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TTFields in Mesothelioma Still Has Something to Prove

Tumor Treating Fields (TTFields) for the first-line treatment of unresectable mesothelioma showed promise when added to standard chemotherapy, even landing an FDA approval, but questions remain absent any randomized data in this setting.

In the single-arm STELLAR trial, treatment with the NovoTTF-100L TTFields device plus standard chemotherapy yielded a median overall survival (OS) of 18.2 months in 80 patients with unresectable malignant pleural mesothelioma, which topped a historical control of 12.1 months, reported Giovanni Ceresoli, MD, of the Cliniche Humanitas Gavazzeni in Bergamo, Italy, and colleagues.

As described in the Lancet Oncology, OS rates at 1 and 2 years were 62.2% and 41.9%, respectively. The 53 patients with epithelioid-type mesothelioma had a median OS of 21.2 months while the 27 patients with the more aggressive non-epithelioid disease had an OS of 12.1 months, a post-hoc analysis found.

While Ceresoli and colleagues concluded that TTFields to the thorax in combination with pemetrexed and platinum was active and safe, they cautioned that the results need confirmation in a larger randomized trial. Despite any randomized data in mesothelioma, TTFields received FDA approval earlier this year via the agency’s Humanitarian Device Exemption pathway (A randomized trial showed an OS benefit when TTFields was added to temozolomide [Temodar] maintenance for patients with glioblastoma).

Still, Ceresoli’s group argued that there’s a “strong rationale” for the use of TTFields in mesothelioma.

“The alternating electric fields used to target mitotic events in the tumor are distributed regionally in the thorax, and can therefore cover the entire disease burden of malignant pleural mesothelioma without causing systemic toxicity. Additionally, preclinical data show high sensitivity of mesothelioma cells to TTFields, with and without chemotherapy,” they wrote.

“From a biological perspective, TTFields target microtubule stability, disrupting the mitotic spindle; however, the molecular determinants which affect sensitivity remain elusive,” wrote Dean Fennell, MD, PhD, of University Hospitals of Leicester NHS Trust in England, in an accompanying editorial. “Identifying predictive biomarkers of efficacy could play a role in enabling selection of patients who are likely to benefit from TTFields.”

Fennell said the task of improving upon the standard of care in mesothelioma “has proven to be virtually insurmountable since 2004” — the previous time an agent received FDA approval for mesothelioma — and cautioned that “single-arm trials are notoriously subject to potential sampling bias in what is a particularly heterogeneous cancer such as mesothelioma.”

Furthermore, post-study therapy in STELLAR — such as vinorelbine (Navelbine) in 22%, gemcitabine (Gemzar) in 14%, or immunotherapy in 9% — might have confounded the survival benefit of TTFields, “particularly given the similarity in response and progression-free survival relative to historical controls.”

At first follow-up, 40% of patients had a partial response and an additional 57% had stable disease. Median progression-free survival was 7.6 months for the full group (8.3 months in the epithelioid subset and 6.5 months in the non-epithelioid subset).

Investigators argued that the signal for TTFields’ activity in STELLAR should be viewed in light of two recent randomized trials in malignant pleural mesothelioma — MAPS and LUME-Meso.

In the positive MAPS trial, median OS in the group that received bevacizumab (Avastin) on top of standard therapy was 18.8 months, though this included a larger percentage of patients with epithelioid histology than STELLAR. In LUME-Meso, which exclusively enrolled patients with epithelioid histology, median OS was 16.1 months in a control arm that outperformed the investigational arm of nintedanib (Ofev) added to standard treatment.

“Systemic therapy remains the first-line therapy for mesothelioma, but STELLAR presents a promising signal of efficacy that urgently needs reinforcement via the gold-standard of randomized evaluation,” Fennell concluded.

From 2015 to 2017, Ceresoli and colleagues treated 80 malignant mesothelioma patients with TTFields (NovoTTF-100L at a frequency of 150 kHz) with intravenous pemetrexed and either cisplatin or carboplatin every 3 weeks for up to six cycles. Over the first 3 months of treatment, patients used the TTFields device an average of 16.3 hours per day.

Common grade 1/2 adverse events included skin reactions in 66% of patients, where transducers were placed on the skin. Grade 3/4 events occurred in 36% of patients and three patients died due to an adverse event (4%). The most common grade ≥3 adverse events were anemia (11%), neutropenia (9%), thrombocytopenia (5%), and device site reactions (5%). Two patients were hospitalized for anemia, but neither these nor any other serious event were found related to the TTFields.

The STELLAR trial was funded by Novocure.

Ceresoli disclosed relevant relationships with Novocure, Boehringer-Ingelheim, Merck Sharp & Dohme (MSD), Astellas, and Pfizer.

Fennell disclosed support from Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, and MSD, as well as relevant relationships with Roche, Paredox Therapeutics, Atara, Boehringer Ingelheim, and Bayer.


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