Local Salvage Therapy After Durvalumab Progression in Stage III NSCLC: A Multicenter Real-World Study

Local Salvage Therapy After Durvalumab Progression in Stage III NSCLC: A Multicenter Real-World Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Local Salvage Therapy After Durvalumab Progression in Stage III NSCLC: A Multicenter Real-World Study Maja Lisik-Habib, Krzysztof Smółka, Rafał Stando, Grzegorz Chmielewski, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9159013/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Patients with unresectable stage III non–small cell lung cancer (NSCLC) who experience disease progression after chemoradiotherapy and consolidation durvalumab represent a growing population with poor outcomes and no established standard of care. Despite the survival benefit demonstrated in the PACIFIC trial, early disease progression remains frequent, and optimal management in this setting is not well defined. In this multicenter retrospective real-world study, we analyzed patterns of disease progression and post-progression treatment strategies in 60 patients treated with chemoradiotherapy followed by durvalumab, with a particular focus on time to next systemic treatment (TNST) as a clinically relevant endpoint reflecting treatment sequencing. Disease progression was heterogeneous in both timing and location. Locoregional progression was associated with a longer time to subsequent treatment compared with distant or combined progression. Importantly, the use of radical local salvage therapy was associated with a clinically meaningful delay in the initiation of subsequent systemic treatment, with median TNST of 29.1 months compared with 12.6 months in patients receiving palliative or no local intervention. TNST showed strong associations with other key clinical outcomes. These findings support its role as a pragmatic real-world endpoint capturing treatment trajectories after consolidation immunotherapy. These findings suggest that carefully selected patients with limited post-durvalumab progression may benefit from radical local salvage therapy, which may delay the need for subsequent systemic treatment in a setting with no established standard of care. Our results support the integration of local ablative strategies into multidisciplinary decision-making and highlight TNST as a clinically meaningful endpoint in this context. Biological sciences/Cancer Health sciences/Oncology non–small cell lung cancer durvalumab oligometastatic progression local salvage therapy stereotactic radiotherapy time to next systemic treatment Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 INTRODUCTION Concurrent chemoradiotherapy (cCRT) followed by durvalumab consolidation is the current standard of care for patients with unresectable stage III non–small cell lung cancer (NSCLC) [ 1 , 2 ]. Established by the PACIFIC trial, this strategy significantly improves progression-free and overall survival compared with chemoradiotherapy alone [ 3 , 4 ]. Despite these advances, disease recurrence remains common, with a substantial proportion of patients developing locoregional or distant relapse after consolidation immunotherapy [ 4 , 5 ]. Patterns of relapse after durvalumab are heterogeneous in both timing and location and may influence subsequent management. However, most available evidence derives from randomized clinical trials conducted in highly selected populations and may not fully reflect routine clinical practice. Real-world studies have reported considerable variability in treatment delivery, including the proportion of patients completing the planned 12 months of durvalumab, which ranges from less than one-third to approximately one-half of treated patients [ 6 , 7 ]. In addition, treatment-related factors such as radiotherapy-induced lymphopenia may influence the efficacy of consolidation immunotherapy [ 8 , 9 ]. Currently, the optimal management of patients who develop disease progression after durvalumab remains poorly defined, particularly in routine clinical practice [ 10 ]. In particular, there is little consensus on whether local treatment approaches, such as stereotactic radiotherapy or surgical resection may provide benefit in selected patients of oligometastatic or locoregional relapse. Similarly, the impact of the timing and pattern of progression on subsequent treatment strategies has not been well characterized. To address these gaps, we conducted a retrospective multicenter analysis of patients with stage III NSCLC treated with cCRT followed by durvalumab. The aim of this study was to characterize patterns of disease progression and evaluate post-progression treatment strategies in a real-world cohort. Because treatment decisions after post-durvalumab progression are highly individualized, endpoints reflecting real-world treatment trajectories, such as time to next systemic treatment (TNST), may provide clinically meaningful insights into treatment sequencing. Materials and Methods Study Design and Population This retrospective multicenter study included patients with stage III NSCLC treated with concurrent chemoradiotherapy followed by durvalumab at five tertiary oncology centers in Poland. Patients were eligible if they had histologically confirmed stage III NSCLC, completed concurrent chemoradiotherapy consisting of platinum-based chemotherapy administered during radiotherapy with a total dose ≥ 54 Gy, and received at least two cycles of durvalumab consolidation initiated within two months after completion of chemoradiotherapy. Patients were required to have adequate organ function, including hepatic, renal, and hematologic parameters, and no history of autoimmune disease. Patients were excluded if follow-up data after progression were unavailable, if a second uncontrolled malignancy was present, or if tumors had mixed small-cell and non-small-cell histology. Clinical data were retrospectively collected from medical records using a standardized eCRF. Information included patient demographics, tumor characteristics, treatment details, disease progression, and follow-up outcomes. Procedures In Poland, durvalumab consolidation is reimbursed through a national drug program and is administered for up to 12 months or until disease progression or unacceptable toxicity. Continuation of durvalumab beyond radiographic progression was not permitted. Radiological assessment with computed tomography (CT) was performed at baseline and every three months during treatment or when clinically indicated. Disease progression was assessed according to RECIST version 1.1. criteria. Radiotherapy was delivered once daily in high-volume centers with established expertise in the treatment of lung cancer. All participating institutions had access to advanced techniques, including stereotactic body radiotherapy (SBRT), stereotactic fractionated radiotherapy (SFRT), stereotactic radiosurgery (SRS), intensity-modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT), and image-guided radiotherapy (IGRT) using cone-beam computed tomography (CBCT). In selected cases, four-dimensional computed tomography (4DCT) imaging was also performed to account for respiratory motion. Endpoints The primary endpoint was time to next systemic treatment (TNST), defined as the interval between the start of cCRT—or, in patients who received induction chemotherapy, the start of the first induction cycle—and the initiation of the first subsequent systemic anticancer therapy administered after disease progression. This endpoint was selected to reflect the overall real-world treatment trajectory following definitive therapy, rather than the isolated effect of post-progression interventions. The analysis evaluated the association between the pattern of progression (locoregional, distant, or combined) and the type of post-progression local treatment (radical vs. palliative) with TNST using both univariable and multivariable models. Disease progression was classified based on radiological assessment according to RECIST criteria and categorized into locoregional, distant, or combined progression. Locoregional progression was defined as progression occurring within the thorax, including the primary tumour site and/or regional lymph nodes, without evidence of extrathoracic disease. Distant progression was defined as the appearance or progression of metastatic lesions outside the thorax (e.g. brain, liver, bone, adrenal glands, or extrathoracic lymph nodes) without concurrent locoregional progression. Combined progression was defined as the simultaneous presence of locoregional and distant disease progression at the time of first documented relapse. Secondary endpoints included time to next treatment (TNT), progression-free survival 1 (PFS1), progression-free survival 2 (PFS2), and OS. TNT was defined as the time from the start of cCRT (or induction chemotherapy, if applicable) to the initiation of any subsequent anticancer treatment, either local (surgery or radiotherapy) or systemic. PFS1 was defined as the time from the start of cCRT (or induction chemotherapy) to the first documented disease progression or death from any cause, whichever occurred first. PFS2 was defined as the time from the first documented disease progression after durvalumab to the subsequent progression or death, reflecting the duration of disease control achieved with post-progression management strategies. OS was defined as the time from the start of cCRT (or induction chemotherapy, if applicable) to death from any cause or last follow-up. Statistics The data cutoff for progression-related endpoints was January 31, 2024, corresponding to the predefined date by which all included patients were required to have experienced disease progression. Data collection and follow-up for survival analyses continued until March 9, 2025, which served as the final censoring date. Continuous variables were summarized as medians with interquartile ranges (IQR), and categorical variables as frequencies and percentages. Differences between groups were analyzed using the two-sided Mann–Whitney U test for continuous non-normally distributed data and the χ² test or Fisher’s exact test for categorical variables, as appropriate. Time-to-event outcomes (TNT, TNST, PFS1, PFS2, OS) were estimated using the Kaplan–Meier method, with 95% confidence intervals reported where applicable. Comparisons between subgroups were performed using the log-rank test, which was considered the primary inferential method for survival analyses. Breslow (generalized Wilcoxon) and Tarone–Ware tests were applied to explore early and intermediate differences in survival curves. Statistical significance was set at a two-tailed p value < 0.05. To explore independent factors associated with time to next systemic treatment (TNST), a multivariable Cox proportional hazards regression model was constructed. Missing values in covariates were imputed using k-nearest neighbors (kNN) imputation. Collinearity between dosimetric variables was assessed, and due to moderate correlation and model instability, mean lung dose was excluded from the final model. The proportional hazards (PH) assumption was formally evaluated using Schoenfeld residuals, and the final model satisfied the PH assumption. Hazard ratios (HR) with 95% confidence intervals (95% CI) were reported. Model performance was summarized using the concordance index (C-index), and overall model fit was assessed using the likelihood ratio test (LRT). All statistical analyses were conducted using Python (version 3.14) with the pandas, SciPy [ 11 ], scikit-learn [ 12 ], and lifelines packages. The study was conducted in accordance with the Declaration of Helsinki and applicable national regulations. According to the Bioethics Committee at the Medical University of Łódź, this retrospective, non-interventional study based on anonymized medical records does not constitute a medical experiment and does not require ethics committee approval or informed consent. This is consistent with Polish national regulations, including the Polish Act of 5 December 1996 on the Professions of Physician and Dentist, as amended. The study was conducted in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines [ 13 ]. Reporting was additionally aligned with recently proposed GROW criteria for real-world evidence studies [ 14 ]. The ChatGPT (version 5.0; OpenAI, San Francisco, CA, USA) language model was used solely for language editing and stylistic refinement of the manuscript, without any involvement in data processing, statistical analysis, or interpretation of results. Results Baseline Characteristics A total of 60 patients with unresectable stage III NSCLC were included. The median age was 66 years. Most patients (98%) had ECOG performance status 0–1 at baseline. Squamous cell carcinoma was the most common histological subtype (70%). PD-L1 expression was available in 69.5% of patients, while 30.5% had no recorded PD-L1 result. Baseline patient characteristics are summarized in Table 1 . Table 1 Baseline demographic, clinical, and treatment characteristics of the study cohort. Age (years) Summary (median (min-max), IQR or number (%)) - 66 (48 – 84; IQR 8.5) Sex M 41 (68.3%) F 19 (31.7%) Smoking history previous 33 (55.0%) current 23 (38.3%) never 4 (6.7%) Histopathologic tumor type squamous cell carcinoma 42 (70.0%) adenocarcinoma 14 (23.3%) NOS NSCLC 2 (3.3%) large cell carcinoma 2 (3.3%) PD-L1 status %TPS 1–49% 20 (33.9%) no data 18 (30.5%) ≥ 50% 12 (20.3%) < 1% 9 (15.3%) ECOG before CRT - 1 (0 – 2; IQR 1) Induction chemotherapy no 43 (71.7%) yes 17 (28.3%) Radiotherapy PTV volume (cm 3 ) - 382 (140 – 1267; IQR 278) Radiotherapy mean lung dose (Gy) - 14.1 (8.4 – 26.6; IQR 3.6) Radiotherapy mean heart dose (Gy) - 7.0 (1.0 – 26.7; IQR 9.1) Best response to chemoradiotherapy PR 32 (53.3%) SD 26 (43.3%) CR 2 (3.3%) CRT – chemoradiotherapy; ECOG – Eastern Cooperative Oncology Group performance status; Gy – gray; IQR – interquartile range; NOS – not otherwise specified; NSCLC – non-small cell lung cancer; PD-L1 – programmed death-ligand 1; PTV – planning target volume; TPS – tumor proportion score; PR – partial response; SD – stable disease; CR – complete response. Chemoradiotherapy and Durvalumab Treatment All patients completed concurrent conventionally fractionated chemoradiotherapy with a minimum dose of 54 Gy (median 60 Gy) and a median treatment duration of 1.1 months, followed by durvalumab consolidation therapy (median duration 6.1 months). Disease progression occurred in all patients during or after durvalumab, as per protocol requirements. Platinum-based doublets included cisplatin-based (71.7%) and carboplatin-based (28.3%). Induction chemotherapy was administered in 28.3% of patients. Durvalumab consolidation therapy was initiated within a median of 39 days post-CRT. The median number of durvalumab cycles administered was 8 (range: 2–26). The Gantt diagram illustrates the treatment sequence (Fig. 1 A). The most common reason for durvalumab discontinuation was disease progression (68.3%), followed by immune-related toxicity (10.3%), 20.0% of patients completed therapy. Figure 1 B illustrates treatment pathways, including CRT with or without induction chemotherapy, duration of durvalumab therapy, and reasons for treatment discontinuation. Disease Progression All patients experienced disease progression during or after durvalumab. The median time from durvalumab initiation to progression was 6.6 months (Fig. 1 A). Progression sites included the lung (n = 25), brain (n = 12), liver (n = 7), lymph nodes (n = 5), adrenal glands (n = 4), bones (n = 3), contralateral lung (n = 2), and other sites (n = 2). Patients were categorized based on the pattern of progression: 48.3% had locoregional progression, 35.0% distant-only, and 16.7% both local and distant. Pattern of progression is summarized in Table 2 . Patients who experienced locoregional progression had a significantly longer TNT compared with those who developed distant or combined progression, with median TNT of 17.1 versus 9.9 months, respectively (p = 0.0088; Fig. 2 ). A statistically significant difference in time to next systemic treatment (TNST) was observed in Kaplan–Meier analysis, with patients experiencing locoregional progression demonstrating longer TNST than those with distant or combined failure (median 16.4 vs. 11.8 months; log-rank p = 0.0396; Fig. 3 ). The distribution-based Mann–Whitney U test did not reach statistical significance, although a numerical difference was observed (p = 0.1391), reflecting the different methodological assumptions between distribution-based and time-to-event analyses. Across all progression sites (lung, liver, lymph nodes, and other locations), no significant differences in TNST or PFS2 were observed. Progression in the brain similarly did not differ from all other sites, and outcomes were also comparable between pre-existing lesions, new lesions, and combined progression patterns (Fig. S2-S3). Oligometastatic progression was defined as the presence of 1–3 metastatic lesions. In Kaplan–Meier analyses, PFS2 was significantly longer in patients with oligometastatic progression (log-rank p = 0.0335), with separation of the survival curves emerging during later follow-up. A more pronounced and consistent effect was observed for OS, with patients in the oligometastatic group demonstrating a longer median OS (41 vs. 19 months) and higher long-term survival rates (log-rank p < 0.0001; Fig. 3 A, B). Table 2 Patterns and characteristics of disease progression after durvalumab. Type of progression 1 locoregional 29 (48.3%) distant 21 (35.0%) both 10 (16.7%) Nature of progression 1 new 31 (51.7%) preexisting 18 (30.0%) both 11 (18.3%) Region of main progression 1 lung 25 (41.7%) brain 12 (20.0%) liver 7 (11.7%) lymph nodes 5 (8.3%) adrenal 4 (6.7%) bone 3 (5.0%) contralateral lung 2 (3.3%) other 2 (3.3%) No. of progressive lesions 1 26 (43.3%) 2–3 13 (21.7%) 4–5 9 (15.0%) > 5 12 (20.0%) Post-Progression Therapy After disease progression 54 patients (90%) received additional oncological therapy. Among them, 47 (87%) received systemic treatment, and 33 (61%) underwent local treatment (either radical or palliative) (Fig. 1 A). Among the remaining patients, seven received local treatment only, while six did not receive any further oncological therapy due to clinical deterioration or other factors. The median TNT and TNST were 11.6 and 13.2 months, respectively. Radical local treatment was delivered to 23% of patients, mostly stereotactic radiotherapy (SRS/SBRT) to the brain or lung, whereas 31.7% of patients received palliative radiotherapy only. Patients with oligometastatic progression were more frequently treated with radical local therapy compared with those with non-oligometastatic progression (57.9% vs. 28.6%). Patients who received radical local treatment had longer time to next systemic treatment (TNST) compared with those who received palliative radiotherapy or no local therapy (median 29.1 vs. 12.6 months). This difference was statistically significant in distribution-based analysis (Mann–Whitney U test, p = 0.016), while survival analysis using Kaplan–Meier curves showed a trend toward longer TNST in the radical treatment group (log-rank p = 0.076; Fig. 5 A). A consistent, although not statistically significant, trend toward improved PFS2 and OS was observed in patients treated with radical local therapy, with median PFS2 of 29.4 versus 19.0 months (p = 0.10) and median OS of 25.3 versus 14.3 months (p = 0.16), respectively (Fig. 5 B–C). Correlation analysis demonstrated strong associations between TNST, PFS1, PFS2, and OS, with Spearman correlation coefficients ranging from 0.73 to 0.96 (Fig. S1). Of the 60 patients, 47 (87%) received systemic therapy after progression. The most commonly used regimens included platinum doublets (n = 27) and docetaxel monotherapy (n = 13). Immunotherapy was rechallenged only in one patient. No significant differences in median PFS2 or OS were observed across systemic treatment strategies administered at oligoprogression (Fig. S4A–B). Multivariable analysis of TNST In multivariable Cox regression analysis (N = 47; events = 47), receipt of radical local therapy prior to second-line systemic treatment was independently associated with a significantly lower hazard of initiating subsequent systemic therapy (HR = 0.11, 95% CI 0.03–0.40; p < 0.001; Fig. 7 ). Extrapulmonary progression was associated with a higher hazard of starting next systemic treatment (HR = 3.23, 95% CI 1.39–7.49; p = 0.006). A higher number of durvalumab cycles was associated with a lower hazard of treatment escalation (HR = 0.85, 95% CI 0.80–0.91; p < 0.001). Other covariates, including mean heart dose, PTV volume, ECOG performance status, chemotherapy agent, best response to chemoradiotherapy, and new-lesion progression, were not statistically significant (all p > 0.05). The overall model fit was statistically significant (LRT = 40.45; df = 9; p < 0.001), and the model demonstrated moderate-to-good discriminatory ability (C-index = 0.787). Based on adjusted survival estimates derived from the Cox model, the predicted median TNST was 25 months (95% CI 17–38 months) in patients treated with radical local therapy compared with 12 months (95% CI 7–34 months)in those without radical local therapy (Fig. 8 ). DISCUSSION This multicenter real-world study addresses a clinically relevant and increasingly common scenario of disease progression after consolidation durvalumab, for which no standard treatment strategy exists. Our findings suggest that selected patients with limited (locoregional or oligometastatic) progression may benefit from radical local salvage therapy, which can delay the need for subsequent systemic treatment. These results support a more active, multidisciplinary treatment approach in this setting. Our findings should be interpreted in the context of existing evidence on post-durvalumab progression. While the PACIFIC trial established concurrent chemoradiotherapy followed by durvalumab as the standard of care, disease recurrence remains common, and patterns of progression are heterogeneous. Most available data derive from clinical trials conducted in highly selected populations, whereas our cohort reflects routine clinical practice, including heterogeneous PD-L1 status and limited molecular profiling. These differences may contribute to variability in both disease behavior and treatment decisions observed after progression. Approximately 50% of patients in the PACIFIC trial did not complete the planned course of durvalumab, with disease progression being the leading cause of treatment discontinuation in this group (31%)[ 3 ]. Early disease failure was also frequent in our cohort, with 71% of patients progressing within 12 months and 43% within 6 months of durvalumab initiation, consistent with previous real-world reports. In real-world data from Arunachalam et al. among 262 patients who initiated durvalumab following concurrent chemoradiotherapy, more than half (51.5%) discontinued treatment prematurely, with 28.4% due to disease progression [ 15 ]. In another retrospective analysis, nearly 70% of patients failed to complete the planned 12 months of durvalumab, most often due to either disease progression or pulmonary toxicity [ 16 ]. In a recent retrospective analysis by Park et al., early progression within six months was reported in 37.3% of patients [ 17 ]. Together, these findings underscore the unmet clinical need in this setting. In the PACIFIC exploratory analyses disease progression occurred in 45.4% of patients receiving durvalumab compared with 64.6% in the placebo group. The majority of first failures were intrathoracic (80.6% vs. 74.5%), while the proportion of patients experiencing distant-only progression was 15.3% and 20.3%, respectively. Importantly, the distribution of distant lesions was similar across arms, with the brain (62% vs. 67%), bone (14% vs. 8%), and liver (14% vs. 13%) as the most common sites. Most patients with distant relapse presented with a limited number of lesions, supporting the potential role of local salvage strategies [ 18 ]. Our real-world findings are broadly consistent with the observations [ 18 ]. In our cohort, 48.3% of patients developed locoregional progression, which was associated with a significantly longer time to next