Everolimus (mTOR inhibitor) + NECTAR salvage delivers 75% ORR in pediatric/AYA R/R T-ALL/T-LL

Everolimus is an oral mTORC1 inhibitor combined here with NECTAR chemotherapy (nelarabine + cyclophosphamide + etoposide) in the multisite ENCERT Phase 1 dose-escalation study in children/young adults with relapsed/refractory T-ALL/T-LL (n=8; NCT03328104). No dose-limiting toxicities were seen; the highest tested dose was everolimus 5 mg/m²/day (DL2; n=5) and toxicities were described as expected and largely hematologic. ORR (CR+CR with incomplete platelet recovery+PR) was 75% (6/8) overall—100% in T-ALL (5/5) vs 33% in T-LL (1/3)—and all responders proceeded to allogeneic HSCT; notably, post-HSCT veno-occlusive disease contributed to 2/6 deaths, while 2/6 were alive at reporting (2/6 died of progressive disease). For context, nelarabine-based salvage in pediatric first marrow relapse T-ALL has been reported around ~55% response (dropping to ~27% in ≥2nd relapse), and adding cyclophosphamide/etoposide (NECTAR) has not consistently improved response rates beyond single-agent nelarabine—so the 100% T-ALL response signal here is intriguing but very small-n and confounded by mixed response definitions (PR included) and transplant outcomes.