Dr Vonderheide on Responses With RAS(ON) Inhibition in Preclinical Pancreatic Cancer Models

"In our model of pancreatic cancer, the KRAS(ON) multiselective inhibitor shrank the tumors in an unprecedented way. [Additionally], in animals where we have eliminated the key elements of the immune system—the T cells—the effect [of this approach] is lessened. Finally, we found that by adding immune therapies…to KRAS inhibition, the tumor regressions were deeper."

Robert Herman Vonderheide, MD, DPhil, director of the Abramson Cancer Center and the John H. Glick Abramson Cancer Center Professor at Penn Medicine, discussed preclinical data supporting the role of the adaptive immune system in enhancing the antitumor efficacy of RAS(ON) multi-selective inhibitors in pancreatic ductal adenocarcinoma (PDAC).

RAS(ON) multi-selective inhibitors, including agents such as RMC-6236 and RMC-7977, target the active, GTP-bound state of both mutant and wild-type RAS isoforms and have demonstrated potent antitumor activity in PDAC murine models. In a series of studies using immunocompetent mouse models of PDAC, Vonderheide and colleagues investigated whether the adaptive immune system is required for the full therapeutic effect of these inhibitors.

The findings revealed 3 primary observations, according to Vonderheide. First, treatment with KRAS(ON) multi-selective inhibitors resulted in marked tumor regression, with effects more profound than previously observed in laboratory models. Second, in mice lacking T cells, the antitumor efficacy of KRAS inhibition was significantly diminished, indicating that T cells contribute meaningfully to therapeutic response. Third, the addition of immune-based therapies, including checkpoint blockade, enhanced the depth and durability of tumor regressions. In some cases, mice achieved complete and sustained remissions even after discontinuation of the KRAS inhibitor, suggesting an immunologic memory response.

These preclinical findings suggest that the antitumor activity of RAS(ON) multi-selective inhibitors is, at least in part, immune mediated. Vonderheide noted that these results support the clinical evaluation of RAS(ON) inhibitors in combination with immunotherapy for patients with PDAC. Clinical trials evaluating agents like RMC-6236 are currently underway, including a phase 1/1b study (NCT05379985) of RMC-6236 in patients with KRAS G12-mutant solid tumors.