treatment compared with distant or combined progression (median 17.1 vs. 9.9 months), suggesting a more indolent disease course and delayed need for subsequent treatment. In contrast, TNST and PFS2 were not influenced by specific metastatic sites, lesion number, or whether progression occurred in pre-existing or newly developed lesions, supporting the concept that early post-durvalumab relapse is influenced predominantly by systemic disease behavior rather than locoregional factors alone. This observation is consistent with exploratory analyses from the PACIFIC trial, suggesting that durvalumab primarily delays recurrence rather than fundamentally altering metastatic behavior. In our study, the lung and brain were the most frequent sites of relapse, followed by liver, lymph nodes, and adrenal glands reflecting known patterns of metastatic spread in NSCLC. Notably, consistent with the PACIFIC dataset where > 90% of patients with distant relapse had ≤ 5 lesions, many of the distant failures in our study were limited in number, thus potentially amenable to radical local therapy [ 3 ]. In addition to its clinical relevance, the use of time to next systemic treatment (TNST) as a primary endpoint in our analysis is supported by its strong association with other key clinical outcomes. As shown in Supplementary Figure S1, TNST demonstrated very strong correlations with time to next treatment, progression-free survival (PFS1 and PFS2), and overall survival, with Spearman correlation coefficients ranging from 0.73 to 0.96. Importantly, TNST should not be interpreted solely as a surrogate endpoint, but rather as a composite measure reflecting both disease biology and clinical decision-making in real-world practice. These findings suggest that TNST reflects a combination of disease behavior, treatment durability, and real-world clinical decision-making. Importantly, TNST may better capture real-world treatment trajectories than conventional progression-based endpoints, particularly in settings where post-progression management is heterogeneous, not protocol-driven, and often involves local therapy and individualized treatment sequencing. From a clinical perspective, TNST represents a highly relevant outcome in patients progressing after consolidation durvalumab, a setting in which no established standard of care exists and subsequent systemic options are limited. The ability to delay initiation of further systemic therapy may translate into clinically meaningful treatment-free intervals, and potentially help preserve functional status. Importantly, our results highlight the critical role of treatment sequencing in determining the impact of local salvage strategies. When radical local treatment was administered prior to second-line systemic therapy, a marked and statistically significant prolongation of TNST was observed. In contrast, when radical local therapy was analyzed irrespective of timing, its association with longer PFS2 and overall survival was attenuated, indicating that the benefit of local salvage strategies depends on appropriate patient selection and timely integration rather than on their use per se. In multivariable analysis, radical local therapy prior to second-line systemic treatment remained independently associated with prolonged TNST. Although this association should not be interpreted causally given the retrospective design and potential treatment-selection bias, it supports the hypothesis that carefully selected patients with limited post-durvalumab progression may derive clinically meaningful benefit from integrated local strategies. A key novel contribution of our study is the demonstration that patients receiving radical local salvage therapy, most commonly stereotactic radiotherapy, had significantly longer TNST compared with those treated with palliative radiotherapy or no local intervention (median 29.1 vs. 12.6 months; p = 0.016). Our data provide real-world evidence that local salvage treatment can meaningfully delay the need for systemic therapy and thereby prolong the treatment-free interval in selected patients. This also raises the hypothesis that, similar to the oligoprogression setting where immunotherapy is continued with local treatment, a comparable strategy might be beneficial here. The CURB trial demonstrated that adding SBRT to standard therapy in oligoprogressive NSCLC significantly prolonged PFS (10.0 vs. 2.2 months), allowing 85% of patients to continue systemic treatment beyond progression, thus supporting the role of local ablative approaches in prolonging TNST[ 19 ]. In our study, most patients received SBRT, which—owing to its high precision—provides an ablative effect with a low complication rate, allowing continuation of systemic therapy when clinically appropriate[ 20 ]. However, although current data are insufficient to support such an approach (local ablative treatment and continuation of immunotherapy) in routine practice, our findings provide preliminary evidence suggesting its potential clinical relevance and justify further prospective evaluation. In the setting of primary metastatic NSCLC, the use of local ablative therapy for oligometastatic disease has consistently been shown to prolong disease control. Multiple studies have demonstrated that ablative radiotherapy can improve PFS and significantly delay TNST in both driver-mutated and wild-type NSCLC [ 21 – 23 ]. In the randomized phase II trial by Gomez et al., patients with oligometastatic NSCLC who received local consolidative therapy after first-line systemic treatment achieved markedly longer PFS compared with those managed with maintenance therapy or observation (11.9 vs. 3.9 months). This improvement in disease control was accompanied by a notable prolongation of overall survival (41.2 vs. 17.0 months), underscoring the clinical value of aggressive local treatment in this setting [ 24 ]. Similarly, in the phase III SINDAS trial, the addition of upfront SBRT to EGFR-TKI therapy significantly improved both OS (25.5 vs. 17.4 months) and PFS (20.2 vs. 12.5 months)[ 25 ]. Consistent with these data, local ablative treatment in our study was associated with the greatest benefit in TNST and PFS, with more modest effects observed for overall survival, likely reflecting the limited sample size. The optimal management of patients who experience disease progression following consolidation durvalumab remains an area of clinical uncertainty. No standardized evidence-based algorithms are available. Systemic treatment options are often limited, and outcomes in this setting are generally poor with reported median overall survival ranging from approximately 11 to 13 months in contemporary real-world cohorts [ 10 , 26 , 27 ]. Our study is limited by its retrospective design and incomplete molecular profiling, although the national drug program ensured uniform monitoring. A key limitation is selection bias: patients with limited disease burden were more likely to receive SBRT and achieve favorable outcomes, whereas those with extensive disease or poor clinical condition received palliative radiotherapy and experienced worse outcomes. This confounding by indication, combined with immortal time bias, suggests that TNST differences partly reflect clinical decision-making regarding treatment sequencing rather than solely biological efficacy. Consequently, our findings are hypothesis-generating, and future randomized trials are essential to overcome these biases and confirm the benefit of local salvage strategies. CONCLUSION In conclusion, early progression after durvalumab remains common but biologically heterogeneous. Our findings suggest that oligometastatic or limited progression after PACIFIC may represent a therapeutic opportunity. Patients treated with radical local therapy experienced a substantially longer time to next systemic treatment, supporting the role of integrated local strategies in delaying treatment escalation. Salvage SBRT or other local modalities may extend disease control and allow postponement of subsequent systemic therapy in selected patients. Given the absence of a standardized post-durvalumab strategy, TNST emerges as a clinically meaningful endpoint reflecting real-world treatment dynamics. Prospective studies integrating ctDNA monitoring, novel agents, and local therapy are warranted to further refine treatment selection and optimize outcomes in this population. Abbreviations CBCT – Cone-beam computed tomography cCRT – Concurrent chemoradiotherapy CT – Computed tomography ctDNA – Circulating tumor DNA ECOG – Eastern Cooperative Oncology Group EGFR – Epidermal growth factor receptor ESMO – European Society for Medical Oncology Gy – Gray IMRT – Intensity-modulated radiotherapy IGRT – Image-guided radiotherapy IQR – Interquartile range MDT – Multidisciplinary tumor board NSCLC – Non-small cell lung cancer OS – Overall survival PACIFIC – Durvalumab after chemoradiotherapy in stage III NSCLC trial PD-L1 – Programmed death-ligand 1 PET-CT – Positron emission tomography–computed tomography PFS – Progression-free survival PFS1 – Progression-free survival from the start of CRT to first progression or death PFS2 – Progression-free survival from post-durvalumab progression to subsequent progression or death PTV – Planning target volume RECIST – Response Evaluation Criteria in Solid Tumors SBRT – Stereotactic body radiotherapy SFRT – Stereotactic fractionated radiotherapy SRS – Stereotactic radiosurgery STROBE – Strengthening the Reporting of Observational Studies in Epidemiology TKI – Tyrosine Kinase Inhibitor TNST – Time to next systemic treatment TNT – Time to next treatment TPS – Tumor proportion score VMAT – Volumetric-modulated arc therapy WHO – World Health Organization Declarations Acknowledgments The authors wish to thank all participating radiotherapy centers and investigators for their contributions to data collection. Ethics statement: According to the Bioethics Committee at the Medical University of Łódź, this retrospective, non-interventional study based on anonymized medical records does not constitute a medical experiment and does not require ethics committee approval or informed consent. This is consistent with Polish national regulations, including the Polish Act of 5 December 1996 on the Professions of Physician and Dentist (Journal of Laws 2023, item 1516, as amended). An official statement issued by the Bioethics Committee confirming this has been provided as a supplementary document. Funding of the research statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest statement: ŁK, JF, MLH, KG declare receiving honoraria for lectures, as well as travel and accommodation support, from AstraZeneca Pharma Poland Sp. z o.o. RS declares receiving honoraria for lectures from AstraZeneca Pharma Poland Sp. z o.o. MP received travel grants and lecture honoraria from AstraZeneca, Roche, Novartis, Eli Lilly, Janssen, Gilead and Amgen. Artificial intelligence involvement statement: Artificial intelligence tools (ChatGPT ver. 5) were utilized solely for rephrasing individual sentences originally written by humans and were not employed for content creation, data analysis, or the development of visual concepts. Authors contribution: Maja Lisik-Habib: Conceptualization; Methodology; Data curation; Investigation; Formal analysis; Writing—orginal draft; Project administration Rafał Stando: Investigation Grzegorz Chmielewski: Investigation Mateusz Bilski: Investigation Katarzyna Galwas: Investigation Mirosława Puskulluoglu: Investigation Agnieszka Roman: Investigation Damian Tworek: Investigation Krzysztof Smółka: Formal analysis; Data curation; Visualization Jacek Fijuth: Writing— review and editing; Supervision. Barbara Alicja Jereczek-Fossa: Writing— review and editing; Supervision. Łukasz Kuncman: Conceptualization; Methodology; Formal analysis; Writing— review and editing, and Supervision. Authorship Responsibility Statement: We confirm that all authors of this manuscript meet the criteria for authorship as outlined by the International Committee of Medical Journal Editors (ICMJE). Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. References Early and locally advanced non-small-cell lung cancer: an update of the ESMO Clinical Practice Guidelines focusing on diagnosis, staging, systemic and local therapy - Annals of Oncology. https://www.annalsofoncology.org/article/S0923-7534(21)04279-4/fulltext Riely, G. J. et al. NCCN Guidelines® Insights: Non–Small Cell Lung Cancer, Version 7. (2025). https://doi.org/10.6004/jnccn.2025.0043 (2025) doi:10.6004/jnccn.2025.0043. Antonia, S. J. et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl. J. Med. 379 , 2342–2350 (2018). Friedes, C. et al. Patterns of Failure, Low-Volume Relapse, and Subsequent Ablative Management in Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation and Consolidation Immune Checkpoint Inhibitors. Int. J. Radiation Oncology*Biology*Physics . 118 , 1435–1444 (2024). Spigel, D. R. et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer. J. Clin. Oncol. 40 , 1301–1311 (2022). Sankar, K. et al. Real World Outcomes versus Clinical Trial Results of Durvalumab Maintenance in Veterans with Stage III Non-Small Cell Lung Cancer. Cancers (Basel) . 14 , 614 (2022). Girard, N. et al. Treatment Characteristics and Real-World Progression-Free Survival in Patients With Unresectable Stage III NSCLC Who Received Durvalumab After Chemoradiotherapy: Findings From the PACIFIC-R Study. J. Thorac. Oncol. 18 , 181–193 (2023). Jing, W. et al. Severe Radiation-Induced Lymphopenia Attenuates the Benefit of Durvalumab After Concurrent Chemoradiotherapy for NSCLC. JTO Clin. Res. Rep. 3 , 100391 (2022). Kuncman, Ł. et al. Early lymphocyte levels and low doses radiation exposure of lung predict lymphopenia in radiotherapy for lung cancer. Front Immunol 15 , (2024). Remon, J. et al. Current challenges of unresectable stage III NSCLC: are we ready to break the glass ceiling of the PACIFIC trial? Ther. Adv. Med. Oncol. 14 , 17588359221113268 (2022). Virtanen, P. et al. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat. Methods . 17 , 261–272 (2020). Pedregosa, F. et al. Scikit-learn: Machine Learning in Python. MACHINE LEARNING IN PYTHON . von Elm, E. et al. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ: Br. Med. J. 335 , 806 (2007). ESMO Guidance for Reporting Oncology real-World evidence (GROW). - Annals of Oncology. https://www.annalsofoncology.org/article/S0923-7534(23)04018-8/fulltext Arunachalam, A., Sura, S., Murphy, J., Conkling, P. & Goldschmidt, J. Real-world treatment patterns and outcomes among unresectable stage III non-small cell lung cancer. PLOS ONE . 19 , e0314156 (2024). Pennock, M. et al. Exploring causes and consequences of early discontinuation of durvalumab after chemoradiotherapy for non-small cell lung cancer. Clin. Transl Radiat. Oncol. 41 , 100643 (2023). Park, J. E. et al. Factors predicting early recurrence in patients with unresectable stage III non-small cell lung cancer on durvalumab consolidation after chemoradiotherapy. Transl Lung Cancer Res. 14 , 1149–1157 (2025). Rimner, A. et al. Chicago, IL, USA,. Patterns of disease progression with durvalumab in stage III non-small cell lung cancer (PACIFIC). in (2019). Tsai, C. J. et al. Consolidative Use of Radiotherapy to Block (CURB) Oligoprogression - Randomised Study of Standard-of-Care Systemic Therapy with or without Stereotactic Body Radiotherapy in Patients with Oligoprogressive Cancers of the Breast and Lung. Lancet 403 , 171–182 (2024). Kuncman, Ł. et al. Definition and requirements for stereotactic radiotherapy: a systematic review. Radiother Oncol. 211 , 111107 (2025). Weickhardt, A. J. et al. Local Ablative Therapy of Oligoprogressive Disease Prolongs Disease Control by Tyrosine Kinase Inhibitors in Oncogene-Addicted Non–Small-Cell Lung Cancer. J. Thorac. Oncol. 7 , 1807–1814 (2012). Chan, O. S. H. et al. The Role of Radiotherapy in Epidermal Growth Factor Receptor Mutation-positive Patients with Oligoprogression: A Matched-cohort Analysis. Clin. Oncol. 29 , 568–575 (2017). Friedes, C. et al. Isolated progression of metastatic lung cancer: Clinical outcomes associated with definitive radiotherapy. Cancer 126 , 4572–4583 (2020). Gomez, D. R. et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non–Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J. Clin. Oncol. 37 , 1558–1565 (2019). Wang, X. S. et al. Randomized Trial of First-Line Tyrosine Kinase Inhibitor With or Without Radiotherapy for Synchronous Oligometastatic EGFR-Mutated Non-Small Cell Lung Cancer. J. Natl. Cancer Inst. 115 , 742–748 (2022). Stalker, M. et al. Outcomes Following Treatment for Progression in Patients Treated With Durvalumab Consolidation in LA-NSCLC. Clin. Lung Cancer . 26 , 124–130e1 (2025). Evers, G. et al. 1300P Treatment and clinical outcome in recurrent/refractory locally advanced NSCLC following chemoradiotherapy and consolidative durvalumab. Ann. Oncol. 34 , S749 (2023). Additional Declarations No competing interests reported. Supplementary Files supplementaryfigures.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 27 Apr, 2026 Editor assigned by journal 27 Apr, 2026 Editor invited by journal 27 Apr, 2026 Submission checks completed at journal 17 Apr, 2026 First submitted to journal 17 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9159013","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":633405262,"identity":"266a8766-0feb-456d-aab0-832ed1b3b6b6","order_by":0,"name":"Maja Lisik-Habib","email":"","orcid":"","institution":"Copernicus Memorial Hospital in Lodz Comprehensive Cancer Center and Traumatology","correspondingAuthor":false,"prefix":"","firstName":"Maja","middleName":"","lastName":"Lisik-Habib","suffix":""},{"id":633405263,"identity":"60addb4f-ae1e-4266-b7d0-5dbbe74c72c5","order_by":1,"name":"Krzysztof Smółka","email":"","orcid":"","institution":"Lodz 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Milan","correspondingAuthor":false,"prefix":"","firstName":"Alicja","middleName":"Jereczek-Fossa","lastName":"Barbara","suffix":""},{"id":633405276,"identity":"48fa5173-9ed4-4ef3-a845-44eb9ae7be02","order_by":11,"name":"Łukasz Kuncman","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDUlEQVRIie3QPWvCQBjA8acEzuXU9ST1O1wJZDHoV8khnIuDY0dL4Jz0mxTsEjqeBNIltOuFFOpSpxbaLYKFHomLxSsZC73/cjzD794AbLY/WAdQtdLjHNTDFhy9OvNzBP0gvB7Cilw0IkkDQjj7LA/g0SJ6Xe/vn9jtIlpDeD0YgXtjIomLMfj0OfXzZVawOEtnEGYTBy43BjKZu0AgoGqKVFtooqYUmEgQEGYi0b6kNcm/xCOLX94qgs2EpwSH+mKaFG0h9Sm4IsRI8I4PsCReT3G/6IuxF2d8JvVbKDK8pdviXl4egquVGu/ydzHsxw/J3fZD/1jXjeQ5coycjrK+8y+g2T42m832b/sGZp9iR1ykACwAAAAASUVORK5CYII=","orcid":"","institution":"Medical University of Lodz","correspondingAuthor":true,"prefix":"","firstName":"Łukasz","middleName":"","lastName":"Kuncman","suffix":""}],"badges":[],"createdAt":"2026-03-18 11:53:52","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9159013/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9159013/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108941548,"identity":"7370ea8c-b19a-43f2-bf07-4663a933b5cf","added_by":"auto","created_at":"2026-05-11 05:35:54","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":148097,"visible":true,"origin":"","legend":"\u003cp\u003eA. Treatment sequences for all patients shown as a Gantt chart, illustrating the duration of CRT, durvalumab, and subsequent therapies.\u003c/p\u003e\n\u003cp\u003eB. Sankey diagram showing treatment pathways, including CRT with or without induction chemotherapy, durvalumab duration, and reasons for treatment discontinuation.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9159013/v1/c98d14911c28a80a9d29e892.png"},{"id":108978185,"identity":"4e2fcd36-77d3-456a-a72b-acc35e902052","added_by":"auto","created_at":"2026-05-11 11:34:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":116409,"visible":true,"origin":"","legend":"\u003cp\u003eTime to next treatment (TNT) in patients with locoregional versus distant or combined progression.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9159013/v1/cc45facc339b7722a2e1fc64.png"},{"id":108941551,"identity":"8636c08c-fabb-4e07-a95c-a15898798035","added_by":"auto","created_at":"2026-05-11 05:35:54","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":117458,"visible":true,"origin":"","legend":"\u003cp\u003eTime to next systemic treatment (TNST) in patients with locoregional versus distant or combined progression.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9159013/v1/54f22c96e36450fe2e84fca6.png"},{"id":108977970,"identity":"ce6f6928-6415-4e34-9ed9-c24806e47fc9","added_by":"auto","created_at":"2026-05-11 11:33:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":123683,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival outcomes according to the presence of oligometastatic progression.\u003c/p\u003e\n\u003cp\u003e(A) Progression-free survival 2 (PFS2) in patients with oligometastatic progression compared with those without oligometastatic progression.\u003c/p\u003e\n\u003cp\u003e(B) Overall survival (OS) in patients with oligometastatic progression compared with those without oligometastatic progression.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9159013/v1/30914b360d6c43c9ad052534.png"},{"id":108941555,"identity":"aebf8c2d-772c-4992-831c-d6e96d50847e","added_by":"auto","created_at":"2026-05-11 05:35:54","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":176293,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival outcomes according to the use of radical local treatment prior to second-line systemic therapy.\u003c/p\u003e\n\u003cp\u003e(A) Time to next systemic treatment (TNST).\u003c/p\u003e\n\u003cp\u003e(B) Progression-free survival 2 (PFS2).\u003c/p\u003e\n\u003cp\u003e(C) Overall survival (OS).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-9159013/v1/d61a5bcc221ffbe306f5ad11.png"},{"id":108941552,"identity":"4d4def2d-b2e6-4262-97bc-be2594b3550e","added_by":"auto","created_at":"2026-05-11 05:35:54","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":117911,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival outcomes according to radical local treatment administered at any time prior to PFS2 and OS assessment.\u003c/p\u003e\n\u003cp\u003e(A) Progression-free survival 2 (PFS2) stratified by the use of radical local treatment.\u003c/p\u003e\n\u003cp\u003e(B) Overall survival (OS) stratified by the use of radical local treatment.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-9159013/v1/9b8a53edf8fcef74a9e48627.png"},{"id":108977517,"identity":"a92751bb-d63f-4f51-bd92-2bec45212568","added_by":"auto","created_at":"2026-05-11 11:31:58","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":126153,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of hazard ratios (HR) with 95% confidence intervals from the multivariable Cox model for time to next systemic treatment (TNST) (N = 47; events = 47).\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-9159013/v1/9a7374249c15a4d90ce71ae3.png"},{"id":108978232,"identity":"a858cdd9-1a61-4f68-971a-22ee24dd5f8d","added_by":"auto","created_at":"2026-05-11 11:35:15","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":88517,"visible":true,"origin":"","legend":"\u003cp\u003eAdjusted TNST curves from the multivariable Cox model comparing patients treated with radical local therapy prior to second-line systemic treatment versus those without radical local therapy (N = 47).\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-9159013/v1/5bbfc76d7f058c83b8e7b9ae.png"},{"id":108979952,"identity":"d1f7b9ff-d27c-4f1a-be78-f14adb006d33","added_by":"auto","created_at":"2026-05-11 12:02:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1212742,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9159013/v1/fdef0f54-96b8-4a7d-85b4-9fd91d8d7122.pdf"},{"id":108977698,"identity":"5aede151-da3d-4b57-ab23-b4791c63661f","added_by":"auto","created_at":"2026-05-11 11:32:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1163718,"visible":true,"origin":"","legend":"","description":"","filename":"supplementaryfigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-9159013/v1/1087e517967cc5ef4bb1bbc5.