Addition of TTFields to Gemcitabine/Nab-Paclitaxel Boosts OS in Locally Advanced PDAC

Locally Advanced PDAC |
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Treatment with tumor-treating fields (TTFields) in combination with gemcitabine and nab-paclitaxel (Abraxane) led to a statistically significant improvement in superior overall survival (OS) compared with gemcitabine plus nab-paclitaxel alone in patients with locally advanced pancreatic ductal adenocarcinoma (PDAC), according to data from the phase 3 PANOVA-3 trial (NCT03377491).1,2

Findings presented at the 2025 ASCO Annual Meeting and published in the Journal of Clinical Oncology showed that patients who received TTFields experienced an 18% reduced risk of death 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. Skin toxicity associated with TTFields was reported, but it was generally low-grade.1 

“PANOVA-3 is the first phase 3 trial in patients with unresectable, locally advanced adenocarcinoma of the pancreas to show an OS benefit over gemcitabine/nab-paclitaxel,” said Vincent J. Picozzi, MD, director of the Pancreaticobiliary Program at Virginia Mason Medical Center in Seattle, Washington, in his presentation.

TTFields use an electrical field delivered by a portable device and arrays placed on the front, back, and sides of the patient in order to disrupt cancer cell division and trigger an enhanced immune response. In the phase 2 PANOVA pilot trial (NCT01971281), TTFields plus gemcitabine and nab-paclitaxel demonstrated favorable progression-free survival (PFS) and OS compared with historical control with no serious adverse events (AEs) related to TTFields, leading to the phase 3 trial.3

The global phase 3 PANOVA-3 trial enrolled 571 patients across 20 countries in North and South America, Europe, and Asia with locally advanced pancreatic adenocarcinoma and randomly assigned them on a 1:1 basis 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, with or without 150 kHz TTFields using the NovoTTF-200T system for 18 hours a day.1 They received follow-up every 4 weeks with CT scans every 8 weeks, and after disease progression had 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. 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. Eighty-seven 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, which Picozzi said could suggest unrecognized occult metastatic disease.

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 them 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).

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).

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 with an HR of 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 it was 51.9% vs 41.8%, respectively (P = .027).

A post-hoc analysis of distant PFS was performed and did show 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; Picozzi said that full quality-of-life data would be presented in the near future.

In terms of 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.

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. The majority 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.

“PANOVA-3 establishes TTFields with gemcitabine/nab-paclitaxel as a potential new standard treatment paradigm for unresectable, locally advanced pancreatic cancer,” Picozzi concluded.

References

1. Picozzi V, Babiker HM, Chandana SR, et al. PANOVA-3: Phase 3 study of tumor treating fields (TTFields) with gemcitabine and nab-paclitaxel for locally advanced pancreatic ductal adenocarcinoma (LA-PAC). J Clin Oncol. 2025;43(suppl 17): LBA4005. doi:10.1200/JCO.2025.43.17_suppl.LBA4005
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. Published online May 31, 2025. 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