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.