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

Simple Summary Concurrent platinbased chemoradiotherapy followed by maintenance treatment with the PD-L1 inhibitor durvalumab is the new standard of care for inoperable stage III NSCLC. The present study compares the oncological outcome of patients treated with chemoradiotherapy to those treated with chemoradiotherapy and durvalumab (CRT-IO) in the real-world setting. Median follow-up for entire cohort was 33.1 months and median overall survival was 27.2 months. In the CRT-IO cohort after a median follow-up of 20.9 (range: 6.3–27.4) months, local-regional-progression-free-survival, progression-free, and overall survival (PFS, OS) were significantly improved compared to the historical cohort of conventional chemoradiotherapy patients. This real-world analysis demonstrated that durvalumab after chemoradiotherapy (CRT) led to significant improvement of local-regional control, PFS, and OS in PD-L1 expressing inoperable stage III NSCLC patients compared to a historical cohort. Abstract Concurrent chemoradiotherapy (CRT) followed by maintenance treatment with the PD-L1 inhibitor durvalumab is a new standard of care for inoperable stage III NSCLC. The present study compares the oncological outcome of patients treated with CRT to those treated with CRT and durvalumab (CRT-IO) in the real-world setting. The analysis was performed based on the retro- and prospectively collected data of 144 consecutive inoperable stage III NSCLC patients treated between 2011–2020. Local-regional-progression-free-survival (LRPFS—defined as progression in the mediastinum, hilum and/or supraclavicular region at both sites and the involved lung), progression-free survival (PFS), and overall survival (OS) were evaluated from the last day of thoracic radiotherapy (TRT). Median follow-up for the entire cohort was 33.1 months (range: 6.3–111.8) and median overall survival was 27.2 (95% CI: 19.5–34.9) months. In the CRT-IO cohort after a median follow-up of 20.9 (range: 6.3–27.4) months, median PFS was not reached, LRPFS (p = 0.002), PFS (p = 0.018), and OS (p = 0.005) were significantly improved vs. the historical cohort of conventional CRT patients. After propensity-score matching (PSM) analysis with age, gender, histology, tumor volume, and treatment mode, and exact matching for T-and N-stage, 22 CRT-IO patients were matched 1:2 to 44 CRT patients. Twelve-month LRPFS, PFS, and OS rates in the CRT-IO vs. CRT cohort were 78.9 vs. 45.5% (p = 0.002), 60.0 vs. 31.8% (p = 0.007), and 100 vs. 70.5% (p = 0.003), respectively. This real-world analysis demonstrated that durvalumab after CRT led to significant improvement of local-regional control, PFS, and OS in PD-L1 expressing inoperable stage III NSCLC patients compared to a historical cohort.


Introduction
Inoperable stage III non-small-cell lung carcinoma (NSCLC) represents a complex and heterogeneous disease with significant differences regarding patient, tumor, and treatment characteristics [1][2][3][4][5][6][7][8]. In the real-world setting, there is also significant variations in patient prognosis with median survival ranging from 15-30 months and five-year survival rates from 15-32% [9][10][11][12][13]. Continuously during the last decades, chemotherapy and conventionally fractionated thoracic radiotherapy (TRT) represented the standard of care. Several phase III trials including RTOG 73-01, CALGB 8433, RTOG 9410, and RTOG 0617 established platinum-based concurrent chemoradiotherapy (CRT) to a cumulative dose of 60 Gy without induction and consolidation chemotherapy as the most effective strategy accompanied by a moderate acute toxicity profile [14][15][16][17][18]. This treatment paradigm was modified after the pivotal phase III PACIFIC trial showing an unprecedented improvement of progression-free survival (PFS) and overall survival (OS) after consolidation therapy with the Programmed death-ligand 1 (PD-L1) inhibitor durvalumab following platinumbased CRT [19][20][21]. Importantly, histology and molecular tumor profile, including tumor cell PD-L1 expression were not primary stratification factors in this trial. PACIFIC demonstrated very robust PFS improvement across all patient subgroups and led to a rapid implementation of this novel tri-modal approach overseas. However, domestically, based on the results of a post-hoc analysis, the European Medicines Agency (EMA) approved durvalumab consolidation only for PD-L1 positive tumors (≥1%) on initial biopsy.
After PACIFIC, several randomized trials were initiated to confirm and further optimize this novel tri-modal treatment for inoperable Union for International Cancer Control (UICC) stage III NSCLC [22]. In spite of the swift translation of this new standard into the clinical practice, there are still limited data reporting on efficacy of durvalumab consolidation in the real-world setting. Most studies were devoted to the evaluation of patient eligibility for maintenance treatment [23][24][25] or estimation of the risk of pneumonitis after durvalumab [26][27][28]. Hitherto, to the best of our knowledge, there are only a few published reports evaluating its efficacy in a real-life patient cohort. Offin [29][30][31].
The purpose of the present study was to analyze oncological outcome of PD-L1 expressing inoperable stage III NSCLC patients and compare it with a historical cohort treated with CRT alone.

