Pilot study of nivolumab in pediatric patients with hypermutant cancers.

Abstract

10011 Background: Responses to immune checkpoint inhibitors (ICI) in unselected pediatric solid tumors have been disappointing. We hypothesized that pediatric cancers with an increased tumor mutation burden (TMB) and/or replication repair deficiency (RRD) may be uniquely susceptible to ICI therapy. Methods: OZM-075 (NCT2992964) is a multicenter pilot study in patients (pts) aged 1-25 yrs with relapsed/refractory cancers (including CNS tumors). Pts were eligible only if tumor showed evidence of RRD (based on immunohistochemistry showing loss of expression of relevant RR protein) or elevated TMB > 5mut/Mb determined by gene panel DNA sequencing. Pts with measurable or evaluable disease were eligible. Enrolment began in May 2017 and was completed in Nov 2020. Pts received programmed death-1 (PD-1) inhibitor nivolumab (NIVO) at a fixed dose of 3mg/kg every 2 weeks. Primary objective was objective response rate (ORR) by iRECIST or iRANO for those with measurable disease. Tumor tissue and serial blood samples were collected for analysis of biomarkers of response and survival. Results: As of 26Jan2021, 6 male and 5 female patients aged 9-18 yrs received treatment with NIVO (5 glioblastoma (GBM), 2 anaplastic astrocytoma (AA), 2 neuroblastoma, 1 colorectal adenocarcinoma (CRC), 1 adrenocortical carcinoma). 3pts had TMB 5-10mut/Mb, 5pts had TMB > 10mut/Mb (range 14-837, median 64), 3 pts enrolled on basis of RRD. Time on treatment ranged from 0-21 months and 2 pts remain on therapy. Best OR was partial response (PR) in 2 pts (both GBM), with an additional patient with CRC achieving pathological CR. Remarkably one of the pts with PR showed early evidence of progression on imaging and elected to discontinue NIVO. Without further therapy, subsequent imaging 7 months later showed PR. Best response of stable disease was demonstrated in 5 further pts, lasting ≥5 months in 3 pts. Median overall survival (OS) not reached. Of 7 patients with relapsed GBM/AA, 5 were alive for ≥12 months following start of NIVO including 4 pts with confirmed TMB > 10mut/Mb. Conclusions: This pilot study showed evidence of impressive clinical benefit particularly for relapsed GBM/AA patients for whom median survival is typically ̃6 months (JCO 1995 13(1):112-). These data contrast previous pediatric data and suggest that in the context of RRD and hypermutation ICI therapy may provide profound long-term response and survival for these children. Analysis of other correlative biomarkers is ongoing. Clinical trial information: 2992964.