The BRACELET-01 trial has revealed promising results for pelareorep, an investigational oncolytic virus immunotherapy, when combined with paclitaxel chemotherapy in patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. The Phase II randomized study, published in Clinical Cancer Research, offers new hope for a patient population that has shown limited response to immunotherapy approaches.
Trial Design and Patient Population
The study enrolled 48 patients between June 2020 and June 2022, with a median age of 55 years. All participants had unresectable metastatic HR+ HER2- breast cancer and had experienced disease progression after receiving at least one line of endocrine therapy with a cyclin-dependent kinase 4/6 inhibitor. Most participants were White, non-Hispanic, and postmenopausal.
Following a safety run-in phase, 45 patients were randomized 1:1:1 into three treatment groups: paclitaxel alone, paclitaxel plus pelareorep, or paclitaxel combined with pelareorep and avelumab. Patients remained on study until progression or unacceptable toxicity occurred.
Key Efficacy Results
The primary endpoint was objective response rate (ORR) at 16 weeks, which showed notable differences across treatment arms. The paclitaxel-pelareorep combination achieved a 31% ORR, compared to 20% for paclitaxel alone and 14% for the triple combination including avelumab.
Progression-free survival (PFS) results were even more striking. The median PFS was 12.1 months for the paclitaxel-pelareorep combination, significantly longer than the 6.4 months observed with paclitaxel monotherapy. However, the addition of avelumab resulted in a shorter median PFS of 5.8 months.
"There were numerically higher ORR and PFS in the Pac/Pel group, compared to Pac alone, but more adverse events were reported in the combination arms," said Dr. Amy S. Clark, a medical oncologist at Penn Medicine in Philadelphia and first author of the report.
Immunological Insights
A critical finding emerged regarding T-cell proliferation, which is crucial for immunotherapy efficacy. By cycle 4, patients receiving paclitaxel plus pelareorep exhibited a pronounced boost in T-cell clones, suggesting enhanced immune potential with the combination. This effect was not observed in patients receiving paclitaxel alone.
"Notably, a boost in T-cell clones was seen by cycle 4 in the Pac/Pel arm but not in the Pac arm, suggesting enhanced immune potential with the combination," Dr. Clark explained.
The addition of avelumab to the combination further increased toxicity and blunted T-cell responses without providing an obvious increase in efficacy, suggesting potential immune exhaustion or immunosuppressive effects when all three agents were combined.
Mechanism of Action
Pelareorep is a naturally occurring, non-pathogenic oncolytic virus with two key complementary actions when administered intravenously. First, it stimulates anti-tumor immune responses by selectively infecting and lysing tumor cells, releasing tumor-associated antigens. Second, it enhances the immune system's ability to recognize and respond to tumors by modulating the tumor microenvironment.
The trial tested the hypothesis that exposure to paclitaxel and pelareorep can upregulate PD-L1 expression, thereby sensitizing HR+ HER2- tumors to checkpoint inhibition with avelumab. This approach was based on intriguing findings from the Canadian Cancer Trials Group, where pooled data from four separate trials across various solid tumors suggested that the paclitaxel-pelareorep combination improved overall survival compared to paclitaxel alone in the HR+ HER2- metastatic breast cancer cohort.
Safety Profile
The combination arms showed increased adverse events compared to paclitaxel monotherapy, with the triple regimen being particularly challenging in terms of tolerability. The observed toxicity underscores the importance of carefully balancing immune activation against immune-related adverse events.
"Our study results support further investigation of the paclitaxel-pelareorep combination while monitoring acute toxicity. Until now, immunotherapy in patients with HR+ HER2- metastatic breast cancer has been largely unsuccessful, prompting the trial to test if paclitaxel and pelareorep could enhance sensitivity to checkpoint inhibition with avelumab," said Dr. Clark.
Clinical Implications
The results are particularly significant for HR+ HER2- metastatic breast cancer, a subtype that has historically been refractory to immunotherapy approaches. The capacity of pelareorep to render 'cold' tumors immunologically 'hot' offers an innovative avenue toward overcoming therapeutic resistance.
"These intriguing results from PrECOG 0113 merit additional study of this novel treatment," said Peter J. O'Dwyer, MD, chief executive officer of PrECOG.
The BRACELET-1/PrECOG 0113 study was coordinated by PrECOG, LLC and funded by Oncolytics Biotech, Pfizer, and Merck KGaA, Darmstadt, Germany. The findings provide a compelling rationale for further exploration of refined regimens and dosing strategies to harness the full potential of integrated immuno-viral and chemotherapeutic synergy in this challenging patient population.
