Real-world outcomes of consolidative durvalumab after concurrent chemoradiotherapy in stage III non-small cell lung cancer: the prognostic role of clinical frailty in the post-PACIFIC era

Introduction

Background

Among newly diagnosed non-small cell lung cancer (NSCLC) patients, stage III NSCLC accounts for around 30% (1). Most of these cases are considered unresectable and the standard of care for these patients is concurrent chemoradiotherapy (CCRT) followed by consolidative durvalumab (2). The well-known PACIFIC trial demonstrated that durvalumab, a programmed death-ligand 1 (PD-L1) inhibitor, significantly improves overall survival (OS) (42.9% vs. 33.4%), and progression-free survival (PFS) (33.1% vs. 19.0%) compared to placebo (3). This trial played a key role on the establishment of consolidative durvalumab after CCRT, as endorsed by current clinical practice guidelines (4).

Rationale and knowledge gap

However, real-world data on this consolidation therapy have shown conflicting results (5-9), raising questions about its effectiveness outside controlled trial environments. Although diagnosed as stage III NSCLC, not all patients are treated with CCRT in a curative intent (10). Moreover, it is inevitable that a portion of patients may be ineligible for consolidative durvalumab because of toxicity after CCRT, disease progression, and patients’ unwillingness. On the other hand, up to 20% of patients already show remission after CCRT, which obviates the actual need for adjuvant therapy (11,12). All these reasons and variations in patient characteristics and treatment adherence among different studies may lead to the diversities in overall results reported, although the treatment practice looks similar in general.

Objective

This study aims to investigate the outcomes of consolidative durvalumab with real-world data and identify prognostic factors that may impact treatment efficacy in stage III NSCLC patients treated with radical-aimed CCRT. We present this article in accordance with the TREND reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0059/rc).

Methods

Patients

A retrospective review was conducted of patients with inoperable stage III NSCLC treated at Incheon St. Mary’s Hospital, Incheon, Republic of Korea, between 2017 and 2022.

Inclusion criteria included adults aged ≥40 years with Eastern Cooperative Oncology Group (ECOG) performance status ≤2, pathologically confirmed NSCLC, and receipt of platinum-based chemotherapy concurrently with radiotherapy at a dose ≥50 Gy. Patients with prior lung cancer treatment or synchronous malignancy were excluded.

Baseline demographic, clinical, and treatment characteristics were obtained from electronic medical records. Histologic classification was based on World Health Organization (WHO) criteria, and tumor-node-metastasis (TNM) staging followed the 8th edition of the American Joint Committee on Cancer (AJCC) Staging Manual.

The Clinical Frailty Scale (CFS) and ECOG performance status were assessed at the initiation of CCRT as part of routine baseline evaluation. CFS scores were retrospectively assigned based on pre-CCRT clinical documentation, including physician notes, functional assessments, comorbidity burden, and level of independence. Scoring was performed according to standardized CFS definitions. For analysis, CFS score was categorized as <4 versus ≥4. Serial frailty assessments after completion of CCRT were not uniformly available and were therefore not included.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Incheon St. Mary’s Hospital (IRB No. OC23RASI01090), and informed consent was waived due to the retrospective design.

Treatment allocation analysis

Because consolidative durvalumab was administered according to routine clinical practice rather than randomized assignment, potential baseline differences between groups were anticipated. To evaluate factors associated with durvalumab initiation, multivariable logistic regression analysis was performed including age, CFS score, tumor stage, PD-L1 expression, and radiation dose. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.

PD-L1 status and other clinically relevant baseline covariates were included in all multivariable survival models to account for potential treatment allocation differences.

Follow-up and outcome definitions

Patients underwent regular follow-up after CCRT and durvalumab, including physical examination, laboratory testing, and chest imaging. CT scans were generally performed every 3–6 months for the first 2 years and less frequently thereafter. Tumor response was assessed according to RECIST version 1.1.

OS was defined from the date of initiation of CCRT to death from any cause. PFS was defined from CCRT initiation to disease progression or death from any cause.

PFS was analyzed as a composite endpoint including local, regional, or distant progression, or death. Given the limited number of events in individual failure categories and potential competing-risk considerations, site-specific progression analyses were considered exploratory and were not included in primary multivariable models.

To mitigate potential immortal time bias related to durvalumab initiation, a landmark analysis was performed at 42 days following completion of CCRT, corresponding to the median time to durvalumab initiation (35.5 days) and a pragmatic 6-week window used to reduce immortal time bias.

Statistical analysis

The primary endpoints were OS and PFS. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate analyses were performed using the log-rank test, and multivariable analyses were conducted using Cox proportional hazards regression models. Hazard ratios (HRs) with 95% CIs were reported.

All statistical analyses were performed using SPSS version 25 (IBM Corp., Armonk, NY). A two-sided P value <0.05 was considered statistically significant.

