial response," said lead study author Adrian Sacher, MD, a thoracic oncologist and affiliate scientist of Princess Margaret Cancer Centre of the University of Toronto.
Safety and Tolerability
AMG 193 demonstrated an acceptable safety profile. In the dose-expansion phase, any-grade and grade 3 treatment-related adverse events (AEs) occurred in 83.9% and 18.4% of patients, respectively. The most common AEs were nausea (57.5%; 4.6%), vomiting (34.5%; 3.4%), and fatigue (25.3%; 1.1%). Notably, there was no clinically significant myelosuppression observed.
Further Insights
Pharmacokinetics data showed dose-proportional exposure up to 1200 mg, with a 13-hour half-life amenable to once-daily dosing. Exposure-response modeling linked higher exposure with greater tumor size reduction and a higher likelihood of achieving PR. Target engagement was confirmed via symmetric dimethylarginine (SDMA) reduction, indicating PRMT5 inhibition. Antitumor activity was also associated with reductions in circulating tumor DNA.
Ongoing and Future Studies
AMG 193 is currently being explored in combination with chemoimmunotherapy regimens in NSCLC (NCT06333951), with chemotherapy in pancreatic cancer (NCT06360354), and with the MAT2A inhibitor IDE397 in patients with MTAP-null solid tumors (NCT05975073). These studies aim to further evaluate the potential of AMG 193 in treating MTAP-deleted solid tumors.
