Final Analysis of Consolidative Use of Radiotherapy to Block (CURB) Oligoprogression Trial - A Randomized Study of Stereotactic Body Radiotherapy for Oligoprogressive Metastatic Lung and Breast Cancers

Purpose/Objective(s) To assess if stereotactic body radiotherapy (SBRT) for oligoprogressive metastatic lung or breast cancer prolongs progression-free survival (PFS), overall survival (OS), and alters circulating tumor (ct)DNA profile. Materials/Methods We enrolled patients with metastatic non-small-cell lung cancer (NSCLC) or breast cancer with ≤5 oligoprogressive lesions after ≥1 line of systemic therapy. Stratification factors included number of oligoprogressive lesions, prior immunotherapy, primary site, and receptor/mutation status. Patients were randomized 1:1 to standard of care (SOC) with or without SBRT to all progressive sites. The primary endpoint was PFS. Secondary endpoints included OS, toxicity, and quality-of-life (QoL). Blood was collected at baseline and at 8 weeks for ctDNA analysis. A hybridization capture and deep sequencing assay was used to identify genomic alterations and calculate estimated variant allele frequencies (VAFs) of tumor-derived mutations. Patients were followed for 12 months for PFS and until death or last contact for OS. One-sided stratified log-rank test was used to assess survival outcomes. Results From January 2019 to July 2021, 106 patients were randomized - 59 with NSCLC and 47 with breast cancer. Most (75%) had >1 site of oligoprogression and 47% had >5 total lesions. The majority of NSCLCs (86%) had no actionable driver mutation and 66% of breast cancers were triple-negative. Median PFS was 3.2 months in SOC arm vs. 7.2 months in SBRT arm (p=0.002). Stratified analysis showed that NSCLC patients derived substantial PFS benefit from SBRT (2.2 months in SOC vs. 10 months in SBRT arm; p=0.002), whereas breast cancer patients did not (4.2 vs. 4.4 months, p=0.2). No difference in OS between arms has yet been seen in either cohort. Grade ≥2 toxicities occurred in 8 patients after SBRT. There was no difference in QoL between treatment arms. The study was closed to accrual after a preplanned interim analysis crossed a prespecified efficacy threshold. Analysis of 52 pairs of baseline and 8-week blood samples with detectable ctDNA showed significant reduction of median VAFs over time comparing SBRT to SOC in the NSCLC cohort (p=0.03), but not the breast cancer cohort (p=0.56). Increasing median VAFs at 8 weeks was predictive of subsequent disease progression (Hazard Ratio: 1.17, 95% CI: 1.02-1.36, p=0.03), independent of treatment arm or primary site. Conclusion In this first and largest randomized trial of radiotherapy for oligoprogressive metastatic cancer, we observed a more than 4-fold PFS benefit in patients with oligoprogressive metastatic NSCLC receiving SBRT, with corresponding decrease in ctDNA VAFs. There was no PFS benefit or change in ctDNA after SBRT for breast cancer, suggesting a more diffusely systemic pathophysiology. The benefit of SBRT in oligoprogressive metastatic NSCLC will require validation in a larger study and the distinction in oligoprogressive biology between these diseases warrants further evaluation. To assess if stereotactic body radiotherapy (SBRT) for oligoprogressive metastatic lung or breast cancer prolongs progression-free survival (PFS), overall survival (OS), and alters circulating tumor (ct)DNA profile. We enrolled patients with metastatic non-small-cell lung cancer (NSCLC) or breast cancer with ≤5 oligoprogressive lesions after ≥1 line of systemic therapy. Stratification factors included number of oligoprogressive lesions, prior immunotherapy, primary site, and receptor/mutation status. Patients were randomized 1:1 to standard of care (SOC) with or without SBRT to all progressive sites. The primary endpoint was PFS. Secondary endpoints included OS, toxicity, and quality-of-life (QoL). Blood was collected at baseline and at 8 weeks for ctDNA analysis. A hybridization capture and deep sequencing assay was used to identify genomic alterations and calculate estimated variant allele frequencies (VAFs) of tumor-derived mutations. Patients were followed for 12 months for PFS and until death or last contact for OS. One-sided stratified log-rank test was used to assess survival outcomes. From January 2019 to July 2021, 106 patients were randomized - 59 with NSCLC and 47 with breast cancer. Most (75%) had >1 site of oligoprogression and 47% had >5 total lesions. The majority of NSCLCs (86%) had no actionable driver mutation and 66% of breast cancers were triple-negative. Median PFS was 3.2 months in SOC arm vs. 7.2 months in SBRT arm (p=0.002). Stratified analysis showed that NSCLC patients derived substantial PFS benefit from SBRT (2.2 months in SOC vs. 10 months in SBRT arm; p=0.002), whereas breast cancer patients did not (4.2 vs. 4.4 months, p=0.2). No difference in OS between arms has yet been seen in either cohort. Grade ≥2 toxicities occurred in 8 patients after SBRT. There was no difference in QoL between treatment arms. The study was closed to accrual after a preplanned interim analysis crossed a prespecified efficacy threshold. Analysis of 52 pairs of baseline and 8-week blood samples with detectable ctDNA showed significant reduction of median VAFs over time comparing SBRT to SOC in the NSCLC cohort (p=0.03), but not the breast cancer cohort (p=0.56). Increasing median VAFs at 8 weeks was predictive of subsequent disease progression (Hazard Ratio: 1.17, 95% CI: 1.02-1.36, p=0.03), independent of treatment arm or primary site. In this first and largest randomized trial of radiotherapy for oligoprogressive metastatic cancer, we observed a more than 4-fold PFS benefit in patients with oligoprogressive metastatic NSCLC receiving SBRT, with corresponding decrease in ctDNA VAFs. There was no PFS benefit or change in ctDNA after SBRT for breast cancer, suggesting a more diffusely systemic pathophysiology. The benefit of SBRT in oligoprogressive metastatic NSCLC will require validation in a larger study and the distinction in oligoprogressive biology between these diseases warrants further evaluation.