Treatment Pattern and Overall Survival of Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: A Multicentric Real-World Study in China (CTONG1506)

Background: CTONG1506, an observational study assessed the real-world treatment patterns and overall survival (OS) of Chinese advanced non-squamous non-small cell lung cancer (NSCLC) patients in current treatment practices. Patients initiated with 1st line therapy were identied from 12 tertiary hospitals across China. Survival data were collected 1- and 2-years after study initiation. OS was estimated using the Kaplan-Meier method. was better compared to alone both in PFS and OS in EGFR + NSCLC patients. our study the median OS in EGFR + patients receiving TKI alone was 27.9 months compared to 14.5 months in EGFR- patients who received chemotherapy. Results from our real-world study support the ecacy of EGFR TKIs as established in clinical trials.


Background
Lung cancer is the leading cause of mortality with incidence of 2.1 million new cases and 1.8 million deaths in 2018 world-wide (1). In China, lung cancer remains the most common issue, accounting for 18.1% of new cases and is also the leading cause of cancer death (2). It has been reported that the 5-year survival of patients diagnosed with lung cancer is around 17.8% and patients die within one year of diagnosis (3). The 5-year survival rate for lung cancer in China remains low in men with frequency of 16.8% and 25.1% in women from 2012-2015 (4). Additionally, an increase in the incidence and mortality with age in both the genders is observed (5).
The international treatment guidelines recommend chemotherapy, programmed death ligand 1 (PDL-1), or combination of PDL1 and chemotherapy, as rst line treatment for NSCLC without oncogenic driver mutations (6). In patients with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, tyrosine kinase inhibitors (TKIs) are the recommended rst-line treatment.
Approximately, 19.2% of Western and 47.9% of Asian population with NSCLC-adenocarcinoma subtype harbour EGFR mutation (7). Thus, TKIs directed against EGFR, such as Erlotinib, and Ge tinib, have demonstrated promising outcomes for this subgroup of patients (8); thereby representing as a standard rst-line treatment for EGFR mutated NSCLC (9).
Additionally, superiority of EGFR TKIs over platinum-doublet chemotherapy in providing better progression free survival (PFS) in EGFR + NSCLC has also been demonstrated by various randomized, phase III studies (10)(11)(12)(13)(14)(15)(16). Similar ndings have also been reported in other studies wherein prolonged PFS relative to chemotherapy was observed with Afatinib but overall survival (OS) was similar in both groups (17). Evidence suggests that treatment with EGFR TKI in rst line setting improves PFS but did not show much bene t in OS compared to chemotherapy (10)(11)(12).
Despite growing evidence in proving the e cacy of various therapeutic strategies, limited information concerning the use of appropriate treatment modality for advanced NSCLC in a real-world setting raises a serious concern to the clinicians. Therefore, data from real-world will help generate evidence on the effectiveness and use of medical products in daily practice (18), will provide insights on patient response, disease patterns, along with clinical outcomes in patients of all ages (19). This study was thus conducted to assess the treatment patterns and OS of advanced non-squamous NSCLC patients in a Chinese population in current treatment practices (CTONG 1506).

Study design
This retrospective, series of cross-sectional study extracted data from medical charts of patients

Study outcome
Survival information OS was collected one and two years after patients received initial treatment. Followup data was obtained from medical chart abstraction or telephonic interview.

Statistical analysis
Age (< 65, ≥ 65), sex (male, female), hospital location (hospital location, developed area), smoking status (never smoker, former smoker, current smoker), histological subtype (adenocarcinoma, other), ECOG PS (0, 1, ≥ 2) at baseline were described. The categorical data were presented as frequencies and percentages. OS were evaluated by Kaplan-Meier (KM) method with 95% con dence intervals (CIs). Patients who lost the follow-up or could not be con rmed about survival status at any follow-up were not included in the survival analysis. Two-tailed P-values, less than 0.05 will be considered statistically signi cant. All analysis was performed using R software (Version 3.5.1).

