Pelareorep Plus Paclitaxel Induces Responses in Metastatic HR+/HER2– Breast Cancer

The combination of the oncolytic reovirus pelareorep and paclitaxel generated responses in patients with metastatic hormone receptor (HR)–positive/HER2-negative breast cancer, according to data from the phase 2 BRACELET-1 trial (NCT04215146) presented at the 2023 ASCO Annual Meeting.^1,2

Notably, findings also showed that the addition of avelumab (Bavencio) to pelareorep and paclitaxel increased toxicity without an obvious increase in efficacy.

At week 16, the overall response rate (ORR) was 31% (95% CI, 11%-59%) in patients treated with pelareorep plus paclitaxel (n = 16). The ORR was 20% (95% CI, 4%-48%) in patients who were given paclitaxel alone (n = 15) and 14% (95% CI, 2%-43%) in those who received pelareorep, avelumab, and paclitaxel (n = 14).

The disease control rate was 62% (95% CI, 35%-85%) for the pelareorep/paclitaxel arm, 47% (95% CI, 21%-73%) for the paclitaxel arm, and 64% (95% CI, 35%-87%) for the pelareorep/avelumab/paclitaxel arm.

Updated data showed that confirmed ORR over the course of the trial was 37.5% for pelareorep plus paclitaxel, 13.3% for paclitaxel alone, and 17.6% for the triplet.²

“BRACELET-1’s positive results complement prior phase 2 data showing a statistically significant increase in overall survival [OS] when pelareorep was combined with paclitaxel by demonstrating similar robust improvements in progression-free survival [PFS] and ORR in less heavily pretreated patients,” Matt Coffey, PhD, president and chief executive officer of Oncolytics Biotech, stated in a news release. “Given this exciting finding, our next step is to discuss our data with the FDA to investigate incorporating dual PFS and OS end points into our breast cancer program's registrational study. Including a PFS endpoint could substantially reduce the time to a pivotal readout from the registrational trial, thereby accelerating pelareorep’s path to potential approval as we work to address the urgent needs of [patients with] HR-positive/HER2-negative breast cancer.”

Pelareorep is a type 3 reovirus that invades and lyses tumor cells and promotes an inflammatory tumor microenvironment.¹ Data from a prior phase 2 trial showed that the combination of the oncolytic reovirus plus paclitaxel resulted in a median OS of 17.4 months vs 10.4 months with paclitaxel alone.³

BRACELET-1 was designed to further evaluate the efficacy of pelareorep plus paclitaxel and investigate the efficacy of the addition of avelumab to the doublet.

The study included patients with metastatic estrogen receptor– or progesterone receptor–positive/HER2-negative breast cancer who progressed on at least 1 hormone-based therapy with a CDK4/6 inhibitor. Other key inclusion criteria included an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, and adequate organ and hematologic function. No prior chemotherapy for metastatic disease was permitted.

Patients were randomly assigned 1:1:1 to receive paclitaxel alone, pelareorep plus paclitaxel, or pelareorep plus avelumab and paclitaxel. Paclitaxel was given on days 1, 8, and 15 of each 28-day cycle. Pelareorep was administered on days 1, 2, 8, 9, 15, and 16, and avelumab was given on days 3 and 17.

ORR at week 16 served as the trial’s primary end point. Secondary end points included ORR at the end of study, OS, PFS, safety, tolerability, and biomarker assessments, including PD-L1 expression and T-cell clonality.

The study was designed to include 15 patients in each cohort, plus 3 patients for a safety run-in with the triplet. Notably, power calculation was not performed, and formal tests of statistical significance were not planned.

Between June 2020 and June 2022, the study enrolled 48 patients. Three patients from the paclitaxel arm withdrew consent prior to starting therapy. One patient in the pelareorep/paclitaxel arm and another in the pelareorep/avelumab/paclitaxel arm discontinued treatment at 1 week, and they were considered nonresponders and censored for PFS. Notably, 27% of patients (n = 9/33) discontinued pelareorep and 35% of patients (n = 6/17) discontinued avelumab due to toxicity.

Among all 48 patients, the median age was 55.5 years (range, 37-74), and the majority of patients were White (77%) and non-Hispanic (90%), postmenopausal (62%), had an ECOG performance status of 0 (65%), and had visceral disease (83%). Prior therapy included neoadjuvant or adjuvant taxane (31%), alpelisib (Piqray; 6%), everolimus (Afinitor; 10%), and a CDK4/6 inhibitor (100%).

Additional data showed that the median PFS was 9.6 months (95% CI, 6.5-not reached [NR]) for pelareorep/paclitaxel, 6.4 months (95% CI, 2.0-NR) for paclitaxel, and 5.8 months (95% CI, 3.5-NR) for the triplet. The 6-month PFS rates were 86% (95% CI, 54%-96%), 62% (95% CI, 28%-84%), and 50% (95% CI, 18%-74%), respectively. OS data continue to mature.

Regarding safety, more than one-third of patients treated with pelareorep experienced fever, chills, and/or influenza-like symptoms. Infusion reactions were also more common in those treated with pelareorep with or without avelumab.

The most common any-grade adverse effects (AEs) as attributed to study drugs included alopecia (50% for paclitaxel; 56% for pelareorep/paclitaxel; 47% for the triplet), anemia (58%; 31%; 59%), anorexia (33%; 31%; 29%), chills (0%; 44%; 29%), diarrhea (8%; 38%; 47%), fatigue (42%; 75%; 47%), infusion-related reaction (8%; 19%; 53%), leucopenia (17%; 19%; 65%), liver-function test abnormality (25%; 38%; 53%), lymphopenia (25%; 19%; 24%), nausea (33%; 44%; 47%), neuropathy (25%; 50%; 59%), neutropenia (25%; 31%; 59%), proteinuria (17%; 38%; 24%), and pyrexia (0%; 50%; 65%).

Pharmacokinetic data showed that significant expansion of T-cell clones was observed by cycle 4 in patients treated with pelareorep plus paclitaxel, but not in patients given pelareorep plus paclitaxel and avelumab.

References

1. Clark AS, Zhao F, Klein P, et al. BRACELET-1 (PrE0113): Inducing an inflammatory phenotype in metastatic HR+/HER2- breast cancer with the oncolytic reovirus pelareorep in combination with paclitaxel and avelumab. J Clin Oncol. 2023;41(suppl 16):1012. doi:10.1200/JCO.2023.41.16_suppl.1012
2. Oncolytics Biotech announces updated randomized phase 2 data from BRACELET-1 metastatic breast cancer trial that show pelareorep driving robust increases in progression-free survival and confirmed overall response rate. News release. Oncolytics Biotech. June 5, 2023. Accessed June 29, 2023. https://ir.oncolyticsbiotech.com/press-releases/detail/601/oncolytics-biotech-announces-updated-randomized-phase-2
3. Bernstein V, Ellard SL, Dent SF, et al. A randomized phase II study of weekly paclitaxel with or without pelareorep in patients with metastatic breast cancer: final analysis of Canadian Cancer Trials Group IND.213. Breast Cancer Res Treat. 2018;167(2):485-493. doi:10.1007/s10549-017-4538-4