Neurological Complications Induced by Anti-PD-1 or Anti-PD-L1: Prevalence, Clinical Description and Treatment: 5-Years Experience of a National Network

Introduction: Neurological immune-related adverse events (n-irAEs) are a rare complication of anti-PD-1/anti-PD-L1 immunotherapies that can be life threatening and lead to immunotherapy withdrawal. Given the rarity of n-irAEs, few data are available regarding prevalence, clinical spectrum, management and outcome. Material and Methods: Adult patients treated by anti-PD-1 or anti-PD-L1 immunotherapies given alone or in combination with other treatment, who had n-irAEs of CTCAE grade ≥ 2 were identified in the Reisamic registry and in the national ImmunoTOX assessment board at Gustave Roussy cancer center in Villejuif, France. Results: Forty patients with n-irAEs were identified: 26 (65%) patients received anti-PD-1 or PD-L-1 alone and 14 (35%) patients a combination of anti-PD-1 and anti-CTLA4 antibodies. Prevalence of n-irAEs was estimated at 1.2%. Nineteen patients (47.5%) presented with exclusively peripheral nervous system (PNS) n-irAEs: inflammatory demyelinating polyneuropathy, cranial nerve palsy, myasthenia gravis. Fourteen patients (35%) had exclusively central nervous system (CNS) n-irAEs: encephalitis, meningitis. Seven patients (17.5%) had both PNS and CNS n-irAE. The maximum grade of toxicity was 2 in 14 patients, 3-4 in 23 patients, and three (8%) patients died due to n-irAEs. The immunotherapy was permanently discontinued in 37 cases and temporary held in 3 cases. Three patients were rechallenged without recurrence of their n-irAE. Systemic steroids were given in 30/40 patients and led to improvement in 86.7% with significant reduction of disability and modified Rankin Scale. Anti-tumoral overall response rate was 65%. Conclusion: N-irAEs occur in approximatively 1% (11/899) of patients treated with PD1/PDL1 The clinical spectrum of n-irAEs is wide, including both PNS and CNS manifestations in a same patient. As required by international guidelines, N-irAEs treatment should remain based on corticosteroids first, effective in 87% of cases. Funding Statement: This study was funded by Gustave Roussy and belongs to the GRIP (Gustave Roussy Immunotherapy Program) launched in 2015. Declaration of Interests: Dr Olivier Lambotte: paid expert testimony and consultancy fees from BMS France, MSD, Astra Zeneca; consultancy fees from Incyte, expert testimony for Janssen. Dr Stephane Champiat has received honoraria from AstraZeneca, BMS, Janssen, MSD, Novartis, and Roche Dr Aurelien Marabelle: Scientific Advisory Boards of Merck Serono, eTheRNA, Lytix pharma, Kyowa Kirin Pharma, Bayer, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, GSK, Oncovir, Pfizer, Seattle Genetics, Flexus Bio, Roche/Genentech, OSE pharma, Transgene, Gritstone Dr Jean-Marie Michot: Advisory board: Bristol-Myers Squibb, Pfizer, Roche, Novartis, Janssen, Astra-Zeneca, Cellgene, Gilead. Dr Nicolas Noel: speaker fees from BMS and Janssen outside the submitted work Dr Cecile Cauquil has received honoraria from BMS Dr Christian Denier : speakers fees from Bohringer. Dr Alexandre Maria : has received fees from Abbvie, Actelion, CSL Behring, Experf, Novartis and Shire and declares speaking fees from Astra-Zeneca and BMS in the last 5 years. All other authors declare no conflicts of interest. Ethics Approval Statement: All patients gave oral informed consent for the study. This study was approved by the institutional review board of Gustave Roussy cancer center and the REISAMIC registry was declared at the Commission Nationale de l’Informatique et des Libertes (N°2098694v0).