TTFields a new treatment paradigm for unresectable pancreatic cancer?

Tumour treating fields (TTFields) added to first-line chemotherapy (gemcitabine and nab-paclitaxel [GnP]) extends survival in individuals with locally advanced pancreatic adenocarcinoma (LA-PAC) in the PANOVA-3 study.

“PANOVA-3 is the first phase III trial using any therapy in LA-PAC and the first to show a significant overall survival (OS) benefit,” noted Dr Vincent Picozzi from Virginia Mason Medical Center, Seattle, Washington, US, at ASCO 2025.

The median OS was significantly longer with TTFields + GnP vs GnP alone in both intention-to-treat (ITT; 16.2 vs 14.2 months; hazard ratio [HR], 0.82; p=0.039) and modified ITT cohorts (18.3 vs 15.1 months; HR, 0.77; p=0.023). [ASCO 2025, abstract LBA4005]

There were progression-free survival (PFS) trends favouring TTFields, but the between-group differences fell short of statistical significance (median 10.6 vs 9.3 months; HR, 0.85; p=0.137 [PFS] and 12.5 vs 10.4 months; HR, 0.84; p=0.151 [local PFS]).

Other improvements with the experimental vs control regimen were distant PFS (median 13.9 vs 11.5 months; HR, 0.74; p=0.022), pain-free survival (median 15.2 vs 9.1 months; HR, 0.74; p=0.027), and deterioration-free survival in global health status, pain, and digestive problems (median time to deterioration 7.1 vs 5.7 months; HR, 0.77; p=0.023).

“[These imply that] TTFields produce benefit not just in terms of quantity of life, but quality of life (QoL) as well,” said Picozzi.

Skin toxicities (eg, dermatitis, rash, pruritus) were the most common device-related adverse events (AEs), but these were mostly grade 1/2 and were managed with the appropriate skincare regimen. Apart from this, no new safety signals were observed, and there were no deaths attributable to TTFields.

Poor survival

The current 5-year survival rate in PAC is <8 percent, and only a small fraction of patients with locally advanced disease are eligible for potentially curative surgery, noted Picozzi. “The remaining patients are incurable and will experience debilitating symptoms, especially pain.”

The current standard of care for unresectable LA-PAC remains chemo ± radiation. However, there have been relatively few trials in this space, and most have focused on combinations for metastatic disease, he continued.

“TTFields are electric fields that disrupt processes critical for cancer cell division and may trigger an enhanced antitumour response. These are delivered noninvasively to the tumour site via a portable device consisting of a field generator and arrays placed on the skin,” Picozzi explained. This therapy has been approved for use in other cancers, including glioblastomas, metastatic pleural mesothelioma, and metastatic non-small cell lung cancer.

TTFields therapy with gemcitabine ± nab-paclitaxel was feasible, safe, and impressively successful in the phase II PANOVA pilot trial. [Pancreatology 2019;19:64-72] This provided the background for this phase III trial evaluating 571 LA-PAC patients with previously untreated, inoperable disease (median age 67 years, 52.4 percent women, 15.4 percent Asian). They were randomized 1:1 to TTFields 150 kHz 18h/day ± gemcitabine 1,000 mg/m² and nab-paclitaxel 125 mg/m².

In summary, the survival benefit with TTFields + GnP is supported by the significantly improved QoL and pain-free survival, and the only frequent toxicity was localized skin reactions. “PANOVA-3 establishes TTFields with GnP as a potential new standard treatment paradigm for unresectable LA-PAC,” Picozzi said.

Takeaways

However, discussant Professor Brian Wolpin from Harvard Medical School, Boston, Massachusetts, US, noted that the OS benefit with TTFields was relatively modest. Other caveats he cited were the lack of PFS benefit, the skin toxicities, and the inconvenience of wearing the device.

Picozzi noted that the exact survival data relative to the frequency of usage is currently under analysis. “Interestingly, [prolonged use may not be necessary] to produce a threshold of benefit. I think key research questions going forward will be, ‘Exactly how [long] does a patient need to use it, and what should be the timing relative to chemo?’, because lesser use would imply improved compliance and perhaps less toxicity.”

Wolpin underlined the importance of the QoL improvement. “These are patients who often have substantial pain from large pancreatic cancers. The more data we have about [QoL and pain escalation], the better for us to help patients make decisions.”

“Assuming appropriate regulatory approvals, TTFields + GnP appears to be [a suitable treatment option] for patients with LA-PAC,” he added.

The potential of other chemo regimens that can be used with TTFields should also be explored, as not all clinicians prefer GnP for locally advanced disease. “It would be beneficial to get a further hand on the mechanism of action of this approach so we can build on it to make further improvements for patients.”