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Jang, Song, Shin, Kim, Choi, Kim, Lee, Lee, Choi, Yoon, and Kim: 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
Original Article
Lung and Thoracic cancer

Cancer Res Treat 2024;56(3):785-794.

Published online: 16 January 2024

DOI: https://doi.org/10.4143/crt.2023.1014

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

Jeong Yun Jang1, 2, Si Yeol Song2, Young Seob Shin2, Ha Un Kim2, Eun Kyung Choi2, Sang-We Kim3, Jae Cheol Lee3, Dae Ho Lee3, Chang-Min Choi3, 4, Shinkyo Yoon3, Su Ssan Kim2

1Department of Radiation Oncology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea

2Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

3Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

4Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence: Su Ssan Kim, Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: 82-2-3010-5680 Fax: 82-2-3010-6950 E-mail: watermountain@hanmail.net

Received 6 September 2023       Accepted 14 January 2024

Copyright © 2024 by the Korean Cancer Association

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

This study aimed to assess the real-world clinical outcomes of consolidative durvalumab in patients with unresectable locally advanced non–small cell lung cancer (LA-NSCLC) and to explore the role of radiotherapy in the era of immunotherapy.

Materials and Methods

This retrospective study assessed 171 patients with unresectable LA-NSCLC who underwent concurrent chemoradiotherapy (CCRT) with or without consolidative durvalumab at Asan Medical Center between May 2018 and May 2021. Primary outcomes included freedom from locoregional failure (FFLRF), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS).

Results

Durvalumab following CCRT demonstrated a prolonged median PFS of 20.9 months (p=0.048) and a 3-year FFLRF rate of 57.3% (p=0.008), compared to 13.7 months and 38.8%, respectively, with CCRT alone. Furthermore, the incidence of in-field recurrence was significantly greater in the CCRT-alone group compared to the durvalumab group (26.8% vs. 12.4%, p=0.027). While median OS was not reached with durvalumab, it was 35.4 months in patients receiving CCRT alone (p=0.010). Patients positive for programmed cell death ligand 1 (PD-L1) expression showed notably better outcomes, including FFLRF, DMFS, PFS, and OS. Adherence to PACIFIC trial eligibility criteria identified 100 patients (58.5%) as ineligible. The use of durvalumab demonstrated better survival regardless of eligibility criteria.

Conclusion

The use of durvalumab consolidation following CCRT significantly enhanced locoregional control and OS in patients with unresectable LA-NSCLC, especially in those with PD-L1–positive tumors, thereby validating the role of durvalumab in standard care.

Keywords: Non-small-cell lung carcinoma, Concurrent chemoradiotherapy, Radiotherapy, Immunotherapy, Durvalumab

Introduction

Lung cancer is responsible for the highest cancer incidence and mortality globally, with 2 million new cases and 1.8 million deaths annually, and it has been identified as the most prevalent type of fatal cancer in both sexes in domestic data [1,2]. Over 30% of patients who are initially diagnosed with lung cancer have locally advanced non–small cell lung cancer (LA-NSCLC). For these patients, particularly those with unresectable tumors, the historical standard of care (SoC) was definitive concurrent chemoradiotherapy (CCRT) alone, and, despite progress in chemotherapy and radiotherapy (RT), the median overall survival (OS) rate for patients with LA-NSCLC has remained disappointingly low at 9-34 months [3,4]. However, the PACIFIC trial, a phase III randomized controlled trial (RCT), demonstrated a dramatic improvement in progression-free survival (PFS) and OS for patients with stage III non–small cell lung cancer (NSCLC) who received durvalumab following definitive CCRT, which established consolidative durvalumab as the new SoC [5]. The recently released 5-year survival outcomes further confirmed the robust success of durvalumab, with a median OS of 47.5 months compared to 29.1 with a placebo [6].
However, there are some discrepancies between RCTs and real-world clinical settings. The PACIFIC trial included patients with unresectable stage III NSCLC and a European Cooperative Oncology Group performance status (ECOG PS) of 0-1 while excluding those who experienced grade ≥ 2 radiation pneumonitis (RP) after CCRT and had a known history of tuberculosis. Furthermore, protocol regulations included constraints such as mean lung dose (MLD) < 20 Gy, a volume of lung receiving at least 20 Gy (V20) < 35%, and mean esophagus dose < 34 Gy. The stringent criteria in clinical trials and the variations in patient characteristics and healthcare systems across countries highlight the need for validation to ensure the real-world safety and efficacy of the results obtained from RCTs [7].
Durvalumab received the Food and Drug Administration approval in the United States in February 2018, followed by its approval in South Korea in April 2020. Hence, while a considerable number of patients are currently undergoing immunotherapy in real-world settings, there is a scarcity of publications on the assessment of long-term oncologic outcomes in the domestic context. Therefore, we aimed to present the real-world clinical outcomes of consolidative durvalumab at a single center and explore the role of RT in the era of immunotherapy.

