ABSTRACT
Stereotactic ablative radiotherapy (SABR) may extend the clinical benefit of immune checkpoint inhibitors (ICI) in patients with oligoprogressive disease. However, individual benefit varies, and validated biomarkers to guide patient selection are lacking. We hypothesize that cell-free DNA (cfDNA) and the neutrophil-to-lymphocyte ratio (NLR) may be associated with outcomes after SABR in this setting. This prospective observational study included patients with oligoprogression under ICI therapy who received concomitant SABR to all oligoprogressive lesions (cohort A). Cohort B was a parallel biomarker cohort of oligometastatic patients receiving only SABR. Blood samples were collected before SABR (T1), after the first (T2) and last (T3) fractions, and two months after SABR (T4). The objective response rate (ORR) was evaluated by iRECIST in all lesions. Prespecified cfDNA and NLR time points were explored in relation to modified progression-free and overall survival (OS). We assessed 104 patients. With a median follow-up of 12 months, ORR was 59% in cohort A and 65% in cohort B. In cohort A, cfDNA <0.37 ng/µL at T3 was associated with improved 1-year OS (91% vs 62%, p = 0.031), while NLR <1.8 at T1 was associated with improved 1-year OS (100% vs 70%, p = 0.01). In cohort B, a >3% increase in cfDNA from T2 to T4 and NLR <4 at T4 were associated with improved OS. These findings support further evaluation of cfDNA and NLR as accessible biomarkers for patient stratification in oligoprogressive disease treated with SABR while maintaining an ICI.
Keywords: Oligoprogression, oligometastasis, stereotactic ablative radiotherapy, immunotherapy, cell-free DNA, neutrophil-to-lymphocyte ratio
Introduction
The treatment of metastatic cancer has traditionally been based on systemic therapy alone. 1 However, the concept of oligometastatic disease (OMD) has paved the way for the use of local treatments in patients with a limited number of metastases (usually up to five lesions in up to three organs). 2 , 3 Stereotactic ablative radiotherapy (SABR) is a non-invasive technique that delivers high doses of radiation in few fractions with extreme precision and minimal toxicity. These characteristics make it an ideal option for patients with OMD. 4 Several studies in recent years have shown the benefit of SABR in these patients, either combined with systemic therapy or alone. 5-8
Parallel to the introduction of SABR in metastatic cancer, immunotherapy in the form of immune checkpoint inhibitors (ICI) has revolutionized the standard of care (SoC). 9 Compared with traditional chemotherapy (ChT), ICIs offer improved results in both progression-free survival (PFS) and overall survival (OS) with a better toxicity profile. ICI monotherapy or with ChT is currently the SoC in many metastatic cancers, including non-small cell lung cancer (NSCLC) and melanoma. 10 , 11 Despite these advances, important challenges remain. Up to 80% of patients do not respond to ICI, and subsequent lines of systemic therapy offer limited survival in most cases. 12 Combinations such as dual ICI or ICI plus ChT can improve results, but at the cost of higher toxicity. 13 , 14
Concurrently with advances in systemic therapies, the concept and clinical definition of OMD have evolved substantially, leading to more refined patient selection and therapeutic decision-making. 15 In this context, the reported benefit of SABR for OMD can offer an opportunity to improve the effect of ICI. Oligoprogression is a special form of OMD in which patients experience disease progression in a limited number of lesions under active systemic therapy. 3 SABR can extend the clinical benefit and delay the need for a change in systemic therapy, as shown in several studies. 16 , 17 Oligoprogression under ICI may represent a clinically relevant model of limited acquired resistance in which local ablation of resistant lesions could allow for the continuation of otherwise effective ICI while providing interesting synergies owing to the immunogenic effects of radiotherapy (RT), which may modulate systemic antitumor immunity. 18 Even though there is growing evidence of the benefit of combining immunotherapy with SABR (I-SABR), not all patients seem to benefit from this approach, with both positive and negative trials in this setting. 16 , 19 At present, there are no biomarkers that can guide the use of I-SABR or even define the concept of OMD beyond a set number of lesions. Circulating tumor DNA (ctDNA) and other analytes in liquid biopsy are increasingly being studied in clinical trials as potential biomarkers. 20 Nonetheless, many of these biomarkers are difficult to generalize owing to their cost, technical complexity and variety of laboratory pipelines. 21 We hypothesize that more accessible and platform-agnostic blood biomarkers, such as cell-free DNA (cfDNA) and the neutrophil-to-lymphocyte ratio (NLR) may be associated with outcomes after I-SABR in oligoprogressive disease (OPD). Therefore, we performed an exploratory analysis of these translational readouts as part of a prospective study. Proof-of-concept results in a small subset of patients from this protocol have been reported elsewhere, showing preliminary translational results associated with early response. 22 In the present study, we expand on those findings by incorporating more patients, updated follow-up, and further translational analyses evaluating circulating biomarkers associated with survival.
