The results of first phase II, open-label, randomised controlled study of stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites in patients with metastatic breast cancer or non-small cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as 5 or less progressive lesions on PET/CT or CT show increase in progression-free survival (PFS) in the SBRT plus standard-of-care group compared with standard-of-care only among patients with oligoprogressive metastatic NSCLC. However, no benefit was observed in patients with oligoprogressive breast cancer.
Analyses of paired pre-randomisation and post-randomisation blood samples showed that radiotherapy led to changes in ctDNA metrics in patients with NSCLC, but not in patients with breast cancer. The findings are published by Dr. Chiaojung Jillian Tsai of the Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network in Toronto, ON, Canada and colleagues of the Consolidative Use of Radiotherapy to Block (CURB) oligoprogression study group on 14 December 2023 in The Lancet.
Several prospective randomised clinical trials have shown that ablative radiotherapy in patients with oligometastatic cancer can improve PFS and overall survival (OS). However, its benefit is unclear in the context of oligoprogression, where patients with extensive metastatic disease on systemic therapy manifest primarily stable disease except for progression at a few sites.
Oligoprogression arises from clonal heterogeneity and tumour evolution, where a few progressive lesions are driven by resistant clones not substantially present in other metastatic sites; it can occur in patients with oligometastatic cancer or with widespread metastatic or polymetastatic disease. As a more recently described term, oligoprogressive disease does not have a universally accepted definition and remains a complex and not fully understood concept, with most studies using an arbitrary cut-off of 3 to 5 progressive lesions.
Selective local therapy of oligoprogressive sites aims to prolong disease control of an otherwise effective systemic therapy, since the non-progressive widespread disease is not comprehensively irradiated. By contrast, local ablative therapy for oligometastatic disease aims to achieve durable cancer remission by treating all disease sites.
Randomised controlled trials investigating the clinical impact of local ablative therapy in patients with oligoprogressive disease have not been published yet. Considering the success of ablative radiotherapy for oligometastatic disease and advances elucidating the role of tumour heterogeneity in resistance to therapy, the CURB study investigators hypothesised that ablative radiotherapy could benefit patients with oligoprogressive metastatic cancer.
Patients aged 18 years or older were enrolled from a tertiary cancer centre and 6 affiliated regional centres in US, with a 1:1 randomisation between standard-of-care group and SBRT plus standard-of-care 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 PFS measured up to 12 months. The study investigators did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. As an exploratory objective, they also assessed possible changes in cell-free DNA because liquid biomarkers have been shown to be associated with prognosis and treatment outcomes.
From 1 January 2019 to 31 July 2021, a total of 106 patients were randomly assigned, of whom 51 to standard-of-care (23 patients with breast cancer and 28 patients with NSCLC) and 55 to SBRT plus standard-of-care (24 patients with breast cancer and 31 patients with NSCLC). Among 47 patients with breast cancer, 16 (34%) had triple-negative disease, and 51 of 59 patients with NSCLC (86%) 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 pre-planned 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 plus standard-of-care group.
The median PFS was 3.2 months (95% confidence interval [CI] 2.0–4.5) for patients in the standard-of-care group versus 7.2 months (95% CI 4.5–10.0) for patients in the SBRT plus standard-of-care group (hazard ratio [HR] 0.53, 95% CI 0.35–0.81; p = 0.0035). The median PFS was higher for patients with NSCLC in the SBRT plus standard-of-care group than for those with NSCLC in the standard-of-care group only, 10.0 versus 2.2 months (HR 0.41, 95% CI 0.22–0.75; p = 0.0039), but no difference was found for patients with breast cancer, 4.4 versus 4.2 months (HR 0.78, 95% CI 0.43–1.43; p = 0.43).
Grade 2 or worse adverse events occurred in 21 patients (41%) in the standard-of-care group and 34 patients (62%) in the SBRT plus standard-of-care group. Nine patients (16%) in the SBRT plus standard-of-care group had grade 2 or worse side effects related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts.
The authors commented that the study was not powered to detect an OS benefit and was closed early due to a larger than anticipated PFS benefit. Any survival effect could have been compromised by the fact that 59% of patients in the standard-of-care group received off-protocol SBRT treatment after disease progression. A large phase III clinical trial will be required to show the presence or absence of an OS benefit. Nonetheless, prolonged PFS, preserving disease control without requiring a shift to a new and potentially more toxic systemic therapy, is arguably a meaningful benefit for patients with metastatic disease, even in the absence of a definitive survival benefit.
Several ongoing randomised trials are currently investigating the potential benefits of ablative radiotherapy in patients with oligoprogressive cancer, all with PFS as their primary endpoint. A phase II, randomised STOP study has completed accrual, and results are expected to be reported soon. Additionally, 2 ongoing randomised studies are specifically investigating the potential benefit of SBRT in patients with oligoprogressive NSCLC, the HALT and the SUPPRESS-NSCLC trials with results expected to provide further insights into the efficacy of SBRT.
In an accompanied comment, Drs. Gerard G Hanna of the Department of Oncology, Belfast Health and Social Care Trust and Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, both in Belfast, UK and Fiona McDonald of the Department of Radiotherapy, The Royal Marsden NHS Foundation Trust in London, UK wrote that CURB study provides the first randomised evidence of benefit from SBRT in patients with oligoprogressive NSCLC, albeit in a subset of a phase II study. A phase III study should be undertaken to better understand the potential benefit, including the effect on OS.
Many questions remain regarding the role of SBRT to treat various oligometastatic disease states, including the biological mechanisms of action. The optimal sequence and safety of systemic agents in combination with SBRT should also be further understood. At present, definitive evidence as to the optimal number of known metastases to be treated is not available; however, a subset analysis of the ORIOLE study suggested that treating all metastases is associated with improved survival outcomes. Predictive and prognostic biomarkers should also be developed to better identify patients who would benefit the most from SBRT and from consolidative therapy after SBRT. The analysis of ctDNA from the CURB study provides a valuable insight into the potential utility of this technology.
The CURB study was funded by the US National Cancer Institute Cancer Center Support Grant.
References
- Tsai CJ, Yang JT, Shaverdian N, et al. on behalf of the CURB Study Group. 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. The Lancet; Published online 14 December 2023. DOI: https://doi.org/10.1016/S0140-6736(23)01857-3
- Hanna GG, McDonald F. SBRT for oligoprogressive disease: using the evidence to maximise the benefits. The Lancet; Published online 14 December 2023. DOI: https://doi.org/10.1016/S0140-6736(23)02351-6