Abstract CT568: β-2 adrenergic receptor (AR): Another immune checkpoint (IC)" A phase II clinical trial of propranolol (P) with pembrolizumab (Pem) in patients with unresectable stage III and stage IV melanoma

Abstract

Background: Adrenergic stress (AS) reduces anti-tumor response by decreasing the frequency and function of CD8+ T- cells in the tumor microenvironment (TME), resulting in an increase in those with an “exhausted” phenotype.1 Additionally, AS increases the quantity and immunosuppressive phenotype of myeloid-derived suppressor cells (MDSC) in the TME.2 The data above suggests that β-2 AR acts akin to a tumorigenic IC which can be abrogated by using P, a well-known and highly cost efficient non-selective β-blocker. Synergistic activity of anti-PD-1 with P has been reported in several murine tumor models, including the B-16 OVA mouse model.3,4 A retrospective study has shown an improvement in overall survival (OS) in patients (pts) with metastatic melanoma (MM) treated concurrently with non-selective β-blocker and immunotherapy.5 This formed the basis for our phase I study of the combination of P (at dose levels; 10 mg, 20 mg BID, and 30mg BID) and pem 200 mg every 3 weeks in pts with MM. Our published phase I results found all 3 dose levels of P to be well tolerated, and an objective response was observed in 7/9 pts.6 A decrease in perceived stress score (PSS) in pts over time was observed. Intra-tumor ratio of (CD4+T cells + CD8+T-cells)/(MDSC+ Treg) >1 in the pre-treatment biopsy was predictive of treatment response. Based on the results of the phase I study, we chose P 30 mg BID as the recommended phase II dose. These results, though preliminary, strongly support our subsequent phase II clinical trial. Methods: In this prospective, single-arm, phase II, multicenter trial, pts with unresectable stage III/IV MM and measurable disease per RECIST v1.1 will be treated with P (30 mg BID) + Pem. Pts with active CNS disease, prior therapy with PD-1/PD-L1 inhibitors, or contraindications to β-blocker are excluded. The primary objective is to evaluate the overall response rate (ORR) by immune-modified RECIST v1.1. The secondary objectives are the assessment of progression free survival and OS. A Simon two-stage design will be employed, requiring a minimum of 29 pts (17 in stage 1 and 12 in stage 2) to achieve approximately 80% power to detect a 20% increase (0.35 to 0.55) in the ORR. As an exploratory analysis, we will further report a) Baseline and on-treatment PSS and b) Chronotropic effect of P after 5-minute treadmill walk as a biomarker of response; c) Post therapy changes in the TME, with a 12 week on therapy optional biopsy d) Peripheral blood changes in T cell and MDSC subsets, and cytokines/chemokines. To date, 10 pts have been accrued on the study (NCT0384836). Citation Format: Benjamin Switzer, Manu R. Pandey, Alexandra Valentine, Agnieszka Witkiewicz, Erik Knudsen, Kristopher Attwood, Joseph Tario, Pauline Funchain, Joseph J. Drabick, Hemn Mohammadpour, Marc S. Ernstoff, Igor Puzanov, Elizabeth A. Repasky, Shipra Gandhi. β-2 adrenergic receptor (AR): Another immune checkpoint (IC)" A phase II clinical trial of propranolol (P) with pembrolizumab (Pem) in patients with unresectable stage III and stage IV melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT568.

Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity

“…This trial noted no dose-limiting toxicities within the 9 enrolled patients and provocative signals of both enhanced objective responses and a reduced toxicity profile compared to historical observations of pembrolizumab monotherapy [31]. In effort to validate these encouraging findings, our group is leading a multicenter phase II portion of this trial (NCT03384836) [91]. In addition, a large review of the EORTC 1325/KEYNOTE-054 trial for patients with resected stage IIIA, IIIB, and IIIC melanoma treated with adjuvant ICI (pembrolizumab) versus placebo noted that although no independent effect on recurrence-free survival was observed in the 10% (n = 99) of patients treated with ICI who also received some form of β-AR blockade within 30 days of starting the trial, there was compelling improvement in those on combination ICI plus β-AR blockade (HR = 0.34) compared to those on ICI without β-AR blockade (HR = 0.59) [92].…”

“…Antagonism of β2-ARs has now exhibited repeated evidence of restoring anti-tumoral immunogenicity as well as enhancing effectiveness of ICI therapies within both pre-clinical and clinical melanoma models [28,66,71]. Our group’s aforementioned multicenter phase II clinical trial observing the benefits of nonselective β-AR when combined with ICI (pembrolizumab) in patients with advanced melanoma is actively enrolling patients, and is expected to provide a more definitive answer regarding the clinical benefit of this combination in the setting of advanced melanoma [91].…”