Results

Patient characteristics

A total of 184 advanced lung cancer patients were screened, and 108 patients with stage III NSCLC who met inclusion criteria were included in the final analysis. Among them, 50 patients received consolidative durvalumab and 58 did not.

The median age of the cohort was 68 years, and 83% were male. More than half had squamous cell carcinoma. Baseline characteristics are summarized in Table 1. There were no significant differences in demographic variables between groups, except for PD-L1 expression, which was more frequently ≥1% in the durvalumab group.

Treatment characteristics

Nearly 90% of patients received paclitaxel-cisplatin as concurrent chemotherapy. The median radiation dose was 66 Gy delivered in 33 fractions, and all patients were treated with intensity-modulated radiotherapy. The median duration of CCRT was 50 days.

In the durvalumab group, treatment was initiated a median of 35.5 days after completion of CCRT. The standard dosing schedule (10 mg/kg every two weeks) was applied. The median duration of durvalumab therapy was 8.8 months, with a median of 16 cycles administered.

In multivariable logistic regression analysis, PD-L1 expression ≥1% was independently associated with durvalumab initiation. Age, clinical frailty status (CFS score), tumor stage, and radiation dose were not significantly associated with treatment allocation (Table 2).

Survival outcomes

The median follow-up duration was 16.5 months (range, 3.5–82.6 months).

OS

In the overall cohort (N=108), the median OS was 27.1 months (95% CI: 15.4–38.8), with 52 death events observed during follow-up. The 1-year OS rate was 62% in the non-durvalumab group and 84% in the durvalumab group (log-rank P=0.047). Median OS was 16.8 months in patients who did not receive durvalumab and 33.3 months in those who did. In multivariable Cox regression analysis, consolidative durvalumab was independently associated with improved OS (HR 0.16, 95% CI: 0.06–0.39; P<0.001). No other clinical or treatment variables were significantly associated with OS (Table 3). In landmark analysis performed 42 days after completion of CCRT, the survival difference was attenuated but remained directionally consistent (log-rank P=0.059).

PFS

The median PFS for the overall cohort was 18.8 months (95% CI: 12.8–24.8). In multivariable analysis, durvalumab was not independently associated with PFS (HR 0.84, 95% CI: 0.44–1.58; P=0.59). Kaplan-Meier curves for OS (P=0.047) and PFS (P=0.35) are shown in Figure 1A,1B.

Figure 1 Kaplan-Meier curves for survival outcomes according to consolidative durvalumab use. (A) Overall survival; (B) progression-free survival.

PD-L1 subgroup analysis

In patients with PD-L1 ≥1%, durvalumab remained independently associated with improved OS (Table 4). However, durvalumab was not independently associated with PFS in this subgroup (HR 0.80, 95% CI: 0.35–1.85; P=0.60).

Prognostic factors

Multivariable Cox regression analyses for OS and PFS are summarized in Table 3.

For OS, consolidative durvalumab was the only variable independently associated with improved outcome (HR 0.16, 95% CI: 0.06–0.39; P<0.001). Age, sex, clinical frailty status, tumor stage, PD-L1 expression, and radiation dose were not independently associated with OS.

For PFS, PD-L1 expression ≥1% was independently associated with PFS (HR 2.999, 95% CI: 1.542–5.831; P=0.001), whereas durvalumab was not (HR 0.84, 95% CI: 0.44–1.58; P=0.59). Female sex was also associated with improved PFS (HR 0.284, 95% CI: 0.117–0.691; P=0.006). Age, clinical frailty status, tumor stage, and radiation dose were not significantly associated with PFS.

After verification of model specifications and standardized adjustment for clinical covariates, radiation dose was not independently associated with OS or PFS. Additionally, there was no significant difference in delivered radiation dose according to baseline frailty status (P=0.30).

In the subgroup of patients with PD-L1 expression ≥1%, consolidative durvalumab remained independently associated with improved OS (HR 0.43, 95% CI: 0.21–0.87; P=0.02), while no independent association with PFS was observed (HR 0.80, 95% CI: 0.35–1.85; P=0.60) (Table 4).

Site-specific progression analyses were exploratory and are not included in the primary multivariable results.

Adverse events

In the overall cohort (N=108), grade ≥3 adverse events occurred in 9 patients (8.3%). Grade 3 pneumonitis was observed in 8 patients (7.4%), and no grade 4 or 5 adverse events were recorded. Among patients receiving durvalumab, grade ≥3 adverse events occurred in 4 patients (8%), all of which were grade 3 pneumonitis. No grade 4 or 5 treatment-related adverse events were observed.