Baseline and demographic details
The demographic and baseline clinical characteristics of the overall study population was categorized based on mutational status as presented in Table 1. Among the 12 tertiary hospitals that were included in the study, majority of hospitals belonged to developed area in China. A total of 540 patients who had a 2year follow-up survival data were included in the study. There were 183 patients with EGFR-/ALKwild type and most of them were < 65 years of age (72.1%). It was seen that 74.6% of the included patients were < 65 years. A total of 87 (42.8%) patients had exon 19 deletion and 82 (40.3%) patients had EGFR exon 21 L858R mutation in EGFR + group. On the other hand, chemotherapy only was the most common mode of treatment in ALK + patients in 1st (58.5%) and 2nd (59.1%) line. However, chemotherapy and TKI was prescribed as 1st line to 2.0% EGFR + and 4.6% ALK + patients in 2nd line. None of the patients received this pattern at 3rd line (Table 2). The median OS for 540 patients was 21.4 months (95% CI: 18.1-25.5), 1-year and the 2-year OS rate was 69.5% (95% CI: 66.0-74.0) and 46.3% (95% CI: 42.0-51.0), respectively (Fig. 1A). It was seen that the median OS for patients with EGFR mutation (n = 203), ALK rearrangement (n = 24), and wild-type EGFR with negative ALK rearrangement (n = 183) were 27.9 months (95% CI: 23.4-NA), 24.5 months (95% CI: 18.1-NA), and 15.7 months (95% CI: 13.1-21.1), respectively (Fig. 1B).
Median OS was not reached in patients with EGFR exon 19 deletion and it was 21.4 months (95% CI: 16.7-35.6) in EGFR exon 21 L858R mutation patients. Statistically signi cant difference (P = 0.038) was seen in OS between the groups (Fig. 2 respectively with log rank test: P = 0.25 (Fig. 4).

