Discussion
tumor, thymomas, toxicities, myositis, toxicity, thymoma, SD, thymic carcinoma, hepatitis, lymphoma achieved disease, non-lymphoma, cancers, DLTs, HL, plexus papillary carcinoma, NK/T lymphoma, effusion, lymphoma, tumors
TUMOR, CANCERS, THYMOMAS, ADVERSE EVENTS, PEDIATRIC CANCER, DISEASE, THYMOMA, PEDIATRIC SOLID TUMOR, PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA, SOLID TUMORS, THYMIC CARCINOMA, MYOSITIS, EFFUSION, AMPLIFICATION, LYMPHOMA, TUMORS, HEPATITIS, DIFFUSE LARGE B-CELL LYMPHOMA
During this phase I trial, it was observed that sintilimab demonstrated good tolerability in children, with no DLTs reported, even at the highest dose of 10 mg/kg. The frequency and nature of adverse events associated with this drug were in line with what has been documented in adults.Sintilimab showed a flat exposure-safety/efficacy relationship in adult patients. Our study found that sintilimab did not exhibit a dose-dependent safety profile within the range of 1-10 mg/kg. This suggests that there are no differential exposure/dose- dependent response relationships between adult and pediatric patients or between sintilimab and other anti-PD-1 drugs.Considering the anticipated similar exposure between adult and pediatric patients, the observed near-saturated levels of PD-1 receptor occupancy across a various dose levels (1 to 10 mg/kg), the flat exposure/dose-safety relationship in adult and pediatric patients and the absence of clinically meaningful effects on sintilimab PK in adult patients with bodyweights ranging from 36-124.4 kg when administrated at a dose of 200 mg Q3W, the 3 mg/kg Q3W dose regimen is likely positioned within the plateauing region of the exposure-response curves (We observed a lower frequency of grade 3 or grade 4 hematological and non-hematological toxicity in our study compared to that reported in adults, indicating better tolerance in children. Notably, one patient with thymomas experienced irAEs, including myositis and grade 3 hepatitis. Supportive care and corticosteroids were administered to the patient, resulting in symptomatic improvement in the effusion. This finding is consistent with previous literature on the safety of PD-1 in patients with thymomas. In a phase I trial, the administration of avelumab to seven patients with thymoma and one patient with thymic carcinoma resulted in the occurrence of myositis and grade 3-4 irAEs in 38% and 25% of patients, respectively. As a result of these toxicities, five patients had to discontinue the treatment.Among the 29 patients treated, two patients in the cohort discontinued the study before their initial scheduled imaging evaluation. Among the 27 patients evaluated for response, two were noted to have disease progressed in an external hospital and withdrew from the study, making it impossible to determine the specific tumor size for these two individuals. Patients with lymphoma showed clinical benefit with sintilimab. Of the ten patients with HL, six achieved an objective best response (2 CR, 4 PR), and four showed SD, with a response rate similar to that reported in adults with HL. The remaining three patients with lymphoma achieved disease control (1 patient with NK/T lymphoma achieved CR, 1 patient with a diffuse large B-cell lymphoma achieved PR, and 1 patient with a primary mediastinal large B-cell lymphoma had SD). Amplification of PD-L1 is thought to play a role in the elevated response rate observed with ICIs.Our study focused on assessing TMB, but its impact on pediatric tumors was limited. Prior research has suggested that roughly 5% of sporadic pediatric solid tumors fall into the category of hypermutant. Grobner et al. reported that mutation frequencies in pediatric cancer types were 14 times lower overall than those in adult cancers.Despite the promising activity observed in lymphoma, the ORR appears to be lower in solid tumors, as previous reported in other studies. In our study, we did not find any indications for single-agent activity of sintilimab in non-lymphoma pediatric solid tumors. However, some pediatric tumor histologies, including thymoma and choroid plexus papillary carcinoma, showed a response to PD-1 treatment and demonstrated a durable clinical benefit. We utilized germline mutations identified through WES to predict the response to ICIs. Our findings revealed previously unreported CDC27 and FGFR1 mutations in thymoma. CDC27 was found to be positively correlated with PD-L1 in T-LBL,In conclusion, our study demonstrates the tolerability of sintilimab in children. Although single-agent efficacy was not evident in most of the solid tumors in this study, we observed anti-tumor activity in HL. Future research should explore the use of sintilimab or other PD-1/PD-L1 inhibitors, either in monotherapy or as part of combination therapies with other drugs. This exploration should focus on specific pediatric patient populations with solid tumors identified through biomarkers indicating increased tumor immunogenicity.