Stacey L. Berg

Background: APEC1621 arm M, a subprotocol of the NCI-COG Pediatric MATCH clinical trial, is a phase 2 study evaluating tipifarnib, a farnesyl transferase inhibitor, in patients with relapsed or refractory solid tumors harboring HRAS mutations at codons G12, G13, Q61, or A146 (NCT04284774). Methods: Patients identified by the MATCH screening protocol and enrolled to the arm M subprotocol received tipifarnib at 350 mg/m2/dose (maximum 600 mg/dose) orally twice daily on an intermittent dosing schedule (days 1-7 and 15-21, every 28 days) until disease progression or intolerable toxicity. The primary aim was to determine the objective response rate (ORR), and secondary objectives included estimating progression-free survival (PFS) and assessing the tolerability of tipifarnib on the intermittent dosing schedule in children. Results: Seven patients matched to the tipifarnib subprotocol and five patients (71%) enrolled. Two matched patients were ineligible for treatment. Diagnoses for the enrolled patients were rhabdomyosarcoma (n = 4) and angiosarcoma (n = 1). HRAS mutations identified in those tumors included G13R (n = 2) and G12S, G12C, and Q61L (n = 1 each). Treatment was associated with grade 1/2 adverse events (AE) consistent with those expected from prior studies. Grade 3 or higher AEs on treatment were disease progression, dyspnea, and pleural effusion, not related to protocol therapy. One patient had stable disease (SD) at the end of cycle 2 and remained on protocol therapy for 4 cycles. There were no objective responses (OR). Conclusions: This US cooperative group study was successful at identifying pediatric patients with tumors that harbored oncogenic mutations in HRAS. The frequency of the mutations identified and patients enrolled was lower than anticipated, and the study closed before accrual was complete. The adverse effect profile of tipifarnib in pediatric patients on the intermittent dosing schedule was acceptable. Limited single-agent efficacy of tipifarnib was observed in this biomarker-selected cohort of refractory pediatric tumors.

Supplementary Figure 1. Nivolumab (A) and Ipilumumab (B) peak and trough concentrations in treatment cycles 1 – 4.

Purpose:In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors.Patients and Methods:ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 mg/kg nivolumab plus 3 mg/kg ipilimumab) in Ewing sarcoma and rhabdomyosarcoma. Tumor response was measured using RECIST v1.1. Pharmacokinetics and PD-L1 expression on archival tissues were assessed.Results:Fifty-five eligible patients enrolled. Based on safety, tolerability, and similar drug exposure to the same doses administered in adults, DL2 was defined as the pediatric RP2D. Among 41 patients treated at the RP2D, 2 patients experienced dose-limiting toxicities during cycle 1, and 4 patients experienced toxicities beyond that period. Two patients had clinically significant sustained partial responses (1 rhabdomyosarcoma, 1 Ewing sarcoma) and 4 had stable disease. Among 8 patients treated at DL3, 3 dose-limiting toxicities (DLT) occurred, all immune-related adverse events; no objective responses were observed.Conclusions:The RP2D of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) is well tolerated in children and young adults with solid tumors and shows some clinical activity. Increased dose of ipilimumab (3 mg/kg) plus nivolumab (1 mg/kg) was associated with increased toxicity without clinical benefit.

PURPOSE: Precision oncology trials have generally focused on tumor testing to identify actionable alterations. The National Cancer Institute—Children's Oncology Group Pediatric MATCH trial incorporated return of germline results to assess feasibility of reporting in a cooperative group setting and characterize germline cancer predisposition in patients with refractory cancers. PATIENTS AND METHODS: Tumor and blood DNA from patients 1-21 years of age with treatment-refractory solid tumors, non-Hodgkin lymphomas, or histiocytic disorders underwent cancer gene panel sequencing. Clinical germline reports returned to 151 study sites included pathogenic/likely pathogenic (P/LP) germline variants found in 38 cancer predisposition genes (CPGs). European Society of Medical Oncology (ESMO) recommendations for germline follow-up of tumor variants in CPGs were assessed. RESULTS: Both tumor and germline reports were completed for 1,167 patients (87.5% of enrolled). A total of 295 tumor reports (25%) included 361 CPG variants of which 70 variants (19.4%) were found in the germline sample. Three additional germline-only CPG variants resulted in 73 (6.3%) of 1,167 germline reports containing variants across 21 CPGs previously associated with pediatric and/or adult cancers. Among frequently mutated CPGs in tumors, concurrent germline findings ranged from 8/32 NF1 (25.0%) and 25/163 TP53 (15.3%) to zero of 27 ALK and 18 PTEN tumor variants. ESMO guidelines recommended clinical follow-up for 110 (30.5%) of 361 tumor CPG variants which included 40 (57.1%) of 70 germline variants. CONCLUSION: Coordinated germline and tumor panel testing was feasible and revealed P/LP CPG variants in 6.3% of the Pediatric MATCH cohort. Tumor variant fraction, germline association of CPG with tumor type, and adult-oriented guidelines were not predictive of germline status, emphasizing the need for systematic germline follow-up after tumor genomic testing for pediatric patients.

