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The efficacy and safety of osimertinib in treating nonsmall cell lung cancer

Abstract Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the primary treatment in treating with EGFR mutant nonsmall cell lung cancer (NSCLC). This systematic review and meta-analysis aimed to evaluate the efficacy and safety of the third-generation EGFR-TKI, osimertinib, and summarize the risk factors associating with outcome after osimertinib treatment. Method: The Ovid Medline, Embase, Cochrane Library, and Pubmed were systematically searched due to December 10, 2019. All the studies that mentioned the overall survival (OS), progression-free survival (PFS), treatment response, and adverse events (AEs) of osimertinib were involved in our study. Hazard ratio (HR) with 95% confidence intervals was used for comparing OS and PFS. Result: A total of 47 studies were included in the systematic review, of which 14 studies were used to compare the efficacy between osimertinib and other EGFR-TKI or chemotherapy. Patients treating with osimertinib favors a higher OS and PFS in all the patients (HR = 0.56 and 0.38, P < .001, respectively), and in subgroup analysis, compared with other treatments. Median 55% T790 mutant NSCLC patients might experience partial response, and 25% of patients remained as stable disease. The incidence of severe AE ranged from 0% to 5%, and the most common severe AE was pneumonia (3%). Patients with the T858R mutation may have a better OS than Del 19 mutation (HR = 0.55, P = .037), while patients who have a smoking history may have a higher risk of progression than never-smoker patients (HR = 1.47, P = .028). Conclusion: Osimertinib has an impressive antitumor activity compared with prior EGFR-TKI and chemotherapy with an acceptable response and tolerable AEs. EGFR mutation type and smoking status were the risk factors for mortality and progression in NSCLC patients.


Introduction
Lung cancer is the most common cancer globally, and its incidence is still increasing. [1] Most recently, the research report shows that 222,500 new lung cancer cases occurred in the United States in 2017, accounting for 13.3% of all new tumors. [2] In China, more than 800,000 lung cancer patients were newly diagnosed each year, and the mortality rate ranks first in malignant tumors. [3] Nonsmall cell lung cancer (NSCLC) accounts for about 80% of the total number of lung cancers, and the epidermal growth factor receptor (EGFR) is one of the most common driver genes of NSCLC. [4] Paez, Lynch, and other studies confirmed that EGFR mutations are related to the efficacy of gefitinib, and further revealed the molecular mechanism of NSCLC's sensitivity to EGFR tyrosine kinase inhibitor (EGFR-TKI). [5] Subsequently, several prospective clinical studies have confirmed that EGFR-sensitive mutations play a pivotal role in screening TKIs predominant populations (such as Asian, female, adenocarcinoma, and nonsmoking). [6,7] Currently, the firstgeneration EGFR-TKI, gefitinib and erlotinib, and secondgeneration EGFR-TKI afatinib and dacotinib were widely used in treating EGFR-positive mutations. [8] A large number of randomized phase III clinical trials have concluded that gefitinib, erlotinib, and afatinib are more effective when applied to untreated advanced NSCLC with mutations in the EGFR gene, with longer survival rate and lower toxicity than standard platinum 2-drug combination chemotherapy. [9,10] As a result, EGFR-TKI is currently recommended as a first-line treatment for patients with advanced EGFR-mutant NSCLC. [11,12] Unfortunately, most patients undergoing initial EGFR-TKI treatment will progress within 10 to 12 months after initial treatment and develop resistance, and several mechanisms of first-generation EGFR-TKI acquired resistance have been reported. [13] In more than half of the cases, a common drug resistance mechanism is a unique missense mutation in exon 20, the so-called T790 M mutation, in which threonine at 790th is replaced by methionine. [14] Compared with reversible EGFR-TKIs such as gefitinib and erlotinib, it has an increased affinity for ATP, and ATP competes for alternative drugs in the binding site, thus making the tumor resistant to the reversible EGFR-TKI inhibition. [15] Osimertinib is an oral, selective third-generation EGFR-TKI inhibitor, which has an excellent inhibitory effect on the T790 M mutation. It can selectively and irreversibly target mutant EGFR and T790 while retaining wild-type EGFR tyrosine kinase, and targeting EGFR gene catalysis through the formation of covalent bonds. The C797 of the ATP-binding site of the domain forms a covalent bond, thereby irreversibly binding to a specific EGFR mutant form, inhibiting downstream signal pathway activity, and exerting a role in inhibiting tumor cell proliferation and promoting apoptosis. [16] The third-generation EGFR-TKI osimertinib has achieved significant results in patients with NSCLC who have progressed to T790 M mutation after treatment with EGFR-TKIs. [17,18] The AURA3 study showed that it reached 71% overall response rate (ORR) and 10.1 month progressionfree survival (PFS) in treating T790 M mutant NSCLC patients. [19] Moreover, in terms of adverse reactions, osimertinib has a lower rate of grade 3 adverse events (AEs) than the firstgeneration TKIs, especially for the patients with central nervous system (CNS) metastasis. [20] Due to the excellent efficacy of the AURA series, osimertinib is currently the standard treatment protocol for obtaining T790 M mutation after the first-line application of EGFR-TKIs in patients with advanced NSCLC with EGFR mutations. [21] Based on the results of the FLAURA study in October 2017, osimertinib is recommended as a first-line treatment for patients with advanced NSCLC with EGFR mutations, and it is listed as a priority recommendation by the National Comprehensive Cancer Network guidelines in 2019. [20] Although some meta-analysis showed the efficacy of osimertinib was superior to other treatments in treating NSCLC, the safety and the outcome evaluation of osimertinib itself had not fully reported yet. Moreover, due to the strict criteria that the randomized control studies (RCT) involved, the results seemed contrarious with mixed results with the real-world trial data. Thus, we designed this systematic review and meta-analysis, aiming to evaluate the response rate, AEs, and survival outcome in NSCLC patients treating with osimertinib. In this study, we included observational, real-world, cohort, and RCT to summarize the risk factors associated with outcome after osimertinib treatment.