Patient Characterstics
This study included 144 consecutive patients who received concurrent or sequential conventionally fractionated CRT with or without consolidation durvalumab as part of the multimodal approach for UICC 8th edition stage IIIA/B/C NSCLC between 2011 and 2020. All 22 patients treated with durvalumab were enrolled starting October 2018 after the European Medicines Agency (EMA) approval. Patients treated without durvalumab either had PD-L1 <1% or were treated prior to durvalumab approval. Patients with follow-up <6 months were excluded. All prospectively enrolled patients gave their informed consent for the use of their data for research purposes. Furthermore, the local ethics committee granted approval to conduct this study .
All patients were treated at a single tertiary cancer center. Prior to the actual treatment, basic patient characteristics such as tobacco consumption, Eastern Cooperative Oncology Group (ECOG) performance status, and comorbidities, were assessed. As part of the pretreatment work-up, radiographic imaging was performed using computed tomography (CT) for 9 (6%) patients and positron emission tomography (PET)-CT in 135 (94%) patients. Cranial contrast-enhanced magnetic resonance imaging (MRI) was performed in 79 (55%) patients, while the others received a contrast-enhanced head computed tomography scan (CT). In addition, all patients received routine blood work to assess kidney function as well as complete blood count (CBC) and underwent pulmonary function testing. Patients in the CRT-IO cohort were given durvalumab intravenously at a dose of 10 mg/kg every two weeks up to 12 months (24 cycles), until progression or unacceptable toxicity according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 5. During the course of treatment and prior to application of durvalumab, complete blood work was performed. In addition, pulmonary function tests were performed routinely every 3 months.
All patients were discussed prior to treatment at the multidisciplinary tumor board and all patients were deemed inoperable by an experienced group of thoracic surgeons, pulmonologists, and radiation oncologists. Patients with an initial performance status ECOG > 1, poor lung function (DLCO < 40%, FEV1 < 1l or on long-term oxygen therapy), total RT dose < 60 Gy were excluded from this analysis.

Chemoradiotherapy
All patients underwent PET-CT and/or were planning CT in the treatment position; TRT was planned and delivered in supine position with arms positioned overhead in a WingSTEPT M (Innovative Technologie Völp, Innsbruck, Austria). The gross tumor volume (GTV) and clinical target volume (CTV) were defined according to an in-house standard operating procedure (SOP) in close accordance to the later published ESTRO ACROP guidelines [32]. If patients received induction chemotherapy, only the residual primary tumor volume was contoured, but initially involved lymph-node stations were included in the planning target volume (PTV). To generate the PTV, a margin of 6 mm (axial) and 9 mm (cranio-caudal) added to the CTV.
Conventionally fractionated TRT was administered to the primary tumor and the involved lymph node to a median total dose of 66 Gy. Radiation was delivered on a linear accelerator (LINAC) with a megavoltage capability of (6-15 MV) using 3D-CRT in 48 (33%) patients and intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) in 95 (66%) patients. Inter-fraction motion was routinely assessed on cone-beam CT.

