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

This is a multicenter, randomized, open-label study of Tumor Treating Fields (TTFields) at 150 kHz to the thorax using the NovoTTF-200T System with IV pembrolizumab in subjects previously untreated for advanced or metastatic, PD-L1 positive non-small cell lung cancer (NSCLC). The primary objective is to evaluate the progression-free survival (PFS) by RECIST 1.1 in subjects with TPS ≥1 percent, 1L metastatic/current advanced NSCLC treated with TTFields concomitant with pembrolizumab compared to those treated with pembrolizumab alone.

The device is an experimental, portable, battery operated device for chronic administration of alternating electric fields (termed TTFields) to the region of the malignant tumor, by means of surface, insulated electrode arrays.

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.

Eligibility Criteria:
Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of stage III or metastatic NSCLC without EGFR sensitizing mutation or ALK translocation
* Age ≥ 22 years
* Have a PD-L1 positive (TPS≥1%) tumor by local laboratory assessment
* Have evaluable (measureable or non-measureable) disease in thorax per RECIST 1.1
* ECOG performance status of 0 to 1
* Have not received prior treatments for metastatic or current advanced NSCLC. Palliative treatment is allowed and subjects who received adjuvant, neoadjuvant chemotherapy or chemoradiotherapy with curative intent for non-metastatic disease are eligible if therapy completed at least 12 months prior to the development of metastatic or current advanced disease.
* Life expectancy of at least 3 months
* Able to operate the NovoTTF-200T device

Exclusion Criteria:

* Has known active or untreated CNS metastases and/or carcinomatous meningitis
* Has an EGFR sensitizing mutation and/ or ALK translocation
* Can be treated with curative intent with either surgical resection and/or chemoradiation
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent directed to another stimulatory or co-inhibitory T cell receptor within the past 12 months
* Has received prior systemic anti-cancer therapy for metastatic or current advanced NSCLC (palliative radiotherapy is allowed)
* Being unable to operate the NovoTTF-200T device independently or with the help of a caregiver
* Pregnancy or breastfeeding
* Received live vaccine in the past 30 days or had major surgery in the last 3 weeks
* Is expected to require any other form of systemic or localized antineoplastic therapy while on study