A groundbreaking phase I trial has assessed the efficacy and safety of AG-270/S095033, a first-in-class inhibitor targeting methionine adenosyltransferase 2 A (MAT2A), particularly for patients with advanced malignancies characterized by homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene. This trial, conducted by researchers from various institutions and sponsored by Agios Pharmaceuticals and the Institut de Recherches Internationales Servier, marks significant progress in cancer treatment options.
Homozygous MTAP deletion occurs in approximately 15% of various cancers, creating vulnerabilities due to the increased reliance on S-adenosylmethionine (SAM). AG-270/S095033 exploits this vulnerability by inhibiting MAT2A, which is primarily responsible for SAM synthesis. The recent study, registered under ClinicalTrials.gov Identifier NCT03435250, enrolled 40 patients whose tumors showed this genetic alteration.
Patients were administered AG-270/S095033 either once daily or twice daily over 28-day cycles. The primary goal was to determine the maximum tolerated dose (MTD), with secondary objectives including assessments of safety and preliminary efficacy. Throughout the treatment, participants provided valuable data concerning the drug's performance and its effect on tumor growth.
Results revealed promising findings. The patients experienced manageable side effects, with common adverse effects including fatigue, nausea, and anemia. Notably, plasma concentrations of AG-270/S095033 increased proportionally with dosage, consistently leading to reduced levels of SAM by 54% to 70% across treatments. Overall, the trial witnessed two partial responses and several cases of stable disease lasting more than 16 weeks, indicating clinical activity, especially among patients with significant prior treatment history.
While the challenge of treatment-resistance was noted, as indicated by the authors of the article: "While MAT2A inhibition appears to be promising, our study indicates a high rate of resistance in unselected patient populations." This emphasizes the need for targeted application and continued investigation. The study authors assert, "AG-270/S095033 has a manageable safety profile. Our data provide preliminary evidence of clinical activity and proof-of-mechanism for MAT2A inhibition."
Although the initial trial results offer hope, they also pinpoint the necessity for advancing our understandings of MTAP-deleted tumors and developing strategic combinations of MAT2A inhibitors with other treatment modalities. Attention is being directed toward combining AG-270/S095033 with conventional chemotherapeutics like taxanes, as preclinical results suggest enhanced antitumor activity through synergistic effects. There is also interest in future studies evaluating the effectiveness of MAT2A inhibitors when paired with PRMT5 inhibitors.
The research team acknowledges the importance of additional clinical investigations, which will refine our approach to targeting MAT2A and possibly offering breakthrough treatments for patients suffering from advanced malignancies linked to MTAP genomic loss. This developing area holds potential not only for individual patients but suggests broader avenues for future cancer therapeutic strategies.