Clinical Trial Endpoints in PLGG: Rebound Regrowth, and the Unanswered Question of Tumor Senescence

In this segment, Dr. Abdelbaki, Dr. Chintagumpala, Dr. Margol, and Dr. Chi debate which clinical trial endpoints best capture treatment benefit in pediatric low-grade glioma (PLGG) and confront persistent gaps in long-term survivorship data.

A key challenge distinguishing targeted therapies from chemotherapy is rebound regrowth—tumor regrowth within six months of stopping therapy—which is far more common with targeted agents. Recent tovorafenib data presented at the Society for Neuro-Oncology meeting examined time to next treatment (TTNT) and treatment-free interval (TFI) as alternative endpoints to capture this phenomenon. The panel weighs these alongside traditional measures: progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (which includes stable disease). Overall survival is not informative because the vast majority of patients survive.

No single endpoint emerges as ideal. TTNT is appealing because it reflects real-world decision-making, but the panel notes it is inherently subjective—dependent on individual clinicians' thresholds for re-treatment, which vary across institutions. Duration of response is proposed as a potential surrogate, but it too has limitations. The underlying challenge is biologic unpredictability: tumors with identical molecular alterations can follow vastly different trajectories, making any time-based endpoint difficult to interpret. The panel frames the overarching goal as giving children the fewest therapies possible to reach tumor senescence while preserving function and suggests that the number of therapies required and the intervals between them over a 10–15-year period may ultimately be the most meaningful measures for families.

The discussion surfaces a more fundamental gap: despite decades of treating chiasmatic-hypothalamic tumors, no large-scale study has documented when these tumors become senescent, when patients can safely stop follow-up, or what the long-term morbidity and second malignancy risks are. Patients transition to adult services and are lost to pediatric follow-up, leaving these questions unanswered. The panel notes that surgery may re-emerge as an option after targeted therapy shrinks a previously unresectable tumor, adding another variable to long-term outcome assessment. A multi-institutional, IRB-approved retrospective study examining TTNT and TFI in patients treated with targeted therapies versus chemotherapy outside of clinical trials is announced as a step toward addressing these gaps. The PLGG/Pediatric Low-Grade Astrocytoma (PLGA) Coalition is also actively gathering long-term data.

In the next episode, "Side Effects of Targeted Therapies for PLGG," the panel reviews the side effect profiles of MEK inhibitors and tovorafenib, and discusses how toxicities and decreased growth velocity influence treatment timing and selection.