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Local Salvage Therapy After Durvalumab Progression in Stage III NSCLC: A Multicenter Real-World Study","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eConcurrent chemoradiotherapy (cCRT) followed by durvalumab consolidation is the current standard of care for patients with unresectable stage III non\u0026ndash;small cell lung cancer (NSCLC) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Established by the PACIFIC trial, this strategy significantly improves progression-free and overall survival compared with chemoradiotherapy alone [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Despite these advances, disease recurrence remains common, with a substantial proportion of patients developing locoregional or distant relapse after consolidation immunotherapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Patterns of relapse after durvalumab are heterogeneous in both timing and location and may influence subsequent management. However, most available evidence derives from randomized clinical trials conducted in highly selected populations and may not fully reflect routine clinical practice. Real-world studies have reported considerable variability in treatment delivery, including the proportion of patients completing the planned 12 months of durvalumab, which ranges from less than one-third to approximately one-half of treated patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In addition, treatment-related factors such as radiotherapy-induced lymphopenia may influence the efficacy of consolidation immunotherapy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrently, the optimal management of patients who develop disease progression after durvalumab remains poorly defined, particularly in routine clinical practice [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In particular, there is little consensus on whether local treatment approaches, such as stereotactic radiotherapy or surgical resection may provide benefit in selected patients of oligometastatic or locoregional relapse. Similarly, the impact of the timing and pattern of progression on subsequent treatment strategies has not been well characterized.\u003c/p\u003e \u003cp\u003eTo address these gaps, we conducted a retrospective multicenter analysis of patients with stage III NSCLC treated with cCRT followed by durvalumab. The aim of this study was to characterize patterns of disease progression and evaluate post-progression treatment strategies in a real-world cohort. Because treatment decisions after post-durvalumab progression are highly individualized, endpoints reflecting real-world treatment trajectories, such as time to next systemic treatment (TNST), may provide clinically meaningful insights into treatment sequencing.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Population\u003c/h2\u003e \u003cp\u003e This retrospective multicenter study included patients with stage III NSCLC treated with concurrent chemoradiotherapy followed by durvalumab at five tertiary oncology centers in Poland.\u003c/p\u003e \u003cp\u003ePatients were eligible if they had histologically confirmed stage III NSCLC, completed concurrent chemoradiotherapy consisting of platinum-based chemotherapy administered during radiotherapy with a total dose\u0026thinsp;\u0026ge;\u0026thinsp;54 Gy, and received at least two cycles of durvalumab consolidation initiated within two months after completion of chemoradiotherapy. Patients were required to have adequate organ function, including hepatic, renal, and hematologic parameters, and no history of autoimmune disease.\u003c/p\u003e \u003cp\u003ePatients were excluded if follow-up data after progression were unavailable, if a second uncontrolled malignancy was present, or if tumors had mixed small-cell and non-small-cell histology. Clinical data were retrospectively collected from medical records using a standardized eCRF. Information included patient demographics, tumor characteristics, treatment details, disease progression, and follow-up outcomes.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProcedures\u003c/h3\u003e\n\u003cp\u003eIn Poland, durvalumab consolidation is reimbursed through a national drug program and is administered for up to 12 months or until disease progression or unacceptable toxicity. Continuation of durvalumab beyond radiographic progression was not permitted. Radiological assessment with computed tomography (CT) was performed at baseline and every three months during treatment or when clinically indicated. Disease progression was assessed according to RECIST version 1.1. criteria. Radiotherapy was delivered once daily in high-volume centers with established expertise in the treatment of lung cancer. All participating institutions had access to advanced techniques, including stereotactic body radiotherapy (SBRT), stereotactic fractionated radiotherapy (SFRT), stereotactic radiosurgery (SRS), intensity-modulated radiotherapy (IMRT) or volumetric-modulated arc therapy (VMAT), and image-guided radiotherapy (IGRT) using cone-beam computed tomography (CBCT). In selected cases, four-dimensional computed tomography (4DCT) imaging was also performed to account for respiratory motion.\u003c/p\u003e\n\u003ch3\u003eEndpoints\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was time to next systemic treatment (TNST), defined as the interval between the start of cCRT\u0026mdash;or, in patients who received induction chemotherapy, the start of the first induction cycle\u0026mdash;and the initiation of the first subsequent systemic anticancer therapy administered after disease progression. This endpoint was selected to reflect the overall real-world treatment trajectory following definitive therapy, rather than the isolated effect of post-progression interventions. The analysis evaluated the association between the pattern of progression (locoregional, distant, or combined) and the type of post-progression local treatment (radical vs. palliative) with TNST using both univariable and multivariable models. Disease progression was classified based on radiological assessment according to RECIST criteria and categorized into locoregional, distant, or combined progression. Locoregional progression was defined as progression occurring within the thorax, including the primary tumour site and/or regional lymph nodes, without evidence of extrathoracic disease. Distant progression was defined as the appearance or progression of metastatic lesions outside the thorax (e.g. brain, liver, bone, adrenal glands, or extrathoracic lymph nodes) without concurrent locoregional progression. Combined progression was defined as the simultaneous presence of locoregional and distant disease progression at the time of first documented relapse. Secondary endpoints included time to next treatment (TNT), progression-free survival 1 (PFS1), progression-free survival 2 (PFS2), and OS. TNT was defined as the time from the start of cCRT (or induction chemotherapy, if applicable) to the initiation of any subsequent anticancer treatment, either local (surgery or radiotherapy) or systemic. PFS1 was defined as the time from the start of cCRT (or induction chemotherapy) to the first documented disease progression or death from any cause, whichever occurred first. PFS2 was defined as the time from the first documented disease progression after durvalumab to the subsequent progression or death, reflecting the duration of disease control achieved with post-progression management strategies. OS was defined as the time from the start of cCRT (or induction chemotherapy, if applicable) to death from any cause or last follow-up.\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eThe data cutoff for progression-related endpoints was January 31, 2024, corresponding to the predefined date by which all included patients were required to have experienced disease progression. Data collection and follow-up for survival analyses continued until March 9, 2025, which served as the final censoring date.\u003c/p\u003e \u003cp\u003eContinuous variables were summarized as medians with interquartile ranges (IQR), and categorical variables as frequencies and percentages. Differences between groups were analyzed using the two-sided Mann\u0026ndash;Whitney U test for continuous non-normally distributed data and the χ\u0026sup2; test or Fisher\u0026rsquo;s exact test for categorical variables, as appropriate.\u003c/p\u003e \u003cp\u003eTime-to-event outcomes (TNT, TNST, PFS1, PFS2, OS) were estimated using the Kaplan\u0026ndash;Meier method, with 95% confidence intervals reported where applicable. Comparisons between subgroups were performed using the log-rank test, which was considered the primary inferential method for survival analyses. Breslow (generalized Wilcoxon) and Tarone\u0026ndash;Ware tests were applied to explore early and intermediate differences in survival curves. Statistical significance was set at a two-tailed p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003eTo explore independent factors associated with time to next systemic treatment (TNST), a multivariable Cox proportional hazards regression model was constructed. Missing values in covariates were imputed using k-nearest neighbors (kNN) imputation. Collinearity between dosimetric variables was assessed, and due to moderate correlation and model instability, mean lung dose was excluded from the final model. The proportional hazards (PH) assumption was formally evaluated using Schoenfeld residuals, and the final model satisfied the PH assumption. Hazard ratios (HR) with 95% confidence intervals (95% CI) were reported. Model performance was summarized using the concordance index (C-index), and overall model fit was assessed using the likelihood ratio test (LRT).\u003c/p\u003e \u003cp\u003eAll statistical analyses were conducted using Python (version 3.14) with the pandas, SciPy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], scikit-learn [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and lifelines packages.\u003c/p\u003e \u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki and applicable national regulations. According to the Bioethics Committee at the Medical University of Ł\u0026oacute;dź, this retrospective, non-interventional study based on anonymized medical records does not constitute a medical experiment and does not require ethics committee approval or informed consent. This is consistent with Polish national regulations, including the Polish Act of 5 December 1996 on the Professions of Physician and Dentist, as amended.\u003c/p\u003e \u003cp\u003eThe study was conducted in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Reporting was additionally aligned with recently proposed GROW criteria for real-world evidence studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The ChatGPT (version 5.0; OpenAI, San Francisco, CA, USA) language model was used solely for language editing and stylistic refinement of the manuscript, without any involvement in data processing, statistical analysis, or interpretation of results.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Characteristics\u003c/h2\u003e \u003cp\u003eA total of 60 patients with unresectable stage III NSCLC were included. The median age was 66 years. Most patients (98%) had ECOG performance status 0\u0026ndash;1 at baseline. Squamous cell carcinoma was the most common histological subtype (70%). PD-L1 expression was available in 69.5% of patients, while 30.5% had no recorded PD-L1 result. Baseline patient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline demographic, clinical, and treatment characteristics of the study cohort.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSummary\u003c/p\u003e \u003cp\u003e(median (min-max), IQR or number (%))\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66 (48\u003cb\u003e\u0026ndash;\u003c/b\u003e84; IQR 8.5)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (68.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (31.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eSmoking history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eprevious\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (55.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ecurrent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (38.