2252P - KRAS G12C inhibition using MRTX849: A novel radio-sensitizing partner

Background

KRAS activating mutations are the most common oncogenic drivers and are correlated with radioresistance of multiple cancers including NSCLC and colorectal cancers. Multiple KRAS inhibitors were developed recently such as MRTX849 (Adagrasib,Mirati Therapeutics) showing promising clinical efficacy in early phase trials. However, only scarce data exploring the combination of radiotherapy (RT) and a KRAS inhibitor in KRAS^G12C mutated tumors are available. We explore the efficacy of the association between RT and MRTX1257, a selective and covalent KRAS^G12C inhibitor analogous to MRTX849, in animal models of cancer.

Methods

We assessed in vitro the efficacy of the combination MRTX1257 at various concentrations and different RT doses in CT26 WT and CT26 KRAS^G12C+/+ cell lines using clonogenic survival assays.We then explored the combination in LL2 NRAS^-/- and WT cell lines. Subsequently, we explored the efficacy of combination MRTX1257 and RT in athymic nude mice bearing CT26 KRAS^G12C+/+ tumors and in immunocompetent BALB/c mice bearing subcutaneous CT26 WT or CT26 KRAS^G12C+/+ tumors.On day of randomization (D-1 before RT), D+1 and D+3 after RT, mice received oral MRTX1257 at 50 mg/kg dose. At D0, mice randomized into RT only and combination groups received 1x 6 Gy to the tumor. On D4 post RT, tumours were collected for IHC and flow cytometry analysis of the tumour microenvironment.

Results

MRTX1257 increased the cytotoxic effect of RT in different KRAS ^G12C mutated cell lines and murine tumors, but not in their KRAS ^G12C wild type counterparts. In vitro and in vivo radio-sensitizing effects were observed in a time and dose dependent manner. The use of RT and MRTX1257 in BALB/c mice bearing CT26 KRAS^G12C+/+ tumors resulted in a 20% cure rate. Tumor microenvironment analysis of murine CT26 KRAS^G12C+/+ tumors following RT and MRTX1257 showed an increase in conventional CD4⁺ T cells, DCs type 2 and inflammatory monocytes. Expression of PD-L1 was reduced within tumor and myeloid cells, illustrating TME polarization towards a pro-inflammatory phenotype following the combination.

Conclusions

This work constitutes a first step towards new combinatorial approaches involving RT and MRTX1257 in KRAS G12C mutated cancers, with the aim of providing new therapeutic strategies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Mirati Therapeutics.

Disclosure

All authors have declared no conflicts of interest.