Comparison of Efficacy and Safety of First-Line Treatment Options for Unresectable Stage III Non-Small Cell Lung Cancer: A Retrospective Analysis

Background Based on PACIFIC trial, durvalumab as consolidation therapy following concurrent chemoradiotherapy (cCRT) has been a new standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). In clinical applications, there are heterogeneous adjustments or novel strategies following specialized discussions in experienced multidisciplinary teams. This study retrospectively compared the efficacy and safety of different first-line treatments for unresectable stage III NSCLC. Methods We retrospectively analyzed 397 patients who received first-line treatment for unresectable stage III NSCLC. Comparisons and statistical analyses of treatment were made in terms of efficacy and safety. Adverse events and responses were assessed using CTCAE v5.0 and RECIST v1.1. The progression-free survival (PFS) was estimated using the Kaplan–Meier method or the Cox survival regression model and compared using the log-rank test. Results In wild-type driver genes group, the objective response rate (ORR), disease control rate (DCR), and median PFS (mPFS) were prolonged in the radiotherapy group compared to those in the nonradiotherapy group (ORR: 50.94% vs. 30.06%, p < 0.001; DCR: 98.11% vs. 80.37%, p < 0.001; and mPFS: 21.00 vs. 8.20 months, p < 0.001). The incidence of pneumonia at any grade in the radiotherapy group was higher than that in the nonradiotherapy group (9.43% vs. 2.45%, p = 0.008). In the radiotherapy group, the chemoradiotherapy (CRT) plus immunotherapy subgroup had longer mPFS than the CRT subgroup, with increased toxicity at any grade (24.60 vs. 17.90 months, p = 0.025, and 83.17% vs. 65.52%, p = 0.011). In the nonradiotherapy group, the DCR and mPFS were higher in the chemotherapy plus immunotherapy subgroup than in the chemotherapy subgroup, with increased toxicity at any grade (DCR: 93.67% vs. 67.86%, p < 0.001; mPFS: 13.53 vs. 5.07 months, p < 0.001; and 68.35% vs. 41.67%, p = 0.001). In the mutant driver genes group, the efficacy did not significantly differ among the radiotherapy subgroup, targeted therapy subgroup, and radiotherapy plus targeted therapy subgroup (ORR: p = 0.633; mPFS: p = 0.450). Conclusions For unresectable stage III NSCLC patients with wild-type driver genes, the combination of radiotherapy and immunotherapy in the initial treatment was essential to significantly improve the efficacy. For patients with mutant driver genes, radiotherapy, targeted therapy, and the combination of radiotherapy and targeted therapy showed similar short-term efficacy.


