Pilot Study Shows Clinical Benefit with Nivolumab in Pediatric Patients with Hypermutant Cancers

The immune checkpoint inhibitor nivolumab (Opdivo) appears to be effective in pediatric patients with hypermutant or ultra-hypermutant cancers, according to results from a pilot study presented during the American Society of Clinical Oncology 2021 annual meeting.

Among patients with hypermutant, relapsed glioblastoma (GBM) or anaplastic astrocytoma, the median overall survival (OS) was approximately 16 months, which far exceeds the typical median survival of 6 months for this patient population.

These findings contrast with previous pediatric studies of immune checkpoint inhibitors and suggest that in the context of replication repair deficiency (RRD) and hypermutation, immune checkpoint inhibition therapy may provide long-term response and improved survival for children, reported Daniel Morgenstern, MB BChir, PhD, Director, Therapeutic MIBG Program, The Hospital for Sick Children, and Assistant Professor, Hematology/Oncology, University of Toronto, Canada, and colleagues.

“The evidence of prolonged stable disease and prolonged OS, particularly in these patients with hypermutant, relapsed GBM or anaplastic astrocytoma, is encouraging and appears to be better than historical control,” he said. “These data suggest that immune checkpoint inhibitor therapy may be very useful for these patients after all.”

Although immune checkpoint inhibitors have been successful in several types of cancer in adults, published pediatric studies of nivolumab, pembrolizumab (Keytruda), and atezolizumab (Tecentriq) have shown response rates in non-lymphoma solid tumors that are disappointing. Given data in adult patients that showed increased responsiveness to immunotherapy among patients with increased tumor mutational burden (TMB), Dr Morgenstern and colleagues hypothesized that pediatric cancers with higher TMB and/or RRD may be uniquely susceptible to immune checkpoint inhibition.

The multicenter, international pilot study enrolled patients (aged 1-25 years) with relapsed/refractory solid tumors, including primary central nervous system disease. All patients treated on study were required to have evidence of either RRD, as evidenced by loss of mismatch repair protein expression by immunohistochemistry, or confirmation of elevated TMB, as determined by cancer gene panel sequencing via an approved laboratory test.

The primary end point was objective response rate by iRECIST or iRANO for those with measurable disease.

Evidence of Prolonged Survival, Stable Disease

Of the 20 patients who were screened, 11 were deemed eligible and received the PD-1 inhibitor nivolumab at a fixed dose of 3 mg/kg every 2 weeks. The majority of patients had aggressive brain tumors, either GBM (N = 5) or anaplastic astrocytoma (N = 2). However, the cohort also included 2 patients with neuroblastoma, 1 with colorectal carcinoma, and 1 with adrenal cortical carcinoma. A total of 3 patients were enrolled based on RRD, and 8 patients were enrolled based on TMB.

Among the 11 patients treated, 1 patient withdrew after the initial dose. Of the remaining 10 patients, 6 patients experienced a total of 9 serious adverse events.

“Overall, nivolumab was well-tolerated with limited immune-related adverse toxicity,” said Dr Morgenstern. “For patients with brain tumors, however, there was an issue with tumor-associated inflammation, leading to hydrocephalus, cerebral edema, or other neurological symptoms.”

Early evidence of progression posed a challenge for clinicians due to difficulty in determining the difference between pseudoprogression (inflammation caused by immune-related changes) and true disease progression.

Of the 10 patients assessed, 2 patients achieved a partial response (both GBM), 6 had stable disease, and 2 experienced disease progression.

The median time on therapy was 4.2 months (range, 0-21 months), and 1 patient remains on therapy. The median OS for the overall population was 16.5 months.

“These survival data compare favorably with historical controls, particularly for patients with relapsed high-grade gliomas,” said Dr Morgenstern. “One would typically expect OS of only 6 months in the context of relapsed disease.”

The investigators also identified a correlation between TMB and response. Of 7 patients with relapsed GBM or anaplastic astrocytoma, 5 were alive for at least 12 months following the start of nivolumab, including 4 patients with confirmed TMB ≥10 mut/Mb.

“Patients on study the longest are those with ultra-hypermutated brain tumors, while those with lower mutation burdens did not respond to nivolumab,” Dr Morgenstern noted.

The investigators also collected tumor tissue and serial blood samples for analysis of biomarkers of response and survival, and this analysis remains ongoing.

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