Phase I clinical trial of combination propranolol and pembrolizumab in locally advanced and metastatic melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity
Mené sur 9 patients atteints d'un mélanome de stade métastatique et de stade localement avancé, cet essai de phase I évalue la dose maximale tolérée du propranolol en combinaison avec le pembrolizumab et l'efficacité, du point de vue du taux de réponse objective à 6 mois, de cette combinaison
Purpose: Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment. Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR provides a more favorable anti-tumor microenvironment that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immune suppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here we report the results of dose escalation of a non-selective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. Experimental Design: A 3 + 3 dose-escalation study for propranolol BID with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, antitumor activity and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. Results: Nine metastatic melanoma patients received increasing doses of propranolol in cohorts of 10, 20 and 30 mg BID. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue and vitiligo, observed in 44% patients. One patient developed two ≥ grade 3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFN-γ and a decrease in IL-6 was noted in responders. Conclusions: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg BID was selected as RP2D in addition to pembrolizumab based on safety, tolerability and preliminary antitumor activity.