Materials and Methods

1. Patients

We retrospectively reviewed the medical records of patients who underwent definitive CCRT with unresectable LA-NSCLC at Asan Medical Center from May 2018 to May 2021. The key inclusion criteria were: patients (1) aged ≥ 18 years, (2) with unresectable LA-NSCLC who require definitive CCRT based on National Comprehensive Cancer Network guidelines, (3) who had received at least two cycles of chemotherapy concurrently with RT, and (4) who had never received RT to the thorax or underwent pulmonary surgery [8]. A total of 171 patients were included for analysis, with 89 receiving consolidative durvalumab after CCRT and 82 receiving CCRT alone (S1 Fig.). The patient’s clinical stage was evaluated based on the 8th edition of the American Joint Committee on Cancer staging system.

2. Treatments

Four-dimensional simulated computed tomography (CT) scans of 2.5-mm slices were performed for all patients in the supine position while free-breathing using a respiratory management system (RPM, Varian Medical Systems, Palo Alto, CA) to create ten respiratory phases. Gross tumor volume was delineated with reference to chest CT and positron emission tomography (PET)–CT images, and lymph nodes (LN) suspected of malignancy were included if they had an axial diameter of 1 cm or larger on CT or demonstrated high fluorodeoxyglucose uptake on PET-CT. A clinical target volume was generated, taking into account microscopic tumor extension, and elective nodal irradiation was not performed. The internal target volume (ITV) was established considering the movement of the tumor during each phase of respiration, and the planning target volume (PTV) was set with a margin of 5-7 mm from the ITV. All patients were treated with an intensity-modulated radiation therapy plan, ensuring that 95% of the PTV received 95% of the prescribed radiation dose. The organs at risk and the constraints applied to these were consistent with those described in previous reports [9]. The median total dose was 60 Gy (range, 50 to 73 Gy), and the fraction size ranged from 1.8 to 2.2 Gy. Patients received concurrent chemotherapy agents of either a paclitaxel-based or etoposide-based regimen or cisplatin in combination with pemetrexed.
Consolidated durvalumab was initiated after the completion of CCRT, with a median time of 34 days (range, 0 to 172 days). Durvalumab was administered at a dose of 10 mg/kg every 2 weeks, and treatment was discontinued if disease progression or unacceptable complications occurred. The median number of cycles administered was 17 (range, 2 to 26).

3. Follow-up and outcomes

Regular follow-up after CCRT included history taking, physical examinations, chest X-rays, and blood tests. Chest CT scans were performed every 6 months for 2 years, followed by annual CT scans for the subsequent 5 years. Freedom from locoregional failure (FFLRF) was defined as the period from the end of CCRT to the occurrence of locoregional failure (LRF), and in-field and out-field recurrence were identified based on the PTV margin. Distant metastasis-free survival (DMFS) was defined as the period from the end of CCRT to the occurrence of distant metastasis or death. In this study, recurrence or progression in the lung, mediastinum, hilum, and/or supraclavicular region at ipsilateral side was classified as LRF, while the progression at the contralateral lung or any pleural metastasis was classified as distant metastasis. PFS and OS were defined as the durations from the end of CCRT to the occurrence of any progression or death and to death from any cause, respectively. RP grade ≥ 2 was assessed using criteria established by the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer.

4. Statistical analysis

Statistical analyses were performed using R ver. 4.2.2 (R Development Core Team, Vienna, Austria). To compare the distribution of characteristics between the durvalumab and CCRT-alone groups, an independent-sample T-test was performed for continuous variables, and a chi-square test was performed for noncontinuous variables. Survival outcomes were calculated using the Kaplan-Meier method, and to identify clinical factors related to each oncologic outcome, univariate and multivariate analyses were performed using Cox regression analysis. A receiver operating characteristic curve was generated to identify an optimal cutoff value for each dosimetry parameter in predicting RP. A p-value < 0.05 indicated statistical significance for all analyses.

Results

1. Patients characteristics

A total of 171 patients were included in the final analysis, and their characteristics are presented in Table 1. The median age of the entire study population was 65 years (range, 36 to 85 years), and 154 patients (90.1%) had an ECOG PS of 0-1. There were 81 patients (47.4%) with squamous cell carcinoma and 82 (48.0%) with adenocarcinoma. In total, 85 patients (49.7%) had cT3-4 disease, 137 (80.1%) had cN2-3 disease, and 154 (90.1%) were diagnosed with stage III disease. In the programmed cell death ligand 1 (PD-L1) (SP263) Assay (Roche Diagnostics, F. Hoffmann-La Roche Ltd., Basel, Switzerland), expression of ≥ 1% was defined as PD-L1–positive, and out of the 158 patients, 102 (59.6%) were found to be PD-L1–positive.

