Abstract 1536P
Background
Immunomodulation has emerged as an active therapeutic option in some solid tumors; however, the efficacy of immunotherapy-based regimens is limited in sarcomas or restricted to a few specific subtypes. IMMUNOSARC was a phase Ib/II trial testing the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab) in bone and soft-tissue sarcoma (STS). In this latter cohort, the trial met its primary endpoint, with 48% of patients free of progression at 6 months (m). We present here, part of the correlative studies associated with the STS cohort.
Methods
Paraffin tumor blocks were prospectively collected at baseline (before sunitinib initiation). Direct transcriptomics was performed using HTG Molecular Oncology Biomarker panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA). Differential gene expression was analyzed accordingly to 6-m progression-free survival (PFS).
Results
Among the 65 STS patients enrolled in the trial, 61 samples at baseline were used for this analysis. Of 2,549 transcripts analyzed, 369 genes were significantly and differently overexpressed according to 6-m PFS: 192 and 177 genes were associated with better or worse outcome, respectively. Gene ontology (GO) analysis showed that genes associated with worse PFS were related with biological processes, such as DNA metabolism (GO:0006259; combined score (CS): 771.10, p<0.001), DNA repair (GO:0006281; CS: 292.93, p<0.001), cellular response to DNA damage (GO:0006974; CS: 231.39, p<0.001), or positive regulation of cell cycle (GO:0090068; CS: 512.62, p<0.001). On the other hand, genes associated with a PFS >6-m were related with GO biological processes such as cellular response to cytokine stimulus (GO:0071345; CS: 160.05, p<0.001) or cytokine-mediated signaling (GO:0019221; CS: 134.90, p<001).
Conclusions
DNA damage repair (DDR) and cell cycle-related processes seemed to be associated with worse outcome to immunotherapy-based schemes. Further studies are warranted to understand the potential added value of cell cycle inhibitors or DDR-targeted therapies to immunotherapy.
Clinical trial identification
NCT03277924.
Editorial acknowledgement
Legal entity responsible for the study
J. Martín-Broto.
Funding
Sarcoma Foundation of America - SFA.
Disclosure
D. Moura: Financial Interests, Personal, Other: Pfizer. N. Hindi: Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Sponsor/Funding: Eli Lilly; Financial Interests, Institutional, Sponsor/Funding: AROG; Financial Interests, Institutional, Sponsor/Funding: Bayer; Financial Interests, Institutional, Sponsor/Funding: Eisai; Financial Interests, Institutional, Sponsor/Funding: Lixte ; Financial Interests, Institutional, Sponsor/Funding: Karyopharm; Financial Interests, Institutional, Sponsor/Funding: Deciphera; Financial Interests, Institutional, Sponsor/Funding: GSK; Financial Interests, Institutional, Sponsor/Funding: Novartis; Financial Interests, Institutional, Sponsor/Funding: Blueprint; Financial Interests, Institutional, Sponsor/Funding: Nektar; Financial Interests, Institutional, Sponsor/Funding: Forma; Financial Interests, Institutional, Sponsor/Funding: Amgen; Financial Interests, Institutional, Sponsor/Funding: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: PharmaMar; Financial Interests, Personal, Other: PharmaMar. G. Grignani: Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Personal, Other: PharmaMar; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Other: Lilly; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other: Bayer; Financial Interests, Personal, Other: Eisai. A. Redondo: Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Personal, Other: PharmaMar; Financial Interests, Personal, Other: Lilly; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Tesaro; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Other: Roche; Financial Interests, Institutional, Research Grant: Eisai. S. Stacchiotti: Financial Interests, Personal and Institutional, Other: Bayer; Financial Interests, Personal and Institutional, Other: Lilly; Financial Interests, Personal and Institutional, Other: PharmaMar; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Pfizer. J.A. Lopez-Martin: Financial Interests, Personal, Other: PharmaMar; Financial Interests, Personal, Other: Eli Lilly; Financial Interests, Personal, Other: Bayer; Financial Interests, Personal, Other: Eisai; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: BMS; Financial Interests, Personal, Other: MSD; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: Celgene; Financial Interests, Personal, Other: Pierre Fabre; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other: GSK; Financial Interests, Personal, Other: Daiichi Sankyo; Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other: Chobani. J. Martin Broto: Financial Interests, Personal, Expert Testimony, Honoraria: Lilly; Financial Interests, Personal, Expert Testimony, Honoraria: PharmaMar; Financial Interests, Personal, Expert Testimony, Honoraria: Eisai; Financial Interests, Personal, Expert Testimony, Honoraria: Bayer; Financial Interests, Personal, Invited Speaker: PharmaMar; Financial Interests, Institutional, Invited Speaker: PharmaMar; Financial Interests, Institutional, Invited Speaker: Eisai; Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Invited Speaker: IMMIX Biopharma; Financial Interests, Institutional, Invited Speaker: Lixte; Financial Interests, Institutional, Invited Speaker: Karyopharm; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Invited Speaker: Celgene; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: BMS; Financial Interests, Institutional, Invited Speaker: Blueprint; Financial Interests, Institutional, Invited Speaker: Deciphera; Financial Interests, Institutional, Invited Speaker: Nektar; Financial Interests, Institutional, Invited Speaker: Forma; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: Arog; Financial Interests, Institutional, Invited Speaker: Adaptimmune; Financial Interests, Institutional, Invited Speaker: GSK. All other authors have declared no conflicts of interest.