Therapeutic efficacy of sacituzumab govitecan in recurrent refractory germ cell tumors.

PURPOSE: Recurrent refractory testicular germ cell tumors (rrTGCT) represent very rare disease with limited therapeutic options. Antibody-drug conjugate Sacituzumab govitecan (ADC-SG) targeting TROP2 protein (TACSTD2 gene) demonstrated anti-tumor activity in solid tumors. Our study aimed to investigate efficacy of ADC-SG in rrTGCT.

EXPERIMENTAL

DESIGN

TROP2 expression in tumor samples (n = 71) and cell line-derived xenografts (CDXs) by immunohistochemistry (IHC); and TACSTD 2 expression by qRT-PCR was determined. Cytotoxicity was evaluated in adherent and spheroid conditions. We generated CDXs, TGCT cell-derived metastatic model, and TGCT patient-derived xenografts (PDXs, n = 4) to test ADC-SG cytotoxic activity in vivo. Clinical efficacy of the ADC-SG was evaluated in a rrTGCT patient with progressive disease.

RESULTS

TROP2 expression was confirmed in 98.6 % of TGCTs with significantly higher expression in tumor compared to normal testis, and in non-seminoma versus seminoma (p = 0.00007). TROP2 expression is ubiquitous in GCTs without any significant correlation to overall or disease-free survival, tumor grade or tumor stage. TROP2 was significantly increased in cisplatin (CPT) resistant CDXs. ADC-SG exhibited cytotoxicity at nanomolar concentrations in vitro. ADC-SG treatment significantly increased survival in a metastatic model derived from TGCT cells and decreased PDXs' volume (n = 4). Our case study demonstrated tumor regression accompanied by decrease in serum markers, reduction in lesion size, and improved ECOG performance status in the rrTGCT patient with progressive disease treated with ADC-SG.

CONCLUSION

Our preclinical work on CDX and PDX together with proof-of-concept clinical case provide rationale for further studies. Refractory relapsing TGCTs represent another clinical entity for treatment with ADC-SG.