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003enever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eHistopathologic tumor type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003esquamous cell carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (70.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eadenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (23.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNOS NSCLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003elarge cell carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003ePD-L1 status %TPS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026ndash;49%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (33.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eno data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (30.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (20.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (15.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG before CRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (0\u003cb\u003e\u0026ndash;\u003c/b\u003e2; IQR 1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eInduction chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eno\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (71.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eyes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (28.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy PTV volume (cm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e382 (140\u003cb\u003e\u0026ndash;\u003c/b\u003e1267; IQR 278)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy mean lung dose (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.1 (8.4\u003cb\u003e\u0026ndash;\u003c/b\u003e26.6; IQR 3.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy mean heart dose (Gy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.0 (1.0\u003cb\u003e\u0026ndash;\u003c/b\u003e26.7; IQR 9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eBest response to chemoradiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (53.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (43.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eCRT \u0026ndash; chemoradiotherapy; ECOG \u0026ndash; Eastern Cooperative Oncology Group performance status; Gy \u0026ndash; gray; IQR \u0026ndash; interquartile range; NOS \u0026ndash; not otherwise specified; NSCLC \u0026ndash; non-small cell lung cancer; PD-L1 \u0026ndash; programmed death-ligand 1; PTV \u0026ndash; planning target volume; TPS \u0026ndash; tumor proportion score; PR \u0026ndash; partial response; SD \u0026ndash; stable disease; CR \u0026ndash; complete response.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eChemoradiotherapy and Durvalumab Treatment\u003c/h3\u003e\n\u003cp\u003eAll patients completed concurrent conventionally fractionated chemoradiotherapy with a minimum dose of 54 Gy (median 60 Gy) and a median treatment duration of 1.1 months, followed by durvalumab consolidation therapy (median duration 6.1 months). Disease progression occurred in all patients during or after durvalumab, as per protocol requirements. Platinum-based doublets included cisplatin-based (71.7%) and carboplatin-based (28.3%). Induction chemotherapy was administered in 28.3% of patients. Durvalumab consolidation therapy was initiated within a median of 39 days post-CRT. The median number of durvalumab cycles administered was 8 (range: 2\u0026ndash;26). The Gantt diagram illustrates the treatment sequence (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The most common reason for durvalumab discontinuation was disease progression (68.3%), followed by immune-related toxicity (10.3%), 20.0% of patients completed therapy. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eB illustrates treatment pathways, including CRT with or without induction chemotherapy, duration of durvalumab therapy, and reasons for treatment discontinuation.\u003c/p\u003e\n\u003ch3\u003eDisease Progression\u003c/h3\u003e\n\u003cp\u003eAll patients experienced disease progression during or after durvalumab. The median time from durvalumab initiation to progression was 6.6 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Progression sites included the lung (n\u0026thinsp;=\u0026thinsp;25), brain (n\u0026thinsp;=\u0026thinsp;12), liver (n\u0026thinsp;=\u0026thinsp;7), lymph nodes (n\u0026thinsp;=\u0026thinsp;5), adrenal glands (n\u0026thinsp;=\u0026thinsp;4), bones (n\u0026thinsp;=\u0026thinsp;3), contralateral lung (n\u0026thinsp;=\u0026thinsp;2), and other sites (n\u0026thinsp;=\u0026thinsp;2). Patients were categorized based on the pattern of progression: 48.3% had locoregional progression, 35.0% distant-only, and 16.7% both local and distant. Pattern of progression is summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Patients who experienced locoregional progression had a significantly longer TNT compared with those who developed distant or combined progression, with median TNT of 17.1 versus 9.9 months, respectively (p\u0026thinsp;=\u0026thinsp;0.0088; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A statistically significant difference in time to next systemic treatment (TNST) was observed in Kaplan\u0026ndash;Meier analysis, with patients experiencing locoregional progression demonstrating longer TNST than those with distant or combined failure (median 16.4 vs. 11.8 months; log-rank p\u0026thinsp;=\u0026thinsp;0.0396; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The distribution-based Mann\u0026ndash;Whitney U test did not reach statistical significance, although a numerical difference was observed (p\u0026thinsp;=\u0026thinsp;0.1391), reflecting the different methodological assumptions between distribution-based and time-to-event analyses. Across all progression sites (lung, liver, lymph nodes, and other locations), no significant differences in TNST or PFS2 were observed. Progression in the brain similarly did not differ from all other sites, and outcomes were also comparable between pre-existing lesions, new lesions, and combined progression patterns (Fig. S2-S3). Oligometastatic progression was defined as the presence of 1\u0026ndash;3 metastatic lesions. In Kaplan\u0026ndash;Meier analyses, PFS2 was significantly longer in patients with oligometastatic progression (log-rank p\u0026thinsp;=\u0026thinsp;0.0335), with separation of the survival curves emerging during later follow-up. A more pronounced and consistent effect was observed for OS, with patients in the oligometastatic group demonstrating a longer median OS (41 vs. 19 months) and higher long-term survival rates (log-rank p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, B).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatterns and characteristics of disease progression after durvalumab.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of progression 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003elocoregional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29 (48.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003edistant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21 (35.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eboth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eNature of progression 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003enew\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31 (51.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003epreexisting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18 (30.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eboth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (18.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e \u003cp\u003eRegion of main progression 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003elung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25 (41.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebrain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eliver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (11.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003elymph nodes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eadrenal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (5.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003econtralateral lung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eother\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (3.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003eNo. of progressive lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26 (43.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13 (21.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (15.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePost-Progression Therapy\u003c/h2\u003e \u003cp\u003eAfter disease progression 54 patients (90%) received additional oncological therapy. Among them, 47 (87%) received systemic treatment, and 33 (61%) underwent local treatment (either radical or palliative) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Among the remaining patients, seven received local treatment only, while six did not receive any further oncological therapy due to clinical deterioration or other factors. The median TNT and TNST were 11.6 and 13.2 months, respectively. Radical local treatment was delivered to 23% of patients, mostly stereotactic radiotherapy (SRS/SBRT) to the brain or lung, whereas 31.7% of patients received palliative radiotherapy only. Patients with oligometastatic progression were more frequently treated with radical local therapy compared with those with non-oligometastatic progression (57.9% vs. 28.6%). Patients who received radical local treatment had longer time to next systemic treatment (TNST) compared with those who received palliative radiotherapy or no local therapy (median 29.1 vs. 12.6 months). This difference was statistically significant in distribution-based analysis (Mann\u0026ndash;Whitney U test, p\u0026thinsp;=\u0026thinsp;0.016), while survival analysis using Kaplan\u0026ndash;Meier curves showed a trend toward longer TNST in the radical treatment group (log-rank p\u0026thinsp;=\u0026thinsp;0.076; Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). A consistent, although not statistically significant, trend toward improved PFS2 and OS was observed in patients treated with radical local therapy, with median PFS2 of 29.4 versus 19.0 months (p\u0026thinsp;=\u0026thinsp;0.10) and median OS of 25.3 versus 14.3 months (p\u0026thinsp;=\u0026thinsp;0.16), respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e5\u003c/span\u003eB\u0026ndash;C). Correlation analysis demonstrated strong associations between TNST, PFS1, PFS2, and OS, with Spearman correlation coefficients ranging from 0.73 to 0.96 (Fig. S1). Of the 60 patients, 47 (87%) received systemic therapy after progression. The most commonly used regimens included platinum doublets (n\u0026thinsp;=\u0026thinsp;27) and docetaxel monotherapy (n\u0026thinsp;=\u0026thinsp;13). Immunotherapy was rechallenged only in one patient. No significant differences in median PFS2 or OS were observed across systemic treatment strategies administered at oligoprogression (Fig. S4A\u0026ndash;B).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eMultivariable analysis of TNST\u003c/h2\u003e \u003cp\u003eIn multivariable Cox regression analysis (N\u0026thinsp;=\u0026thinsp;47; events\u0026thinsp;=\u0026thinsp;47), receipt of radical local therapy prior to second-line systemic treatment was independently associated with a significantly lower hazard of initiating subsequent systemic therapy (HR\u0026thinsp;=\u0026thinsp;0.11, 95% CI 0.03\u0026ndash;0.40; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e7\u003c/span\u003e). Extrapulmonary progression was associated with a higher hazard of starting next systemic treatment (HR\u0026thinsp;=\u0026thinsp;3.23, 95% CI 1.39\u0026ndash;7.49; p\u0026thinsp;=\u0026thinsp;0.006). A higher number of durvalumab cycles was associated with a lower hazard of treatment escalation (HR\u0026thinsp;=\u0026thinsp;0.85, 95% CI 0.80\u0026ndash;0.91; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eOther covariates, including mean heart dose, PTV volume, ECOG performance status, chemotherapy agent, best response to chemoradiotherapy, and new-lesion progression, were not statistically significant (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The overall model fit was statistically significant (LRT\u0026thinsp;=\u0026thinsp;40.45; df\u0026thinsp;=\u0026thinsp;9; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the model demonstrated moderate-to-good discriminatory ability (C-index\u0026thinsp;=\u0026thinsp;0.787).