PURPOSE: The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with tumors that harbored prespecified genomic alterations in the cyclinD-CDK4/6-INK4a-Rb pathway with intact Rb expression were assigned and treated with the cdk4/6 inhibitor palbociclib. METHODS: Patients received palbociclib orally once daily for 21 days of 28-day cycles until disease progression, intolerable toxicity, or up to 2 years. The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival. RESULTS: Twenty-three patients (median age, 15 years; range, 8-21) were enrolled; 20 received protocol therapy and were evaluable for toxicity and response. Of the evaluable patients, the most common diagnoses were osteosarcoma (n = 9) and rhabdomyosarcoma (n = 6). A single actionable gene amplification was found in 19 tumors ( CDK4 , n = 11, CDK6 , n = 2, CCND3 , n = 6), with one tumor harboring two amplifications ( CDK4 and CCND2 ). Hematologic toxicities were the most common treatment-related events. No objective responses were seen. Two patients with tumors harboring CDK4 amplifications (neuroblastoma and sarcoma) had best response of stable disease for six and three cycles. Six-month progression was 10% (95% CI, 1.7 to 27.2). CONCLUSION: The CDK4/6 inhibitor palbociclib at 75 mg/m ² orally daily was tolerable in this heavily pretreated cohort. No objective responses were observed in this histology-agnostic biomarker-selected population with treatment-refractory solid tumors, demonstrating that pathway alteration alone is insufficient in pediatric cancers to generate a response to palbociclib monotherapy.

PURPOSE: Patients age 1-21 years with relapsed or refractory solid and CNS tumors were assigned to phase II studies of molecularly targeted therapies on the National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial. Patients whose tumors harbored predefined genetic alterations in the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway and lacked mitogen-activated protein kinase pathway activating alterations were treated with the PI3K/mTOR inhibitor samotolisib. METHODS: Patients received samotolisib twice daily in 28-day cycles until disease progression or unacceptable toxicity. A rolling 6 limited dose escalation was performed as, to our knowledge, this was the first pediatric study of samotolisib. The primary end point was the objective response rate; secondary end points included progression-free survival (PFS) and the recommended phase II dose and toxicity of samotolisib in children. RESULTS: A total of 3.4% (41/1,206) of centrally tested patients were matched to this arm. Seventeen patients were treated. Among treated patients, the most common diagnoses included osteosarcoma (n = 6) and high-grade glioma (n = 5) harboring alterations in phosphatase and tensin homolog (n = 6), PIK3CA (n = 5), and tuberous sclerosis complex 2 (n = 3). No objective responses or prolonged stable disease were observed. Three-month PFS was 12% (95% CI, 2 to 31). Two patients experienced dose-limiting toxicities (mucositis and pneumonitis). Dose level 2 (115 mg/m²/dose twice daily) was determined to be the recommended phase II dose of samotolisib in children. CONCLUSION: This nationwide study was successful at identifying patients and evaluating the efficacy of molecularly targeted therapy for rare molecular subgroups of patients in a histology-agnostic fashion. Unfortunately, there was no activity of samotolisib against tumors with PI3K/mTOR pathway alterations. Prospective trials such as the NCI-COG Pediatric MATCH are necessary to evaluate the efficacy of molecularly targeted therapies given their increasing use in clinical practice.

Supplementary Figure 1. Nivolumab (A) and Ipilumumab (B) peak and trough concentrations in treatment cycles 1 – 4.

Supplementary Figure 1. Nivolumab (A) and Ipilumumab (B) peak and trough concentrations in treatment cycles 1 – 4.