Targeting KRAS in Pancreatic Cancer With Biomarkers, Device Therapy

Advancements in precision oncology are rapidly transforming the management of metastatic pancreatic cancer (mPC), introducing novel biomarkers, device-based therapies, and targeted agents that oncologists must integrate into their multifaceted treatment planning. Recent key developments highlight the growing utility of circulating tumor DNA (ctDNA) for monitoring in mPC and the demonstrated overall survival (OS) benefit of tumor-treating fields (TTFields) in locally advanced disease, in addition to encouraging initial data from next-generation RAS inhibitors.

“The era of precision oncology has reached pancreatic cancer, and an important early step is to obtain ctDNA and tissue molecular testing to determine driver mutations from both blood and tissue samples,” Hani M. Babiker, MD, told Targeted Therapies in Oncology during an interview. Babiker explained that future documentation and consideration will consider not only the patient’s age, sex, and stage of disease but also their molecular makeup. A common obstacle in using next-generation sequencing (NGS) to find driver mutations is not having enough tissue, so he recommends doing blood NGS testing in addition to obtaining tissue.

ctDNA and Survival

ctDNA shows promise as a valuable treatment monitoring approach in mPC. For example, findings from the observational ARTEMIS-PC trial (NCT06043921) demonstrated that ctDNA could be a useful predictor of improved objective response, disease control, and progression-free survival (PFS). Taro Shibuki et al showed that variant allele frequency (VAF) was an accurate biomarker for disease control, underscoring its potential utility in treatment monitoring in patients with unresectable pancreatic cancer.¹

Investigators evaluated 99 untreated patients with histopathologically confirmed unresectable pancreatic cancer and determined that 92 were eligible for enrollment.¹ Minimal residual disease (MRD) positivity at enrollment was 88.0%, comprising 73.3% of those with stage III disease and 95.2% with stage IV (P = .007). During follow-up, ctDNA clearance was achieved in 33 patients (40.7%) and was associated with a significantly higher objective response rate (ORR; 61.5% vs 17.6%, P = .001) and disease control rate (100% vs 64.7%, P = .002) compared with those who did not achieve clearance.¹

Patients who achieved ctDNA clearance had significantly longer PFS than those who did not (9.0 vs 3.5 months, respectively; HR, 0.2; P < .001). The predictive performance of select biomarkers (VAF, CEA, CA19-9) was evaluated using area under the curve (AUC) for treatment response and disease control. For disease control, VAF showed superior predictive performance, with AUCs of 0.84 at enrollment and 0.97 at both week 4 and week 8, compared with CEA (AUCs: 0.65, 0.73, 0.60, respectively) and CA19-9 (AUCs: 0.51, 0.57, 0.56).¹

“ARTEMIS-PC looked at the use of ctDNA prospectively in patients with stage III and IV disease, and the investigators noted a correlation for MRD status and ctDNA to PFS, and this was significant,” Babiker said. “It’s exciting to see these results now in pancreatic cancer, as there are some data showing the role of ctDNA in colorectal cancer to aid in clinical decisions.”

PANOVA-3

Also significant, according to Babiker, were results from the global phase 3 PANOVA-3 trial (NCT03377491), which evaluated the addition of tumor-treating fields (TTFields) to gemcitabine plus nab-paclitaxel (Abraxane).²

Patients who received TTFields had an improvement in overall survival (OS) vs chemotherapy alone (HR, 0.82; 95% CI, 0.68-0.99; P = .039), as well as benefits to quality of life and pain-free survival.² Skin toxicity associated with TTFields was reported, but it was generally low grade.

TTFields use an electrical field delivered by a portable device and arrays placed on the patient’s front, back, and sides to disrupt cancer cell division and trigger an enhanced immune response. The phase 2 PANOVA pilot trial (NCT01971281) previously demonstrated favorable PFS and OS compared with historical control, with no serious adverse events (AEs) related to TTFields, which supported the phase 3 study.³

PANOVA-3 enrolled 571 patients across 20 countries in North and South America, Europe, and Asia with locally advanced pancreatic adenocarcinoma. Patients were randomly assigned 1:1 to receive gemcitabine at 1000 mg/m² and nab-paclitaxel at 125 mg/m² on days 1, 8, and 15 of each 28-day cycle, either with or without 150 kHz TTFields using the NovoTTF-200T system for 18 hours a day.² They received follow-up every 4 weeks and CT scans every 8 weeks; after disease progression, they received monthly survival follow-up.

Patients were stratified by ECOG performance status and region. “The primary end point was OS, with secondary end points including PFS, pain-free survival, and safety,” Babiker said. “The end points were reported both in the full intent-to-treat [ITT] population and in the modified ITT [mITT] population, which included all patients who received at least 1 full cycle of chemotherapy and/or at least 28 days with TTFields.”²

The investigators reported that 87 patients in the TTFields arm and 79 in the comparator arm were excluded from the mITT analysis but were included in the safety population.