Methods and materials
Participants
This ongoing prospective observational study was conducted at eight hospitals in Spain and started recruitment in February 2022. Cohort A includes metastatic patients from any primary tumor type with OPD (up to 5 extracranial lesions) while under ICI (monotherapy or with other agents) but maintaining the same line due to clinical benefit 23 and referred for SABR. The exclusion criteria include: (1) Eastern Cooperative Oncology Group (ECOG) performance status of 3–4; (2) brain metastases; (3) pseudo-progression or hyperprogression; (4) severe immune-related adverse effects; or (5) previous RT that would interfere with further treatment. Cohort B includes patients receiving only SABR due to de novo or oligorecurrent disease from any primary tumor type (up to 5 extracranial lesions). Oligorecurrent patients must not have received systemic therapy at least three months before progression. Cohort B was included as a parallel cohort for exploratory evaluation of blood-based biomarkers. It was not designed as a clinical control group for cohort A. Baseline disease extent was assessed by computed tomography (CT) scan. Positron emission tomography-computed tomography (PET-CT) was additionally available in 12 patients in cohort A and 16 patients in cohort B. Brain magnetic resonance imaging was not performed as part of baseline staging, as all included patients had a recent brain CT without evidence of intracranial disease. The study protocol was approved by the Provincial Ethics Board of Malaga (Approval number: “02/2022.PI8”) and followed the standards of the Declaration of Helsinki. 24 Written informed consent was obtained from all participants. An early subset of these cohorts has been previously reported. 22 The current study includes expanded cohorts with longer follow-up times and additional translational readouts not included in the prior publication.
Clinical protocol
Treatment in cohort A closely followed the protocol of a previous study in OPD. 17 Patients received RT to all their progressing lesions (up to 5). SABR was delivered in 35 Gy/5 fractions (fx) on alternate days or 24 Gy/3 fx in case of dose limitations, based on previously published data. 17 Organ-at-risk (OAR) dose constraints in both cohorts followed UK SABR Consortium recommendations. 25 Systemic therapy was maintained per standard protocol concomitantly with SABR and continued until further progression, severe toxicity or medical/patient decisions were reached. In the case of subsequent OPD, new courses of SABR were accepted if the clinical benefit was maintained (up to three courses). This was considered an extension of clinical benefit and, therefore, was not viewed as disease progression in our protocol. In cohort B, SABR was delivered in ablative doses to all lesions (up to 5), adapted to lesion location and OAR constraints, according to the protocol in each hospital. Up to three courses of SABR were permitted in cases of further limited progression. The response was evaluated by Immune Response Evaluation Criteria in Solid Tumors (iRECIST) and RECIST 1.1 with CT two months after SABR and then every three months. 26 , 27 The response was assessed by two independent radiologists. The study size was established by consecutive sampling, recruiting patients referred for SABR who fulfilled the inclusion criteria. Given the few data on OPD available at the design of the study, the sample size was calculated by assuming a 25% objective response rate (ORR) with ICI in the metastatic population and an expected 42% ORR with I-SABR in our cohort, according to previous data. 17 , 28 Considering a 20% drop-out rate, a sample size of 72 patients in each cohort for paired within-patient biomarker analyses across sampling time points was estimated to be enough to detect meaningful changes in biomarkers with a 90% confidence interval (CI) and a power of 80%.
Translational protocol
We collected blood samples from patients in both cohorts at several time points: recruitment (T1); after the first (T2) and last (T3) SABR fx; two months after the end of SABR (T4); and in the case of further progression (TP). To analyze cfDNA, we gathered samples in CellSave tubes (Menarini Silicon Biosystem Inc., Castel Maggiore, Italy) and then centrifuged them at 1600 rpm for 10 min. The remaining plasma was centrifuged at 4750 rpm for 10 min. The plasma samples were stored at −80 °C in 3 mL cryovials. cfDNA was isolated from plasma with the QIAamp Circulating Nucleic Acid kit (Qiagen, Germantown, MD, 55114, USA) according to the manufacturer’s protocol. cfDNA was measured using 1X Qubit High Sensitivity instrument (Thermo Fisher Scientific, Waltham, MA, USA). The fragment size, quality, and quantity of random samples were evaluated with a Bioanalyzer 2100 instrument (Agilent Technologies, Santa Clara, CA, USA). cfDNA was measured across all time points. The NLR was calculated from the absolute neutrophil and lymphocyte count in a standard hemogram at T1 and T4.
