Clinical Summary: 

• Design/Population: This phase 1 study evaluated the combination of the KRAS G12D-selective RAS(ON) inhibitor zoldonrasib and the multi-selective RAS(ON) inhibitor daraxonrasib in patients with previously treated KRAS G12D-mutated metastatic pancreatic ductal adenocarcinoma. Following dose escalation, patients received the recommended phase 2 doses in second- and third-line expansion cohorts.
• Key Outcomes: The combination demonstrated a manageable safety profile and encouraging preliminary efficacy, with objective response rates of 50% in the second-line setting and 47% in the third-line setting. Disease control rates exceeded 90% in both cohorts, with limited treatment discontinuations due to adverse events.
• Clinical Relevance: These findings support dual RAS inhibition as a promising therapeutic strategy and provide the rationale for the ongoing phase 3 RASolute 309 trial.

Nilofer Azad, MD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, discusses results from a phase 1 study evaluating zoldonrasib plus daraxonrasib in patients with previously treated KRAS G12D-mutated metastatic pancreatic ductal adenocarcinoma. 

The combination demonstrated a manageable safety profile and encouraging preliminary antitumor activity, with objective response rates approaching 50% in both second- and third-line settings. Dr Azad also discusses how these findings support advancing dual RAS inhibition into the global phase 3 RASolute 309 trial comparing zoldonrasib plus daraxonrasib with gemcitabine plus nab-paclitaxel in the first-line setting.

Transcript: 

Hi, my name is Nilofer Azad, and I am a medical oncologist and a clinical researcher from Johns Hopkins. Today, I'm going to talk about the data that has just been presented looking at the safety and efficacy of zoldonrasib and daraxonrasib in patients with second-line-plus pancreatic cancer with a KRAS G12D mutation.

Pancreatic cancer is the most commonly mutated cancer when it comes to KRAS. KRAS G12D, that particular mutant allele, is present in about 40% of patients that have pancreatic cancer. Patients with KRAS G12D overall have a poorer prognosis than patients with other RAS mutations or with RAS wild-type disease. In the second-line setting, in the advanced cancer setting, the response rate with chemotherapy, which is the standard of care, is about 3% to 7%, and the median progression-free survival is about 2 to 3 months, with a median overall survival in the 6-month range. In the third line, there are pretty similar response rates, but a PFS that's really around 2 months and a median overall survival that's 5 months. Now, that's with standard chemotherapy.

Just recently, daraxonrasib, which is a multi-RAS inhibitor, was presented at ASCO in the RASolute 302 trial. In that study, daraxonrasib, which is an oral agent, was given to patients in the second line. The overall response rate was 33%, with a median progression-free survival of 7.3 months and an overall survival of 13 months. That same drug has been looked at in the third line in a smaller group of patients, but the overall response rate was about 20%, with a median overall survival of 8.6 months. That likely is going to be the new benchmark for second-line therapy.

Now, these 2 drugs we're going to talk about today—daraxonrasib is the same drug I just mentioned, so it's a multiselective inhibitor of RAS in the RAS(ON) conformation, and zoldonrasib is a similar agent that also forms an inhibitory tri-complex to inhibit RAS, but it is an allele-specific G12D inhibitor. The preclinical data really suggested that when we give these 2 drugs together, we might have more pathway suppression of the RAS pathway and we might have higher response rates and delayed resistance. That was seen in animal models as well as in in vitro models with the combination.

Today, what we are talking about is the clinical trial of that hypothesis. Both zoldonrasib and daraxonrasib were given to patients with mutant KRAS G12D. Initially, the 2 drugs were escalated in part 1 of the study in advanced solid tumors that had previously been treated. Then, the second part of the study was a dose expansion in patients with pancreatic cancer in either the second or the third line.

Both zoldonrasib and daraxonrasib were able to be escalated to their single-agent phase 2 doses, so zoldonrasib at 1,200 milligrams and daraxonrasib at 300 milligrams, and that was the dose that was selected for the expansion because there were no dose-limiting toxicities that were seen in the part 1 portion. The patients who were enrolled in this trial really were a very standard advanced pancreatic cancer group when you look at the demographic features. This study predominantly had an end point of safety. 

When we look at the treatment-related adverse events, zoldonrasib really did not seem to add much toxicity to daraxonrasib. The data that were reported in terms of toxicity really showed daraxonrasib toxicities, which are most commonly rash and GI side effects like diarrhea and nausea, also some stomatitis. This is a well-tolerated regimen, and how we know that is that very few patients had to discontinue the drug. Only 1 patient had to discontinue zoldonrasib out of the 60 patients treated, and 3 patients discontinued daraxonrasib. In fact, the median dose intensity for zoldonrasib was 96%. It was 82% for daraxonrasib.

But the really exciting data were the response rates and the other clinical efficacy end points. The response rate in both the second and third lines was close to 50%. It was 50% in the second line and 47% in the third line. The median progression-free survival was 9.6 months in the second line, and it was 7.6 months in the third line. The median overall survival hadn't been reached yet in the second line, and it was 10.5 months in the third line. So, really exciting data, basically showing that the combination of an allele-specific inhibitor with zoldonrasib and daraxonrasib in G12D-mutated pancreatic cancer was safe, was tolerable, and really had very compelling efficacy.

This has formed the basis of moving this regimen forward in the first line in pancreatic cancer in RASolute 309. This is a trial that will open later this year, and it is a 1:1 randomization to the doublet of zoldonrasib and daraxonrasib versus gemcitabine plus nab-paclitaxel. We're very excited to see the results of these data as they emerge in the next couple of years.

Source: 

Azad N, Kim D, Oberstein P, et al. Safety and efficacy of zoldonrasib (RMC-9805) plus daraxonrasib (RMC-6236) in patients with 2L+ KRAS G12D metastatic pancreatic adenocarcinoma (mPDAC). Presented at ESMO Gastrointestinal Cancers Congress. July 1-4, 2026. Munich, Germany. Abstract 341O.