Standard-of-care systemic therapy with or without stereotactic body radiotherapy in patients with oligoprogressive breast cancer or non-small-cell lung cancer (Consolidative Use of Radiotherapy to Block [CURB] oligoprogression): an open-label, randomised, controlled, phase 2 study

Abstract

Background: Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes.

Methods: We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete.

Findings: From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts.

Interpretation: The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted.

Funding: National Cancer Institute.

Figure 1.. CONSORT Diagram.

Illustration of patients enrolled on study and arm assignment

Figure 2.. Progression Free Survival.

A.) Median PFS in the entire cohort was increased in the SBRT arm vs. No SBRT arm (7.2 vs 3.2 months, stratified log-rank p=0∙003).B.) Median PFS was not different in patients with breast cancer in each arm (4.2 vs. 4.4 months; stratified log-rank p=0.2). C.) Median PFS increased 4-fold in patients with NSCLC treated with SBRT (10 vs. 2.2 months, stratified log-rank p=0∙004). SBRT: stereotactic body radiotherapy

Figure 2.. Progression Free Survival.

A.) Median PFS in the entire cohort was increased in the SBRT arm vs. No SBRT arm (7.2 vs 3.2 months, stratified log-rank p=0∙003).B.) Median PFS was not different in patients with breast cancer in each arm (4.2 vs. 4.4 months; stratified log-rank p=0.2). C.) Median PFS increased 4-fold in patients with NSCLC treated with SBRT (10 vs. 2.2 months, stratified log-rank p=0∙004). SBRT: stereotactic body radiotherapy

Figure 2.. Progression Free Survival.

A.) Median PFS in the entire cohort was increased in the SBRT arm vs. No SBRT arm (7.2 vs 3.2 months, stratified log-rank p=0∙003).B.) Median PFS was not different in patients with breast cancer in each arm (4.2 vs. 4.4 months; stratified log-rank p=0.2). C.) Median PFS increased 4-fold in patients with NSCLC treated with SBRT (10 vs. 2.2 months, stratified log-rank p=0∙004). SBRT: stereotactic body radiotherapy

Figure 3.. Patterns of Disease Progression.

A.) Visual illustration indicating distinct patterns of disease progression after treatment, including (i) stable disease (ii) progression in pre-existing lesions, (iii) development of new sites of metastatic disease. B.) Patterns of disease progression by disease type and treatment arm. There was a significant difference in the anatomic pattern of progression in patients who did not receive SBRT; most patients with breast cancer developed new lesions whereas only a minority of NSCLC patients developed new lesions (61% vs. 14%, p=0.001). In patients with oligoprogressive NSCLC, SBRT significantly reduced progression in pre-existing lesions (68% vs 26%, p=0.002). C.) Assessment of systemic disease burden with analysis of pre- and 8-weeks post-enrollment ctDNA analysis. In NSCLC, SBRT leads to a reduction in ctDNA (p=0.02), which does not occur with standard of care therapy. In contrast, in breast cancer, neither SBRT nor standard of care influence ctDNA dynamics. Of note, the 5 patients who dropped out of the study before completing one year of follow up were categorized as having stable disease at the time of study withdrawal. SBRT: stereotactic body radiotherapy

Figure 3.. Patterns of Disease Progression.

A.) Visual illustration indicating distinct patterns of disease progression after treatment, including (i) stable disease (ii) progression in pre-existing lesions, (iii) development of new sites of metastatic disease. B.) Patterns of disease progression by disease type and treatment arm. There was a significant difference in the anatomic pattern of progression in patients who did not receive SBRT; most patients with breast cancer developed new lesions whereas only a minority of NSCLC patients developed new lesions (61% vs. 14%, p=0.001). In patients with oligoprogressive NSCLC, SBRT significantly reduced progression in pre-existing lesions (68% vs 26%, p=0.002). C.) Assessment of systemic disease burden with analysis of pre- and 8-weeks post-enrollment ctDNA analysis. In NSCLC, SBRT leads to a reduction in ctDNA (p=0.02), which does not occur with standard of care therapy. In contrast, in breast cancer, neither SBRT nor standard of care influence ctDNA dynamics. Of note, the 5 patients who dropped out of the study before completing one year of follow up were categorized as having stable disease at the time of study withdrawal. SBRT: stereotactic body radiotherapy

Figure 3.. Patterns of Disease Progression.

A.) Visual illustration indicating distinct patterns of disease progression after treatment, including (i) stable disease (ii) progression in pre-existing lesions, (iii) development of new sites of metastatic disease. B.) Patterns of disease progression by disease type and treatment arm. There was a significant difference in the anatomic pattern of progression in patients who did not receive SBRT; most patients with breast cancer developed new lesions whereas only a minority of NSCLC patients developed new lesions (61% vs. 14%, p=0.001). In patients with oligoprogressive NSCLC, SBRT significantly reduced progression in pre-existing lesions (68% vs 26%, p=0.002). C.) Assessment of systemic disease burden with analysis of pre- and 8-weeks post-enrollment ctDNA analysis. In NSCLC, SBRT leads to a reduction in ctDNA (p=0.02), which does not occur with standard of care therapy. In contrast, in breast cancer, neither SBRT nor standard of care influence ctDNA dynamics. Of note, the 5 patients who dropped out of the study before completing one year of follow up were categorized as having stable disease at the time of study withdrawal. SBRT: stereotactic body radiotherapy