Introduction
Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer death, with an estimated 2.2 million new cases and 1.8 million deaths in 2020 [1].Nonsmall cell lung cancer (NSCLC) accounts for about 85% of all the diagnosed lung cancer cases and stage III disease accounts for approximately one third of these cases.Te expected 5-year survival rate for patients with unresectable stage III NSCLC is between 13% and 36% [2].
Te treatment goal for patients with unresectable stage III NSCLC is to prevent local recurrence and reduce the occurrence of distant metastases.Concurrent chemoradiotherapy (cCRT) is the traditional standard therapy for this population, which has reported positive results in several phase III clinical trials and meta-analyses.In the RTOG 9410 trial, cCRTshowed a long-term survival beneft compared with sequential chemoradiotherapy (sCRT) (median overall survival: 17.0 vs. 14.6 months; 5-year survival rate: 16% vs. 10%) [3].Unfortunately, most patients progress after cCRT, with median progression-free survival (mPFS) of 8-12 months and a 5-year overall survival (OS) rate of 15-25% [4].Subsequent phase II/ III trials on the cCRT-based integrated approach (CALGB III, RTOG0617 phase II, and SWOGS0023 phase III) similarly failed to show improved survival in such patients [5][6][7].
In 2017, the PACIFIC trial, a phase III placebocontrolled trial, demonstrated that patients with unresectable stage III NSCLC who were treated with durvalumab, as consolidation therapy following cCRT, experienced significantly better survival outcomes compared to placebo (PFS: 16.8 vs. 5.6 months; HR = 0.52; 95% CI, 0.42-0.65,p < 0.001; 5-year rates for OS: 42.9% vs. 33.4%;and 5-year rates for PFS: 33.1% vs. 19.0%)[8,9].Based on these encouraging results, programmed death ligand-1 (PD-L1) inhibitors durvalumab as consolidation therapy following cCRT has been a new standard treatment for unresectable stage III NSCLC.Since then, some further studies (LUN14-179 trial and DETERRED trial) have confrmed that other checkpoint inhibitors as consolidation therapy after cCRT are similar to the efcacy of durvalumab, supporting the importance of immunotherapy in this new era of treatment [10,11].
Stage III NSCLC comprises a heterogeneous group of patients, for whom dedicated discussion within an experienced multidisciplinary team is mandatory.A retrospective series showed that only half of the patients with stage III NSCLC are treated with CRT in clinical practice [12].Besides, not all the patients treated with cCRT are eligible for adjuvant durvalumab due to residual toxicity and disease progression [13,14].Te update results from the PACIFIC trial showed that PFS and OS in the epidermal growth factor receptor (EGFR) mutation-positive group were signifcantly lower than those in the whole group and the EGFR mutation-negative group [9,15].Also, in multiple immunotherapy-related clinical trials for advanced lung cancer, results have shown that patients with EGFR mutation do not beneft from immunotherapy [16][17][18].According to these, in some clinical applications, targeted monotherapy or combination therapy is used to treat unresectable stage III NSCLC patients carrying driver gene mutations.An exploratory analysis from the pacifc study also suggests that durvalumab treatment given early (≤14 days) after cCRT may beneft more [8].Terefore, the simultaneous combination of programmed cell death protein-1 (PD-1)/PD-L1 inhibitors with cCRT has potential clinical benefts.As of now, several larger phase III trials of immunosynchronous therapy modalities are ongoing, including NCT03519971 and NCT04092283.In some clinical applications, the time of immunotherapy combined with CRT is advanced, that is, from immunotherapy consolidation therapy to immunotherapy synchronization therapy.Te aim of this study was to analyze and compare the efcacy and safety of diferent frst-line treatment options for unresectable stage III NSCLC.

Data Collection and Response
Assessment.Medical records were reviewed and extracted on clinical pathologic features and treatment histories.Treatment outcomes were the extracted objective response rate (ORR) and the disease control rate (DCR), along with PFS after the start of frst-line therapy.Te ORR was defned as the complete response (CR) or partial response (PR) rate.Te DCR was defned as the percentage of patients with the ORR and stable disease (SD).Te PFS was defned as the time between the date of treatment initiation and the date of progressive, death, or last follow-up.Response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.1(a)).Furthermore, in the radiotherapy group, the CRT plus immunotherapy subgroup had longer mPFS than the CRT subgroup (24.60 vs. 17.90 months, p = 0.025, Figure 1(b)).
With or without radiotherapy was a signifcant factor affecting the PFS in the wild-type driver genes group (p < 0.001, Table 3).Age, sex, history of smoke, ECOG score, and histology were not the major factors afecting the PFS in both groups.4, in the wild-type driver genes group, 65.53% (211/322) of the patients experienced treatment-related AEs and 19.88% (64/322) patients experienced grade 3 or 4 treatment-related AEs.Te most common treatment-related AEs was anemia (23.29%), followed by leukopenia (21.43%), neutropenia (21.43%), thrombocytopenia (14.60%), and elevated alanine aminotransferase (ALT) or aspartate transaminase (AST) (9.63%).No grade 5 treatment-related AEs was reported.Compared to the nonradiotherapy group, the incidence of AEs at any grade was higher in the radiotherapy group (76.73% vs. 54.60%,p < 0.001).Tere was no signifcant diference in the incidence of AEs at grade 3 and grade 4 between the two groups (22.64% vs. 17.28%,p = 0.219).Te incidence of pneumonia at any grade in the radiotherapy group was higher than that in the nonradiotherapy group (9.43% vs. 2.45%, p = 0.008), among which radiation-related pneumonia accounted for 73.33%.But the diference in the incidence of pneumonia at grade 3 and grade 4 between the two groups was not statistically signifcant (1.89% vs. 0.61%, p = 0.367).In the nonradiotherapy group, the incidence of AEs at any grade in the chemotherapy plus immunotherapy subgroup was signifcantly higher compared to that in the chemotherapy subgroup (68.35% vs. 41.67%,p = 0.001) and there was no signifcant diference in the incidence of AEs at grade 3 and grade 4 between the two groups (20.25% vs. 14.29%,p = 0.313).In the radiotherapy group, the incidence of AEs at any grade in the CRT plus immunotherapy group was signifcantly higher than that in the chemotherapy group (83.17% vs. 65.52%,p = 0.011); however, grade 3 or 4 toxicity was similar in both groups (23.76% vs. 20.69%,p = 0.656).