2. A pattern of failure with the use of durvalumab

During a median follow-up period of 25.9 months, 108 patients (63.2%) experienced progression or death; the pattern of failure is shown in Table 2. The number of LRF was significantly higher in the CCRT-alone group compared to the durvalumab group, with 48 and 33 cases, respectively (p=0.008). Furthermore, incidence of in-field recurrences was higher within the CCRT-alone group (p=0.027). However, there was no significant difference in distant failures between the two groups (p=0.644). The most common sites of first failure in both groups were lung, regional LN, brain, and bone, in that order.
The median FFLRF in the durvalumab group was not reached, compared to 19.8 months in the CCRT-alone group, and the 3-year rate was 57.3% versus 38.8% (p=0.008), with an absolute difference of 18.5% (Fig. 1A). Although there was a tendency toward prolonged median DMFS with the addition of durvalumab (CCRT alone vs. CCRT+durvalumab, 24.3 months vs. 37.8 months, p=0.270), but with no significant difference (Fig. 1B).

3. Progression-free survival and overall survival

The median PFS was 13.7 months for the CCRT-alone group compared to 20.9 months for the durvalumab group, with corresponding 3-year PFS rates of 28.3% and 46.3%, respectively (p=0.048) (Fig. 1C). The median follow-up period for mortality was 28.2 months, during which 41 patients in the CCRT-alone group and 26 patients in the durvalumab group expired. The median OS with durvalumab was not reached, compared to 35.4 months with CCRT alone (p=0.010) (Fig. 1D). In line with this, the univariate analysis also revealed that the use of durvalumab was associated with improved PFS and OS (Table 3). The multivariate analysis for OS further demonstrated that advanced age, stage IIIC, and receiving CCRT alone were associated with inferior survival (S2 Fig.).

4. Oncologic outcomes by PD-L1 expression

The OS for each group, categorized by PD-L1 expression status and the use of durvalumab, is presented in S3 Fig. In the PD-L1–positive population with PD-L1 expression over 1%, the use of durvalumab resulted in improvements in FFLRF, DMFS, PFS, and OS (3-year rate, CCRT alone vs. CCRT+durvalumab; FFLRF 34.4% vs. 61.3%, DMFS 31.7% vs. 56.3%, PFS 24.7% vs. 50.9%, OS 46.1% vs. 73.8%). However, in the PD-L1–negative population, no significant differences were observed between the two groups (Table 4). Furthermore, this trend was also observed in the analysis of patients, whether stratified by PD-L1 expression levels below or above the 10% cutoff (S4 Fig.).
Among the 102 patients who were PD-L1–positive, the durvalumab group exhibited a higher proportion of younger age and advanced stage. The CCRT-alone group showed a higher percentage of patients receiving induction chemotherapy, with the groups otherwise maintaining a well-balanced distribution (S5 Table). Within this population, a more pronounced survival benefit with durvalumab was observed across all oncologic outcomes compared to the overall population analysis, with an absolute difference of 27.7% in the 3-year OS rates between the two groups (Fig. 2).

5. RP of grade 2 or higher

The occurrence of RP grade ≥ 2 was noted at a median of 2.8 months (range, 0.3 to 25.2 months) following the completion of CCRT. There were 34 cases (41.5%) in the CCRT-alone group and 40 cases (44.9%) in the durvalumab group, with no significant difference observed between the two groups (p=0.761) (Fig. 3). With each threshold value used to predict RP, it was consistently observed that patients with higher values of PTV, MLD, a volume of lung receiving at least 5 Gy (V5), and V20 were associated with a significantly higher incidence of pneumonitis for each parameter (S6 and S7 Figs.). No significant differences in dosimetry values were found between the durvalumab and CCRT-alone groups (S8 Table).

6. Evaluating eligibility criteria for the PACIFIC study

Real-world adherence to the eligibility criteria of the PACIFIC trial was assessed, identifying 100 patients (58.5%) classified as ineligible, with the reasons documented in S9 Table. In the eligible group, there were 31 patients in the CCRT-alone group and 40 patients in the durvalumab group. The 3-year freedom from local progression (FFLP) for CCRT-alone and durvalumab group were 42.1% and 61.8%, respectively (p=0.220), while the 3-year OS were 60.6% and 73.2%, respectively (p=0.017). In the non-eligible group, which included 51 patients in the CCRT-alone group and 49 patients in the durvalumab group, the 3-year FFLP were 36.4% and 56.7%, respectively (p=0.310), while the 3-year OS were 40.7% and 66.1%, respectively (p=0.013). Furthermore, there was no significant difference in the occurrence of grade ≥ 2 RP based on the use of durvalumab in both eligible and non-eligible patients.

