TY - JOUR
T1 - Phase I clinical trial of combination propranolol and pembrolizumab in locally advanced and metastatic melanoma
T2 - safety, tolerability, and preliminary evidence of antitumor activity
AU - Gandhi, Shipra
AU - Pandey, Manu R.
AU - Attwood, Kristopher
AU - Ji, Wenyan
AU - Witkiewicz, Agnieszka K.
AU - Knudsen, Erik S.
AU - Allen, Cheryl
AU - Tario, Joseph D.
AU - Wallace, Paul K.
AU - Cedeno, Carlos D.
AU - Levis, Maria
AU - Stack, Suzanne
AU - Funchain, Pauline
AU - Drabick, Joseph J.
AU - Bucsek, Mark J.
AU - Puzanov, Igor
AU - Mohammadpour, Hemn
AU - Repasky, Elizabeth A.
AU - Ernstoff, Marc S.
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Purpose: Increased b-adrenergic receptor (b-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly b2-AR, provides a more favorable TME that enhances the activity of anti–PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective b-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. Patients and Methods: A 3 þ 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II 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 patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. 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 IFNg and a decrease in IL6 was noted in responders. Conclusions: Combination of propranolol with pembrolizumab in treatment-nave metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.
AB - Purpose: Increased b-adrenergic receptor (b-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly b2-AR, provides a more favorable TME that enhances the activity of anti–PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective b-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. Patients and Methods: A 3 þ 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II 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 patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. 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 IFNg and a decrease in IL6 was noted in responders. Conclusions: Combination of propranolol with pembrolizumab in treatment-nave metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.
UR - http://www.scopus.com/inward/record.url?scp=85098235955&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098235955&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-2381
DO - 10.1158/1078-0432.CCR-20-2381
M3 - Article
C2 - 33127652
AN - SCOPUS:85098235955
SN - 1078-0432
VL - 27
SP - 87
EP - 95
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -