SABR to Oligoprogressive Lesions Delays Systemic Therapy Change in ER+ Advanced Breast Cancer

Steven David, MBBS, FRANZCR

Administration of stereotactic ablative body radiotherapy (SABR) to oligoprogressive lesions delayed a change in combination CDK4/6 inhibitor and aromatase inhibitor (AI) therapy in patients with estrogen receptor (ER)–positive/HER2-negative breast cancer enrolled to the prospective phase 2 AVATAR trial (ACTRN12620001212943).¹

Data presented at the 2023 ASTRO Annual Meeting showed 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 on a CDK4/6 inhibitor plus an 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, 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. Recent studies have indicated that this combinatorial approach can provide a PFS advantage of approximately 2 years, David noted. However, no SOC has been established following disease progression, and next-line systemic treatments have proven to have limited efficacy. “Most patients end up on chemotherapy within 1 year,” David said.

Almost half (~42%) of patients experience oligoprogression as their first progression. “In this study, this is defined as limited metastatic areas progressing whilst on systemic therapy on 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 phase 2 AVATAR study, David and colleagues hypothesized that this approach, when administered to 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, which was conducted at 13 clinical sites throughout Australia, enrolled patients with ER-positive/HER2-negative metastatic breast cancer who had been on a CDK4/6 inhibitor and an AI for at least 6 months and had not progressed. Patients needed to have 1 to 5 oligoprogressive lesions that were all amenable to SABR with at least 1 extracranial lesion.

Participants received SABR to all their oligoprogression sites, with the CDK4/6 inhibitor and AI maintained. Patients were followed up with a computed tomography (CT) scan and a bone scan or positron emission tomography/CT 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 on 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 a size of 32 patients who 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 modified 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 (91%), followed by anastrozole (6%) and exemestane (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%), and 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. “…These results and predictive biomarkers can be developed with further follow-up and larger trials.”

Disclosures: Dr David did not report any disclosures.

Reference

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. Presented at: 2023 American Society for Radiation Oncology Annual Meeting; September 30-October 4, 2023. Abstract LBA 09.