Discussion

In our study, the addition of consolidative durvalumab following CCRT for patients with unresectable LA-NSCLC was found to improve PFS and OS, and its safe application was confirmed through real-world data (RWD) analysis.
A remarkable finding is that the application of durvalumab led to a dramatic improvement in locoregional control (LRC), and it is expected to have contributed to the enhancement of survival outcomes, even though we had a considerable proportion of high-risk patients with stage IIIB (48.0%) and IIIC (14.6%) disease. It is particularly noteworthy that the improvement in LRC was even more pronounced in PD-L1–positive patients, which can be explained by preclinical results elucidating the synergistic effect between RT and immunotherapy [10-12]. Durvalumab functions by blocking the immunosuppressive interaction between PD1 and CD80, leading to the increased activation of T-cells and subsequent detection and elimination of tumor cells. RT can play a role in counteracting tumor immune escape by enhancing MHC-I expression, releasing Toll-like receptor 4, generating tumorspecific cytotoxic T cells, and upregulating PD-L1 expression [13,14]. These synergistic effects are anticipated to be further augmented through the administration of immune checkpoint inhibitors (ICIs) following the completion of CCRT. The optimal timing for implementing ICI remains a subject of debate, with ongoing studies investigating the most optimal treatment sequence [15,16]. Our findings are supported by other clinical data as well. Taugner et al. [17] reported a significant improvement in 1-year FFLRF with respective rates of 78.9% compared to 44.5% for the durvalumab group versus CCRT alone (p=0.002). Similarly, Abe et al. [18] observed a 1-year local control of 86% compared to 62% with the addition of durvalumab (p=0.005). In the PACIFIC trial, despite not specifically suggesting LRF rate as an outcome, the pattern of failure analysis reveals that the durvalumab group exhibited a higher incidence of new lung lesions compared to the placebo group (17.3% vs. 11.8%) [19]. In the Korean extension of PACIFIC (PACIFIC-KR), LRF emerged as the most common type of failure, accounting for 56.2% of cases, and lung and LN involvement were the most prevalent, representing 60.3% and 35.6%, respectively [20].
In our study, we were also able to observe enhancements in both PFS and OS with the addition of durvalumab. Despite the criticism in many studies regarding the disparity in patient inclusion between real-world situations and RCTs, we could confirm, as seen in S10 Table, the improvement of clinical outcomes in various forms of RWD [20-28]. Similarly, despite including a higher proportion of elderly patients and approximately 10% of patients with an ECOG PS of 2, which categorized approximately 58.5% of the patients as ineligible according to clinical trial criteria, our study still demonstrated superior survival compared to RCTs. Furthermore, there was a survival improvement with the use of durvalumab even among those belonging to the ineligible group. Hence, we propose a cautious expansion of durvalumab application in the real-world setting, leveraging these RWD.
Age, clinical stage, and the use of consolidative durvalumab were identified as clinical factors associated with OS, and these findings align with results reported in previous studies. However, in our study, there was a trend towards better survival among patients with epidermal growth factor receptor (EGFR) mutations, which could be attributed to the fact that 40.9% of these individuals received adjuvant tyrosine kinase inhibitor (TKI) treatment. The 3-year OS for patients with EGFR wild type, mutation without TKI, and mutation with TKI were 62.5%, 61.5%, and 88.9%, respectively, with the PACIFIC trial reporting a TKI therapy usage rate of only around 10%.
While we observed comparable incidences of RP grade ≥ 2 across cohorts, suggesting the safe use of durvalumab, our study, in line with previous research, emphasized that the primary determinant for RP occurrence was not the inclusion of durvalumab, but rather the influence of dosimetry factors. This underscores the necessity for increased vigilance during the radiation therapy planning process [29].
Our study had limitations. First, as a retrospective study, it may have had inherent selection bias. Additionally, while our study had a longer follow-up period compared to other investigator-initiated studies, a more mature follow-up is still necessary. On the other hand, this study’s strength lay in its comprehensive exploration of oncologic outcomes, including OS, setting it apart from the majority of non-early access program studies that primarily focused on RP and offered limited information. Additionally, with a substantial patient population, our study, as the largest single-center analysis to date, enhanced the understanding of treatment efficacy by conducting a detailed evaluation of patterns of failure.
In conclusion, this real-world study demonstrated that consolidative durvalumab following CCRT improved LRC, PFS, and OS in patients with unresectable LA-NSCLC. The benefits were more pronounced in patients with PD-L1–positive tumors. These findings support the use of durvalumab as an SoC in this patient population, validating the results of previous clinical trials. Further research and longer follow-up periods are warranted to confirm these results and assess long-term survival outcomes.

Notes

Ethical Statement

This study was conducted in accordance with the 1964 Declaration of Helsinki and was approved by the Institutional Review Board of Asan Medical Center (#2023-0946). Written informed consent was waived due to the retrospective nature of this study.

Author Contributions

Conceived and designed the analysis: Jang JY, Kim SS.