Study endpoints
The primary clinical endpoint was the ORR in terms of complete (CR) and partial (PR) responses evaluated in all lesions during follow-up. For biomarkers, cfDNA and NLR were explored in relation to modified progression-free survival (mPFS) and overall survival (OS). mPFS was defined by a subsequent progression that cannot be salvaged with further SABR treatments and requires the start of a new systemic therapy. The secondary endpoints included local control (LC), defined by CR, PR, and stable disease (SD), and toxicity, according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE). The study protocol contemplates an interim analysis 36 months after the start of recruitment and a final analysis once recruitment is completed with at least 18 months of follow-up for each patient. Biomarker sampling time points and endpoints were prespecified by the protocol. However, the specific survival associations, optimal timepoints, and candidate cutoffs were identified through exploratory analysis.
Statistical analysis
For this interim analysis, we employed SPSS version 26.0 (IBM) and RStudio 12.0 (https://cran.r-project.org). OS and mPFS were estimated with the Kaplan–Meier method, and survival curves were compared using the log-rank test. Data for patients who were alive were censored for OS at the time of the last follow-up. Data for those who were alive and had no tumor progression were censored to evaluate mPFS and LC at the last assessment. Both continuous and categorical variables were explored to identify possible differences in Kaplan‒Meier survival curves, but quantitative variables were grouped to form categories including: (1) the total number of metastases were grouped into oligometastatic (up to 5) or polymetastatic (more than 5) following the consensus of the European Society for Radiotherapy and Oncology − American Society for Radiation Oncology guidelines 29 ; (2) PD-L1 expression was grouped as ≥50% or <50% according to the tumor proportion score; (3) driver mutations were categorized as yes/no; (4) previous RT was grouped as yes/no; (5) previous systemic lines were grouped as 0, 1, or ≥2; and (6) the number of progressing sites were categorized in 1, 2 or ≥3. The quantitative variables NLR and cfDNA were categorized using optimization via the Maxstat method. 30 To discriminate the differences between two numerical variables, the Wilcoxon rank-sum test (Mann–Whitney U test) was employed. The paired Wilcoxon signed-rank test was used for comparisons involving paired observations between two time points. This test was applied to assess significant changes within paired data points, specifically examining increases or decreases in variables over time. We explored prespecified biomarker time points and longitudinal changes to identify clinically relevant associations. We also evaluated the association of cfDNA and NLR as continuous variables with survival through Cox regression. To control for confounding factors, we employed a Cox multivariate analysis including clinical and molecular variables. Variables with infinite estimations were excluded from these analyses as they did not comply with the model criteria. Two-sided P ≤ .05 was defined as statistically significant.
Results
Baseline characteristics
From February 2022 to February 2025, 163 patients were screened. Of these, 140 completed SABR (23 patients failed screening), and 104 had undergone at least the first imaging reevaluation for this analysis (61 in cohort A and 43 in B). Only one patient from cohort B was lost during follow-up (Figure 1). Patient and treatment characteristics are described in Table 1. In cohort A, the most frequent tumor type was lung cancer (51%, n = 31) under the first line of systemic therapy (56%, n = 34), mainly based on anti-PD-1 (70%, n = 43). Most patients had one lesion in progression (61%, n = 37) due to secondary resistance (after an initial favorable response to ICI, 82%, n = 50%) in the context of a polymetastatic disease (51%, n = 31). The most frequent sites of irradiation were nodal metastases (46%, n = 49 lesions). In cohort B, most patients also had lung cancer (30%, n = 13) with a single lesion (72%, n = 31) located in the lungs (60%, n = 37 lesions) and were initially diagnosed with OMD (84%, n = 36). Forty-two percent had received no previous lines of systemic therapy (n = 18). The median size for target lesions was 2.8 cm (range, 0.5–16 cm) and 1.7 cm for nontarget lesions (range, 0.7–13 cm). Regarding SABR fractionation, in cohort A, 45 of the 49 nodal lesions were treated with 35 Gy in 5 fx, and 4 with 24 Gy in 3 fx. In cohort B, the most frequently used schedules overall were 50 Gy in 5 fx (n = 25), 35 Gy in 5 fx (n = 21), and 54 Gy in 3 fx (n = 6). The lung lesions in cohort B were treated mainly with 50 Gy in 5 fx (n = 25) but also with 54 Gy in 3 fx, 55 Gy in 5 fx, 60 Gy in 8 fx, or 60 Gy in 5 fx.