\u003c/p\u003e \u003cp\u003eBased on adjusted survival estimates derived from the Cox model, the predicted median TNST was 25 months (95% CI 17\u0026ndash;38 months) in patients treated with radical local therapy compared with 12 months (95% CI 7\u0026ndash;34 months)in those without radical local therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis multicenter real-world study addresses a clinically relevant and increasingly common scenario of disease progression after consolidation durvalumab, for which no standard treatment strategy exists. Our findings suggest that selected patients with limited (locoregional or oligometastatic) progression may benefit from radical local salvage therapy, which can delay the need for subsequent systemic treatment. These results support a more active, multidisciplinary treatment approach in this setting.\u003c/p\u003e \u003cp\u003eOur findings should be interpreted in the context of existing evidence on post-durvalumab progression. While the PACIFIC trial established concurrent chemoradiotherapy followed by durvalumab as the standard of care, disease recurrence remains common, and patterns of progression are heterogeneous. Most available data derive from clinical trials conducted in highly selected populations, whereas our cohort reflects routine clinical practice, including heterogeneous PD-L1 status and limited molecular profiling. These differences may contribute to variability in both disease behavior and treatment decisions observed after progression.\u003c/p\u003e \u003cp\u003eApproximately 50% of patients in the PACIFIC trial did not complete the planned course of durvalumab, with disease progression being the leading cause of treatment discontinuation in this group (31%)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Early disease failure was also frequent in our cohort, with 71% of patients progressing within 12 months and 43% within 6 months of durvalumab initiation, consistent with previous real-world reports. In real-world data from Arunachalam et al. among 262 patients who initiated durvalumab following concurrent chemoradiotherapy, more than half (51.5%) discontinued treatment prematurely, with 28.4% due to disease progression [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In another retrospective analysis, nearly 70% of patients failed to complete the planned 12 months of durvalumab, most often due to either disease progression or pulmonary toxicity [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In a recent retrospective analysis by Park et al., early progression within six months was reported in 37.3% of patients [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Together, these findings underscore the unmet clinical need in this setting.\u003c/p\u003e \u003cp\u003eIn the PACIFIC exploratory analyses disease progression occurred in 45.4% of patients receiving durvalumab compared with 64.6% in the placebo group. The majority of first failures were intrathoracic (80.6% vs. 74.5%), while the proportion of patients experiencing distant-only progression was 15.3% and 20.3%, respectively. Importantly, the distribution of distant lesions was similar across arms, with the brain (62% vs. 67%), bone (14% vs. 8%), and liver (14% vs. 13%) as the most common sites. Most patients with distant relapse presented with a limited number of lesions, supporting the potential role of local salvage strategies [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Our real-world findings are broadly consistent with the observations [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In our cohort, 48.3% of patients developed locoregional progression, which was associated with a significantly longer time to next treatment compared with distant or combined progression (median 17.1 vs. 9.9 months), suggesting a more indolent disease course and delayed need for subsequent treatment. In contrast, TNST and PFS2 were not influenced by specific metastatic sites, lesion number, or whether progression occurred in pre-existing or newly developed lesions, supporting the concept that early post-durvalumab relapse is influenced predominantly by systemic disease behavior rather than locoregional factors alone.\u003c/p\u003e \u003cp\u003eThis observation is consistent with exploratory analyses from the PACIFIC trial, suggesting that durvalumab primarily delays recurrence rather than fundamentally altering metastatic behavior. In our study, the lung and brain were the most frequent sites of relapse, followed by liver, lymph nodes, and adrenal glands reflecting known patterns of metastatic spread in NSCLC. Notably, consistent with the PACIFIC dataset where \u0026gt;\u0026thinsp;90% of patients with distant relapse had\u0026thinsp;\u0026le;\u0026thinsp;5 lesions, many of the distant failures in our study were limited in number, thus potentially amenable to radical local therapy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn addition to its clinical relevance, the use of time to next systemic treatment (TNST) as a primary endpoint in our analysis is supported by its strong association with other key clinical outcomes. As shown in Supplementary Figure S1, TNST demonstrated very strong correlations with time to next treatment, progression-free survival (PFS1 and PFS2), and overall survival, with Spearman correlation coefficients ranging from 0.73 to 0.96. Importantly, TNST should not be interpreted solely as a surrogate endpoint, but rather as a composite measure reflecting both disease biology and clinical decision-making in real-world practice. These findings suggest that TNST reflects a combination of disease behavior, treatment durability, and real-world clinical decision-making. Importantly, TNST may better capture real-world treatment trajectories than conventional progression-based endpoints, particularly in settings where post-progression management is heterogeneous, not protocol-driven, and often involves local therapy and individualized treatment sequencing. From a clinical perspective, TNST represents a highly relevant outcome in patients progressing after consolidation durvalumab, a setting in which no established standard of care exists and subsequent systemic options are limited. The ability to delay initiation of further systemic therapy may translate into clinically meaningful treatment-free intervals, and potentially help preserve functional status. Importantly, our results highlight the critical role of treatment sequencing in determining the impact of local salvage strategies. When radical local treatment was administered prior to second-line systemic therapy, a marked and statistically significant prolongation of TNST was observed. In contrast, when radical local therapy was analyzed irrespective of timing, its association with longer PFS2 and overall survival was attenuated, indicating that the benefit of local salvage strategies depends on appropriate patient selection and timely integration rather than on their use per se. In multivariable analysis, radical local therapy prior to second-line systemic treatment remained independently associated with prolonged TNST. Although this association should not be interpreted causally given the retrospective design and potential treatment-selection bias, it supports the hypothesis that carefully selected patients with limited post-durvalumab progression may derive clinically meaningful benefit from integrated local strategies.\u003c/p\u003e \u003cp\u003eA key novel contribution of our study is the demonstration that patients receiving radical local salvage therapy, most commonly stereotactic radiotherapy, had significantly longer TNST compared with those treated with palliative radiotherapy or no local intervention (median 29.1 vs. 12.6 months; p\u0026thinsp;=\u0026thinsp;0.016). Our data provide real-world evidence that local salvage treatment can meaningfully delay the need for systemic therapy and thereby prolong the treatment-free interval in selected patients. This also raises the hypothesis that, similar to the oligoprogression setting where immunotherapy is continued with local treatment, a comparable strategy might be beneficial here. The CURB trial demonstrated that adding SBRT to standard therapy in oligoprogressive NSCLC significantly prolonged PFS (10.0 vs. 2.2 months), allowing 85% of patients to continue systemic treatment beyond progression, thus supporting the role of local ablative approaches in prolonging TNST[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In our study, most patients received SBRT, which\u0026mdash;owing to its high precision\u0026mdash;provides an ablative effect with a low complication rate, allowing continuation of systemic therapy when clinically appropriate[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, although current data are insufficient to support such an approach (local ablative treatment and continuation of immunotherapy) in routine practice, our findings provide preliminary evidence suggesting its potential clinical relevance and justify further prospective evaluation.\u003c/p\u003e \u003cp\u003eIn the setting of primary metastatic NSCLC, the use of local ablative therapy for oligometastatic disease has consistently been shown to prolong disease control. Multiple studies have demonstrated that ablative radiotherapy can improve PFS and significantly delay TNST in both driver-mutated and wild-type NSCLC [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In the randomized phase II trial by Gomez et al., patients with oligometastatic NSCLC who received local consolidative therapy after first-line systemic treatment achieved markedly longer PFS compared with those managed with maintenance therapy or observation (11.9 vs. 3.9 months). This improvement in disease control was accompanied by a notable prolongation of overall survival (41.2 vs. 17.0 months), underscoring the clinical value of aggressive local treatment in this setting [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Similarly, in the phase III SINDAS trial, the addition of upfront SBRT to EGFR-TKI therapy significantly improved both OS (25.5 vs. 17.4 months) and PFS (20.2 vs. 12.5 months)[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Consistent with these data, local ablative treatment in our study was associated with the greatest benefit in TNST and PFS, with more modest effects observed for overall survival, likely reflecting the limited sample size.\u003c/p\u003e \u003cp\u003eThe optimal management of patients who experience disease progression following consolidation durvalumab remains an area of clinical uncertainty. No standardized evidence-based algorithms are available. Systemic treatment options are often limited, and outcomes in this setting are generally poor with reported median overall survival ranging from approximately 11 to 13 months in contemporary real-world cohorts [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study is limited by its retrospective design and incomplete molecular profiling, although the national drug program ensured uniform monitoring. A key limitation is selection bias: patients with limited disease burden were more likely to receive SBRT and achieve favorable outcomes, whereas those with extensive disease or poor clinical condition received palliative radiotherapy and experienced worse outcomes. This confounding by indication, combined with immortal time bias, suggests that TNST differences partly reflect clinical decision-making regarding treatment sequencing rather than solely biological efficacy. Consequently, our findings are hypothesis-generating, and future randomized trials are essential to overcome these biases and confirm the benefit of local salvage strategies.