Data from Efficacy of Nivolumab in Pediatric Cancers with High Mutation Burden and Mismatch Repair Deficiency

• DOI: 10.1158/1078-0432.c.6678040.v1
• Publication Date: 2023-06-02T14:27:22Z
• Authors: Anirban Das; Uri Tabori; Lauren C. Sambira...; Natalie B. Collins; Rebecca Deyell; Rina Dvir; Cecile Faure-Conter; Timothy E. Hassall; Jane E. Minturn; Melissa Edwards; Elissa Brookes; Vanessa Bianchi; Adrian Levine; Simone C. Stone; Sumedha Sudhaman; Santiago Sanchez ...; Ayse B. Ercan; Lucie Stengs; Jill Chung; Logine Negm; Gad Getz; Yosef E. Maruvka; Birgit Ertl-Wagner; Pamela S. Ohashi; Trevor Pugh; Cynthia Hawkins; Eric Bouffet; Daniel A. Morgens...
• Keywords: Microsatellite Instability; Refractory (planetary science)

<div>AbstractPurpose:<p>Checkpoint inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively refractory nonhematologic cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch repair deficiency (MMRD).</p>Patients Methods:<p>Twenty patients were screened, 10 ultimately included in response cohort of whom nine had TMB >10 mut/Mb (three initially eligible based on MMRD) one patient between 5 mut/Mb.</p>Results:<p>Delayed immune responses contributed to best overall 50%, improving initial objective (20%) leading 2-year survival (OS) 50% [95% confidence interval (CI), 27–93]. Four children, including three malignant gliomas are complete remission at a median follow-up 37 months (range, 32.4–60), culminating OS 43% (95% CI, 18.2–100). Biomarker analyses confirmed benefit germline MMRD, microsatellite instability, higher activated lower regulatory circulating T cells. Stochastic accumulation driven by underlying MMRD impacted microenvironment, contributing delayed responses. No was observed single an MMR-proficient 7.4 mut/Mb.</p>Conclusions:<p>Nivolumab resulted durable prolonged time hypermutated gliomas. Novel biomarkers identified here need be translated rapidly clinical care identify who can from checkpoint inhibitors, upfront management cancer.</p></div>