TTFields have demonstrated significant activity in in-vitro and NSCLC pre-clinical models, both as a single modality treatment and in combination with chemotherapies and PD-1 inhibitors. With taxanes, TTFields have been demonstrated to act synergistically, while TTFields have been shown to be additive when combined with PD-1 inhibition.
In a pilot study of 42 patients with advanced NSCLC who had tumor progression after at least one line of prior chemotherapy, all participants 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.
The potency of TTFields combined with checkpoint inhibition has been investigated in pre-clinical models. In an in-vivo experiment, C57Bl/6 mice were injected directly into the lungs with LLC-1 cells. Application of TTFields to the mouse lungs was maintained for 7 days and parallel to the ongoing I.P. injection of anti-PD-1. The combined treatment of TTFields and anti-PD-1 led to a significant decrease in tumor volume as compared to control mice and to mice treated with anti-PD-1 alone. The combined treatment 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 DCs (CD45+/CD11c+) in tumors from mice that were concomitantly treated with TTFields and anti-PD-1. The PD-L1 expression levels of these cells were increased as compared to the control group suggesting an adaptive immune attempt to limit the inflammatory response elicited by the combined treatment. Compatibly, cytotoxic T-cells isolated from tumors treated with TTFields and anti-PD-1 demonstrated increased production of IFN-γ. 061
Taken together, these results suggest that the combination of TTFields and anti-PD-1 augmented the immune response resulting in improved tumor control.
The study will enroll 66 patients, whose tumors are classified as TPS>1% and in whom EGFR or ALK-directed therapy is not indicated, are projected to be enrolled in this study for examination of the effectiveness and safety of TTFields concomitant with pembrolizumab.
In addition, all patients must meet all eligibility criteria.
Subjects will be enrolled after a Screening Phase of up to 28 days to receive TTFields at 150 kHz to the thorax using the NovoTTF-200T System for at least 18 hours a day on average concomitant with pembrolizumab 200 mg IV every 3 weeks. Each subject will participate in the study for approximately 2 years from the time the subject signs the Informed Consent Form (ICF) through the final contact.
Treatment with TTFields and pembrolizumab will continue for 24 months (TTFields) and until either (1) 35 study treatments have been administered (pembrolizumab), (2) there is documented disease progression (per iRECIST criteria), (3) unacceptable adverse event(s), (4) intercurrent illness that prevents further administration of treatment, (5) investigator's decision to withdraw the subject, (6) subject withdraws consent, (7) pregnancy of the subject, (8) non-compliance with study treatment or procedure requirements, or (9) administrative/Sponsor decisions.
In case of discontinuation of either of the study treatments due to reasons other than disease progression, the remaining treatment should continue until disease progression or 24 months (TTFields) / 35 cycles (pembrolizumab).
If an alternative anticancer therapy is initiated, the patient will be removed from the study.
Subjects who discontinue all study treatments prior to disease progression will be monitored for disease status in the Observation Phase until (1) disease progression is confirmed by the site, (2) a non-study cancer treatment is initiated, (3) consent is withdrawn, or (4) the subject is lost to follow-up. Subjects will have post-treatment monthly follow-up by telephone for disease status until death, withdrawing consent, becoming lost to follow-up, or end of the study.