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, early progression after durvalumab remains common but biologically heterogeneous. Our findings suggest that oligometastatic or limited progression after PACIFIC may represent a therapeutic opportunity. Patients treated with radical local therapy experienced a substantially longer time to next systemic treatment, supporting the role of integrated local strategies in delaying treatment escalation.\u003c/p\u003e \u003cp\u003eSalvage SBRT or other local modalities may extend disease control and allow postponement of subsequent systemic therapy in selected patients. Given the absence of a standardized post-durvalumab strategy, TNST emerges as a clinically meaningful endpoint reflecting real-world treatment dynamics. Prospective studies integrating ctDNA monitoring, novel agents, and local therapy are warranted to further refine treatment selection and optimize outcomes in this population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003eCBCT\u003c/strong\u003e \u0026ndash; Cone-beam computed tomography\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ecCRT\u003c/strong\u003e \u0026ndash; Concurrent chemoradiotherapy\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eCT\u003c/strong\u003e \u0026ndash; Computed tomography\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ectDNA\u003c/strong\u003e \u0026ndash; Circulating tumor DNA\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eECOG\u003c/strong\u003e \u0026ndash; Eastern Cooperative Oncology Group\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eEGFR\u003c/strong\u003e \u0026ndash; Epidermal growth factor receptor\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eESMO\u003c/strong\u003e \u0026ndash; European Society for Medical Oncology\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eGy\u003c/strong\u003e \u0026ndash; Gray\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eIMRT\u003c/strong\u003e \u0026ndash; Intensity-modulated radiotherapy\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eIGRT\u003c/strong\u003e \u0026ndash; Image-guided radiotherapy\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eIQR\u003c/strong\u003e \u0026ndash; Interquartile range\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMDT\u003c/strong\u003e \u0026ndash; Multidisciplinary tumor board\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eNSCLC\u003c/strong\u003e \u0026ndash; Non-small cell lung cancer\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eOS\u003c/strong\u003e \u0026ndash; Overall survival\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePACIFIC\u003c/strong\u003e \u0026ndash; Durvalumab after chemoradiotherapy in stage III NSCLC trial\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePD-L1\u003c/strong\u003e \u0026ndash; Programmed death-ligand 1\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePET-CT\u003c/strong\u003e \u0026ndash; Positron emission tomography\u0026ndash;computed tomography\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePFS\u003c/strong\u003e \u0026ndash; Progression-free survival\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePFS1\u003c/strong\u003e \u0026ndash; Progression-free survival from the start of CRT to first progression or death\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePFS2\u003c/strong\u003e \u0026ndash; Progression-free survival from post-durvalumab progression to subsequent progression or death\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePTV\u003c/strong\u003e \u0026ndash; Planning target volume\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eRECIST \u0026ndash;\u0026nbsp;\u003c/strong\u003eResponse Evaluation Criteria in Solid Tumors\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSBRT\u003c/strong\u003e \u003cstrong\u003e\u0026ndash;\u0026nbsp;\u003c/strong\u003eStereotactic body radiotherapy\u003c/li\u003e\n \u003cli\u003eSFRT\u0026nbsp;\u003cstrong\u003e\u0026ndash;\u0026nbsp;\u003c/strong\u003eStereotactic fractionated radiotherapy\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSRS\u003c/strong\u003e \u003cstrong\u003e\u0026ndash;\u0026nbsp;\u003c/strong\u003eStereotactic radiosurgery\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSTROBE\u003c/strong\u003e \u0026ndash; Strengthening the Reporting of Observational Studies in Epidemiology\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTKI\u003c/strong\u003e \u003cstrong\u003e\u0026ndash;\u0026nbsp;\u003c/strong\u003eTyrosine Kinase Inhibitor\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTNST\u003c/strong\u003e \u0026ndash; Time to next systemic treatment\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTNT\u003c/strong\u003e \u0026ndash; Time to next treatment\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTPS\u003c/strong\u003e \u0026ndash; Tumor proportion score\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eVMAT\u003c/strong\u003e \u0026ndash; Volumetric-modulated arc therapy\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eWHO\u003c/strong\u003e \u0026ndash; World Health Organization\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eThe authors wish to thank all participating radiotherapy centers and investigators for their contributions to data collection.\u0026nbsp;\u003c/p\u003e\u003cp\u003eEthics statement: According to the Bioethics Committee at the Medical University of Łódź, this retrospective, non-interventional study based on anonymized medical records does not constitute a medical experiment and does not require ethics committee approval or informed consent. This is consistent with Polish national regulations, including the Polish Act of 5 December 1996 on the Professions of Physician and Dentist (Journal of Laws 2023, item 1516, as amended). An official statement issued by the Bioethics Committee confirming this has been provided as a supplementary document.\u003c/p\u003e\n\u003cp\u003eFunding of the research statement:\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eConflicts of interest statement:\u003c/p\u003e\n\u003cp\u003eŁK, JF, MLH, KG declare receiving honoraria for lectures, as well as travel and accommodation support, from AstraZeneca Pharma Poland Sp. z o.o.\u003c/p\u003e\n\u003cp\u003eRS declares receiving honoraria for lectures from AstraZeneca Pharma Poland Sp. z o.o.\u003c/p\u003e\n\u003cp\u003eMP received travel grants and lecture honoraria from AstraZeneca, Roche, Novartis, Eli Lilly, Janssen, Gilead and Amgen.\u003c/p\u003e\n\u003cp\u003eArtificial intelligence involvement statement:\u003c/p\u003e\n\u003cp\u003eArtificial intelligence tools (ChatGPT ver. 5) were utilized solely for rephrasing individual sentences originally written by humans and were not employed for content creation, data analysis, or the development of visual concepts.\u003c/p\u003e\n\u003cp\u003eAuthors contribution:\u003c/p\u003e\n\u003cp\u003eMaja Lisik-Habib: Conceptualization; Methodology; Data curation; Investigation; Formal analysis; Writing—orginal draft; Project administration\u003c/p\u003e\n\u003cp\u003eRafał Stando: Investigation\u003c/p\u003e\n\u003cp\u003eGrzegorz Chmielewski: Investigation\u003c/p\u003e\n\u003cp\u003eMateusz Bilski: Investigation\u003c/p\u003e\n\u003cp\u003eKatarzyna Galwas: Investigation\u003c/p\u003e\n\u003cp\u003eMirosława Puskulluoglu: Investigation\u003c/p\u003e\n\u003cp\u003eAgnieszka Roman: Investigation\u003c/p\u003e\n\u003cp\u003eDamian Tworek: Investigation\u003c/p\u003e\n\u003cp\u003eKrzysztof Smółka: Formal analysis; Data curation; Visualization\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJacek Fijuth: Writing— review and editing; Supervision.\u003c/p\u003e\n\u003cp\u003eBarbara Alicja Jereczek-Fossa: Writing— review and editing; Supervision.\u003c/p\u003e\n\u003cp\u003eŁukasz Kuncman: Conceptualization; Methodology; Formal analysis; Writing— review and editing, and Supervision.\u003c/p\u003e\n\u003cp\u003eAuthorship Responsibility Statement:\u003c/p\u003e\n\u003cp\u003eWe confirm that all authors of this manuscript meet the criteria for authorship as outlined by the International Committee of Medical Journal Editors (ICMJE).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData Availability Statement:\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEarly and locally advanced non-small-cell lung cancer: an update of the ESMO Clinical Practice Guidelines focusing on diagnosis, staging, systemic and local therapy - Annals of Oncology. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.annalsofoncology.org/article/S0923-7534(21)04279-4/fulltext\u003c/span\u003e\u003cspan address=\"https://www.annalsofoncology.org/article/S0923-7534(21)04279-4/fulltext\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiely, G. 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Oncol.\u003c/em\u003e \u003cb\u003e34\u003c/b\u003e, S749 (2023).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"non–small cell lung cancer, durvalumab, oligometastatic progression, local salvage therapy, stereotactic radiotherapy, time to next systemic treatment","lastPublishedDoi":"10.21203/rs.3.rs-9159013/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9159013/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePatients with unresectable stage III non\u0026ndash;small cell lung cancer (NSCLC) who experience disease progression after chemoradiotherapy and consolidation durvalumab represent a growing population with poor outcomes and no established standard of care. Despite the survival benefit demonstrated in the PACIFIC trial, early disease progression remains frequent, and optimal management in this setting is not well defined.\u003c/p\u003e \u003cp\u003eIn this multicenter retrospective real-world study, we analyzed patterns of disease progression and post-progression treatment strategies in 60 patients treated with chemoradiotherapy followed by durvalumab, with a particular focus on time to next systemic treatment (TNST) as a clinically relevant endpoint reflecting treatment sequencing. Disease progression was heterogeneous in both timing and location. Locoregional progression was associated with a longer time to subsequent treatment compared with distant or combined progression. Importantly, the use of radical local salvage therapy was associated with a clinically meaningful delay in the initiation of subsequent systemic treatment, with median TNST of 29.1 months compared with 12.6 months in patients receiving palliative or no local intervention. TNST showed strong associations with other key clinical outcomes. These findings support its role as a pragmatic real-world endpoint capturing treatment trajectories after consolidation immunotherapy.\u003c/p\u003e \u003cp\u003eThese findings suggest that carefully selected patients with limited post-durvalumab progression may benefit from radical local salvage therapy, which may delay the need for subsequent systemic treatment in a setting with no established standard of care. Our results support the integration of local ablative strategies into multidisciplinary decision-making and highlight TNST as a clinically meaningful endpoint in this context.\u003c/p\u003e","manuscriptTitle":"Local Salvage Therapy After Durvalumab Progression in Stage III NSCLC: A Multicenter Real-World Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 05:35:48","doi":"10.21203/rs.3.rs-9159013/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-04-28T03:38:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-27T13:55:29+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-27T09:20:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-17T16:00:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-04-17T13:13:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9134636f-6a90-4206-a5a2-102ca7034030","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67419537,"name":"Biological sciences/Cancer"},{"id":67419538,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-05-11T05:35:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 05:35:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9159013","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9159013","identity":"rs-9159013","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}