Collected the data: Jang JY, Kim HU.

Contributed data or analysis tools: Jang JY, Song SY, Shin YS, Kim HU, Choi EK, Kim SW, Lee JC, Lee DH, Choi CM, Yoon S, Kim SS.

Performed the analysis: Jang JY, Kim HU, Kim SS.

Wrote the paper: Jang JY, Kim SS.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

References

1. Thandra KC, Barsouk A, Saginala K, Aluru JS, Barsouk A. Epidemiology of lung cancer. Contemp Oncol (Pozn). 2021; 25:45–52.
crossref
2. Jung KW, Kang MJ, Park EH, Yun EH, Kim HJ, Kong HJ, et al. Prediction of cancer incidence and mortality in Korea, 2023. Cancer Res Treat. 2023; 55:400–7.
3. Casal-Mourino A, Ruano-Ravina A, Lorenzo-Gonzalez M, Rodriguez-Martinez A, Giraldo-Osorio A, Varela-Lema L, et al. Epidemiology of stage III lung cancer: frequency, diagnostic characteristics, and survival. Transl Lung Cancer Res. 2021; 10:506–18.
crossref
4. Kim HC, Ji W, Lee JC, Kim HR, Song SY, Choi CM, et al. Prognostic factor and clinical outcome in stage III non-small cell lung cancer: a study based on real-world clinical data in the Korean population. Cancer Res Treat. 2021; 53:1033–41.
crossref
5. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017; 377:1919–29.
6. Spigel DR, Faivre-Finn C, Gray JE, Vicente D, Planchard D, Paz-Ares L, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022; 40:1301–11.
crossref
7. Sheldrick RC. Randomized trials vs real-world evidence: how can both inform decision-making? JAMA. 2023; 329:1352–3.
8. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman JR, Bharat A, et al. NCCN Guidelines(R) insights: non-small cell lung cancer, version 2.2023. J Natl Compr Canc Netw. 2023; 21:340–50.
9. Jang JY, Kim SS, Song SY, Kim YJ, Kim SW, Choi EK. Radiation pneumonitis in patients with non-small-cell lung cancer receiving chemoradiotherapy and an immune checkpoint inhibitor: a retrospective study. Radiat Oncol. 2021; 16:231.
crossref
10. Kalbasi A, June CH, Haas N, Vapiwala N. Radiation and immunotherapy: a synergistic combination. J Clin Invest. 2013; 123:2756–63.
crossref
11. Mansfield AS, Park SS, Dong H. Synergy of cancer immunotherapy and radiotherapy. Aging (Albany NY). 2015; 7:144–5.
crossref
12. Park SS, Dong H, Liu X, Harrington SM, Krco CJ, Grams MP, et al. PD-1 restrains radiotherapy-induced abscopal effect. Cancer Immunol Res. 2015; 3:610–9.
crossref
13. Demaria S, Coleman CN, Formenti SC. Radiotherapy: changing the game in immunotherapy. Trends Cancer. 2016; 2:286–94.
crossref
14. Mielgo-Rubio X, Rojo F, Mezquita-Perez L, Casas F, Wals A, Juan M, et al. Deep diving in the PACIFIC: Practical issues in stage III non-small cell lung cancer to avoid shipwreck. World J Clin Oncol. 2020; 11:898–917.
crossref
15. Tachihara M, Tsujino K, Ishihara T, Hayashi H, Sato Y, Kurata T, et al. Rationale and design for a multicenter, phase II study of durvalumab plus concurrent radiation therapy in locally advanced non-small cell lung cancer: The DOLPHIN Study (WJOG11619L). Cancer Manag Res. 2021; 13:9167–73.
crossref
16. Zhao B, Li H, Wu J, Ma W. Durvalumab after sequential chemoradiotherapy is safe for stage III, unresectable NSCLC: results from phase 2 PACIFIC-6 trial. J Thorac Oncol. 2023; 18:e1–2.
crossref
17. Taugner J, Kasmann L, Eze C, Tufman A, Reinmuth N, Duell T, et al. Durvalumab after chemoradiotherapy for PD-L1 expressing inoperable stage III NSCLC leads to significant improvement of local-regional control and overall survival in the real-world setting. Cancers (Basel). 2021; 13:1613.
crossref
18. Abe T, Saito S, Iino M, Aoshika T, Ryuno Y, Ohta T, et al. Effect of durvalumab on local control after concurrent chemoradiotherapy for locally advanced non-small cell lung cancer in comparison with chemoradiotherapy alone. Thorac Cancer. 2021; 12:245–50.
crossref
19. Faivre-Finn C, Vicente D, Kurata T, Planchard D, Paz-Ares L, Vansteenkiste JF, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC: an update from the PACIFIC trial. J Thorac Oncol. 2021; 16:860–7.
20. Park CK, Oh HJ, Kim YC, Kim YH, Ahn SJ, Jeong WG, et al. Korean real-world data on patients with unresectable stage III NSCLC treated with durvalumab after chemoradiotherapy: PACIFIC-KR. J Thorac Oncol. 2023; 18:1042–54.
crossref
21. Jung HA, Noh JM, Sun JM, Lee SH, Ahn JS, Ahn MJ, 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
22. Miura Y, Mouri A, Kaira K, Yamaguchi O, Shiono A, Hashimoto K, et al. Chemoradiotherapy followed by durvalumab in patients with unresectable advanced non-small cell lung cancer: management of adverse events. Thorac Cancer. 2020; 11:1280–7.
crossref
23. Desilets A, Blanc-Durand F, Lau S, Hakozaki T, Kitadai R, Malo J, et al. Durvalumab therapy following chemoradiation compared with a historical cohort treated with chemoradiation alone in patients with stage III non-small cell lung cancer: a real-world multicentre study. Eur J Cancer. 2021; 142:83–91.
crossref
24. Taugner J, Kasmann L, Eze C, Ruhle A, Tufman A, Reinmuth N, et al. Real-world prospective analysis of treatment patterns in durvalumab maintenance after chemoradiotherapy in unresectable, locally advanced NSCLC patients. Invest New Drugs. 2021; 39:1189–96.
crossref
25. Tsukita Y, Yamamoto T, Mayahara H, Hata A, Takeda Y, Nakayama H, et al. Intensity-modulated radiation therapy with concurrent chemotherapy followed by durvalumab for stage III non-small cell lung cancer: a multi-center retrospective study. Radiother Oncol. 2021; 160:266–72.
crossref
26. Guberina M, Guberina N, Pottgen C, Gauler T, Richlitzki C, Metzenmacher M, et al. Effectiveness of durvalumab consolidation in stage III non-small-cell lung cancer: focus on treatment selection and prognostic factors. Immunotherapy. 2022; 14:927–44.
crossref
27. Yamamoto T, Tsukita Y, Katagiri Y, Matsushita H, Umezawa R, Ishikawa Y, et al. Durvalumab after chemoradiotherapy for locally advanced non-small cell lung cancer prolonged distant metastasis-free survival, progression-free survival and overall survival in clinical practice. BMC Cancer. 2022; 22:364.
crossref
28. Girard N, Bar J, Garrido P, Garassino MC, McDonald F, Mornex F, 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. 2023; 18:181–93.
crossref
29. Mayahara H, Uehara K, Harada A, Kitatani K, Yabuuchi T, Miyazaki S, et al. Predicting factors of symptomatic radiation pneumonitis induced by durvalumab following concurrent chemoradiotherapy in locally advanced non-small cell lung cancer. Radiat Oncol. 2022; 17:7.
crossref

