EF-36/Keynote B36: A Pilot, Randomized, Open-label Study of Tumor Treating Fields (TTFields, 150 kHz) Concomitant With Pembrolizumab for First Line Treatment of Advanced or Metastatic Non-small Cell Lung Cancer

TTFields have demonstrated significant activity in vitro and in NSCLC pre-clinical models, both as a single modality treatment and concomitant with chemotherapies and PD-1 inhibitors. TTFields have demonstrated synergistic activity when administered alongside taxanes; while TTFields used concomitantly with PD-1 inhibition have shown additive effects.

In a pilot study, 42 advanced stage NSCLC patients, who had tumor progression after at least one line of prior chemotherapy, received pemetrexed together with TTFields (150 kHz) applied to the chest and upper abdomen until disease progression. The combination was well tolerated and the only device-related adverse event was mild to moderate contact dermatitis. Efficacy endpoints were remarkably high compared to historical data for pemetrexed alone.

Preclinical models have been used to assess the potency of TTFields concomitant with checkpoint inhibition. In an in vivo experiment, C57Bl/6 mice had LLC-1 cells injected directly into the lungs. TTFields were applied to the mouse lungs for 7 days in parallel to I.P. injections of anti-PD-1. Concomitant TTFields and anti-PD-1 treatments led to a significant decrease in tumor volume compared to control mice and to mice treated with anti-PD-1 alone. The concomitant treatments also resulted in an increase in the percentage of tumor-infiltrating leukocytes (CD45+). Specifically, there was a significantly higher frequency of macrophages (CD45+/CD11b+/F4/80+) and dendritic cells (CD45+/CD11c+) in tumors from mice that were concomitantly treated with TTFields and anti-PD-1. Concomitant therapy upregulated PD-1 expression on macrophages and dendritic cells in mice, suggesting an adaptive immune response to control the inflammation caused by the treatment. Additionally, cytotoxic T-cells isolated from tumors treated with TTFields and anti-PD-1 demonstrated increased production of IFN-γ. Overall, these findings imply that concomitant TTFields and anti-PD-1 therapy enhanced the immune response, which led to better management of the tumor.

The study will enroll 100 patients, whose tumors are classified as TPS>1% and in whom EGFR or ALK-directed therapy is not indicated, for examination of the effectiveness and safety of TTFields concomitant with pembrolizumab.

In addition, all patients must meet all eligibility criteria.