Discussion
Tis study retrospectively compared the efcacy and safety of diferent frst-line treatments for unresectable stage III NSCLC after grouping patients according to wild type or mutant driver genes.In the wild-type driver genes group, the presence of radiotherapy signifcantly improved efcacy.Single-modality radiotherapy was the standard for unresectable stage III NSCLC in the 1980s based on the RTOG 7301 trial [19].In addition, some following studies demonstrated improvement in symptoms after radiation treatment [20].Our results are consistent with these results, which suggest that radiotherapy is associated with improved survival in patients with unresected stage III NSCLC.And, further multivariate analysis showed that radiotherapy was indeed a signifcant factor afecting the PFS in the wild-type driver genes group (p < 0.001).
In order to meet the urgent need for better efcacy, there has been progress in the treatment modalities for unresectable stage III NSCLC.Recently, immunotherapy has International Journal of Clinical Practice     International Journal of Clinical Practice improvement was found in the immunotherapy in combination with the CRT group, which further confrms the results of the PACIFIC trial.Te potential reason might be that the drugs of PD-1/PD-L1 checkpoint inhibition could synergize the efect of CRT.Since radiotherapy generates in situ vaccination which can be substantially potentiated by immunotherapy, the abscopal efect of radiotherapy has become more meaningful [21].Furthermore, radiotherapy can stimulate antitumor adaptive immunity, modulating the tumor microenvironment and inducing tumor PD-L1 levels [21][22][23].
Collectively, for patients with wild-type driver genes, the combination of radiotherapy and immunotherapy is a critical component of defnitive treatment to signifcantly improve outcomes.At present, there are some clinical trials to explore further progress based on the success of the combination of CRT and immunotherapy.An exploratory analysis of the PACIFIC study also suggests that durvalumab treatment given earlier (≤14 days) after cCRT may beneft more.Subgroup analysis found that the subgroup initiated with durvalumab ≤2 weeks after radiotherapy signifcantly delayed disease progression.Tis suggests the potential for simultaneous immunotherapy with CRT, but this model is still in the exploratory stage.Preliminary data from the phase II clinical study DETERRED showed that atezolizumab is feasible when administered concurrently with CRT followed by chemotherapy-atezolizumab consolidation.Tis treatment strategy did not increase the incidence of radiationrelated pneumonia in terms of safety.In terms of efectiveness, the rates of 1-year PFS and OS are 66% and 77%, respectively.It appears to be better on the rate of 1-year PFS (55.9%) compared to the PACIFIC, but the rate of 1-year OS (83.1%) is slightly worse [11].At the same time, the ETOPNICOLAS phase II clinical study also showed that cCRT synchronization with nivolumab and then nivolumab maintenance in unresectable stage III NSCLC was feasible.Also, no increased risk of unintended adverse events or severe pneumonia was observed.Te median PFS was 12.7 months, the median OS was 38.8 months, and the 1-year PFS and OS rates were 53.7% and 75.7%, respectively [24].In our study, the ORR in the synchronization therapy subgroup was lower than that in the consolidation therapy subgroup.However, this was a retrospective, nonrandomized study, which may have led to bias in the results due to the limited sample size.And, there was no statistical diference in mPFS and the rate of pneumonia between the two groups.Our study, like previous trials, suggests the potential for simultaneous immunotherapy with CRT.Several large-scale    Tere is a concern that toxicity could be further aggravated when immunotherapy and radiotherapy are given.Although the radiotherapy group increased the rate of pneumonia at any grade (9.43%), there was no statistical diference in the incidence of grade 3/4 pneumonia between the two groups.Furthermore, in the PACIFIC trial, rates of grade 3/4 AEs of any cause were similar for durvalumab compared with placebo (29.9% vs. 26.1%)[25].Several prospective trials (LUN14-179 and BTCRC LUN16-081) have also confrmed that the toxicity of consolidation immunotherapy after CRT is tolerable [10,26].Similarly, our study showed no diferences in grade 3/4 AEs between the immunotherapy group and the CRT or chemotherapy group.
About patients with EGFR mutations, the subgroup analysis of the PACIFIC trial showed that they might not beneft from maintenance immunotherapy [15].ESMO expert consensus does not recommend the use of adjunctive durvalumab in patients with EGFR mutations.Another treatment should thus be explored for this population.Some studies suggest many stage III NSCLC patients have driver mutations such as EGFR (10-30% of the patients) [27].In our study, EGFR-mutant patients account for about 50% in the mutant driver genes group while others have anaplastic lymphoma kinase gene rearrangements (ALK+), v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations, and so on.Among patients with advanced NSCLC with oncogenic driver mutations, molecular-targeted drugs have been recommended for the frst-line therapy, which dramatically changed the standard treatment.Preclinical studies have shown that EGFR tyrosine kinase inhibitors (TKIs) could have a radiosensitizing efect, which showed the combination of EGFR-TKIs and radiotherapy seems to be a reasonable approach [28,29].However, there are few recommendations indicating whether radiotherapy is efective for patients with mutant driver genes.Tus, it was worth to explore the efcacy of radiotherapy for this population given that it signifcantly improved the survival for patients with wild-type driver genes.In our study, there were no diferences in short-term efcacy among the radiotherapy subgroup, targeted therapy subgroup, and radiotherapy plus targeted therapy group, which showed radiotherapy seemly failed to improve outcomes whether combined with targeted therapy.Although several phase II clinical experiments (RECEL trial and WJOG6911L trial) showed the potential value of concurrent targeted therapy with radiotherapy [30,31], no phase III trials have yet demonstrated similar results.Based on the abovementioned results, it may not be urgent to add radiotherapy to frstline treatment to improve the efcacy for patients with mutant gene driver.However, the limited number of patients and the retrospective nature of this analysis do not lead to obtain frm conclusions, and further prospective studies should aim to confrm these results.
Tere are several limitations in this study.Tis analysis was based on a small sample from a single institution.Also, the study was retrospective in design, which is inherently afected by selection bias and missing data.Moreover, reliance on electronic health records may mean that some events may be underestimated.Terefore, our results suggest the possibility of clinical treatment rather than reaching defnitive conclusions.Larger prospective studies are needed to confrm our fndings.