Patient Follow-Up
CT/PET-CT scans, routine blood sample, pulmonary function testing, and clinical examinations were performed every 3 months for the first two years after radiotherapy, thereafter twice annually for up to five years, according to an in-house aftercare protocol. Contrast-enhanced brain MRI, bone-scintigraphy, and bronchoscopy were only performed if clinically indicated. Local-regional recurrence (LRR)-defined as progression in the mediastinum, hilum, and/or supraclavicular region at both sites and the involved lung-along with new distant metastases (DM) and brain metastasis (BM) were documented with CT, PET-CT, and MRI scans. Histological or cytological confirmation of progressive disease was not obligatory. Median follow-up was calculated as the time from the last day of TRT to last follow-up or loss of follow-up.
Progression-free survival (PFS) was defined as the time from end of TRT until disease progression or death. Similarly, overall survival (OS), local-regional-progression-freesurvival (LRPFS), and time-to-LRR (TLRR) were assessed from the end of TRT.

Statistical Analysis
To evaluate impact of the addition of durvalumab to routine treatment, OS, PFS, and LRPS were evaluated as primary endpoints. Initially, a univariate analysis of durvalumab treatment and other factors OS, PFS, and LRPFS was conducted in the entire cohort. Multivariate analysis ensued for PFS with other common covariates using Cox regression. Thereafter, we applied Propensity Score Matching (PSM) to reduce confounding using the R plug-in for IBM SPSS 26 [33][34][35][36][37]. The impact of durvalumab treatment was then re-assessed in the matched cohort with univariate analysis using Log-rank testing. p < 0.050 were considered significant and p < 0.100 a trend. All statistics were performed using IBM SPSS version 26 (IBM, Armonk, NY, USA).

Comparison of CRT and CRT-IO in the Entire Cohort
Results of univariate analysis in the entire cohort are displayed in Table 2.

PSM with Exact T-and N-Stage Matching
Patients treated with CPI were matched in a 1:2 ratio to patients treated with CRT alone. Patients treated without concurrent chemotherapy were excluded. To each CRT-IO patient, two corresponding patients with exactly the same T-and N-stage were matched. Twenty-two CRT-IO patients were matched to 44 CRT patients. Both subgroups had patients with matched T-and N-stage. In the CRT-IO subgroup, there were 13 (59.1%) patients aged ≥65, 16 (72.7%) males, 11 (50.0%) with SCC or NOS, and 10 (45.5%) patients with PTV ≥ 700cc. In the CRT subgroup there were 27 (61.4%) patients aged ≥65, 27 (61.4%) males, 22 (50.0%) with SCC or NOS and 17 (38.6) patients with PTV ≥ 700cc. A summary of patient and tumor characteristics is shown in Table 3.    After 6 months, rates of brain metastasis and other distant metastasis rates were 0 and 18.1% vs. 7.7 and 26.2% in the CRT-IO vs. CRT cohort.