Discussion

This single-center retrospective study evaluated real-world outcomes of consolidative durvalumab following CCRT in patients with unresectable stage III NSCLC and explored the prognostic role of clinical frailty in this setting. In this heterogeneous real-world cohort, consolidative durvalumab was independently associated with improved OS, whereas no independent association was observed for PFS after multivariable adjustment. Baseline clinical frailty, as measured by the CFS, did not influence treatment allocation and remained an important patient-related prognostic variable.

Clinical frailty as a prognostic biomarker beyond ECOG performance status

Although frailty was not independently associated with survival in adjusted analyses, our findings underscore the importance of incorporating multidimensional fitness assessment in real-world populations. While ECOG performance status remains the standard tool for assessing functional fitness in oncology practice, it may insufficiently capture multidimensional vulnerability, particularly in older or comorbid populations. The CFS provides a broader evaluation of physiological reserve by incorporating functional dependence, comorbidity burden, and overall clinical status (13). Previous studies have demonstrated the prognostic relevance of frailty assessments in patients treated with immune checkpoint inhibitors. Galán et al. reported that frailty independently predicted OS and PFS in advanced NSCLC patients receiving pembrolizumab, highlighting the limitations of ECOG-based evaluation alone (14,15).

In our cohort, baseline frailty was not independently associated with initiation of durvalumab, suggesting that treatment allocation in routine practice was not solely driven by frailty-based selection. This finding strengthens the interpretation that the observed OS benefit of durvalumab is unlikely to reflect simple selection bias. Nevertheless, frailty assessment was retrospective and derived from baseline documentation; thus, misclassification cannot be entirely excluded. Prospective incorporation of standardized frailty assessment may further refine patient selection and prognostic stratification in stage III NSCLC.

Durvalumab and PD-L1 expression in a real-world context

In our cohort, consolidative durvalumab was independently associated with significantly improved OS after adjustment for baseline covariates (HR 0.16, 95% CI: 0.06–0.39; P<0.001). However, no independent association was observed for PFS (HR 0.84; P=0.59).

The apparent discrepancy between OS and PFS may reflect characteristics inherent to retrospective real-world populations. OS is influenced not only by disease progression but also by competing mortality risks, comorbid conditions, and variability in post-progression management. Conversely, PFS events may be sensitive to imaging intervals and documentation heterogeneity, potentially attenuating measurable differences between treatment groups.

In the subgroup of patients with PD-L1 expression ≥1%, durvalumab remained independently associated with improved OS (HR 0.43; P=0.02), whereas no independent association with PFS was observed. This pattern may suggest that PD-L1 expression enriches for durable immunologic benefit, which translates into longer survival rather than early radiographic disease control. However, given the limited number of events within PD-L1 strata, these subgroup findings should be interpreted cautiously and considered hypothesis-generating.

These findings are broadly consistent with prior real-world analyses. A Korean real-world study reported improved progression-related outcomes with durvalumab, while OS benefit was more pronounced among patients with PD-L1-positive tumors (16). Interim results from the PACIFIC-R registry further support these observations, showing numerically higher long-term survival in patients with PD-L1 expression ≥1% (17). Severe treatment-related toxicity was uncommon. Grade ≥3 adverse events occurred in 8.3% of patients overall and in 8% of those receiving durvalumab, with grade 3 pneumonitis representing the most frequent high-grade event. No grade 4 or 5 toxicities were observed. These results support the tolerability of consolidative durvalumab in routine clinical practice, although causal inference is limited by the retrospective design.

Interpretation of survival outcomes in real-world populations

Although no independent association was observed for PFS, OS remained significantly associated with durvalumab after adjusted analysis. This observation underscores the complexity of interpreting survival endpoints in real-world cohorts. While PFS may more directly reflect disease biology and immediate treatment response, OS integrates patient-related factors, comorbidities, and subsequent therapies. In a population with substantial baseline frailty and heterogeneous clinical characteristics, these competing influences may modify traditional trial-based expectations of endpoint concordance.

Although patterns of failure may provide additional biological insight, limited event numbers within individual progression categories reduced statistical precision and increased susceptibility to model instability. Accordingly, we focused on overall PFS as the primary progression endpoint, and site-specific analyses were treated as exploratory.

Limitations

This study has limitations inherent to its retrospective, single-center design. Treatment allocation was not randomized, and unmeasured confounders may persist despite multivariable adjustment. Although radiation dose has been associated with local control in prior studies (18), we did not observe an independent association between radiation dose and survival outcomes in our adjusted analyses. Therefore, radiation dose should be interpreted as an exploratory variable rather than a primary prognostic factor in this study. Frailty assessment was performed retrospectively using baseline clinical documentation and may be subject to misclassification. Post-CCRT changes in functional status were not systematically captured. The modest sample size limited statistical power, particularly for subgroup analyses. Follow-up duration may be insufficient to fully characterize long-term survival outcomes. Finally, PD-L1 testing methods and treatment delivery were not fully standardized throughout the study period.