Figure 1.
Flow diagram of the study.
Table 1.
Patient and treatment characteristics.
| Characteristic | Cohort A (n = 61) | Cohort B (n = 43) |
|---|---|---|
| Sex | ||
| Male | 45 (74%) | 27 (63%) |
| Female | 16 (26%) | 16 (37%) |
| Median age, years (range) | 66 (31–83) | 67(38–81) |
| ECOG | ||
| 0 | 29 (47%) | 21 (49%) |
| 1 | 26 (43%) | 22 (51%) |
| 2 | 6 (10%) | 0 |
| Primary tumor | ||
| Lung | 31 (51%) | 13 (30%) |
| Renal | 6 (10%) | 7 (16%) |
| Urothelial | 6 (10%) | 2 (5%) |
| Melanoma | 8 (13%) | 0 |
| Colorectal | 0 | 7 (16%) |
| Other | 10 (16%) | 14 (33%) |
| PD-L1 status | ||
| <50% | 21 (35%) | 7 (16%) |
| ≥50% | 10 (16%) | 4 (9%) |
| Unknown | 30 (49%) | 32 (75%) |
| Driver mutations | ||
| Yes | 9 (15%) | 4 (9%) |
| No | 52 (85%) | 39 (91%) |
| Number of systemic therapy lines before SABR | ||
| 0 | 0 | 18 (42%) |
| 1 | 34 (56%) | 18 (42%) |
| ≥2 | 27 (44%) | 7 (16%) |
| Previous radiotherapy | ||
| Yes | 26 (43%) | 19 (44%) |
| No | 35 (57%) | 24 (56%) |
| Metastatic stage at diagnosis | ||
| Oligometastatic (1–5 lesions) | 30 (49%) | 36 (84%) |
| Polymetastatic (>5 lesions) | 31 (51%) | 7 (16%) |
| Current ICI | ||
| Anti-PD-1 | 43 (70%) | – |
| Anti-PD-L1 | 9 (15%) | – |
| Other | 9 (15%) | – |
| Primary resistance to ICI | ||
| Yes | 11 (18%) | – |
| No | 50 (82%) | – |
| ICI doses before SABR | ||
| Median (range) | 13 (2–73) | – |
| Irradiated tumor sites | ||
| Nodes | 49 (46%) | 12 (19%) |
| Lung | 26 (24%) | 37 (60%) |
| Bone | 12 (11%) | 6 (10%) |
| Adrenal | 7 (7%) | 3 (5%) |
| Other | 13 (12%) | 4 (6%) |
| Number of progressing lesions | ||
| 1 | 37 (61%) | 31 (72%) |
| 2 | 11 (18%) | 9 (21%) |
| ≥3 | 13 (21%) | 3 (7%) |
| SABR dose | ||
| BED < 100 | 107 (100%) | 27 (44%) |
| BED ≥ 100 | 0 | 35 (56%) |
| Number of SABR courses | ||
| 1 | 55 (90%) | 42 (98%) |
| 2 | 6 (10%) | 1 (2%) |
Outcomes
The treatment results are detailed in Table 2. The median follow-up was 12 months (range, 3–36 months). The best ORR in cohort A was 59% (n = 36), consisting of 26% CR (n = 16) and 33% PR (n = 20). In B, the ORR was 65%, with 37% CR (n = 16) and 28% PR (n = 12). At the end of follow-up, LC in A was 94% (n = 100 lesions) and 97% in B (n = 62 lesions). The clinical benefit after the end of SABR is displayed in Figure 2. In cohort A, 7% of patients (n = 4) completed ICI and remained disease-free at the end of follow-up for this analysis. Ten percent (n = 6) received a second SABR course due to further OPD. Of these, 83% (n = 5) regained clinical benefit and continued the same ICI with no subsequent progression. At the end of follow-up, 75% (n = 46) were alive. Of the 27 patients who progressed after SABR, 13 (48%) died within the first 12 months. In cohort B, 56% (n = 24) were in response to SABR and, therefore, did not require the introduction of systemic therapy. One patient (2%) received a second SABR course due to a new progression, but he presented further distant metastases and had to start systemic therapy. At the end of follow-up, 79% (n = 34) were alive. SABR was well tolerated. The toxicity in Cohort A was mainly grade 1 (21%, n = 13) and 2 (13%, n = 8). No grade ≥ 3 toxicity was reported. In B, Grade 1 side effects were observed in 23% (n = 10) and Grade 2 in 7% (n = 3). Grade 3 toxicity was 5% (n = 2) and consisted of duodenal and gastric bleeding in patients who had received abdominal irradiation prior to SABR. One of these patients had received prior RT to primary pancreatic adenocarcinoma with 50 Gy in 25 fractions. The patient was subsequently treated with 35 Gy in 5 fx to an out-of-field adrenal oligorecurrence, but with some dose overlap in the bowel. The other patient had previously received palliative radiotherapy with 20 Gy in 5 fractions to a thoracic spine metastasis, had a complete response to systemic therapy and later developed an oligorrecurrence in a perigastric node treated with SABR (35 Gy in 5 fx) and with some dosimetric overlap with the previous treatment field.