Discussion
The aim of this study was to analyze the oncological outcome of PD-L1 expressing inoperable stage III NSCLC patients treated with maintenance durvalumab after CRT and to compare it with an otherwise similarly treated historical cohort. Additionally, PSM analysis with matching for principal patient-, tumor-, and treatment characteristics was conducted to account for bias.
The present study revealed a significant improvement across all survival parameters in the CRT-IO versus CRT patients. The most pronounced difference was found for OS. Estimated 6-and 12-month survival rates were 100 vs. 87.7% and 100 vs. 72.1% in the CRT-IO and CRT cohort, respectively. Vis-à-vis PFS, continuously higher rates at 6-, 12-, and 18-months after the end of TRT were achieved in patients treated with versus without durvalumab. Another important finding was a remarkable increase in the local-regional control rates across all tested time points. These results were confirmed after PSM analysis. Comparing the oncological outcome in the 66 matched patients substantial increase in all survival parameters was again revealed.
Hence, the present analysis corroborated PACIFIC findings in the real-world setting. Furthermore, 50%/14% of CRT-IO patients in our study presented with UICC stage IIIB/IIIC disease with a median PTV of 680.3 ccm, thus representing a high-risk cohort. Nevertheless, all started with durvalumab maintenance after completion of CRT and demonstrated promising results especially for the local-regional control.
The role of local-regional control after CRT for patient survival was described. Machtay et al. analyzed 1390 patients treated with CRT within the scope of seven RTOG trials and found a highly significant association of local-regional control and OS [39]. The predicted 18-month LRPFS and OS rates in our analysis of patients treated with CTR-IO were very favorable at about 70 and 91.6%, respectively.
The present study was also in close accordance with a study by Offin et al. on 62 inoperable stage III patients treated with CRT-IO at the Memorial Sloan Kettering Cancer Center (29). Other real-life studies from Jung et al. and Chu et al. included 21 and 31 stage III patients treated with durvalumab after CRT and revealed similar PFS rates [30,31]. Comparing these single-center studies to each other, a plateau of the PFS curves starting after completion of durvalumab treatment could be observed. The same trend was also seen in the original analysis of the PACIFIC trial [19,20]. This interesting finding was not described in earlier CRT studies for inoperable stage III NSCLC. A short review of literature of real-world experiences using chemo/radiation followed by consolidative durvalumab is shown in Table 4.
Therefore, we can hypothesize that an immunological phenomenon may be associated with the establishment of a long-lasting anti-tumor response in these patients. However, a clarification of this phenomenon will be solely possible with longitudinal analyses of immunological cellular and humoral factors across all time points before, during and after durvalumab treatment.
In contrast to previously published studies on durvalumab efficacy, it is pertinent to mention that our durvalumab cohort exclusively included patients with PD-L1 expressing tumors at initial biopsy. Nevertheless, we found similar survival rates, which is also a relevant finding. Recently Desilets et al. reported an improved 12-month OS in durvalumabtreated patients with PD-L1 expression ≥50% [40]. OS and PFS findings were in close accordance to our data. In order to elucidate these findings, a comparison of oncological outcome in PD-L1 expressing and non-expressing tumors should be performed in larger prospective cohorts. Concerning the significant improvement of LRPFS observed in our patients treated with durvalumab maintenance, Abe et al. describe a similarly improved local control in patients treated with cCRT and durvalumab vs. with cCRT alone [41]. According to Ohri et al., the neutrophil-to-lymphocyte ratio (NLR) after RT may be an important prognostic factor for patients enrolled in durvalumab maintenance, especially concerning PFS [42]. Table 4. Short review of literature of real-world experiences using chemo/radiation followed by consolidative durvalumab.
Hyun Ae Jung et al. [30] Real world data of durvalumab consolidation after chemoradiotherapy in stage III non-small-cell lung cancer Notwithstanding, the current analysis had its inherent limitations; the single-center design in a limited number of patients and a relatively short follow up period in the CRT-IO cohort must be mentioned. Nevertheless, the reported survival data were in line with other real-world studies and PACIFIC [19,20,[29][30][31]. Furthermore, a comprehensive statistical evaluation including PSM analysis with exact T-and N-stage matching was conducted to confirm our findings. In addition, durvalumab maintenance treatment after CRT in non-operable stage III NSCLC is depending on PD-L1 status in the European Union. As a result, our study enrolled only patients with PD-L1 ≥ 1% at initial biopsy and our findings cannot be translated in patients with PD-L1 < 1%.
In summary, our analysis confirmed a significant and robust improvement of oncological outcome in PD-L1 expressing inoperable stage III NSCLC patients treated with CRT and consolidation durvalumab compared to a historical cohort. This improvement mostly consisted of a striking increase in local-regional control and PFS. This increase subsequently translated into improved overall survival.

Conclusions
This real-world analysis demonstrates that durvalumab after CRT led to significant improvement of local-regional control, PFS, and OS in PD-L1 expressing inoperable stage III NSCLC patients compared to a historical cohort. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The data presented in this study are available from the corresponding author on reasonable request.