Selpercatinib in Pediatric and Adolescent Patients With RET -Altered Solid Tumors: Safety and Efficacy Results From the Phase I/II LIBRETTO-121 Study
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In the phase I/II LIBRETTO-121 trial, the highly selective RET inhibitor selpercatinib demonstrated durable efficacy—including a 53% objective response rate—and an excellent safety profile in pediatric and adolescent patients with RET-altered solid tumors.
Key Findings
Study Design
Study Limitations
Clinical Significance
This study proves that selpercatinib delivers robust and durable clinical activity alongside a tolerable safety profile in a young, vulnerable population with RET-driven cancers. It reinforces the critical necessity of upfront molecular profiling in pediatric solid tumors and successfully extends the standard-of-care targeted therapies previously established for adults into pediatric and adolescent oncology, providing a highly effective, CNS-active precision medicine option for this age group.
Historical Context
Activating RET genomic alterations (both fusions and point mutations) are key oncogenic drivers in several cancers, notably medullary and papillary thyroid carcinomas, which can occur in pediatric populations (often associated with MEN2 syndromes). While multi-kinase inhibitors were previously used, their off-target toxicities limited their utility. Selpercatinib, a highly selective, CNS-penetrant RET inhibitor, fundamentally changed the treatment paradigm for RET-driven lung and thyroid cancers in adults (driven by the LIBRETTO-001 trial). However, evidence in pediatric patients was limited. The LIBRETTO-121 study was initiated to bridge this gap, specifically evaluating the pharmacokinetics, safety, and efficacy of selpercatinib in children and adolescents, ultimately leading to its regulatory approval in patients aged 2 years and older.
Guided Discussion
High-yield insights from every perspective
Selpercatinib is a highly selective RET inhibitor. What is the normal physiological role of the RET receptor tyrosine kinase, and how do RET fusions versus RET point mutations fundamentally differ in their mechanism of oncogenic activation?
Key Response
Understanding the basic science of receptor tyrosine kinases is crucial. RET normally regulates neural crest and kidney development. Point mutations typically cause ligand-independent constitutive activation, whereas RET fusions involve structural rearrangements bringing RET under the control of an active promoter with a dimerization domain, leading to constitutive aberrant signaling. Selpercatinib binds the ATP-binding pocket to inhibit this.
When managing a pediatric or adolescent patient on selpercatinib for a RET-altered tumor, what are the most common unique adverse events associated with this specific class of targeted therapy that you must monitor for during routine clinic visits?
Key Response
Residents must know how to safely monitor patients on novel oral targeted therapies. Selpercatinib commonly causes hypertension, QT prolongation, hepatotoxicity with elevated AST and ALT, and hypersensitivity reactions. Routine monitoring of blood pressure, serial ECGs for QTc intervals, and liver function tests are essential components of care.
Despite a 53 percent objective response rate, some pediatric patients on selpercatinib will eventually develop acquired resistance. What are the common molecular mechanisms of acquired resistance to selective RET inhibitors, and how might this influence subsequent therapeutic sequencing?
Key Response
Fellows must anticipate treatment failure and understand resistance mechanisms. Acquired resistance often occurs via secondary RET solvent front mutations (e.g., RET G810R) which sterically hinder selpercatinib binding, or via off-target bypass track signaling (e.g., MET amplification). Identifying these via ctDNA or repeat biopsy is critical for enrolling in trials for next-generation RET inhibitors or selecting combination therapies.
Given the high efficacy and favorable safety profile of selpercatinib in LIBRETTO-121, how should this influence our institutional approach to upfront comprehensive molecular profiling for pediatric solid tumors, particularly those with histology not traditionally associated with RET alterations?
Key Response
The attending perspective focuses on systems and clinical paradigms. The robust efficacy of histology-agnostic targeted therapies mandates broad, early Next-Generation Sequencing, including RNA sequencing for fusions, in pediatric solid tumors. Missing a RET alteration deprives a child of a highly effective, less toxic alternative to conventional cytotoxic chemotherapy.
Scholarly Review
Critical appraisal through the lens of expert reviewers and guideline development
In basket trials like LIBRETTO-121 evaluating rare molecular subsets in pediatric populations, traditional randomized controlled designs are often unfeasible. How do adaptive trial designs mitigate type I and II errors in these small cohorts, and what are the statistical limitations of relying on Objective Response Rate as the primary endpoint?
Key Response
PhD-level analysis requires methodological critique. Basket trials often use Bayesian hierarchical models to borrow information across tumor types. While Objective Response Rate provides a rapid efficacy signal, it does not always correlate linearly with Overall Survival or Quality of Life, particularly in slow-growing tumors, highlighting the need for robust time-to-event secondary endpoints.
As a reviewer for this manuscript, how would you critically evaluate the generalizability of the 53 percent ORR, considering the inherent heterogeneity of 'RET-altered solid tumors' and the potential for selective reporting of short-term toxicities in a pediatric cohort where long-term developmental impacts are paramount?
Key Response
Editors must look for flaws and gaps. The ORR might be heavily driven by specific histologies like thyroid cancers that outnumber rarer sarcomas, skewing perceived pan-tumor efficacy. Furthermore, Phase I/II trials often lack follow-up for critical pediatric long-term toxicities, such as impacts on bone growth, fertility, and neurocognitive development, which a stringent reviewer would flag.
Based on the LIBRETTO-121 data, what specific criteria are necessary to elevate selpercatinib to a standard-of-care recommendation for pediatric patients with advanced RET-altered solid tumors, and how does this align with current tissue-agnostic guidelines for similar pediatric targets like NTRK?
Key Response
Guideline committees evaluate evidence strength. While a 53 percent ORR in a Phase I/II trial is compelling Level 2 evidence, elevating it requires considering the lack of Phase III RCTs, which are often impossible in this rare population. Committees must decide if this data warrants a strong upfront recommendation, similar to the integration of TRK inhibitors for NTRK fusions in recent pediatric oncology guidelines.
Clinical Landscape
Noteworthy Related Trials
SCOUT Trial
Tested
Larotrectinib
Population
Pediatric patients with TRK fusion-positive solid tumors
Comparator
None (single-arm)
Endpoint
Safety and Objective response rate (ORR)
LIBRETTO-001 Trial
Tested
Selpercatinib 160 mg twice daily
Population
Adolescents and adults with RET-altered solid tumors
Comparator
None (single-arm)
Endpoint
Objective response rate (ORR)
ARROW Trial
Tested
Pralsetinib 400 mg once daily
Population
Patients with RET fusion-positive NSCLC and other RET-altered solid tumors
Comparator
None (single-arm)
Endpoint
Objective response rate (ORR)
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