Significance of Immune Checkpoint Inhibitors in Patients with Locally Advanced Non-Small Cell Lung Cancer Treated with Chemoradiotherapy Prior to the Approval of Durvalumab

Background: The standard treatment for patients with unresectable locally advanced (LA) non-small cell lung cancer (NSCLC) was chemoradiotherapy (CRT). Consolidation therapy with durvalumab, an anti-programmed death ligand-1 antibody, after CRT demonstrated survival benefits and was approved in Japan in July 2018. The use of immune checkpoint inhibitors (ICIs) is entering routine oncological practice, and we investigate the feasibility of concurrent CRT for LA-NSCLC patients based on the PACIFIC criteria. Methods: We performed a retrospective study to evaluate the feasibility and efficacy of concurrent CRT prior to the approval of durvalumab. We assessed consecutive patients with LA-NSCLC treated with CRT between January 2012 and June 2018 in clinical practice, based on the PACIFIC criteria. Results: We analyzed a total of 108 consecutive patients ( 81 males and 27 females) who received radical thoracic radiotherapy and concurrent platinum-based chemotherapy. Of those, 105 patients (97%) completed the planned radiotherapy. Radiation pneumonitis was observed in 93 patients (85%), with a median of 130 days (range: 41–317 days) from the initiation of radiation to the onset of the complication. Among the patients, 74 (69%) were considered eligible for consolidation therapy with durvalumab. The overall response rate was 64%, and the 2-year survival rate was 63%. Of the 82 patients who relapsed after CRT, 18 patients received treatment with an ICI in the course of treatment. Patients who received an ICI after relapse were associated with significantly better survival than those who did not receive an ICI (2-year survival rate: 87% vs. 41%, respectively; p = 0.001). Conclusion: Prior to the approval of durvalumab, the clinical application of ICIs improved the outcome of patients with relapsed NSCLC after CRT for LA-NSCLC. The treatment strategy of ICI consolidation therapy for patients with LA-NSCLC and the management of radiation pneumonitis are challenges following the approval of durvalumab. This retrospective study included 108 consecutive patients with LA-NSCLC treated with CRT at the (Kanagawa, between January 2012 and June 2018. All patients underwent computed tomography (CT) for three-dimensional conformal TRT, and received concurrent TRT in combination with platinum-based chemotherapy. We examined the clinical records (e.g., date of diagnosis, sex, smoking status, tumor–node– metastasis staging, histology, mutational status, PS, course of treatment, adverse events [AEs] including radiation pneumonitis, and survival time) of each patient.


Background
The current standard treatment for unresectable locally advanced (LA) non-small cell lung cancer (NSCLC) is definitive concurrent chemoradiotherapy (CRT). The efficacy of thoracic radiotherapy (TRT) for LA-NSCLC was evaluated in 1968, when 800 patients with LA-NSCLC were treated with 40-50 Gy of TRT. The overall survival (OS) was significantly improved in the TRT group compared with the placebo group (4.6 vs. 3.7 months, respectively) [1]. In 1990, a combination of TRT with cisplatin plus vinblastine significantly prolonged survival compared with TRT alone (OS: 13.7 vs. 9.6 months, respectively; p = 0.0066) [2], and CRT has been positioned as the standard of care for patients with LA-NSCLC [3][4][5] In the past 20 years, there has been no improvements in outcome (2-year survival rate: 40-60%) [3,[6][7][8]. However, in the PACIFIC Trial, concurrent CRT followed by consolidation therapy with durvalumab resulted in a significant prolongation of progression-free survival (PFS) compared with placebo (PFS: 17.2 vs. 5.6 months, respectively; stratified HR, 0.51; 95% CI: 0.41-0.63) and the OS rate at 24 months (66.3% vs. 55.6%, respectively; stratified HR: 0.68; 99.73% CI: 0.47-0.997) [9, 10]. Based on the results of this study, durvalumab was approved in Japan in July 2018 as consolidation therapy after CRT. The main inclusion criteria in the PACIFIC Trial were (1) patients with stage III, unresectable NSCLC; (2) patients who had received two or more cycles of platinum-based chemotherapy concurrently with TRT (54-66 Gy), in which the mean lung dose was <20 Gy, the V20 (the volume of lung parenchyma that received ≥20 Gy) was <35%, or both; (3) absence of disease progression after CRT; (4) age ≥18 years; (5) a World Health Organization performance status (PS) of 0-1; (6) an estimated life expectancy ≥12 weeks; and (7) completion of the last radiation dose within 1-42 days prior to randomization of consolidation therapy with durvalumab. Key exclusion criteria were active or previous autoimmune disease (within the previous 2 years) or [16] (January 2018) were approved in Japan as the second or subsequent line of therapy against advanced or recurrent NSCLC. Moreover, pembrolizumab monotherapy [17] became available as the initial chemotherapy for programmed death ligand-1-positive advanced NSCLC in December 2016. Furthermore, in December 2018, the use of pembrolizumab [18,19] or atezolizumab [20] plus chemotherapy was expanded to the first-line treatment of metastatic NSCLC. The use of immune checkpoint inhibitors (ICIs) showed durable clinical benefit and long-term remissions in some patients [21][22][23]

Evaluation of response and survival
Tumor response was classified in accordance with the Response Evaluation Criteria for Solid Tumors (version 1.1), based on the results of a complete medical history, physical examination, chest X-ray examination, CT of the chest and abdomen, and other procedures (i.e., magnetic resonance imaging of the brain, positron emission tomography-

Patient characteristics
In total, 108 patients were treated with concurrent CRT combined with platinum-based chemotherapy. Of these, 52 patients were treated between January 2012 and June 2015 and 56 patients were treated between July 2015 and June 2018 (Supplemental Figure 1A).
The characteristics of the patients included in this study are shown in Table 1. The median age was 65 years (range: 36-76 years), 81 of the patients (75%) were male, and only 11 patients (10%) were non-smokers. Notably, 46 patients (43%) had adenocarcinoma, including two patients with epidermal growth factor receptor mutations, four patients with anaplastic lymphoma kinase rearrangements, and one patient with ROS1 mutation. In addition, 38 patients (35%) had squamous cell carcinoma.

