Roswell Park researchers assessing pembrolizumab/propranolol combination in patients with advanced melanoma

  • At AACR Annual Meeting, researchers give update on clinical trial in progress
  • Phase 2 study currently open to accrual at Roswell Park and 2 other centers
  • Team explores whether beta-blockers can redirect immune response to stress

NEW ORLEANS, La. — Combining a beta-blocker with the cancer immunotherapy drug pembrolizumab could be a promising new treatment option for many hard-to-treat solid-tumor cancers. Researchers from Roswell Park Comprehensive Cancer Center demonstrated the safety of this treatment combination in patients with advanced or metastatic melanoma In the first prospective clinical trial of this approach, and will report on a follow-on trial in progress Monday, April 11, at the American Association for Cancer Research (AACR) Annual Meeting 2022.

Image showing beta blocker pills and stethoscope
Researchers at Roswell Park are exploring whether beta-blocker drugs can improve treatment for melanoma. A growing body of evidence suggests that stress-induced beta-2 adrenergic signals are independently dampening a variety of antitumoral immune responses and, in turn, functioning as an immune checkpoint.
Using propranolol — a nonselective beta-blocker commonly prescribed to treat high blood pressure and other conditions — to inhibit these pathways seems to enhance the antitumoral immune response, the Roswell Park team notes. As more research sheds light on the potential of this approach, it may prove to be not only safe but also a highly cost-effective immune checkpoint inhibitor.

“Our recently published data from the phase I dose-escalation portion of this trial not only confirmed that the combination of propranolol plus pembrolizumab appears safe, but a provocative observed overall response rate of 78% suggests that this combination may be achieving a more meaningful anti-tumoral immune response as compared to traditional standards of care with pembrolizumab monotherapy,” says the study’s first author, Benjamin Switzer, DO, MHSA, MS, a hematology/oncology fellow at Roswell Park, who led the study in collaboration with Shipra Gandhi, MD, Assistant Professor of Oncology at Roswell Park.

To confirm and validate the favorable response rates observed in phase I, a phase II trial is underway, with patients being actively enrolled at Roswell Park and two other major academic centers.

For this prospective, single-arm, multicenter trial, patients with unresectable stage III/IV metastatic melanoma are treated with 30mg of propranolol twice a day — the recommended phase II dose. Patients with active central nervous system disease, prior PD-1/PD-L1 immune checkpoint therapy, or contraindications to β-blockers were excluded from the study. The researchers will evaluate overall response rate of this treatment combination, with secondary objectives including the assessment of progression-free and overall survival.

The researchers will also analyze possible impacts related to:

  • Perceived stress
  • The chronotropic effect of propranolol as a biomarker of response
  • The immune profile of post-therapy changes in the tumor microenvironment between pre- and 12-week post-treatment biopsy, and
  • Peripheral blood alterations in T cells, myeloid-derived suppressor cells subsets, and cytokines/chemokines.

No new safety signals or adverse events have been observed to date, with 10 patients treated on the still-accruing study. An interim analysis will be conducted to ensure the efficacy of this combination once an additional seven patients are enrolled.

The research is based on the seminal work of Elizabeth Repasky, PhD, The Dr. William Huebsch Professor in Immunology and Vice Chair of Immunology at Roswell Park, establishing the connections between chronic stress, beta-adrenergic signaling stimulating the immune system, and cancer. Dr. Switzer received a Fellow’s Research Award from the Roswell Park Alliance Foundation, enabling an extensive expansion of correlative analyses as part of this work.

This abstract, 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 CT568/ LB-7806), will be presented Monday, April 11, from 9 a.m. to 12:30 p.m. CT, as part of the Phase II Trials in Progress session. Because Dr. Switzer is participating in the meeting virtually, the poster is being presented as an e-poster.