CTSI-03 IT-IO: INTRATHECAL ADMINISTRATION OF NIVOLUMAB AND IPILIMUMAB IN COMBINATION WITH SYSTEMIC COMBINATION OF NIVOLUMAB AND IPILIMUMAB IN PATIENTS WITH NON-SMALL CELL LUNG CANCER OR MELANOMA AND NEWLY DIAGNOSED LEPTOMENINGEAL METASTASIS, A MULTIC

Abstract BACKGROUND The optimal management of patients with leptomeningeal metastases (LM) from non-small cell lung cancer (NSCLC) or melanoma remains controversial. IT-IO (NCT05598853) is a prospective phase I, multicenter, open label, interventional clinical study aiming at determining the recommended phase 2 dose (RP2D) of intrathecal nivolumab and ipilimumab in patients with newly diagnosed LM from NSCLC or melanoma. METHODS The diagnosis of LM had to be confirmed or probable by EANO ESMO criteria. Planned whole brain radiotherapy (WBRT) was not allowed. Planned or prior craniospinal irradiation were not allowed. The treatment regimen consisted of intrathecal nivolumab (fixed dose 50mg) / ipilimumab (increasing doses) in combination with systemic combined nivolumab/ipilimumab. Three dose levels of IT ipilimumab were planned: 5mg (dose level 1), 10mg (dose level 2), and 20mg (dose level 3). RP2D, the primary endpoint, was determined in a 3+3 design. Secondary endpoints included compartmental efficacy and survival. RESULTS A total of 19 patients, 6 female and 13 male patients, 12 with melanoma and 7 with NSCLC, were enrolled between February 2022 and August 2024. Median KPS at study entry was 80, 12 patients had a positive CSF. The dose escalation phase (n = 12) was completed without dose-limiting toxicity until dose level 3. The RP2D is nivolumab 50mg and ipilimumab 20mg. Sixteen SAE were noted, all unrelated or unlikely related to intrathecal therapy. Two patients are still alive. For the whole cohort, median overall survival was 3 (range 0.6-11) months, for patients with a diagnosis of melanoma 2.9 (range 0.6-11) and for patients with NSCLC 4.5 (range 0.8-10.3) months. OS at 6 months was 20%. Translational research is ongoing. CONCLUSIONS No safety issue was noted. Efficacy data are preliminary and need to be confirmed in larger trials.