Intratumoural administration of ipilimumab plus nivolumab is safe in patients with resectable and non-resectable recurrent glioblastoma and provides early signs of responses, according to phase I study findings presented at the ESMO Immuno-Oncology Virtual Congress 2020, held from 9 to 12 December 2020.
Intravenous (IV) administration of ipilimumab and nivolumab has demonstrated low activity in patients with recurrent glioblastoma. Leading author Julia K. Schwarze of the Department of Medical Oncology, Universitair Ziekenhuis Brussel in Brussels, Belgium and colleagues evaluated intratumoural and intracavitary (IC) administration of this combination in the phase I GlITIpNi (NCT03233152) clinical study. Previously reported findings from cohorts C1 and C2 of this study showed that intratumoural administration of ipilimumab and nivolumab was safe.1
Cohorts C3 and C4 of the study enrolled 17 patients with non-resectable and 15 patients with resectable recurrent glioblastoma, respectively. All patients underwent intratumoural administration in the brain tissue lining the resection cavity of ipilimumab at 5 mg plus nivolumab at 10 mg that was followed by IC nivolumab through an Ommaya reservoir at three different dose levels of 1, 5, or 10 mg every 2 weeks plus nivolumab 10 mg IV every 2 weeks for a maximum of 12 cycles.
Cerebrospinal fluid (CSF) was collected prior to each drug administration for biochemical and cytological analysis, and concentration measurements of ipilimumab and nivolumab were done. Next generation sequencing (NGS) of RNA and/or DNA and gene expression profiling on resected tissue is ongoing.
Cohorts 3 and 4 comprised 32 patients, of whom 23 were male with a median age of 55 years (range, 38-77); 3 patients had IDH1 R132H mutation and one patient’s tumour showed 1p/19q loss of heterozygosity (LOH).
Clinical benefit following intratumoural delivery of ipilimumab/nivolumab was observed in both cohorts
At time of analysis, all patients had received the predefined intratumoural dose of ipilimumab plus nivolumab and 1 patient remained on treatment. The median number of IC/IV nivolumab administrations was 7.5 (range, 3-12) in C3 dose level 1, 4.5 (range, 1-11) in C3 dose level 2, and 4 (range, 1-8) in C3 dose level 3; patients in C4 received a median of 8 administrations (range, 4-8) in dose level 1, 4.5 administrations (range, 4-8) in dose level 2, 3 administrations (range, 2-12) in dose level 3.
The most frequently reported adverse events (AEs) were fatigue in 27 patients, headache in 17, fever in 9, and 5 patients had seizures. Only a few low-grade immune-related AEs were observed. Bacterial colonisation of the Ommaya reservoir occurred that required removal of the Ommaya and antibiotic therapy in 4 patients. There were no Grade 5 AEs.
Regarding the C3 cohort, one patient achieved a complete response that was ongoing after 92 weeks. The best response was disease progression (PD) in all of the other 15 evaluable patients.
60 year old female patient with recurrent glioblastoma (IDH1 wild type, MGMT-promotor unmethylated) in cohort 3 (biopsy only) who previously progressed after concomitant radio-/chemotherapy and 4 cycles of chemotherapy with temozolomide achieved a complete response on study treatment that is still ongoing at 92 weeks.
© Julia K. Schwarze.
In the C4 cohort of patients with resectable glioblastoma, 3 patients completed their 24 weeks of treatment.
Progression-free survival and overall survival of cohort C3 and C4 are immature at present.
Five C3 and 6 C4 patients showed elevated protein levels as well as lymphocytic pleocytosis. No evidence for accumulation of ipilimumab or nivolumab was found in the CSF during therapy.
The other analyses, including cytokine levels, cell-free DNA analysis of CSF, and NGS and gene expression profiling on tumour tissue are ongoing.
Conclusions
Based on these findings the authors concluded that intratumoural administration of ipilimumab plus nivolumab followed by IC and IV administration of nivolumab is feasible and sufficiently safe to warrant further investigation in patients with recurrent glioblastoma.
Funding was reported from Stichting Tegen Kanker, “Live for better days” and the Paul De Knop Fonds.
Citation
- Schwarze JK, et al. ASCO 2020, abstract #2534.
Reference
65MO – Schwarze JK, Bertels C, Awada G, et al. A phase I clinical trial on intratumoural (IT) administration of ipilimumab (IPI) plus nivolumab (NIVO) followed by intracavitary (IC) administration of nivolumab in patients with recurrent glioblastoma. ESMO Immuno-Oncology Virtual Congress 2020 (9-12 December).