Chemoradiotherapy for patients with LA-NSCLC in clinical practice
All patients received radical TRT using a three-dimensional planning system with a median  Table 2.

Treatment outcomes in patients with LA-NSCLC
The overall response rate to CRT was 64% (Table 3)  vs. 54%, respectively (p = 0.042) ( Figure 1D). During the period of this study, the TRT planning method employed in our hospital was not changed. Therefore, we analyzed subsequent chemotherapy for patients with recurrent disease after CRT to assess the difference in OS. Of the 82 patients who relapsed after CRT, 18 patients received treatment with an ICI (i.e., nivolumab [n = 14], pembrolizumab [n = 3], and atezolizumab [n = 1]) ( Table 2). Among the LA-NSCLC patients who relapsed after CRT, the OS of those treated with ICIs was superior to that of patients not treated with an ICI. However, it was not superior to that of patients who received targeted treatment with a TKI ( 2-year survival rates in the durvalumab and placebo groups were 66.3% (95% CI: 61.7-70.4) and 55.6% (95% CI: 48.9-61.8), respectively (p = 0.005) [29]. These findings indicated that durvalumab is an effective treatment option for patients with LA-NSCLC who meet the PACIFIC criteria. However, it is necessary to accumulate additional data regarding the identification of patients who can receive consolidation therapy with durvalumab in the clinical setting. In our retrospective study, concurrent CRT for the treatment of unresectable LA-NSCLC was effective in clinical practice, with acceptable toxicity, prior to the approval of durvalumab. The median OS was 41.8 months (95% CI: 20.1-65.5), the 2-year survival was 63%, and the 5-year survival was 41%.
Prior to their use in the treatment of LA-NSCLC, ICIs were approved for metastatic or  [32]. In this study, patients with LA-NSCLC who relapsed after CRT and were subsequently treated with ICIs were associated with better prognosis than those who did not receive treatment with ICIs (2-year survival rate: 87% vs. 41%, respectively; p = 0.001). There is an increasing body of preclinical and clinical data regarding the radiotherapy-induced immunomodulatory effects in the local tumor microenvironment, supporting the combination strategy [33][34][35]. Radiotherapy modifies the tumor microenvironment, including enhanced antigen presentation, and the upregulation of tumor programmed death ligand-1 and major histocompatibility complex class I expression [33,[36][37][38][39]. In addition to the local effects of irradiation at the tumor site, radiotherapy can also mediate an abscopal effect, which is linked to an immunemediated mechanism [40-42]. The combination of radiotherapy and immunotherapy is considered an effective treatment strategy. In our study, the use of ICI for recurrence after CRT was a favorite prognostic factor for the patients with LA-NSCLC.
In the PACIFIC Trial, the eligibility criteria were stringent compared with those in routine clinical practice. Thus, 74 of the 108 patients (69%) who received concurrent CRT with platinum-based chemotherapy in our study met the PACIFIC criteria in the clinical setting.
Regarding the schedule of the PACIFIC Trial, the patients with LA-NSCLC were randomized for consolidation therapy with durvalumab within 42 days after the completion of TRT based on the concept of immunomodulation through radiotherapy. Furthermore, in the subgroup analysis, the therapeutic effects of early initiation (i.e., within 14 days) were high, and the early use of an ICI was expected. On the other hand, even in relapsed patients with advanced or metastatic NSCLC, previous radiotherapy may increase the effect of treatment with an ICI [32], although the mechanism involved in this process is currently unclear. The optimal treatment method, namely, the timing and duration of immunotherapy combined with radiotherapy, should be verified. Moreover, appropriate patient selection should be performed using reliable and predictive biomarkers, cytotoxic T-cell infiltration and functionality, status of major histocompatibility complex expression, neoantigen burden, metabolic status, and general immune status factors (e.g., neutrophil-to-lymphocyte ratio) [43,44].

Radiation pneumonitis occurs frequently after TRT [45]
, and is characterized by clinically significant toxicity. In our study, radiation pneumonitis was found in approximately 90% of patients. However, its severity was mild/moderate in the majority of cases (CTCAE grade 1: 58%; grade 2: 26%; and grade 3: 1%), and the complication was manageable according to the appropriate radiotherapy plan. In the PACIFIC Trial, the incidence of AEs of any cause was similar in the durvalumab group versus the placebo group for AEs of any grade (97% vs. 95%, respectively), grade 3-4 AEs (30% vs. 26%, respectively), and serious AEs (29% vs. 23%, respectively) [9]. The most common grade 3-4 AEs were pneumonia (4% vs. 4%, respectively) and pneumonitis (3% vs. 3%, respectively). In several retrospective analyses, patients with advanced NSCLC who had received TRT and nivolumab exhibited a higher incidence of drug-induced interstitial lung disease than those without TRT [46, 47].
In the future, real-world data will also be important in selecting the appropriate patients and establishing optimal treatment strategies (e.g., radiation dose, fractionation, field volume, schedule of treatment with ICIs, and treatment period) to combine radiotherapy with ICIs. Furthermore, elucidation of the effects of immune activation by ICIs on radiation pneumonitis is also required.
This study had certain limitations. First, this was a retrospective study conducted at a single institution with a small sample size; hence, the results cannot be considered definitive. Second, the current study included patients with LA-SCLC who could receive