Background: Mitogen-activated protein kinase enzyme (MEK) inhibitors are used in the treatment of pediatric patients with neurofibromatosis, low grade glioma, and astrocytoma, and may demonstrate a unique side effect profile in this population.Inhibition of MEK has been shown to decrease interleukin (IL)-6 production, a proinflammatory cytokine. The inhibition of IL-6 and other proinflammatory cytokines is thought to decrease muscle wasting and may contribute to weight gain.However, there is limited information on the association of MEK inhibition and weight gain in children and adolescents. This study aimed to characterize and define the incidence of significant weight gain associated with MEK inhibitors in pediatric patients.Methods: This was a retrospective chart review conducted at a tertiary pediatric hospital. Children 1-18.99 years old were included if they started a MEK inhibitor from July 1, 2013-October 31, 2021, and continued therapy for at least 6 months. Significant weight gain was defined as ≥5% increase in patient's weight-for-age percentile.Results: Sixty-seven patients were included in the analysis. Sixty-two received trametinib and 5 received selumetinib. An increase in weight-for-age percentile ≥5% was seen in 60% of patients receiving selumetinib and 56% on trametinib. The Dunnett's multiple comparisons test revealed a difference in weight-for-age percentile from baseline to end of data collection (p = .0173). Patients who were obese at baseline were more likely to lose weight during treatment, while underweight patients increased in weight-for-age percentiles.Conclusions: Weight gain may be a notable side effect associated with the use of MEK inhibitors in pediatric patients.
TPS10066 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly rhabdoid tumors, poorly differentiated chordoma, epithelioid sarcoma, and medullary renal cell carcinoma, have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Response to immune checkpoint inhibition (CI) has been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on tumor cells and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. In patients with non-small cell lung cancer, tiragolumab with atezolizumab increased survival compared to atezolizumab alone. Thus, data suggest that SMARCB1/A4 deficient tumors are susceptible to CI; however, monotherapy is unlikely to achieve durable responses; the addition of tiragolumab may enhance response rates. Methods: This is a phase 1/2 trial of tiragolumab monotherapy and in combination with atezolizumab in patients ≥ 12 months of age with SMARCB1/A4 deficient tumors administered IV on Day 1 of 21-day cycles. Part A will evaluate the safety of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if >15 to ≤ 40 kg; 600 mg if > 40 kg or ≥ 18 yrs) based on cycle 1 DLTs in up to 6 evaluable patients <18 yrs of age. Part B will estimate the antitumor activity of tiragolumab in combination with atezolizumab (15 mg/kg [max 1200 mg]) if < 18 yrs or 1200 mg if ≥ 18 yrs) in 6 histology-specific cohorts (renal medullary carcinoma, malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, poorly differentiated carcinoma, epithelioid sarcoma, and other) Each cohort will be conducted using a 6+4 Simon’s two stage design. Up to 13 patients may enroll in each cohort allowing for inevaluable patients (maximum n=78). Enrollment of patients ≥ 18 yrs on Part B may occur concurrently with enrollment of patients < 18 yrs on Part A. If the pediatric dose of tiragolumab is deemed safe, patients <18 yrs old may be enrolled on Part B. Cycle 1 toxicities of the combination therapy will be monitored in Part B using a Bayesian Optimal Interval Design in patients < 12 yrs of age. The secondary objectives are to characterize pharmacokinetics/anti-drug antibody and estimating progression free survival, overall survival, and duration of response. Enrollment is open for all Pediatric Early Phase Clinical Trial Network sites. Clinical trial information: NCT05286801 .
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