Table 2.
Treatment response.
|
N (%) |
||
|---|---|---|
| Endpoint | Cohort A | Cohort B |
| Best objective response rate (ORR) | 36/61 patients (59%) | 28/43 patients (65%) |
| Complete response | 16 (26%) | 16 (37%) |
| Partial response | 20 (33%) | 12 (28%) |
| Stable disease | 8 (13%) | 2 (5%) |
| Progression disease | 17 (28%) | 13 (30%) |
| Local control (LC) | 100/107 lesions (94%) | 60/62 lesions (97%) |
| Complete response | 51 (48%) | 39 (63%) |
| Partial response | 35 (33%) | 15 (24%) |
| Stable disease | 14 (13%) | 6 (10%) |
| Progression disease | 7 (6%) | 2 (3%) |
Figure 2.
Clinical evolution in each patient after SABR: (A) Cohort A; (B) Cohort B.
In terms of survival, with a median follow-up of 12 months (range, 3–36 months), median mPFS in cohort A was 15 months (95% CI, 8 months – not reached), and 21 months (95% CI, 8 months – not reached) in B. Median OS times were not reached. The Kaplan‒Meier curves for mPFS and OS from SABR are displayed in Figure 3. No clinical or treatment variables, such as tumor type, number of SABR courses or lesions, location of irradiated lesions, or number of previous systemic lines, seemed to impact survival.
Figure 3.
Kaplan–Meier curves for modified progression-free survival (mPFS) and overall survival displayed by cohort. (A) mPFS. (B) OS. Abbreviations: CI = confidence interval; NR = not reached.
The analysis of cfDNA suggested differences in survival at specific time points and longitudinal changes. In cohort A, a decrease in the cfDNA concentration of more than 14% from T1 to T4 (from baseline to two months after SABR) was associated with a better median mPFS (not reached vs 8 months, p = 0.015). At T3 (at the end of SABR), levels lower than 0.37 ng/µL were also associated with improved OS: medians were not reached, but 1-year OS was 91% vs 62% (p = 0.031). In contrast, in cohort B, an increase of more than 3% across treatment (from T2 to T4) was associated with better median mPFS (not reached vs 7.8 months, p = 0.042) and OS (not reached vs 9.9 months, p = 0.004). The Kaplan‒Meier curves are displayed in Figure 4. Finally, in cohort A, low NLR (<1.84) at T1 was associated with a better median mPFS (not reached vs 7.5 months, p = 0.034). For NLR <1.81, median OS times were not reached, but 1-year OS was 100% vs 70%, p = 0.01. In B, there were no significant differences at T1. However, a low NLR (<4) at T4 was associated with improved median mPFS (not reached vs 3.1 months, p = 0.001) and OS (not reached vs 9.9 months, p = 0.005). The survival curves are detailed in Figure 5. As an exploratory analysis, biomarker-associated survival patterns identified within each cohort were also visualized across both cohorts (Figures E1 and E2). These analyses were intended to explore the consistency of biomarker patterns across distinct clinical settings. Given the clinical heterogeneity between cohorts, no inference regarding relative treatment efficacy was made from these analyses. In cohort A, statistically significant associations between low cfDNA and better survival were also found from T2 to T4, T3 to T4, and at T4 for mPFS and at T4 for OS. For cohort B, changes in cfDNA from T3 to T4 were also associated with mPFS and OS. As for the NLR, no other significant differences in time points or longitudinal changes were obtained. Univariate analyses found no systematic imbalances in survival according to patient or treatment characteristics. The cfDNA data for each cohort and time point are detailed in Table E1. Although not all differences were statistically significant, continuous analyses showed the same tendency, further supporting the Kaplan‒Meier findings (Table E2).
Figure 4.
