Phase 1 Study: Beta-Blocker May Improve Melanoma Treatment Response

Walter Alexander

December 10, 2020

Response rates were high without dose-limiting toxicities in a small phase 1 study that evaluated the addition of propranolol to pembrolizumab in treatment-naive patients with metastatic melanoma.

"To our knowledge, this effort is the first prospective clinical trial to show that the combination of propranolol with pembrolizumab is safe, and additionally suggests preliminary synergistic antitumor activity in treatment-naive metastatic melanoma," wrote the two co-first authors, Shipra Gandhi, MD, and Manu Pandey, MBBS, from the Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and coauthors.

The need for combinations built on anti-PD1 checkpoint inhibitor therapy strategies in metastatic melanoma that safely improve outcomes is underscored by the high (59%) grade 3 or 4 treatment-related adverse event (TRAE) rates when an anti-CTLA4 agent (ipilimumab) was added to an anti-PD-1 agent (nivolumab), they noted. In contrast, a TRAE rate of only 17% has been reported with pembrolizumab monotherapy.

The phase 1b study was stimulated by preclinical, retrospective observations of improved overall survival (OS) in cancer patients treated with beta-blockers. These were preceded by murine melanoma studies showing decreased tumor growth and metastasis with the nonselective beta-blocker propranolol. "Propranolol exerts an antitumor effect," the authors stated, "by favorably modulating the tumor microenvironment (TME) by decreasing myeloid-derived suppressor cells and increasing CD8+ T-cell and natural killer cells in the TME." Other research in a melanoma model in chronically-stressed mice has demonstrated synergy between an anti-PD1 antibody and propranolol.

"We know that stress can have a significant negative effect on health, but the extent to which stress may impact the outcome of cancer therapy is not well understood at all," Ghandi said in a statement provided by Roswell Park. "We set out to better understand this relationship and to explore its implications for cancer treatment."

The investigators recruited nine White adults (median age 65 years) with treatment-naive, histologically confirmed unresectable stage III or IV melanoma and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 to the open-label, single arm, nonrandomized, single-center, dose-finding study. Patients received standard of care intravenous pembrolizumab 200 mg every 3 weeks and, in three groups, propranolol doses of 10 mg, 20 mg, or 30 mg twice a day until 2 years on study or disease progression or the development of dose-limiting toxicities (DLTs). Assessing the safety and efficacy (overall response rate [ORR] within 6 months of starting therapy) of pembrolizumab with the increasing doses of propranolol and selecting the recommended phase 2 dose were the study's primary objectives.

Objective responses (complete or partial responses) were reported in seven of the nine patients, with partial tumor responses in two patients in the propranolol 10-mg group, two partial responses in the 20-mg group, and three partial responses in the 30-mg group.

While all patients experienced TRAEs, only one was above grade 2. The most commonly reported TRAEs were fatigue, rash and vitiligo, reported in four of the nine patients. Two patients in the 20-mg twice-a-day group discontinued therapy because of TRAEs (hemophagocytic lymphohistiocytosis and labyrinthitis). No DLTs were observed at any of the three dose levels, and no deaths occurred on study treatment.

The authors said that propranolol 30 mg twice a day was chosen as the recommended phase 2 dose, because in combination with pembrolizumab, there were no DLTs, and preliminary antitumor efficacy was observed in all three patients. Also, in all three patients, the investigators observed a trend toward higher CD8+T-cell percentage, higher ratios of CD8+T-cell/ Treg and CD8+T-cell/ polymorphonuclear myeloid-derived suppressor cells. They underscored, however, that the small size and significant heterogeneity in biomarkers made a statistically sound and meaningful interpretation of biomarkers for deciding the phase 2 dose difficult.

"In repurposing propranolol," Pandey said in the Roswell statement, "we've gained important insights on how to manage stress in people with cancer – who can face dangerously elevated levels of mental and physical stress related to their diagnosis and treatment."

In an interview, one of the two senior authors, Elizabeth Repasky, PhD, professor of oncology and immunology at Roswell Park, said, "it's exciting that an extremely inexpensive drug like propranolol that could be used in every country around the world could have an impact on cancer by blocking stress, especially chronic stress." Her murine research showing that adding propranolol to immunotherapy or radiotherapy or chemotherapy improved tumor growth control provided rationale for the current study.

"The breakthrough in this study is that it reveals the immune system as the best target to look at, and shows that what stress reduction is doing is improving a patient's immune response to his or her own tumor," Repasky said. "The mind/body connection is so important, but we have not had a handle on how to study it," she added.

Further research funded by Herd of Hope grants at Roswell will look at tumor effects of propranolol and nonpharmacological reducers of chronic stress such as exercise, meditation, yoga, and Tai Chi, with first studies in breast cancer.

The study was funded by Roswell Park, private, and NIH grants. The authors had no disclosures.

SOURCE: Gandhi S et al. Clin Cancer Res. 2020 Oct 30. doi: 10.1158/1078-0432.CCR-20-2381

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