Patient characteristics were generally well balanced between the arms, although there were more women than men in the comparator arm (56.3%) and fewer in the TTFields arm (48.4%). The investigators reported that 29.2% of patients across both arms had CA 19-9 values greater than 1000 U/mL.²

In the TTFields arm, patients received a median of 6 cycles of nab-paclitaxel and 6 cycles of gemcitabine. In the comparator arm, patients received a median of 5 cycles of nab-paclitaxel and 6 cycles of gemcitabine. Patients on the TTFields arm used TTFields for a median of 62.1% of the day (range, 0%-99.0%), with a median duration of exposure of 27.6 weeks (range, 0.1-234.4).²

In the ITT population, the median OS was 16.2 months with TTFields vs 14.2 months in the comparator arm. The 1-year OS rate was 68.1% vs 60.2%, respectively (P = .029). In the mITT population, the median OS was 18.3 months vs 15.1 months, respectively, with an HR favoring TTFields of 0.77 (95% CI, 0.62-0.97; P = .023). The 1-year OS rate in the mITT population was 75.1% with TTFields vs 65.9% without TTFields (P = .022).²

There was a median PFS of 10.6 months in the TTFields arm vs 9.3 months in the comparator arm for the ITT population. However, this failed to reach statistical significance (HR, 0.85; 95% CI, 0.68-1.05; P = .137). Similarly, in the mITT population, median PFS was 12.5 months vs 10.4 months, respectively, but with no statistically significant difference (HR, 0.84; 95% CI, 0.67-1.06; P = .151). The 1-year PFS rate was statistically significant in both groups: In the ITT population, it was 43.9% vs 34.1% (P = .026) for TTFields vs chemotherapy alone, and in the mITT population, it was 51.9% vs 41.8%, respectively (P = .027).²

A post hoc analysis of distant PFS was performed. It showed a significant benefit with TTFields, with an HR of 0.74 (95% CI, 0.57-0.96; P = .022). The 1-year distant PFS rate was 58.5% with TTFields vs 47.6% without (P = .024).

Pain-free survival also appeared to show benefit with TTFields (HR, 0.74; 95% CI, 0.56-0.97). This was defined as the time to a 20-point or greater increase in patient-reported visual analogue scale from baseline for pain or death. The median time to deterioration of global health status, pain, and digestive problems were extended significantly in patients who received TTFields.²

Regarding safety, rates of AEs were similar in both arms, with AEs such as neutropenia, fatigue, thrombocytopenia, and diarrhea being most common, as expected with nab-paclitaxel plus gemcitabine. Serious AEs of any grade were reported in 53.6% in the TTFields arm and 48.0% in the chemotherapy arm. In the TTFields arm, there were 23 AEs (8.4%) that led to discontinuation of the TTFields device, 2.6% of which were grade 3 or higher.²

Higher rates of skin toxicities were reported in the TTFields arm than with chemotherapy alone, including dermatitis (29.9% vs 2.9%), rash (25.9% vs 8.4%), and pruritus (22.3% vs 8.4%). Other device-related AEs included erythema, skin irritation or reaction, skin ulcer, or blister. Most of these events were grade 1 or 2 and were manageable with skin care, but 7.7% of patients reported a grade 3 skin AE.²

“What was interesting with this trial was that the population were patients who had locally advanced disease who often have unmet needs therapeutically and who might benefit from this noninvasive approach,” Babiker emphasized.

KRAS and the Pipeline

“Perhaps the Holy Grail in pancreatic cancer is the protein KRAS, which drives a lot of the aggressiveness of this and other cancers,” Babiker said. “It forms a wall around the tumor through stroma deposition, making it difficult to deliver drug to the cancer, and changes the tumor microenvironment, thus making the tumor microenvironment immunosuppressive,” Babiker explained.

Promising updated results from a phase 1 study (NCT05379985) of daraxonrasib (RMC-6236), an oral direct RAS(ON) multiselective inhibitor, demonstrated encouraging efficacy among patients with KRAS G12X–mutant pancreatic ductal adenocarcinoma (PDAC).⁴ Based on these results, the FDA granted breakthrough therapy designation to the agent for previously treated metastatic PDAC with KRAS G12 mutations.⁵

Among 22 patients with second-line metastatic PDAC and KRAS G12X mutations who received daraxonrasib at 300 mg daily, the median PFS was 8.8 months (95% CI, 8.5 to not evaluable).⁴ For this cohort, ORRs were 36% compared with 27% in the broader RAS-mutant population, and the respective disease control rates were 91% and 95%.⁴

Daraxonrasib is being investigated in the global phase 3 RASolute-302 study (NCT06625320), comparing it with standard-of-care chemotherapy in patients with previously treated metastatic PDAC.⁶ The study’s primary end points are PFS and OS in the KRAS G12X–mutant population.

“These are encouraging results, and we’re excited to see how these trials read out,” Babiker said. “It also demonstrates the importance of ordering molecular testing earlier in patients with pancreatic cancer.”