Kaplan‒Meier curves according to the concentration of cfDNA: (A) mPFS differences from T1 to T4 in Cohort A according to a decrease in cfDNA higher or lower than 14%; (B) OS differences at T3 in Cohort A according to cfDNA levels higher or lower than 0.37 ng/µL; (C) mPFS differences from T2 to T4 in Cohort B according to an increase in cfDNA higher or lower than 3%; (D) OS differences from T2 to T4 in Cohort B according to an increase in cfDNA higher or lower than 3%. Abbreviations: cfDNA = cell-free DNA; mPFS = modified progression-free survival; OS = overall survival.
Figure 5.
Kaplan‒Meier curves according to the NLR: (A) mPFS differences at T1 in Cohort A according to an NLR higher or lower than 1.84; (B) OS differences at T1 in Cohort A according to an NLR higher or lower than 1.81; (C) mPFS differences at T4 in Cohort B according to an NLR higher or lower than 4; (D) OS differences at T4 in Cohort B according to an NLR higher or lower than 4. Abbreviations: NLR = neutrophil‒lymphocyte ratio; mPFS = modified progression-free survival; OS = overall survival.
Multivariate analysis for mPFS yielded results for cfDNA from T1 to T4, NLR at T1 (cohort A), and cfDNA from T2 to T4 (cohort B). For OS, cfDNA at T3 (A) and NLR at T4. Plots are displayed in Figure E3. The absence of a > 14% decrease from T1 to T4 in cohort A showed a non-significant tendency towards worse mPFS (HR 4.78, 95% CI 0.79–28.82, p = 0.09). In B, an increase > 3% also showed a non-significant trend towards improved mPFS (HR 0.24, 95% CI 0.05–1.09, p = 0.06). For OS, in cohort A, cfDNA levels > 0.37 ng/µL at T3 were significantly associated with decreased survival (HR 3.69, 95% CI 1.04–13.10, p = 0.04). In B, NLR > 4 at T4 was significantly associated with worse OS (HR 71.45, 95% CI, 1.89, 2694.30, p = 0.02). No clinical variables evidenced significant associations with survival.
Discussion
Despite its practice-changing results, response rates to ICI remain low, and there are few useful biomarkers for patient selection and monitoring. Although the role of SABR in the metastatic setting is evolving, the definition of OMD is still imprecise and based on data from clinical trials and not on molecular characteristics. There is currently a severe lack of biomarkers to assess the benefit of SABR in patients with OMD, including OPD. This limitation may explain the variable success that SABR has shown in different clinical trials.
Particularly for OPD under ICI, clinical evidence was scarce until recently. In 2022, a prospective study on NSCLC and melanoma reported an ORR of 42% and a median PFS of 14.2 months, although with high variability between patients. 17 Furthermore, in the randomized phase II CURB trial, patients with NSCLC or breast cancer received either systemic therapy or SoC plus SABR. Despite a lack of benefit in breast cancer, patients with NSCLC in the SABR arm had a PFS four times higher than those treated with the SoC. 16 In contrast, the randomized phase II trial STOP tested this same approach in non-hematologic tumors, and no benefit in PFS was found. However, there was suboptimal protocol adherence in the SoC arm, and crossover was allowed, which could partly explain these results. Furthermore, 13% of patients had breast cancer (who saw no benefit in the CURB trial), and only 27% had ICI as systemic therapy. 19 These conflicting data reflect the need for biomarkers to guide which patients may benefit the most from SABR. 31
In our study, we report an ORR of 59% and a median mPFS of 15 months. These are comparable with previously published results and reinforce the idea that SABR can extend the clinical benefit of ICI in OPD. Clinical outcomes in cohort B are reported descriptively and should not be interpreted as a comparator for cohort A, as the cohorts represent distinct clinical settings and were not designed for comparative effectiveness analyses, but rather to provide a parallel clinical context for the exploratory evaluation of biomarkers related to SABR alone. Importantly, 56% of patients in cohort B remained free from systemic therapy after SABR alone, highlighting the potential of local treatment to defer systemic therapy in appropriately selected patients with OMD.
In addition to patient characteristics, treatment variables such as dose and fractionation are also under debate. For cohort A, we opted for subablative doses of mainly 35 Gy/5 fx following successful results from previous studies. 17 , 32 It has been suggested that higher doses of radiation can unleash immunosuppressive effects. 33 However, positive results have also been achieved with higher doses together with ICI. 34 Despite the subablative fractionation used in cohort A, LC was 94%, which could suggest that ablative doses may not be required when combined with ICI. Although encouraging, this finding should be considered hypothesis-generating and does not establish equivalence with conventional ablative SABR regimens.