Fig. 1.
Kaplan-Meier curve for the overall population (n=171). (A) Freedom from locoregional failure (FFLRF), and 1-, 2-, 3-, and 4-year FFLRF rates. (B) Distant metastasis-free survival (DMFS), and 1-, 2-, 3-, and 4-year DMFS rates. (C) Progression-free survival (PFS) and 1-, 2-, 3-, and 4-year PFS rates. (D) Overall survival (OS), and 1-, 2-, 3-, and 4-year OS rates. CCRT, concurrent chemoradiotherapy.
crt-2023-1014f1.tif
Fig. 2.
Kaplan-Meier curve for the patients with programmed cell death ligand 1-positive tumors (n=102). (A) Freedom from locoregional failure (FFLRF), and 1-, 2-, 3-, and 4-year FFLRF rates. (B) Distant metastasis-free survival (DMFS), and 1-, 2-, 3-, and 4-year DMFS rates. (C) Progression-free survival (PFS) and 1-, 2-, 3-, and 4-year PFS rates. (D) Overall survival (OS), and 1-, 2-, 3-, and 4-year OS rates. CCRT, concurrent chemoradiotherapy.
crt-2023-1014f2.tif
Fig. 3.
Cumulative incidence of radiation pneumonitis ≥ grade 2 according to the addition of durvalumab in patients with concurrent chemoradiotherapy (CCRT) for unresectable locally advanced non–small cell lung cancer.
crt-2023-1014f3.tif
Table 1.
Characteristics of patients according to the use of durvalumab (n=171)
Characteristic CCRT alone (n=82) CCRT+Durvalumab (n=89) p-value
Age (yr), median (range) 68 (45-85) 63 (36-78) < 0.001
Sex
 Male 68 (82.9) 70 (78.7) 0.607
 Female 14 (17.1) 19 (21.3)
ECOG PS
 0-1 74 (90.2) 80 (89.9) > 0.99
 2-3 8 (9.8) 9 (10.1)
Underlying lung disease
 No 66 (80.5) 79 (88.8) 0.196
 Yes 16 (19.5) 10 (11.2)
Smoking status
 Never-smoker 20 (24.4) 23 (25.8) 0.966
 (Ex-)Smoker 62 (75.6) 66 (74.2)
PFT
 FVC (%) 82.2±13.0 81.9±13.6 0.856
 FEV1 (L) 2.2±0.6 2.3±0.6 0.145
 FEV1 (%) 75.0±17.7 75.0±16.6 > 0.99
 DLCO (%) 72.1±16.8 73.3±18.2 0.670
Tumor histology
 Squamous cell carcinoma 44 (53.7) 37 (41.6) 0.139
 Adenocarcinoma 33 (40.2) 49 (55.1)
 Others 5 (6.1) 3 (3.4)
Clinical T category
 cT1-2 43 (52.4) 43 (48.3) 0.700
 cT3-4 39 (47.6) 46 (51.7)
Clinical N category
 cN0-1 23 (28.0) 11 (12.4) 0.017
 cN2-3 59 (72.0) 78 (87.6)
Stage
 IIB 13 (15.8) 4 (4.5) 0.037
 IIIA 24 (29.3) 23 (25.8)
 IIIB 32 (39.0) 50 (56.2)
 IIIC 13 (15.9) 12 (13.5)
EGFR mutation
 Negative 23 (28.0) 32 (36.0) > 0.99
 Positive 9 (11.0) 13 (14.6)
 Not checkable 50 (61.0) 44 (49.4)
PD-L1 expression (SP263)
 < 1% 21 (25.6) 15 (16.9) 0.189
 1-5% 7 (8.5) 12 (13.5)
 5-10% 2 (2.4) 6 (6.7)
 > 10% 31 (37.8) 44 (49.4)
 Not checkable 21 (25.6) 12 (13.5)
Total RT dose (Gy) 66.0 (50.0-73.0) 60.0 (56.0-70.4) 0.488
Fraction size (Gy/fx) 2.0 (1.8-2.2) 2.0 (2.0-2.2) 0.250
Induction chemotherapy before CCRT
 No 76 (92.7) 88 (98.9) 0.098
 Yes 6 (7.3) 1 (1.1)
Chemotherapy agent
 Paclitaxel/Cisplatin 52 (63.4) 75 (84.3) 0.031
 Paclitaxel/Carboplatin 17 (20.7) 7 (7.9)
 Etoposide/Cisplatin 9 (11.0) 6 (6.7)
 Etoposide/Carboplatin 3 (3.7) 1 (1.1)
 Cisplatin/Pemetrexed 1 (1.2) 0
Interval between CCRT and durvalumab (day) - 34 (0-172) -

