Zoldonrasib combinations show encouraging response rates in KRAS G12D-mutant pancreatic cancer

In the dismal landscape of metastatic pancreatic cancer, where there are no approved targeted therapies and the 5-year survival rate is approximately 3% (Eur J Cancer. 2024;198:113471), targeting KRAS mutations – which account for around 90% of all cases, with G12D being the most common variant present in almost 40% of these patients (Cancer Discov. 2022;12:924–937) – has emerged as a promising research area that may eventually lead to a paradigm change in treatment.

Despite being reported in small patient populations, novel data presented at the ESMO Gastrointestinal Cancers Congress 2026 (Munich, 1–4 July) provide further support for this approach with two targeted therapy combinations.

In a first phase I/II study, 81 patients with metastatic pancreatic ductal adenocarcinoma (PDAC) who had not received prior treatment for metastatic disease received the oral RAS(ON) G12D-selective inhibitor, zoldonrasib, plus modified (m) FOLFIRINOX or gemcitabine with nab-paclitaxel (GnP) (Abstract 340O). Objective response rates (ORRs) were 82% and 61%, respectively, and corresponding disease control rates (DCRs) were 96% and 90%. There was a ≥50% reduction in G12D variant allele frequency in circulating tumour DNA (ctDNA) in patients in both groups, with complete ctDNA clearance in 47% in the zoldonrasib plus mFOLFIRINOX arm and in 71% in the zoldonrasib plus GnP arm.

“These findings are very positive since the ORR with the combination treatment (82%) is more than double the rates reported with FOLFIRINOX alone and GnP alone (32% and 23% respectively) (BMC Cancer. 2021;21:853),” highlights Dr Teresa Macarulla Mercade from Hospital Clínic Barcelona, Spain. “This ORR comes with safety data that were consistent with known chemotherapy-associated adverse events, with no additional toxicities reported.”

The most common treatment-related adverse events (TRAEs) for zoldonrasib plus mFOLFIRINOX were diarrhoea (78%), nausea (61%) and fatigue (51%), and for zoldonrasib plus GnP were fatigue (80%), nausea (70%) and decreased neutrophil count (55%). There was a lower incidence of grade ≥3 TRAEs with zoldonrasib plus mFOLFIRINOX (61%) than for zoldonrasib plus GnP (80%), and no grade 5 TRAEs were reported.

In a second presentation at the Congress, a different strategy of combining two targeted therapies – zoldonrasib alongside the oral RAS(ON) multiselective, tri-complex inhibitor, daraxonrasib – was evaluated in a phase I study of 60 patients with KRAS G12D-mutated metastatic PDAC who had received ≥1 line of therapy for metastatic disease (Abstract 341O).

In previous research, daraxonrasib led to significantly longer overall survival (OS) and progression-free survival (PFS) than chemotherapy in 500 patients with metastatic PDAC who had received prior treatment for metastatic disease – 92% of whom had RAS G12D-mutated disease – enrolled in the phase III RASolute 302 trial (N Engl J Med. 2026 May 31).

The zoldonrasib plus daraxonrasib combination was associated with an ORR of 50% in 30 patients who had received 2 lines of prior therapy, and 47% in 30 patients after ≥3 lines of prior therapy, with a respective DCR of 97% and 90%. The respective 6-month PFS and OS rates were 71% and 89% in patients who had received 2 lines of prior therapy, and 59% and 82% in those who had received ≥3 lines of prior therapy. The most common TRAEs were rash (90%), diarrhoea (63%), nausea (57%) and stomatitis/mucositis (53%). Grade ≥3 TRAEs were reported in 35% of patients, with rash (12%) and anaemia (10%) being most common. There was one grade 5 TRAE of intestinal perforation. Commenting on the results, Macarulla Mercade notes, “The idea with this combination is to reduce the emergence of resistance that can be problematic in heavily pre-treated patients. Considering the number of previous lines of therapy, the response rates reflect a very active combination, even in this refractory situation.”

Macarulla Mercade is cautiously optimistic about the development of zoldonrasib, remarking that the results need to be verified in larger groups of patients in a randomised setting, like the ongoing RASolute 305, a phase III study in previously untreated metastatic RAS G12D-mutated PDAC (NCT07621718). “From a biological perspective, it makes sense to move the G12D allele-specific inhibitors to the first-line setting and use a pan-RAS inhibitor in second line to ‘shut down’ secondary mutations,” she concludes “However, it will be interesting to see whether combining both in first-line therapy improves efficacy.”