Exploring Zoldonrasib, Pan-RAS Inhibitors, and Future KRAS Therapies

Alexander I. Spira, MD, PhD, FACP, co-director of Virginia Cancer Specialists Research Institute, director of the Thoracic and Phase I Program, and clinical assistant professor at Johns Hopkins School of Medicine, discusses the next steps in the clinical development of zoldonrasib (RMC-9805) for patients with KRAS G12D pancreatic ductal adenocarcinoma based on preliminary findings presented at the 2025 Gastrointestinal Cancers Symposium.

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0:10 | This is where it gets complicated. RMC-9805 clearly has single-agent activity. There is a pan RAS inhibitor called RMC-6236, which is already in development and already [has begun] in a randomized, phase 3 study in the second-line setting. The questions are: is an allele-specific inhibitor with fewer adverse events going to be better in terms of both efficacy and tolerability? And how do you study those differences? These are some of the questions being addressed in the second-line setting. We all believe that, because this drug is so well tolerated, it could also be combined with chemotherapy in the frontline setting.

0:43 | And of course, while this is ASCO GI, there is also data in other tumor types. KRAS G12D makes up about 4% of lung cancer cases. We are seeing activity there, and there are patients enrolled in this study with other tumor types as well. So, there are a lot of different pathways to consider for drug development, including pan-RAS inhibitors.

1:02 | Can you combine a pan-RAS inhibitor with an allele-specific inhibitor? We also know that many resistance mutations that develop after KRAS G12D therapy, based on the KRAS G12C data published several years ago, are other KRAS mutations. So, can combination therapies prevent or delay that resistance? There are lots of good questions and many exciting [possibilities for future research].