Values are presented as median (range), number (%), or mean±SD. Because of rounding off, not all of the percentages total 100. CCRT, concurrent chemoradiotherapy; DLCO, diffusing capacity of the lung for CO; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; PD-L1, programmed cell death ligand 1; PFT, pulmonary function test; RT, radiotherapy; SD, standard deviation.

Table 2.
Recurrence pattern of 171 non–small cell lung cancer patients treated with concurrent chemoradiotherapy
Outcome CCRT alone (n=82) CCRT+Durvalumab (n=89) p-value
Any recurrence 55 (67.1) 47 (52.8) 0.115
 Any LRF 48 (58.5) 33 (37.1) 0.008
 Isolated LRF 18 (22.0) 11 (12.4) 0.143
 Any DM 37 (45.1) 36 (40.4) 0.644
 Isolated DM 7 (8.5) 14 (15.7) 0.231
 Both LRF and DM 30 (36.6) 22 (24.7) 0.129
First site of failure
 Lung and/or regional lymph node 44 (53.7) 28 (31.5) 0.005
  Lung only 20 (24.4) 11 (12.4) 0.066
  Regional lymph node only 8 (9.8) 6 (6.7) 0.661
  Both lung and regional lymph node 16 (19.5) 11 (12.4) 0.284
 Brain 4 (4.9) 5 (5.6) > 0.99
 Bone 1 (1.2) 5 (5.6) 0.252
 Others (liver, adrenal gland, distant LN) 5 (6.1) 7 (7.8) > 0.99
 Both lung and distant organ 1 (1.2) 2 (2.2) > 0.99
Locoregional failure pattern
 In-field failure 22 (26.8) 11 (12.4) 0.027
 Out-of-field failure 11 (13.4) 10 (11.2)
 Botha) 15 (18.3) 12 (13.5)
No. of organ with distant metastasis
 Single organ 15 (18.3) 17 (19.1) 0.807
 Multiple organ 20 (24.4) 18 (20.2)
Site of distant metastasis
 Pleura 13 (15.9) 7 (7.9) 0.189
 Contralateral lung 21 (25.6) 12 (13.5) 0.042
 Bone 13 (15.9) 17 (19.1) 0.855
 Brain 13 (15.9) 14 (15.7) 0.999
 Distant LN 8 (9.8) 10 (11.2) 0.924
 Adrenal gland 5 (6.1) 3 (3.4) 0.582
 Liver 2 (2.4) 3 (3.4) 0.900
 Others 6 (7.3) 0 0.029

Values are presented as number (%). CCRT, concurrent chemoradiotherapy; DM, distant metastasis; LN, lymph node; LRF, locoregional failure.

a) Patients with both in-field failure and out-of-field failure. Logistic regression analysis was performed.

