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Novel RAS Inhibitors for PDAC
An Expert Discussion of Novel Investigational RAS Inhibitors for Pancreatic Cancer

Released: April 14, 2026

Christopher Lieu
Christopher Lieu, MD, FASCO
Wungki Park
Wungki Park, MD, MS
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Key Takeaways
  • RAS-targeted therapies for PDAC include novel approaches such as pan-RAS and allele-specific inhibitors and protein degraders.
  • Pan-RAS inhibitors such as daraxonrasib target multiple KRAS mutations simultaneously and have demonstrated early clinical activity with response rates of approximately 30% to 35% in previously treated metastatic PDAC, albeit with broader toxicity profiles.
  • Allele-specific KRAS G12D inhibitors, including agents such as zoldonrasib and others in development, offer more selective targeting with encouraging response rates and tolerability.

Investigational RAS-Targeted Therapies for PDAC

Christopher Lieu, MD, FASCO:
As we think about investigational RAS-targeted therapies in pancreatic ductal adenocarcinoma (PDAC), it is important to recognize that KRAS remains the dominant oncogenic driver in this disease, present in approximately up to 95% of tumors. Historically, this has been a very challenging therapeutic target, but we are now seeing meaningful progress in the clinical development of RAS inhibitors.

Wungki Park, MD, MS:
A useful way to categorize key emerging therapies is to distinguish between pan-RAS inhibition and allele-specific targeting. Pan-RAS inhibitors are designed to target multiple KRAS variants simultaneously, which is particularly relevant in PDAC given the distribution of mutations; G12D, G12V, and G12R together account for the vast majority of cases. By contrast, allele-specific inhibitors focus on individual mutations, most notably KRAS G12D, which is the most common mutation in this disease.

Christopher Lieu, MD, FASCO:
Another important distinction is whether these agents target the active, GTP-bound “on” state of KRAS or the inactive “off” state, or both. Some novel agents are designed to target the active state, which is particularly important because that is the signaling-competent form that drives tumor growth.

Pan-RAS Inhibitors

Wungki Park, MD, MS:
One of the leading agents in this class is daraxonrasib (RMC-6236). Daraxonrasib is a pan-RAS(ON) tricomplex inhibitor that binds GTP-bound (active) RAS and forms a complex with cyclophilin to lock KRAS in a nonfunctional state, thereby preventing downstream signaling. In early-phase studies in previously treated metastatic PDAC with KRAS G12 mutations, this agent demonstrated an objective response rate of approximately 35% and a disease control rate of 92%, with a median progression-free survival of 8.5 months and median overall survival of 13.1 months.

Christopher Lieu, MD, FASCO:
Those results are quite notable, particularly when we consider that response rates with second-line chemotherapy are typically in the range of 5% to 10%.

Wungki Park, MD, MS:
With daraxonrasib, we see a relatively high incidence of rash, along with gastrointestinal toxicities such as diarrhea, nausea, and vomiting, and occasionally stomatitis or mucositis. These are manageable but will require familiarity as these agents move into broader clinical use.

Christopher Lieu, MD, FASCO:
There are multiple phase III trials ongoing with daraxonrasib, including studies in the previously treated setting, in the first-line setting alone or in combination with gemcitabine and nab-paclitaxel, and in the adjuvant setting after resection.

Allele-Specific RAS Inhibitors

Wungki Park, MD, MS:
In parallel, allele-specific targeting—particularly of KRAS G12D—is an area of interest. Zoldonrasib (RMC-9805) is a G12D-selective RAS(ON) inhibitor that has demonstrated objective response rates of approximately 30% and a disease control rate of approximately 80% in early trials in previously treated PDAC.

Christopher Lieu, MD, FASCO:
One key observation with allele-specific inhibitors is that they potentially could have improved tolerability compared with pan-RAS approaches. With zoldonrasib, for example, the toxicity profile appears to be predominantly low-grade gastrointestinal adverse events with relatively infrequent rash.

Wungki Park, MD, MS:
That highlights an important trade-off in this space. Pan-RAS inhibitors offer broader applicability across multiple KRAS mutations, whereas allele-specific agents may provide more selective targeting and improved tolerability but are limited to a narrower patient population.

Christopher Lieu, MD, FASCO:
Numerous additional KRAS G12D–targeted agents are also in development. Early-phase data with agents such as GFH275, INCB161734, TSN1611, and HRS-4642 suggest favorable activity. Although these data are preliminary and based on small cohorts, they are certainly encouraging in a disease where response rates have historically been quite limited.

Wungki Park, MD, MS:
Another emerging strategy is KRAS protein degradation. Setidegrasib (ASP3082) is a KRAS G12D–targeted degrader that works by labeling the KRAS protein for destruction, thereby reducing oncogenic signaling. In early studies, we have seen single-agent activity with response rates of approximately 24% in heavily pretreated patients (mostly patients receiving third-line therapy), with higher response rates observed in combination with chemotherapy. The safety profile appears manageable, with infusion-related reactions being the most notable adverse event.

In thinking about these therapies as a group, I would emphasize that combination strategies are likely to be critical. We have learned from other diseases, such as colorectal cancer, that moving effective targeted therapies earlier in the disease course and combining them with chemotherapy or other targeted agents can help mitigate resistance and improve outcomes.

Christopher Lieu, MD, FASCO:
There are still many unanswered questions, including the durability of response, mechanisms of resistance, and how best to sequence or combine these therapies. Ongoing phase III trials will be essential to determine whether these promising early signals translate into improvements in progression-free survival and overall survival.

Wungki Park, MD, MS:
Overall, this is a rapidly evolving space. KRAS, which was once considered undruggable, is now a potentially actionable target with multiple therapeutic strategies under active investigation.

Your Thoughts
Do you currently test for RAS mutations for your patients with advanced PDAC? Have you treated a patient with a RAS mutation with a targeted therapy? Join the discussion by adding a comment and answering the polling question.

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