Discussion
This study evaluated the real-world treatment patterns and the survival bene ts provided by EGFR TKIs and other current, systemic anti-cancer therapies in advanced NSCLC with different mutated and nonmutated pro les in China. The treatment pattern observed in current study is in agreement with the Chinese Expert Consensus on the diagnosis and treatment of advanced NSCLC (2016 version) (20) with TKI being the preferred 1st line option. However, platinum-based regimen remains the standard treatment for patients without mutations in China with gemcitabine, docetaxel, paclitaxel and pemetrexed being the most common choices for 1st line chemotherapy (21). A retrospective chart review study examining realworld treatment pattern in Japan revealed EGFR TKIs to be the most commonly prescribed drug for EGFR mutated NSCLC across all treatment lines (22).
Pemetrexed is the preferred regimen in patients with NSCLC adenocarcinoma based on the results of previous randomized studies due to its superior outcomes in terms of PFS (23, 24). Likewise, even in current study, Pemetrexed (30.3%, 22.7%) and Cisplatinum (23.9%, 13.6%) were the most frequently used chemotherapeutic drugs as 1st and 2nd line, respectively whereas, among TKIs, Ge tinib (31.5%, 17.4%) and Icotinib (20.3%, 15.9%) were the frequently used treatment in 1st and 2nd line, respectively. This treatment pattern is not in line with other patterns reported elsewhere wherein docetaxel was used in 14.0-16.0% of patients in 2nd line (25,26).
Our study revealed that although non-signi cant, EGFR + patients who received sequential TKI and chemotherapy had longer median OS. This corroborates ndings from a study by Chung et.al who demonstrated that the 1st line chemotherapy followed by EGFR-TKIs in EGFR + advanced lung adenocarcinoma had better OS than that of 1st line TKIs followed by 2nd-line chemotherapy (median: 662 versus 390 days, P < 0.0001. Similar ndings were reported by another phase III study, OPTIMAL which showed improved OS in patients receiving sequential combination of TKI and chemotherapy than those who received either TKI or chemotherapy (29.7 versus 20.7 or 11.2 months respectively, P < 0.0001) (27). Overall, these ndings strongly support the fact that TKI in combination with chemotherapy is e cient when compared to either TKI or chemotherapy alone for treating EGFR + mutation patients.
In our study, targeted therapy either using TKI alone or sequential chemotherapy was found to have better OS in EGFR + patients compared to EGFRpatients highlighting the importance of TKI in rst line setting for EGFR + patients. This is in line with ndings from a recent trial which reported the OS of Icotinib plus pemetrexed and carboplatin to be 36 months (28). Similarly, another study comparing the e cacy of combination therapy of EGFR-TKI with chemotherapy with EGFR-TKI alone and chemotherapy alone revealed signi cant improved PFS in combination therapy compared to EGFR-TKI alone (29). Additionally, combination therapy was better compared to chemotherapy alone both in PFS and OS in EGFR + NSCLC patients. In our study the median OS in EGFR + patients receiving TKI alone was 27.9 months compared to 14.5 months in EGFRpatients who received chemotherapy. Results from our real-world study support the e cacy of EGFR TKIs as established in clinical trials.
Going forward, remarkable progress made in treatment of NSCLC is due to the discovery of several, clinically relevant activating pathways including EGFR-activating mutations and ALK rearrangements (30) and treatment guidelines recommend the use of rst line EGFR-TKI for patients with exon 19 deletions and the exon 21 L858R mutation (6). Data also re ect that patients harbouring exon 19 deletions or exon 21 L858R point mutations in EGFR show substantially increased bene t from treatment with EGFR TKIs compared to those who do not harbour these mutations (31). This has been attributed to TKI's inhibitory action and its role in downstream signalling of EGFR. The mechanism of action of TKI is to inhibit the kinase activation and signal transduction downstream by binding to the ATP binding site of the kinase domain of EGFR (32). Treatment with TKI has shown around 74.0% response rate with a median PFS of 10.0-14.0 months (12,15). However, recent studies have shown mixed outcomes due to exon 19 and 21 mutations in such patients in response to both EGFR-TKIs and chemotherapy (33)(34)(35). These difference in response between EGFR exon 19 deletions and exon 21 L858R mutation might be related to intrinsic structural basis and differential drug sensitivity (36)(37)(38). In our study, median OS was not reached in patients with exon 19 deletion and it was 21.4 months (95%CI: 16.7-35.6) in those with exon 21 L858R mutation (P = 0.038). This was in agreement with study ndings reported elsewhere. Jiang et.al reported signi cantly improved overall response rate (ORR) and PFS in patients with deletions in exon 19 compared with those with exon 21 mutation following EGFR-TKI treatment for NSCLC (31). The same was re-con rmed by Banno et.al wherein NSCLC patients with EGFR exon 19 deletions had a signi cant advantage following the treatment of Afatinib compared with the patients with EGFR exon 21 mutations (39). These ndings re-substantiate the importance of appropriate treatment selection especially for EGFR + NSCLC patients. With the approval of rst immuno-oncology agent, Opdivo (Nivolumab injection) by China National Drug Administration based on results of pivotal phase III, Checkmate-078 trial that demonstrated signi cantly better OS with nivolumab compared to docetaxel in previously treated non-mutated EGFR/ALK NSCLC, better management is foreseen in this subset of patients (40). ALK-rearrangement has been identi ed in many cancers including NSCLC. ALKrearrangement leads to oncogenic ALK tyrosine kinase that drives cell proliferation by activating downstream signalling pathways (41). ALK-TKIs are preferred option in advanced NSCLC with ALK rearrangements (42,43). Authors Contributions: QZ, YS, XZ, GC and YZ proposed the conception and designed the study. PY, JC, ZY, YH and XS acquired the study data DZ, GF, LY, LZ, XM, XL, YW analyzed, and interpreted the study data. All the authors critically reviewed the manuscript and approved the nal version for submission. All authors have agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.