Phase I study of Androgen deprivation therapy in combination with anti-PD-1 in patients pre- treated with anti-PD-1


 Purpose: Androgen deprivation regenerates the thymus in adults, expanding of T-cell receptor V beta repertoire in blood and lymphoid organs and tumour-infiltrating lymphocytes in human prostate tumours. In melanoma murine models, androgen receptor promotes metastases and androgen blockade potentiates antitumor vaccine efficacy. This phase I study evaluated the safety, efficacy, and pharmocodynamics of androgen deprivation with the gonadotropin releasing hormone (GnRH) agonist triptorelin combined with nivolumab in male melanoma patients resistant to anti-PD-1. Experimental Design: Adult male patients with advanced melanoma who progressed under anti-PD-1 containing regimens received triptorelin 3.75 mg every 4 weeks, nivolumab 3 mg/kg every 2 weeks, and bicalutamide 50 mg once daily during the first 28 days. Tumour response was first assessed after 3 months; adverse events (AEs) were monitored throughout the study. T-cell Receptor Excision Circles (TRECs), a biomarker of thymus activity, were explored throughout the study. Results: Of 14 patients, 4 were locally advanced and 10 had distant metastases. There were no grade 4 or 5 AEs. Five grade 3 AEs were reported in 4 patients. According to RECIST v1.1, best overall response was partial response (PR) in one patient with a pancreas metastasis, stable disease (SD) in 5 patients, and progressive disease in 8 patients. According to iRECIST, a second PR occurred after an initial pseudoprogression, TRECs increased in two patients, one with PR who also had an increase in TILs, and the second with SD. Conclusions: This combination was well tolerated. Disease control in 42.8% (RECIST) and 50% (iRECIST).Thymus rejuvenation was limited.