The use of mPFS in our study was intended to capture treatment-strategy failure rather than radiological progression alone, as limited subsequent progression may still be salvaged with additional SABR without requiring a change in systemic therapy. This concept is increasingly recognized in OPD, where conventional PFS may not fully reflect the benefit of delaying systemic therapy escalation. 35 Interestingly, the START-NEW-ERA-OLIGO phase II trial uses new systemic therapy-free survival as a primary endpoint and has reported a preliminary median of 34 months in patients with oligoprogression during immunotherapy or targeted therapy. 36
Notably, only a minority of patients underwent a second course of SABR (10% in Cohort A and 2% in Cohort B). In cohort A, however, this represented 22% of patients who experienced subsequent progression after the first SABR course (6 of 27). The relatively limited use of repeat SABR may partly reflect the short follow-up of this interim analysis and the real-world nature of treatment decisions after subsequent progression. Repeat local treatment was not protocol-mandated, and management was individualized according to the pattern of progression, available systemic options, and multidisciplinary assessment. In participating centers with broad access to clinical trials, a change in systemic treatment is often considered an appropriate alternative to further local therapy. Nevertheless, 5 of the 6 patients in Cohort A who underwent a second SABR course regained clinical benefit and were able to continue the same ICI without subsequent progression, suggesting that repeat SABR may be valuable in selected patients. Cohort B should be interpreted in a different clinical context, since 18 patients (42%) had not received any lines of systemic treatment prior to SABR. Therefore, subsequent progression frequently represented an appropriate point to initiate systemic therapy rather than pursue repeated local treatment. Accordingly, the proportion of patients receiving a second SABR course in the two cohorts should not be interpreted as reflecting the feasibility or efficacy of repeat SABR itself.
The safe toxicity profile of concomitant RT and ICI has been widely described. 37 A recent early communication of the OligoCare study reported that severe toxicity with concomitant ICI and SABR was only 1.2%. 38 Our results are in line with these findings, as we found no grade ≥3 toxicity in Cohort A. The safety of SABR may partly explain why it has been incorporated into clinical practice without definitive phase III evidence, even leading to the publication of a consensus document to guide the treatment of oligometastatic NSCLC. 39
RT biomarkers remain underdeveloped in OMD, where repeated tissue sampling is often unfeasible. Liquid biopsy makes treatment monitoring through longitudinal sampling much more viable. 40 A recent study in oligometastatic NSCLC treated with SABR showed that low ctDNA was associated with improved PFS and OS. 41 Moreover, patients with NSCLC in the SABR arm of the CURB trial had a significant decrease in ctDNA from baseline to follow-up. 16 Recently, translational analyses of the randomized phase II EXTEND trial showed that detectable ctDNA was associated with worse outcomes in patients with oligometastatic solid tumors, while ctDNA clearance during treatment was associated with improved survival, further supporting the potential role of longitudinal biomarker dynamics in patients undergoing metastasis-directed therapy. 42 These tumor-specific ctDNA approaches should be distinguished from the total cfDNA quantification evaluated in our study, which does not specifically identify tumor-derived DNA. However, ctDNA remains costly, technically complex and methodologically heterogeneous. 43 cfDNA includes ctDNA, but mostly fragments from normal blood cells. While this might add variability, it also makes cfDNA more accessible and, therefore, easier to generalize in clinical practice. It has been linked to tumor burden and advanced stage. 44 , 45 In our independent supportive cohort of patients treated with ICI alone from our network, low cfDNA was also associated with improved survival in both the discovery and validation cohort. 46 These data support further evaluation of cfDNA as a candidate biomarker in SABR-treated patients. In our exploratory analysis, patients with OPD treated with I-SABR (cohort A), which had lower cfDNA after the last SABR fx (T3), reported a significant benefit in 1-year OS (91% vs 62%, p = 0.031). This was two months before the first imaging evaluation. Longitudinally, a decrease of more than 14% from baseline to two months after SABR (T4) was also associated with better PFS. The opposite pattern observed in cohort B, where increasing cfDNA was associated with improved outcomes, may reflect differences in disease setting, treatment context, or the nonspecific biological determinants of total cfDNA. While lower or decreasing cfDNA in cohort A is consistent with the expected relationship with prognosis, and is also concordant with our findings in an independent cohort treated with ICI alone, total cfDNA may capture treatment- or host-related processes beyond the tumor burden. 46 In cohort B, radiation-induced tissue injury could theoretically contribute to cfDNA kinetics after higher doses, reflecting a greater contribution of direct cytotoxic effects to cfDNA release. 47 Conversely, in cohort A, ongoing ICI together with the moderate hypofractionated schedules may have provided a more permissive context for radiation-induced immune activation. 33 Given the clinical heterogeneity between cohorts, these divergent patterns in our study cannot be attributed to the presence or absence of ICI or to differences in the SABR dose but could be considered hypothesis-generating. In patients treated with SABR, a high post-treatment NLR has been previously associated with reduced survival. 48 Our results in cohort B are consistent with these findings. Interestingly, the baseline NLR also appeared to be prognostic in cohort A. To contextualize our findings, Table E3 summarizes key blood-based biomarker papers and highlights how the current study could add to prior evidence.
