TTFields and radiosurgery for 1-10 brain metastases from NSCLC: The Phase 3 METIS study

Abstract

Background: Tumor Treating Fields (TTFields) are non-invasive, loco-regional, antimitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was shown to be safe and to extend overall survival in newly-diagnosed glioblastoma patients. Trial design: The study objectives are to test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Patients (N=270) with 1-10 brain metastases (BM) from NSCLC are randomized in a ratio of 1:1 to receive stereotactic radio surgery (SRS) followed by either TTFields or supportive care alone. Patients are followed-up every two months until 2nd cerebral progression. Patients in the control arm may cross over to receive TTFields at the time of 2st cerebral progression. Key inclusion criteria: Karnofsky performance status (KPS) of 70 or above, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease no brain-directed therapy, no signs of significantly increased intracranial pressure, and no electronic implantable devices in the brain. Endpoints: Time to 1st cerebral progression based on the RANO-BMCriteria or neurological death (primary); time to neurocognitive failure based on the following tests: HVLT,COWAT and TMT; overall survival; radiological response rate; quality of life; adverse events severity and frequency (secondary). Treatment: Continuous TTFields at 150 kHz for at least 18 hours per day are applied to the brain within 7 days of SRS. The treatment systemis a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or a hat for cosmetic reasons. Patients receive the best standard of care for their systemic disease. Statistical Considerations: This is a prospective, randomized, multicenter study for 270 patients. The sample size was calculated using a log-rank test (based on Lakatos 1988 and 2002) and has 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57.