Abstract A28: Targeted sequencing in 388 patients with high-risk or recurrent/refractory pediatric extracranial solid malignancies: An interim report from the GAIN Consortium/iCat2 Study
Authors: Corson Laura B. , Church Alanna J. , Reidy Deirdre , Kao Pei-Chi , Kang Wenjun , Pinto Navin , Maese Luke , Laetsch Theodore W. , Kim AeRang , Vear Susan I. , Macy Margaret E. , Applebaum Mark A. , Lee Lobin A. , Doan Duong , Pinches R. Seth , Choi Seong , Forrest Suzanne J. , Clinton Catherine M. , Crompton Brian D. , MacConaill Laura E. , Volchenboum Samuel L. , Lindeman Neal I. , DuBois Steven G. , London Wendy B. , Janeway Katherine A. 
Published: August 2020

Abstract
Background: Gene variants with potential therapeutic significance have been reported in 30-60% of childhood malignancies. The 12-institution Genomic Assessment Informs Novel therapy (GAIN) consortium is conducting the individualized cancer therapy 2 (iCat2) study (NCT02520713) with the objective of evaluating the impact of tumor profiling on outcome. We provide an interim report on patients enrolled on the ongoing GAIN/iCat2 study.
Methods and Objectives: Patients are eligible if they have a high-risk, recurrent/refractory (RR), or difficult-to-diagnose extracranial solid tumor diagnosed at ≤30 years and adequate sample available for sequencing. A next-generation targeted panel assay is performed. Results are returned with a GAIN report containing clinical interpretation, including an individualized cancer therapy (iCat) recommendation if there is evidence supporting a link between an identified variant and response to molecularly targeted therapy. iCat recommendations are tiered from 1 to 5 based on the level of clinical and preclinical support, with tier 1 being the highest and tier 5 the lowest. Potential extraordinary responders are selected for further review based on having treatment duration of ≥1 year for chemotherapy or ≥4 months or a partial response for targeted therapy.
Results: 388 eligible patients were enrolled by 1/1/2019 with the most common diagnoses being osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma. 366 patients (94%) have had at least one successful sequencing result, with 349 having molecular and GAIN reports suitable for inclusion in this analysis. 68% of patients (237/349) have received iCat recommendations, with 41% (143/349) having the highest tier of 1-2 and 27% (94/349) having a highest tier of 3-5. Common genes for which tier 1-2 iCat recommendations were made include TP53 (15%), SMARCB1 (4%), PIK3CA (3%), CDK4 (2%), and KRAS (2%). Common alterations for which tier 3-5 recommendations were made include EWSR1 fusions (12%), MYC/MYCN amplifications (8%), and CDKN2A deletions (7%). Of 170 RR patients with treatment follow-up data entered as of June 2019, 15% (25/170) have received matched targeted therapy. Six of these (24%) are considered extraordinary responders. Of note, extraordinary responses were also seen with some second-line chemotherapy and multitargeted kinase inhibitors.
Conclusions: The proportion of patients with clinically significant gene variants is higher in this study than in some previous reports. Providing an iCat recommendation for alterations in genes such as TP53 where evidence is mixed, increased availability of molecularly targeted therapy trials, and more evidence may all be responsible for this increased rate. Reassessment of iCat recommendation tiers based on current evidence is ongoing. Extraordinary responses occur in a subset of children with extracranial solid malignancies who receive matched targeted therapy. Study enrollment is ongoing with further assessments of the impact of tumor profiling on outcome planned.
Citation Format: Laura B. Corson, Alanna J. Church, Deirdre Reidy, Pei-Chi Kao, Wenjun Kang, Navin Pinto, Luke Maese, Theodore W. Laetsch, AeRang Kim, Susan I. Vear, Margaret E. Macy, Mark A. Applebaum, Lobin A. Lee, Duong Doan, R. Seth Pinches, Seong Choi, Suzanne J. Forrest, Catherine M. Clinton, Brian D. Crompton, Laura E. MacConaill, Samuel L. Volchenboum, Neal I. Lindeman, Steven G. DuBois, Wendy B. London, Katherine A. Janeway. Targeted sequencing in 388 patients with high-risk or recurrent/refractory pediatric extracranial solid malignancies: An interim report from the GAIN Consortium/iCat2 Study [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A28.