SABR Delays Systemic Therapy Change in ER+ Advanced Breast Cancer

Steven David, MBBS, FRANZCR

Patients with ER-positive/HER2-negative metastatic breast cancer who progress after frontline endocrine therapy have limited treatment options, which usually include systemic chemotherapy. Findings from the phase 2 AVATAR trial (ACTRN12620001212943) suggest stereotactic ablative body radiotherapy (SABR) may postpone the use of systemic therapy, offering these patients another option.

Data presented at the 2023 American Society for Radiation Oncology (ASTRO) Annual Meeting demonstrated that at a median follow-up of 15.8 months, the median event-free survival (EFS) with SABR was 5.2 months (95% CI, 3.1-9.4), with an EFS of 6 months or greater in 47% (95% CI, 29%-65%) of patients, meeting the primary end point of the trial.

The median modified progression-free survival (PFS) was 10.4 months; this was partly due to 31% of patients receiving SABR for further oligoprogression. Notably, 46% of patients maintained treatment with a CDK4/6 inhibitor plus an aromatase inhibitor (AI) for 1 year. The median PFS was 5.2 months (95% CI, 3.1-6.8). The overall survival (OS) rate was 100%, with no deaths occurring during the study period.

“These findings suggest that patients with oligoprogressive ER-positive/HER2-negative breast cancer should be considered for SABR in lieu of a change in systemic therapy,” Steven David, MBBS, FRANZCR, associate professor and radiation oncologist at Peter MacCallum Cancer Centre in Melbourne, Australia, said in a presentation of the data.

The current standard of care (SOC) for patients with ER-positive/HER2-negative metastatic breast cancer is frontline endocrine therapy in the form of a CDK4/6 inhibitor paired with an AI. Data from recent studies have indicated that this combined approach can increase PFS up to approximately 2 years, David noted. However, no SOC has been established following disease progression, and next-line systemic treatments have limited efficacy. “Most patients end up [receiving] chemotherapy within 1 year,” David said.

Close to half (~42%) of patients experience oligoprogression as their first progression. “In this study, this is defined as limited metastatic areas progressing [while the patient is receiving] systemic therapy [with] a background of either oligometastatic or polymetastatic disease,” David explained. “These lesions may represent subclones of disease that have acquired resistance to a CDK4/6 inhibitor and an AI via various pathways.”

SABR has been shown to be a safe and effective option for patients with advanced cancer when administered to limited metastatic sites. For the AVATAR study, David and colleagues hypothesized that this approach, when used for oligoprogressive lesions in this population, would delay a change in systemic treatment by at least 6 months in more than 25% of patients.

The trial was conducted at 13 clinical sites throughout Australia and enrolled patients with ER-positive/HER2-negative metastatic breast cancer who had not progressed after receiving a CDK4/6 inhibitor and an AI for at least 6 months. Patients needed to have 1 to 5 oligoprogressive lesions that were amenable to SABR and with at least 1 extracranial lesion.

Participants received SABR for all their oligoprogression sites, with the CDK4/6 inhibitor and AI maintained. Patients were followed up with a CT scan and a bone scan or positron emission tomography/CT scan every 3 months for 2 years. If patients experienced oligoprogression, they were allowed to receive further treatment with SABR.

“SABR was considered to be meaningful if [at least] 25% of patients remained event free and [were receiving] an AI and a CDK4/6 inhibitor for at least 6 months,” David said. “We expected that about 50% of patients would require a change in therapy at 6 months; this yielded…32 patients [for whom investigators] were required to reject the null hypothesis with [a greater than] 80% power and a 2.5% 1-sided alpha.” EFS served as the trial’s primary end point; this was defined as a change in systemic therapy, progression within 6 months of enrollment, or progression in more than 3 lesions. A key secondary end point was modifi ed PFS, which was defined as a change in systemic therapy or progression that is not amenable to SABR per the treating clinician’s discretion, which was reflective of the real-world time to change in systemic therapy. Other secondary end points included PFS, OS, and treatment-related adverse effects (TRAEs).

In the total population (n = 32), the median age was 61.4 years (range, 37.6-84.1); most (97%) patients were female. Regarding ECOG performance status, 78% of patients had a status of 0, 19% had a status of 1, and 3% had a status of 2. Notably, just under half of patients (44%) had de novo metastatic disease, and 59% of patients had more than 5 metastases in their disease course.

Palbociclib (Ibrance; 69%) was the most common CDK4/6 inhibitor used, followed by ribociclib (Kisqali; 28%) and abemaciclib (Verzenio; 3%).

The most common AI utilized was letrozole (Femara; 91%), followed by anastrozole (Arimidex; 6%) and exemestane (Aromasin; 3%). Additionally, the most common disease site treated for oligoprogression was the bone (71%), followed by node (systemic; 13%), lung (6%), node (regional; 5%), liver (3%), and other (2%). The most common doses of SABR that were utilized were 20 Gy in 1 fraction (17%) and 24 Gy in 2 fractions (43%). The number of lesions treated were 1 (50%), 2 (25%), 3 (19%), or 4 (6%).

Investigators also performed an exploratory analysis to identify potential predictors for PFS with this approach. The multivariable model showed that having more than 5 metastases during the disease course was predictive for disease progression (HR, 3.7; 95% CI, 1.3-10.4; P = .008). “Surprisingly, bone-only oligoprogressing metastases had worse PFS [multivariable HR, 0.3; 95% CI, 0.1-0.9; P = .021],” David noted.

Regarding TRAEs, 14 patients had grade 1 events, and 2 patients had grade 2 events; no grade 3 or higher events were observed. Forty-seven percent of patients did not experience any treatment-related toxicity.

“This is the first prospective trial investigating SABR to delay a change in therapy in this population. The approach was well tolerated,” David concluded. “…Th ese results and predictive biomarkers can be developed with further follow-up and larger trials.”

Disclosures: Dr David did not report any disclosures.

REFERENCE

1. David SP, Siva S, Bressel M, et al. Stereotactic ablative body radiotherapy (SABR) for oligoprogressive ER-positive breast cancer (AVATAR): a phase II prospective multicenter trial. Abstract presented at: 2023 American Society for Radiation Oncology Annual Meeting; October 1-4, 2023; San Diego, CA. Abstract LBA 09.