PAC-MANN-1

Looking ahead, Babiker noted a study by Montoya Mira et al⁷ that evaluated a rapid, noninvasive assay based on a fluorescently labeled protease-sensitive peptide coupled to a magnetic nanosensor to detect protease activity from a small sample of blood.

The assay, termed “PAC-MANN-1,” was optimized to detect all stages of PDAC with better performance than the clinical biomarker CA 19-9. Furthermore, PAC-MANN-1 distinguished PDAC samples not only from healthy controls but also from those with other pancreatic disease states.⁷

The investigators identified a single matrix metalloproteinase–sensitive probe, which could distinguish PDAC from controls with 79% (±6%) accuracy.⁷

In a longitudinal cohort of patients undergoing surgical removal of the primary tumor, the probe cleavage signal was reduced by 16% (±24%) after surgery. In a separate blind retrospective study, the PAC-MANN assay identified PDAC samples with 98% specificity and 73% sensitivity across all stages; it also distinguished 100% of patients with noncancer pancreatic disease relative to patients with PDAC.⁷

Babiker is looking forward to seeing the results from a number of trials, particularly GI-102 (NCT05824975) and RASolute-302. He is also excited about the PRISM-1 trial (NCT06608927), a phase 3 study evaluating the efficacy and safety of quemliclustat in treatment-naive patients with metastatic PDAC.⁸ Quemliclustat is a potent and selective small-molecule CD73 inhibitor that blocks the conversion of AMP to adenosine, restoring immune cell function and possibly reversing the immunosuppressive microenvironment found in PDAC. The phase 1b ARC-8 study (NCT04104672) of quemliclustat-based regimens showed promise in OS for treatment-naive patients with metastatic pancreatic cancer.⁹

“I’m also hopeful of an mRNA neo-antigen vaccine, autogene cevumeran,¹⁰ which continues to show potential to stimulate an immune response,” Babiker said.The therapeutic mRNA cancer vaccine was personalized for each of the 16 participants in the trial based on the mutational profile of each patient’s tumor. Investigators reported that the vaccine was safe, with no serious adverse events reported, and an immune response in half of the patients.

“I’m very enthusiastic about what the future holds,” Babiker said. “It’s very important to refer patients to trials so we can hopefully mitigate this disease.”

REFERENCES

1. Shibuki T, Bando H, Ueno M, et al. Utility of circulating tumor DNA in patients with unresectable pancreatic cancer using a patient-specific panel: ARTEMIS-PC study. J Clin Oncol. 2025;43(suppl 4):684. doi:10.1200/JCO.2025.43.4_suppl.684

2. Babiker HM, Picozzi V, Chandana SR, et al; PANOVA-3 Study Investigators. Tumor treating fields with gemcitabine and nab-paclitaxel for locally advanced pancreatic adenocarcinoma: randomized, open-label, pivotal phase III PANOVA-3 study. J Clin Oncol. 2025;43(21):2350-2360. doi:10.1200/JCO-25-00746

3. Rivera F, Benavides M, Gallego J, Guillen-Ponce C, Lopez-Martin J, Küng M. Tumor treating fields in combination with gemcitabine or gemcitabine plus nab-paclitaxel in pancreatic cancer: results of the PANOVA phase 2 study. Pancreatology. 2019;19(1):64-72. doi:10.1016/j.pan.2018.10.004

4. Garrido-Laguna I, Wolpin BM, Park W, et al. Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol. 2025;43(suppl 4):722. doi:10.1200/JCO.2025.43.4_suppl.722

5. Revolution Medicines announces FDA breakthrough therapy designation for daraxonrasib in previously treated metastatic pancreatic cancer with KRAS G12 mutations. News release. Revolution Medicines, Inc. June 23, 2025. Accessed October 13, 2025. https://tinyurl.com/2s3esvrm

6. Phase 3 study of daraxonrasib (RMC-6236) in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) (RASolute 302). ClinicalTrials.gov. Updated September 16, 2025. Accessed October 13, 2025. https://www.clinicaltrials.gov/study/NCT06625320

7. Montoya Mira JL, Quentel A, Patel RK, et al. Early detection of pancreatic cancer by a high-throughput protease-activated nanosensor assay. Sci Transl Med. 2025;17(785):eadq3110. doi:10.1126/scitranslmed.adq3110

8. Mercade TM, Bekaii-Saab T, Feeney K, et al. Quemliclustat and chemotherapy in previously untreated patients with metastatic pancreatic ductal adenocarcinoma: PRISM-1, a randomized, placebo-controlled, phase III trial. Ann Oncol. 2025;36(suppl 1):S147-S148. doi:10.1016/j.annonc.2025.05.399

9. Data from a phase 1b study of quemliclustat-based regimens showed promising overall survival in treatment-naïve metastatic pancreatic cancer. News release. Arcus Biosciences. January 16, 2024. Accessed October 13, 2025. https://tinyurl.com/88mwck98

10. Rojas LA, Sethna Z, Soares KC, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature. 2023;618(7963):144-150. doi:10.1038/s41586-023-06063-y