OS03.4.A REPEATED INTRACRANIAL ADMINISTRATION OF ANTI-PD-1 ALONE OR IN COMBINATION WITH ANTI-CTLA-4 IMMUNE CHECKPOINT-BLOCKING MONOCLONAL ANTIBODIES IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA

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Abstract BACKGROUND Recurrent high-grade glioma (rHGG) is an invariably fatal malignancy, currently lacking life-prolonging treatment options. Systemic administration of PD-1 and CTLA-4 immune checkpoint blocking monoclonal antibodies has shown limited efficacy. In the Glitipni multi-cohort dose finding phase I clinical trial, the primary aim is to establish safety and feasibility of intra- followed by postoperative intracranial (iCran) administration of nivolumab (NIVO), with or without ipilimumab (IPI), in patients with rHGG amenable for a maximal safe resection (MSR) or stereotactic core needle biopsy (SCNB). MATERIAL AND METHODS Sixty-one patients were enrolled (across 3 cohorts), receiving 10 mg NIVO IV within 24h prior to MSR or SCNB. Forty-three patients underwent MSR, followed by intracerebral (iCer) injection of NIVO (10 mg) and IPI (5 mg) in the brain tissue lining the resection cavity. Among them, 27 received an additional intracavitary injection of NIVO (10 mg) and IPI (1-, 5-, or 10 mg) (iCav, via an Ommaya reservoir) at the end of the neurosurgical procedure. Sixteen patients underwent SCNB followed by the intratumoral (iTum) injection of NIVO (10 mg) and IPI (5 mg). Postoperative iCav administrations were repeated bi-weekly for a maximum of 11 cycles, concurrently with 10 mg NIVO IV. Postoperatively, 1-, 5-, or 10 mg NIVO iCav was administered as a single agent in 28 patients. In the third cohort, postoperative administration of 10 mg NIVO iCav was combined with 1-, 5- or 10 mg IPI iCav in 22 patients. RESULTS No unexpected adverse events (AE) occurred related to the perioperative treatment. Dose limiting toxicity consisted of transient symptomatic grade 3 aseptic neutrophilic pleocytosis in 1- and 3 patients receiving iCav administration of 5- and 10 mg iCav IPI, respectively. The most frequent reported treatment related AE was fatigue (n=49,80%); no grade 5 AE occurred. PFS did not differ between cohorts. OS was superior in patients who underwent a MSR versus SCNB; but was not improved by the addition of iCav IPI (median OS: 15- [95% CI 0-53] vs. 42- [26-57] vs. 35 [29-40] weeks; 1y OS-rate: 12% [95% CI 0-28] vs. 37% [14-60] vs. 29% [12-46]). OS of pts who underwent a MSR compared favorable against a pooled historical control cohort (n=469) treated with VEGF(R)-inhibitors (log rank p.015). CONCLUSION This first-in-human, multi-cohort, phase I clinical trial on intracranial CTLA-4/PD-1 blockade in patients with rHGG, demonstrates that intra- and postoperative iCran administration of NIVO with or without IPI up to a bi-weekly postop iCav dose of 1 mg IPI and 10 mg NIVO can be safely performed. Promising survival is documented in patients amenable for resection.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.