This study has several limitations. The validity of our findings may be limited by the observational design. We accounted for possible biases during the design and statistical interpretation, but the recruitment protocol could be a source of selection bias. Although the clinical and translational results should be validated in a clinical trial, we designed this study to reflect real-world practice, in which SABR is being increasingly used for OMD, alone or in combination with systemic therapy. To this end, we decided to include OMD from different primary tumors. Although it introduces more heterogeneity, it represents clinical practice more accurately. Basket trials such as SABR-COMET have reported positive results across different tumor types. 7 Nonetheless, NSCLC remained the most common subtype in our study. In terms of the results, the median follow-up is still short, and the median times have not been reached. Even if this analysis does not include all recruited patients yet, it is one of the largest cohorts of OPD treated with I-SABR published to date. 16 , 17 We were unable to study ctDNA in our patients to correlate it with cfDNA. We are aware that cfDNA and NLR are not specific biomarkers, which poses a risk of confounding. In particular, total cfDNA quantification cannot distinguish tumor-derived DNA from DNA released by non-malignant cells, and may therefore be influenced by inflammation, tissue injury, and other biological processes unrelated to tumor burden. Future studies evaluating total cfDNA and ctDNA in parallel will be important to determine whether the associations observed here can be validated and further refined using tumor-specific approaches. As external validation was not available, we only have internal supportive evidence for cfDNA from our previously published ICI-alone cohort. Although our current results are merely exploratory and should be confirmed in clinical trials, we believe that they can contribute to the scientific knowledge in a field in which translational data is still quite lacking. Multivariate analysis was not possible for all molecular variables, as certain estimations tended to infinity, and others showed wide confidence intervals (probably because of insufficient sample size and events at this stage of the study). Nonetheless, we found statistically significant associations in terms of OS for cfDNA at T3 (cohort A) and NLR at T4 (cohort B). Because multiple biomarker time points and longitudinal changes were explored, these associations should be interpreted as hypothesis-generating.
Conclusion
In patients with oligoprogression under ICI, the I-SABR was associated with prolonged clinical benefit and favorable survival outcomes. In cohort B, more than half of patients remained free from systemic therapy after SABR, supporting its potential role in delaying systemic therapy in selected patients. cfDNA and NLR seem to be associated with survival from SABR and warrant further study as accessible biomarkers for patient stratification. These results are hypothesis-generating and should be independently validated in larger phase II and III trials.
Supplementary Material
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Table E1.docx
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Supplementary Captions
Acknowledgments
We would like to acknowledge the patients, the nurses, the computational infrastructure (PICASSO, SWEDISH), and our funding institutions.
Funding Statement
This research was funded by the Fundación Científica de la Asociación Española Contra el Cáncer (“CLJUN211613ZAFR”, “PRYES247250BARR”), Instituto de Salud Carlos III, through the projects “PI22/01816” (co-funded by the European Union), “DTS23/00114” and “PI18/01592” (co-funded by the European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”), Fundación la Caixa (CI25-20197), Sociedad Española de Oncología Médica (SEOM21, SEOM23); Servicio Andaluz de Salud, through the projects SA 0263/2017, Nicolás Monardes, PI-0135-2018, PI-0121-2020, RH-0090-2020 and RC-0009-2021, Spanish Group of Melanoma (Award for Best Research Project 2020 and 2023), Fundación Bancaria Unicaja through the project C19048, and University of Malaga Research Plan (B1-2022_28).
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Data availability statement
Research data are stored in an institutional repository and may be shared upon reasonable request to the corresponding author.
Supplementary material
Supplemental data for this article can be accessed at https://doi.org/10.1080/2162402X.2026.2739021.
Ethics approval and consent
The study protocol was approved by the Provincial Ethics Board of Malaga (“Comité de Ética Asistencial de Málaga”) and followed the standards of the Declaration of Helsinki. Approval date February 24, 2022, with the title: “Biomarker analysis of abscopal effect in patients treated with radio-immunotherapy”. Approval number: “02/2022.PI8”. Written informed consent was obtained from all participants.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
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Table E3.docx
Table E1.docx
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Data Availability Statement
Research data are stored in an institutional repository and may be shared upon reasonable request to the corresponding author.