Safety and preliminary efficacy of intrathecal (IT) and intravenous (IV) nivolumab (N) for patients (pts) with leptomeningeal disease (LMD)

9554 Background: Pts with LMD have a dismal prognosis, with median overall survival (OS) < 3 months, no approved therapies and extremely limited clinical trial options. We previously reported initial safety findings from the dose escalation of an open label, single arm, single center phase I/IB trial (NCT03025256) for pts with metastatic melanoma (MM), in which IT/IV N were well tolerated, without any CNS-specific or unexpected toxicity. Here we report an update on safety, maximum tolerated dose (MTD), and dose expansion cohort (including 2 pts with NSCLC) and preliminary efficacy. Methods: Pts aged ≥18 with evidence of LMD by MRI and/or CSF cytology, ECOG PS ≤2 were treated with IT/IV N. Dexamethasone (dexa) ≤4mg/daily and concurrent BRAF/MEK inhibitor(i) therapy (tx) were allowed. For cycle 1, IT N was administered via ommaya reservoir on day (D)1. For subsequent cycles (every 14 days) pts received IT N on D1, followed by IV N 240 mg on D2. IT N doses evaluated were 5, 10, 20, and 50 mg. Blood and CSF were collected at multiple time points for translational research. The primary objectives were to determine safety and/or recommended dose/MTD of IT N given with IV N in pts with LMD and the safety of the MTD in an expansion cohort. OS was a secondary objective. Bayesian mTPI methodology was used to define the MTD. Results: 50 pts were treated: 17 in the dose escalation (2 at 5; 3 at 10; 6 at 20; 6 at 50 mg IT N), 8 in the initial expansion of 20mg, and 25 at the MTD 50 mg IT N. 48 pts had a diagnosis of MM, 2 NSCLC. Median age at LMD was 49 (19-74); 27 pts are male. All pts had radiographic evidence of LMD; 26 pts had positive baseline CSF cytology. 46 pts received prior systemic tx including checkpoint inhibitors (n = 42) and targeted tx (n = 34). 39 pts had prior CNS radiation (RT), including whole brain RT (n = 14). 18 pts used concurrent steroid, with a median dose of 2mg (0.9-4) dexa equivalent and 27 pts used concurrent targeted tx with BRAF/MEKi. The median number of IT N doses was 6 (1- 92). The combination regimen was well tolerated by all evaluable pts (n = 50), with 9 pts (18%) experiencing grade (gr) 3 AEs and no reported gr 4 or 5 toxicities. Rash (58%), nausea (44%), vomiting (34%), and dizziness (22%) were the most common AEs. Thirty pts (60%) experienced AEs after IT N administration, all gr 1/2 and 1 gr 3 (vasogenic edema). At a median follow-up of 4.6 months (mths) (0, 54.8 mths), median OS was 7.0 mths. OS was 66.6% at 3 mths, 53.1% at 6 mths and 34.8% at 12 mths. Conclusions: IT + IV nivo was safe and well-tolerated in MM pts with LMD, with no unexpected toxicities of the 50 mg MTD of IT N. OS rates at 6 and 12 mths are encouraging and support further evaluation of IT immunotherapy for LMD, including in other tumor types. Overall results also demonstrate the feasibility of prospective clinical trials in pts with LMD. Final presentation will also include immunological analysis of longitudinally collected CSF samples collected in the trial. Clinical trial information: NCT03025256 .