Monte Rosa Therapeutics, Inc. presented preclinical data characterizing MRT-2359, an orally bioavailable GSPT1-directed molecular glue degrader designed for the treatment of MYC-driven solid tumors, including lung cancer. The data were presented at the American Association for Cancer Research (AACR) Annual Meeting in Orlando, FL. A summary of the company's data and findings includes: Anti-tumor activity of MRT-2359 was assessed in >80 lung patient-derived xenografts (PDXs) confirming the preferential anti-tumor activity in PDX models of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) where N- and/or L-MYC expression was high, as well as in PDX models of neuroendocrine (NE) lung cancer.

Numerous instances of tumor regressions were observed in these models with MRT-2359 when dosed orally daily or intermittently A causal link was established in vitro between N- and L-MYC expression and sensitivity to MRT-2359; other agents targeting the protein translation machinery or MYC transcription (e.g., CDK9 inhibitor) failed to show differential activity Treatment with MRT-2359 in the N- or L-MYC high cell lines inhibited protein translation and caused a downmodulation of transcription of MYC target genes MRT-2359 had preferential activity over the growth and survival of MYC-driven tumor cells, compared with cell lines with low N- or L-MYC expression, in which little effect was observed following GSPT1 degradation. Collectively, these data support the ongoing clinical evaluation of MRT-2359. Initiated in October 2022, the Phase 1/2 open-label, multicenter study (Identifier: NCT05546268) is primarily assessing the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and preliminary clinical activity of MRT-2359 in patients with previously treated selected solid tumors, including NSCLC, SCLC, high-grade neuroendocrine cancer of any primary site, diffuse large B-cell lymphoma (DLBCL) and solid tumors with L-MYC or N-MYC amplification.

In the Phase 1 portion of the study, patients are receiving escalating doses of MRT-2359 to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Once the RP2D is determined, the anti-tumor activity of MRT-2359 will be assessed as part of the Phase 2 portion of the study, which includes molecular biomarkers for patient stratification and selection.