medwireNews: Supplementing standard systemic therapy with tumor treating fields (TTFields) prolongs the overall survival (OS) of previously treated patients with metastatic non-small-cell lung cancer (NSCLC), show phase 3 trial data.
This benefit “occurred without exacerbating the toxicities associated with systemic therapies,” note Ticiana Leal (Winship Cancer Institute at Emory University, Atlanta, Georgia, USA) and co-investigators in The Lancet Oncology.
They continue: “These data warrant consideration of TTFields therapy as an option for patients with metastatic non-small-cell lung cancer, as an innovative first-in-class treatment method that can be incorporated into daily life and added to existing therapies.”
Giving the background to the study, Leal and colleagues explain that TTFields “are electric fields that disrupt processes critical for cancer cell survival, leading to immunogenic cell death and enhanced antitumour immune response,” and they have been shown to amplify the effects of chemotherapy and immune checkpoint inhibitors (ICIs) in preclinical models of NSCLC.
For the pivotal LUNAR trial, they recruited 276 patients with squamous or nonsquamous metastatic NSCLC who had progressed on or after platinum-based therapy and randomly assigned them to receive standard systemic therapy – investigator’s choice of ICI (nivolumab, pembrolizumab, or atezolizumab) or docetaxel – either with or without TTFields.
The systemic treatments were dosed as per local guidelines, while TTFields therapy at a frequency of 150 kHz was delivered continuously via the NovoTTF device system (Novocure, Root, Switzerland) to the thoracic region with the recommendation to achieve an average usage of at least 75% of each day (18 h/day), explain Leal et al.
Participants were aged a median of 64 years and the majority were men (64%) and had nonsquamous disease (57%). Over the course of the first 3 months, TTFields therapy was delivered for a median of 56% and 57% of each day alongside an ICI or docetaxel, respectively.
After a median follow-up of 9.5–10.6 months, median OS was significantly longer with versus without the use of TTFields alongside standard therapy, at 13.2 and 9.9 months, respectively, which equated to a significant hazard ratio (HR) for death of 0.74 in favor of TTFields. The corresponding 1-year OS rates were 53% and 42%.
The researchers comment that the gain in median OS of more than 3 months with TTFields is “a clinically meaningful improvement that substantiates its use in this burdened patient population that has few other treatment options.”
They also point out that “the overall survival advantage of TTFields therapy in LUNAR was observed despite few patients achieving the recommended daily device usage of 18 h or more that had been chosen based on studies in glioblastoma.”
Of note, subgroup analysis showed that the boost in OS offered by the addition of TTFields was significant among patients who received an ICI, at a median of 18.5 months versus 10.8 months with standard therapy alone, and an HR of 0.63.
By contrast, in the docetaxel subgroup, although the median OS was numerically longer with versus without TTFields therapy, at 11.1 and 8.7 months, respectively, the HR of 0.81 was not statistically significant.
The author of a linked commentary says that “[a] possible explanation is the respective pharmacodynamics of TTFields and docetaxel.”
Dean Fennell, from the University of Leicester in the UK, continues: “Both induce the spindle assembly checkpoint, and, as such, adaptive resistance might be expected to limit both treatments simultaneously and equally, resulting in no prolonged clinical benefit for this combination.”
Both progression-free survival and overall response were comparable between patients who were treated with TTFields in addition to standard therapy and those given standard therapy alone, at a median of 4.8 versus 4.1 months and rates of 20.4% versus 17.3%, respectively.
In terms of the safety, adverse events (AEs) of grade 3–5 occurred in 59% of the TTFields therapy group and 56% of the control group, with serious AEs occurring in a respective 53% and 38%. A total of 36% of patients in the TTFields arm discontinued treatment due to AEs, as did 20% of those in the control arm.
At least one device-related AE was reported by 71% of participants receiving TTFields therapy, but just 6% were of grade 3 and there were no grade 4 AEs attributable to TTFields. The most frequent device-related AEs were grade 1–2 dermatitis (39%), pruritis (12%), rash (9%), and skin ulcers (8%).
No deaths were considered related to TTFields therapy, while three were related to standard therapy, two cases of infection and one of pulmonary hemorrhage.
The commentator says that “the results of LUNAR are unlikely to be practice-changing in the current treatment paradigm.” But he adds that the “robust” OS improvement with the combination of TTFields and immunotherapy “raises the possibility that TTFields could have a role in augmenting immune checkpoint inhibitor in the front-line setting, as suggested by preclinical studies.”
Fennell also thinks it will be of interest to investigate whether TTFields can “potentially re-establish adaptive immunity in the setting of relapse after immune checkpoint inhibitor therapy.”
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Lancet Oncol 2023; 24: 1002–1017
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