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.
After a Screening Phase of up to 28 days, subjects will be enrolled to receive TTFields
(150 kHz) to the thorax using the NovoTTF-200T device for an average of 18 hours a day
concomitant with pembrolizumab 200 mg IV every 3 weeks, or pembrolizumab alone. 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.