Table 3.
Univariate analysis of clinical factors affecting progression-free survival and overall survival (n=171)
Variable Progression-free survival
 Overall survival
HR (95% CI) p-value HR (95% CI) p-value
Age, ≥ 65 yr 1.08 (0.73-1.58) 0.710 1.61 (0.98-2.63) 0.059
Male sex 0.61 (0.39-0.96) 0.031 1.49 (0.76-2.92) 0.246
ECOG PS, 2-3 1.02 (0.53-1.96) 0.950 1.64 (0.81-3.32) 0.166
Underlying lung disease 1.17 (0.70-1.94) 0.552 1.30 (0.69-2.43) 0.412
(Ex-)Smoker 0.80 (0.52-1.21) 0.283 1.73 (0.93-3.23) 0.086
FVC (%) 1.01 (1.00-1.03) 0.181 1.00 (0.98-1.02) 0.772
FEV1 (L) 0.99 (0.71-1.37) 0.931 0.86 (0.57-1.31) 0.487
DLCO (%) 1.00 (0.99-1.01) 0.477 0.99 (0.97-1.00) 0.083
Clinical stage, III 1.50 (1.17-1.93) 0.002 1.56 (1.13-2.15) 0.006
Pathology, SqCC 1.28 (0.92-1.76) 0.141 0.86 (0.55-1.33) 0.487
EGFR, mutation 1.30 (0.74-2.28) 0.362 0.48 (0.18-1.26) 0.137
PD-L1 positive (> 1%) 0.76 (0.48-1.20) 0.242 0.71 (0.39-1.28) 0.259
Total RT dose, ≥ 66 Gy 0.90 (0.61-1.31) 0.582 1.04 (0.65-1.69) 0.860
Chemotherapy, TP 0.68 (0.45-1.03) 0.070 0.57 (0.35-0.95) 0.032
Use of durvalumab 0.68 (0.47-1.00) 0.050 0.53 (0.32-0.87) 0.011
Interval between CCRT and durvalumab, ≤ 42 daysa) 0.62 (0.29-1.30) 0.203 0.62 (0.23-1.71) 0.359

CI, confidence interval; DLCO, diffusing capacity of the lung for CO; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; HR, hazard ratio; PD-L1, programmed cell death ligand 1; RT, radiotherapy; SqCC, squamous cell carcinoma; TP, paclitaxel/cisplatin.

a) Only 89 patients who received durvalumab after concurrent chemoradiotherapy were included.

Table 4.
Survival outcomes in patients with negative or positive PD-L1 expression (n=138)
PD-L1–negative (n=36)
 PD-L1–positive (n=102)
CCRT alone (n=21) CCRT+Durvalumab (n=15) p-value CCRT alone (n=40) CCRT+Durvalumab (n=62) p-value
Median FFLRF 19.8 mo 14.7 mo 0.830 17.4 mo NR 0.002
 1-yr FFLRF rate 65.3 57.1 54.3 73.0
 2-yr FFLRF rate 43.6 32.1 42.8 67.5
 3-yr FFLRF rate 34.9 32.1 34.4 61.3
Median DMFS 23.4 mo 22.5 mo 0.400 22.9 mo 37.8 mo 0.074
 1-yr DMFS rate 66.7 53.3 60.0 69.0
 2-yr DMFS rate 45.7 26.7 49.3 64.1
 3-yr DMFS rate 38.1 26.7 31.7 56.3
Median PFS 16.8 mo 13.3 mo 0.800 7.2 mo 37.8 mo 0.024
 1-yr PFS rate 57.1 53.3 47.5 57.5
 2-yr PFS rate 38.1 20.0 35.0 50.9
 3-yr PFS rate 22.9 20.0 24.7 50.9
Median OS 39.1 mo NR 0.590 35.2 mo NR 0.008
 1-yr OS rate 76.2 93.3 80.0 93.5
 2-yr OS rate 61.5 66.7 59.8 83.9
 3-yr OS rate 54.7 53.3 46.1 73.8

CCRT, concurrent chemoradiotherapy; DMFS, distant metastasis-free survival; FFLRF, freedom from locoregional failure; NR, not-reached; OS, overall survival; PD-L1, programmed cell death ligand 1; PFS, progression-free survival.

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