Conclusions
For unresectable stage III NSCLC patients with wild-type driver genes, the combination of radiotherapy and immunotherapy in the initial treatment was essential to signifcantly improve the efcacy.For patients with mutant driver genes, radiotherapy, targeted therapy, and the combination of radiotherapy and targeted therapy showed similar shortterm efcacy.

Data Availability
Te data used to support this study are available from the corresponding author upon request.

Figure 1 :
Figure 1: Kaplan-Meier curves in the wild-type driver genes group.(a) Progression-free survival (PFS) in the non-radiotherapy group and radiotherapy group.(b) PFS in the CRT group and the CRT plus immunotherapy group.(c) PFS comparison between immunotherapy synchronization therapy and immunotherapy consolidation therapy in the CRT plus immunotherapy group.(d) PFS in the chemotherapy group and the immunotherapy plus chemotherapy group for patients with non-radiotherapy.

Figure 2 :
Figure 2: Kaplan-Meier curves in the mutant driver genes group.PFS in the radiotherapy group, targeted therapy group, and radiotherapy plus targeted therapy group.
Clinical Practice phase III trials of immunosynchronous therapy modalities are ongoing, including NCT03519971 and NCT04092283.
2.1.Patients.We retrospectively reviewed the medical records of 397 patients with unresectable stage III NSCLC from January 1, 2013, to April 30, 2023.Study measures (i.e., patients' basic information, clinical characteristics, and treatment patterns) were summarized with descriptive statistics.Te inclusion criteria were as follows: (1) patients histologically or cytologically diagnosed with unresectable stage III NSCLC; (2) patients who scored 0-2 on the Eastern Cooperative Oncology Group performance status (ECOG PS); (3) patients who had not received any previous treatment; and (4) patients included in this study had at least one measurable disease.Te study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).Te study was approved by the Academic Ethics Committee of Jiangsu Cancer Hospital, approval number (no.[2018]074), and individual consent for this retrospective analysis was waived.

Table 1 :
Clinical characteristics of patients and clinical activity of frst-line treatment.

Table 2 :
Te efcacy of diferent subgroups in the CRT plus immunotherapy group.

Table 3 :
Univariate analysis of factors of progression-free survival.