1777P - Molecular profiling from next-generation sequencing (NGS) reveals new potential therapeutic targets in patients with pediatric-type sarcomas

Background

Effective therapy in pediatric-type sarcomas for adult patients remains an unmet need, with older age being a poor prognostic factor. NGS can identify potential therapeutic targets and characterize the tumor microenvironment (TME) in these patients.

Methods

Whole-exome and whole-transcriptome NGS were performed on samples from 16 patients aged 4–62 years with pediatric-type fusion-driven sarcoma (PTFDS: Ewing sarcoma - EwS, alveolar rhabdomyosarcoma - AlvR) to identify potentially targetable molecular events and classify samples into TME subtypes. The frequency of targetable events was compared between younger and older patients; the selected cutoff of 30 years is a common age limit in disease-specific clinical trials.

Results

Detected genetic events included EWSR1-FLI1 (n = 9), PAX3-FOXO1 (n = 5), and EWSR1-ETV4 (n = 1) fusions; RB1 (n = 1) and PTEN (n = 1) losses; somatic and germline CDKN2A (n = 2) mutations, somatic TP53 (n = 2), PIK3CA (n = 1), ATM (n = 1) and germline BRCA1 (n = 1) mutations; FGFR4 (n = 2), MYC (n = 1), and EZH2 (n = 1) amplifications. We hypothesized that worse outcomes in older PTFDS patients could be associated with increased frequency of additional targetable driver events. We compared the frequency of targetable genetic events between younger (4-28 years, median = 23) and older (32-62 years, median = 40) patients with EwS and AlvR. Targetable events were more common in older (71%, 5/7) compared to younger patients (22%, 2/9), albeit the sample size was too small to reach statistical significance. Transcriptomic-based TME profiling showed that 94% (n =15) of patients had Fibrotic/Immune Desert subtypes associated with a predicted poor response to immune checkpoint inhibitors (ICI). One EwS patient had an Immune-Enriched subtype associated with predicted benefit from ICI. The distribution of TME subtypes within sarcoma types conforms well with previously reported lack of response to ICI in PTFDS patients.

Conclusions

Comprehensive molecular profiling revealed targetable events that may benefit older patients with PTFDS by expanding potential therapeutic options and inclusion in biomarker-driven trials without strict age limits.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

BostonGene, Corp.

Disclosure

A.P. Conley: Financial Interests, Personal, Research Funding: Eli Lilly, EpicentRx, Kronos Bio, Krystal Biotech, Inhbrx, NCI, Roche; Financial Interests, Personal, Research Grant: Chordoma Foundation; Financial Interests, Personal, Speaker, Consultant, Advisor: Aadi Biosciences, Guide Point. A. Aukhadieva, I. Zhuk, M. Voropaeva: Financial Interests, Personal, Financially compensated role: BostonGene, Corp.; Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp. A. Novokreshchenova: Financial Interests, Personal, Financially compensated role: BostonGene, Corp.; Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp.; Financial Interests, Personal, Stocks/Shares: BostonGene, Corp. A.E. Shevkoplias: Financial Interests, Personal, Financially compensated role: BostonGene, Corp.; Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp. K. Zirov: Financial Interests, Personal, Financially compensated role: BostonGene, Corp.; Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp. A. Makarova: Financial Interests, Personal, Financially compensated role: BostonGene, Corp. A. Dubrovskaya: Financial Interests, Personal, Financially compensated role: BostonGene, Corp.; Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp. A. Nadiryan: Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp.; Financial Interests, Personal, Financially compensated role, employee: BostonGene, Corp. L. Balabanian: Financial Interests, Personal, Financially compensated role, employee: BostonGene, Corp.; Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp. A. Bagaev: Financial Interests, Personal, Financially compensated role: BostonGene, Corp.; Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp.; Financial Interests, Personal, Stocks/Shares: BostonGene, Corp.; Financial Interests, Personal, Proprietary Information: BostonGene, Corp. E. Choy: Financial Interests, Personal, Advisory Board: Sonata Therapeutics, Adaptimmune; Financial Interests, Personal, Research Funding: Adaptimmune, Amgen, AstraZeneca, Bayer, Exelixis, GSK, Iterion, Novartis, Merck, Mirati. R. Ratan: Financial Interests, Personal, Advisory Board: SpringWorks, Ipsen; Financial Interests, Personal, Advisory Role: Inhibrx; Financial Interests, Personal, Coordinating PI: Ayala, C4 Therapeutics, SpringWorks; Financial Interests, Personal, Research Funding: SpringWorks, C4 Therapeutics, Ayala; Financial Interests, Personal, Speaker, Consultant, Advisor, Invited Speaker: SpringWorks. L. Bednyagin: Financial Interests, Personal, Financially compensated role: BostonGene, Corp.; Financial Interests, Personal, Full or part-time Employment: BostonGene, Corp.; Financial Interests, Personal, Stocks/Shares: BostonGene, Corp. S.P. Chawla: Financial Interests, Personal, Stocks/Shares, Own stocks.: Cellestia pharma; Financial Interests, Personal, Stocks/Shares, Stocks: Adi Biopharma; Financial Interests, Personal, Ownership Interest, Owner and stocks: Counterpoint; Financial Interests, Institutional, Local PI, Clinical research: Amgen; Financial Interests, Institutional, Local PI, Research: Adi bio, NK Gene, BMS, Rain Therapeutic, Shasqui, Monopar, Ayala, Boeinger; Financial Interests, Personal, Local PI, Research: Rain Therapeutic, Molleculin.