1936P - Targeted therapy of desmoplastic small round cell tumor guided by multilayered molecular profiling

Background

Desmoplastic small round cell tumor (DSRCT) is an ultra-rare soft-tissue sarcoma characterized by an EWSR1::WT1 gene fusion that affects predominantly male adolescents and young adults. Despite intensive multi-modality treatment outcomes remain dismal, with only 25% of patients being alive after five years. Beyond conventional therapies, novel, molecular mechanism-aware therapies are urgently needed.

Methods

Patients with advanced DSRCT underwent multilayered molecular profiling as part of NCT/DKFZ/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a prospective, multicenter observational study that applies whole-genome/exome, transcriptome, methylome, and – more recently – mass spectrometry-based (phospho-)proteome analysis in young adults with advanced malignancies and patients with rare cancers to inform clinical decision-making and the design of molecularly stratified clinical trials.

Results

Between 2013 and 2022, 29 patients with DSRCT were analyzed with a median follow-up of 17 months (range, 0–48). The median age at the time of molecular analysis was 30 years (range, 18–56). The median time between diagnosis and molecular analysis was 12 months (range, 1–216). The median survival and the 4-year survival rate from registration were 2.4 years (95% confidence interval [CI], 1.4–3 years) and 7.4% (95% CI, 1.2–45.2%), respectively. In 8 of 9 samples with available proteomics data, we observed pronounced activation of ERBB (also called HER) signaling and high ERBB2 mRNA expression levels, providing a rationale for personalized therapy with ERBB2-specific antibody-drug conjugates. In addition, selected somatostatin receptor family members, i.e., SSTR3 and 5, were highly expressed in all patients with available transcriptome data, providing the basis for treatment with pasireotide, a novel multireceptor-targeted somatostatin receptor ligand, within an academic clinical trial, which is currently being prepared.

Conclusions

We describe the molecular profiles of patients with DSRCT enrolled in MASTER and demonstrate the utility of broad molecular profiling for the clinical management of this disease, including the application of targeted treatment strategies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

German Cancer Research Center (DKFZ).

Funding

NCT Molecular Precision Oncology Program, German Cancer Consortium.

Disclosure

S. Bauer: Financial Interests, Personal, Advisory Board, Recurring Advisory Role since 2017 in the context of clinical trial development: Deciphera; Financial Interests, Personal, Advisory Board, Advisory role in the context of clinical trial development: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Advisory role for clinical trial development: Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board, Clinical trial development: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, 2017 : Plexxikon; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker, CME-related presentations: PharmaMar; Financial Interests, Personal, Advisory Board, Advisory role drug development: Roche, Exelixis; Financial Interests, Personal, Advisory Board, Advisory role drug development,: GSK; Financial Interests, Personal, Advisory Board, Advisory Board Drug Development: Adcendo; Financial Interests, Personal, Advisory Board, Drug development: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Coordinating PI, PI for Enliven trial: Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI, Local PI for Avelumab phase I trial: Roche; Financial Interests, Institutional, Coordinating PI, PI for Intrigue, Invictus and DCC-2618-phase I trial and Vimseltinib-phase III; Lead PI for INtrigue trial, Scientific Committee for Invictus and Intrigue: Deciphera; Financial Interests, Institutional, Coordinating PI, PI for JGDJ trial phase I Olaratumab plus Doxo/Ifos: Lilly; Financial Interests, Institutional, Coordinating PI, PI for phase I trials cCGM097, HDM201, STI571-2103: Novartis; Financial Interests, Institutional, Coordinating PI, Local PI und national PI for Voyager and Navigator trial (BLU-285 / Avapritinib): Blueprint Medicines; Financial Interests, Institutional, Coordinating PI, PI (national) for Relatlimab (BMS-CA224-020): BMS; Financial Interests, Institutional, Coordinating PI, PI for IIT with ponatinib in GIST; research Grant (institutional for IIT): Incyte; Non-Financial Interests, Advisory Role, Off-label committee (until 2021); External consultant 2022: BfArm; Non-Financial Interests, Member of Board of Directors, Founding Member of German Sarcoma Foundation: Deutsche Sarkomstiftung (German Sarcoma Foundation ). S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illuminna, PharmaMar, Roche. All other authors have declared no conflicts of interest.