Search

Background: The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug., Patients and Methods: We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers., Results: Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p < 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib., Conclusion: A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S. Bauer: Consulting or advisory board membership: Adcendio, Bayer, Blueprint Medicines, Boehringer Ingelheim, Daiichi Sankyo, Deciphera, Eli Lilly, Exelixis, GlaxoSmithKline, Nanobiotix, Novartis, Roche; honoraria: Eli Lilly, Novartis PharmaMar; research funding: Blueprint Medicines, Incyte, Novartis; travel or accommodation expenses: PharmaMar. J.T. Siveke: Consulting or advisory board membership: AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Immunocore, Novartis, Roche, Shire; honoraria: AstraZeneca, Aurikamed, Baxalta, Bayer, Bristol Myers Squibb, Celgene, Falk Foundation, iomedico, Immunocore, Novartis, Roche, Shire; research funding: Bristol Myers Squibb, Celgene, Roche; board of directors membership: Pharma15; minor equity: iTheranostics, Pharma15. N. von Bubnoff: Honoraria: Novartis, Takeda. C.B. Westphalen: Consulting or advisory board membership, honoraria, travel or accommodation expenses: Bayer, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Ipsen, Janssen, MedScape, MerckSerono, MSD Sharp & Dohme, Rafael Pharmaceuticals, RedHill, Roche, Servier, Shire/Baxalta, SirTex, Taiho; research funding: Roche. W. Weichert: Consulting or advisory board membership, honoraria: ADC, Agilent, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Eli Lilly, GlaxoSmithKline, Illumina, MerckSerono, Molecular Health, MSD Sharp & Dohme, Novartis, Pfizer, Roche, Siemens, Takeda; research funding: AstraZeneca, Bristol Myers Squibb, MSD Sharp & Dohme, Roche. U. Keilholz: Consulting or advisory board membership, honoraria, research support: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Glycotope, Innate, Medimmune, MerckSerono, MSD Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Sirtex. C. Heining: Consulting or advisory board membership: Boehringer Ingelheim; honoraria: Novartis, Roche; research funding: Boehringer Ingelheim. A. Stenzinger: Consulting or advisory board membership, honoraria: Aignostics, Amgen, AstraZeneca, AGCT, Bayer, Bristol Myers Squibb, Eli Lilly, Illumina, Incyte, Janssen, MSD Sharp & Dohme, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, Thermo Fisher. Research Funding: Bayer, Bristol Myers Squibb, Chugai, Incyte. R.F. Schlenk: Consulting or advisory board membership: Daiichi Sankyo, Pfizer; honoraria: Daiichi Sankyo, Novartis, Pfizer; research funding: Abbvie, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, PharmaMar, Roche; steering committee membership: Daiichi Sankyo; data monitoring committee membership: BerGenBio, Novartis. S. Fröhling: Consulting or advisory board membership: Bayer, Illumina, Roche; honoraria: Amgen, Eli Lilly, PharmaMar, Roche; research funding: AstraZeneca, Pfizer, PharmaMar, Roche; travel or accommodation expenses: Amgen, Eli Lilly, Illumina, PharmaMar, Roche. The other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)