Pancreatic cancer a new Tx target for TTFields?

Pain and quality of life (QoL) outcomes from the phase III PANOVA-3 trial reinforce the role of tumour treating fields (TTFields) therapy when added to a chemotherapeutic regimen consisting of gemcitabine/nab-paclitaxel (GnP) for the treatment of individuals with locally advanced pancreatic adenocarcinoma.

TTFields therapy utilizes physical means to treat cancer, offering unique advantages that have led to its FDA approvals for the treatment of glioblastoma multiforme and malignant pleural mesothelioma. [Radiol Oncol 2023;57:279-291]

“[In this analysis,] TTFields with GnP improved global health status and many subgroups on the digestive problems scale compared with GnP alone in patients with locally advanced pancreatic cancer,” said presenting author Dr Teresa Macarulla from the Vall d’Hebron Institute of Oncology at Vall d’Hebron University Hospital, Barcelona, Spain, at ESMO GI 2025.

Time to deterioration in global health status was significantly prolonged when TTFields was added to GnP as opposed to the latter alone (median 7.1 vs 5.7 months; hazard ratio [HR], 0.77, 95 percent confidence interval [CI], 0.61–0.97; p=0.023).

This treatment effect was driven by most of the global health status components except for role functioning. [ESMO GI 2025, abstract LBA3]

When looking at the gastrointestinal symptom scales and items in the EORTC QLQ-C30* and QLQ-PAN26**, time to deterioration for most of the symptoms was longer in the TTFields plus GnP vs GnP alone arm. The symptoms were nausea and vomiting (p=0.021), loss of appetite (p=0.017), constipation (p=0.004), diarrhoea (p=0.023), bloating (p=0.034), digestive (p=0.005), loss of taste (p=0.047), flatulence (p=0.015), and weight (p=0.002).

There were no significant differences between treatment arms in terms of time to deterioration for general symptoms in the EORTC PAN26, including perception of side effects. Nonetheless, Macarulla noted that there were nonsignificant improvements in fatigue (p=0.091) and insomnia (p=0.176) with TTFields plus GnP.

TTFields with GnP was also associated with significantly better time to deterioration of pain according to the EORTC QLQ-C30 questionnaire (median 10.1 vs 7.4 months; HR, 0.70, 95 percent CI, 0.54–0.89; p=0.003) and pancreatic pain as per the PAN26 addendum (median 14.7 vs 10.2 months; HR, 0.69, 95 percent CI, 0.52–0.90; p=0.006) compared with GnP alone.

Pain management vital in pancreatic cancer

On post hoc analysis, similar patterns favouring TTFields plus GnP were observed in terms of time to first opioid use in both the intention-to-treat (ITT; median 7.1 vs 5.4 months; HR, 0.80, 95 percent CI, 0.65–1.00; p=0.046) and modified ITT (median 9.3 vs 6.7 months; HR, 0.73, 95 percent CI, 0.56–0.94; p=0.014) cohorts. The modified ITT cohort comprised patients who had had ≥28 days of TTFields plus ≥1 full cycle of GnP.

In the experimental arm in the ITT population, 80 percent of the participants used strong opioids, the most common being oxycodone (36 percent), morphine (33 percent), and fentanyl (30 percent). Tramadol (31 percent) was the most frequently used weak opioid. These patterns were mirrored in the mITT cohort.

Pancreatic cancer is typically diagnosed in the advanced stages of the disease and is associated with debilitating symptoms and poor QoL. [BMC Cancer 2024;24:doi:10.1186/s12885-024-12612-z] Eighty percent of pancreatic cancer patients are usually in pain that warrants management with opioid analgesics. [Dig Dis Sci 2017;62:861-870]

“[Hence,] pain management is recognized as important for improving QoL in patients with pancreatic cancer, with negative mood linked to increased pain,” Macarulla said.

A new standard treatment paradigm?

TTFields are electric fields that affect cancer cell division and may increase antitumor immune response. [Cancer Res 2004;64:3288-3295; Clin Cancer Res 2018;24:266-275; Cancers (Basel) 2020;12:doi:10.3390/cancers12103016]

The therapy is delivered in a noninvasive manner to the site of the tumour through a portable device comprising a field generator and arrays placed on the skin. [https://www.accessdata.fda.gov/cdrh_docs/pdf10/p100034s013c.pdf, https://www.accessdata.fda.gov/cdrh_docs/pdf18/H180002C.pdf, accessed September 9, 2025]

To evaluate the impact of TTFields in pancreatic cancer, the PANOVA-3 investigators randomized 571 participants (median age 67 years, 52 percent women, 15 percent Asian) 1:1 to GnP with or without TTFields therapy (150 kHz). Gemcitabine was administered at a dose of 1,000 mg/m² and nab-paclitaxel at 125 mg/m² on days 1, 8, and 15 of each 28-day cycle.

Participants were eligible if they had previously untreated, biopsy-confirmed disease; ECOG PS 0–2; and a life expectancy of ≥3 months. Half of the participants had their lesions developing at the head of the pancreas, while about a quarter (28 percent) had theirs at the body of the pancreas. Half of the patients had moderate CA 19-9 (38–1,000 U/mL).

In the initial report, PANOVA-3 met its primary endpoint, demonstrating the superiority of TTFields therapy plus GnP as opposed to GnP alone in terms of overall survival (median 16.2 vs 14.2 months; HR, 0.82, 95 percent CI, 0.68–0.99; p=0.039) and pain-free survival (median 15.2 vs 9.1 months; HR, 0.74, 95 percent CI, 0.56–0.97; p=0.027). [ASCO 2025, abstract LBA4005; J Clin Oncol 2025;43:2350-2360]

“Together with its OS benefit and lack of exacerbation of systemic toxicity associated with GnP, these QoL data support the role of TTFields therapy as a potential new standard treatment paradigm in the management of locally advanced pancreatic cancer,” concluded Macarulla.