Prospective Neurocognitive Functions of Patients Treated With Concurrent Nivolumab and Stereotactic Brain Radiosurgery for NSCLC and RCC Brain Metastases

Abstract

Previous studies have suggested activity of anti-PD1 antibodies against brain metastases from non-small cell lung cancer (NSCLC) and renal cell cancer (RCC). Our investigator-initiated phase 2 trial examined the neuropsychological effect of combining nivolumab with radiosurgery (SRS) in the treatment of patients with brain metastases from NSCLC and RCC.This is a multicenter open-label trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated brain metastases, no prior whole brain radiotherapy and no prior immunotherapy were eligible. Study treatment commenced with a dose of nivolumab (240mg or 480mg IV), which was continued until progression for up to 2 years at bi-weekly or monthly intervals. SRS (15-21 Gy) to all visible un-irradiated brain lesions was administered within 14 days of the first dose of nivolumab (cycle 1). Patients were followed by brain MRI and CT scans of the chest, abdomen and pelvis. Neurocognitive assessment was performed using the Hopkins verbal learning test-revised (HVLT-R), the Trail Making Test (TMT) and the Controlled Oral Word Association Test (COWA) RESULTS: 26 study patients (22 NSCLC and 4 RCC) were enrolled between Aug 2017 and January 2020. Patients had a median of 2 (1-9) brain metastases treated with SRS. The median diagnosis-specific graded prognostic assessment (GPA) score was 2 (1-3). Forty-two percent of the patients had received prior cytotoxic chemotherapy, and 1 patient had received prior brain SRS. PD-L1 status was known for 21 of the 22 NSCLC patients (12 with ≥50% PD-L1 expression (DAKO 22C3)). Median icPFS was 5.0 months (6 intracranial progressions and 9 deaths without progression in the brain). Accounting for death as a competing risk, the 1-year cumulative incidence of intracranial relapse was 20%, whereas the rate of extracranial relapse was 48.3% at 1-year. Median overall survival was 14 months. Neuropsychological evaluation was completed in 16 and 9 patients at 3 and 6-month follow-up, respectively. Median age of the 16 patients was 63 (46-77). At 3 months follow up, there was no significant difference on the patient's mean performance in any of the neurocognitive assessments; a deterioration of ≥1 standard deviation in at least 1 assessment from baseline was observed in 8 (50%) patients. At 6 months, participants significantly improved on the TMT- Parts A (P = 0.04) and Parts B (P = 0.03).Neurocognitive assessments suggest that upfront SRS concurrent with nivolumab PD1 inhibition is safe. Patient neurocognitive function showed potential improvements in patients able to complete 6-month assessments. A potential synergy between nivolumab and SRS loco-regionally within the brain may be present, leading to high intracranial control. However, the high rate of extracranial progression does not suggest an abscopal effect triggered by SRS during nivolumab.G.L. Masucci: Research Grant; BMS.O. Boucher: None. F. Marie: None. M. Plourde: None. V. Panet-Raymond: None. M. Pavic: None. S. Owen: None. L. Masson-Cote: None. C. Menard: Research Grant; Siemens Healthcare, Philips, Progenics, Varian. B. Routy: None. M. Tehfe: None. N. Blais: consultant; BMS.D. Roberge: Independent Contractor; CHUM, CDL Proton Therapy. Research Grant; Elekta. Honoraria; BrainLab, Varian Medical Systems, Siemens Medical Systems, EMD Serono, recordati. In-kind Donation; Accuray. ownership stake; afx, croton healthcare. P. Wong: Research Grant; BMS, AstraZeneca, NexPlasmaGen. Advisory Board; BMS, AstraZeneca. Travel Expenses; BMS, AstraZeneca.