Clinical implications and future directions

Despite these limitations, our findings provide clinically relevant insights into the application of consolidative durvalumab in routine practice. Durvalumab demonstrated a significant association with improved OS in a real-world population that included frail patients who are often underrepresented in randomized trials. Baseline frailty assessment did not independently determine treatment allocation but remains an important clinical consideration.

Prospective multicenter studies incorporating standardized frailty metrics and biomarker stratification are warranted to validate these observations and to refine personalized treatment strategies in stage III NSCLC.

Conclusions

In this real-world cohort of unresectable stage III NSCLC, consolidative durvalumab was independently associated with improved OS, including among patients with PD-L1 expression ≥1%. No independent association was observed for PFS after adjustment. Baseline frailty did not determine treatment allocation and remains an important clinical consideration.

These findings support the use of consolidative durvalumab in routine practice while underscoring the need for prospective validation incorporating standardized frailty and biomarker assessment.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0059/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0059/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0059/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0059/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Incheon St. Mary’s Hospital (IRB No. OC23RASI01090), and informed consent was waived due to the retrospective design.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin 2017;67:93-9.
2. Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv1-iv21. [Crossref] [PubMed]
3. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017;377:1919-29. [Crossref] [PubMed]
4. Network NCC. Non-Small Cell Lung Cancer (Version 3.2025) 2025. Available online: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
5. Ho JCS, Cheung KM. Brief report: impact of consolidation durvalumab on unresectable non-small cell lung cancer with driver mutations. Cancer Treat Res Commun 2024;42:100863. [Crossref] [PubMed]
6. Jung HA, Noh JM, Sun JM, et al. Real world data of durvalumab consolidation after chemoradiotherapy in stage III non-small-cell lung cancer. Lung Cancer 2020;146:23-9. [Crossref] [PubMed]
7. Stevens S, Nindra U, Shahnam A, et al. Real world efficacy and toxicity of consolidation durvalumab following chemoradiotherapy in older Australian patients with unresectable stage III non-small cell lung cancer. J Geriatr Oncol 2024;15:101705. [Crossref] [PubMed]
8. Stevens SX, Nindra U, Shahnam A, et al. Effect of delayed consolidation durvalumab and timing of treatment on survival outcomes in patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT). J Clin Oncol 2022;4:e18809.
9. Zukin M, Gondim V, Shimada AK, et al. Durvalumab as consolidation therapy in patients who received chemoradiotherapy for unresectable stage III NSCLC: Real-world data from an expanded access program in Brazil (LACOG 0120). J Bras Pneumol 2025;50:e20240228. [Crossref] [PubMed]
10. Evers J, de Jaeger K, Hendriks LEL, et al. Trends and variations in treatment of stage I-III non-small cell lung cancer from 2008 to 2018: A nationwide population-based study from the Netherlands. Lung Cancer 2021;155:103-13. [Crossref] [PubMed]
11. De Ruysscher D, van Baardwijk A, Wanders R, et al. Individualized accelerated isotoxic concurrent chemo-radiotherapy for stage III non-small cell lung cancer: 5-Year results of a prospective study. Radiother Oncol 2019;135:141-6. [Crossref] [PubMed]
12. Senan S, Brade A, Wang LH, et al. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 2016;34:953-62. [Crossref] [PubMed]
13. Rockwood K, Theou O. Using the Clinical Frailty Scale in Allocating Scarce Health Care Resources. Can Geriatr J 2020;23:210-5. [Crossref] [PubMed]
14. Friedlaender A, Banna GL, Buffoni L, et al. Poor-Performance Status Assessment of Patients with Non-small Cell Lung Cancer Remains Vague and Blurred in the Immunotherapy Era. Curr Oncol Rep 2019;21:107. [Crossref] [PubMed]
15. Jiménez Galán R, Prado-Mel E, Alvarez de Sotomayor M, et al. Impact of Frailty on Outcomes of First-Line Pembrolizumab Monotherapy in a Real-World Population with Advanced Non-Small Cell Lung Cancer. Biology (Basel) 2023;12:191. [Crossref] [PubMed]
16. Jang JY, Song SY, Shin YS, et al. Contribution of Enhanced Locoregional Control to Improved Overall Survival with Consolidative Durvalumab after Concurrent Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer: Insights from Real-World Data. Cancer Res Treat 2024;56:785-94. [Crossref] [PubMed]
17. Filippi AR, Bar J, Chouaid C, et al. Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R. ESMO Open 2024;9:103464. [Crossref] [PubMed]
18. Brower JV, Amini A, Chen S, et al. Improved survival with dose-escalated radiotherapy in stage III non-small-cell lung cancer: analysis of the National Cancer Database. Ann Oncol 2016;27:1887-94. [Crossref] [PubMed]