Methods
This study was designed following the preferred reporting items for systematic review and meta-analysis (PRISMA) guidelines. [22] 2.1. Search strategy A systematic review and meta-analysis was designed to compare the effectiveness of osimertinib with other EGFR-TKI or chemotherapy and to evaluate the efficacy and safety of osimertinib in treating NSCLC. The Ovid Medline, Embase, Cochrane Library, and Pubmed were systematically searched due to December 10, 2019. Besides, the gray literature was undertaken using important related conferences (European Society of Medical Oncology, European Cancer Conference, American Society of Clinical Oncology, and World Conference on Lung Cancer) and Google Scholar. The key words were designed by an experienced librarian. In brief, the keywords included "osimertinib" OR "AZD9291" OR "third-generation EGFR-TKI," and "nonsmall cell lung cancer." All the studies containing abstracts and titles were imported into Endnote X7 to find duplicate studies and then for literature screening.

Inclusion and exclusion criteria
All the studies mentioned the overall survival (OS), PFS, treatment response, and AEs of osimertinib were involved in our study. The inclusion criteria were: The studies enrolled patients with histologically diagnosed as NSCLC with EGFR activating mutation; The studies reported the survival outcome, treatment response rate, or toxicity rate at least in osimertinib treatment group and the data of the outcome could be extracted. The meta-analysis, reviews, conference abstracts, and comments were recorded for the further inclusion of the papers. Only English written papers were involved in systematic reviews.
The exclusion criteria were: in vitro or in vivo experiment; case reports, case series, or the case less than 10; non-English written studies. Data from the same project or center will be selected as one for further meta-analysis.

Literature screening and data extraction
Two researchers (JL and XM L) independently screened the titles and abstracts based on the inclusion and exclusion criteria. The full text was further evaluated if the abstracts could not be determined and the data could not be extracted. The third investigator (JGH) was adapted for discussion if any disagreement existed.
A standard form was designed for data extraction and the data were collected according to the following information: the study characteristics (author, publish year, country, institution, recruitment period, study design, subcategory, etc.), patient characteristics (treatment, total sample, median age, gender, smoking status, Eastern Cooperative Oncology Group Performance status etc.), and outcome assessment (treatment response, toxicity, and survival status). The treatment response, including ORR, disease control rate (DCR), complete response (CR), partial response (PR), stable disease (SD), and progression disease (PD), was assessed in accordance with the Response Evaluation Criteria in Solid Tumors. [23] PFS was defined as the time from randomization to first progression or death. OS was defined as the time from treatment until death from any cause.

Quality assessment
Two researchers (JL and YHS) independently assess the quality of the including papers. Generally speaking, a modified Jadad scale was used to evaluate the quality of the randomized control studies. The scores of low-quality studies ranged from 0 to 3, whereas those of high-quality studies ranged from 4 to 8. For nonrandomized studies, the quality was assessed based on the Newcastle-Ottawa Quality Assessment Scale, with a high quality of 6 to 9, whereas low quality was scored as 0 to 5. [24]

Statistical analysis
The statistical analysis was performed by Stata 15.0 software (Stata Corporation, College Station, TX). P value < .05 was set as significant difference. When comparing the outcome between 2 different treatments or risk factors, the hazard ratio (HR) with 95% confidence intervals (CIs) was extracted. For 1 study, the single proportion, such as AEs rate and response rate, was derived using the Wilson score method. [25] The I 2 statistic and x 2 test were used for heterogeneity assessment (I 2 ≥ 50% indicating the presence of heterogeneity). When the heterogeneity not existed, the fix-effects model was used while the random-effect model was used in the opposite way. Finally, the forest plots were drawn, and funnel plots were used for evaluating the publication bias.

Literature selection
A total of 4051 studies were found according to the search strategy. The literature screening process was shown in the flowchart (Fig. 1). After screening the abstracts and titles, 236 studies were scanned in full-text. After excluding the incompatible studies, a total of 47 studies were included in the systematic review, in which 14 studies were used to compare the efficacy between osimertinib and other EGFR-TKI or chemotherapy, [19,20,[26][27][28][29][30][31][32][33][34][35][36][37] and 40 studies were used to evaluate the treatment response and AEs. [16,20,21,26,28,30,31,34,35, 3.2. The comparison of efficacy between osimertinib and other treatments The characteristics of the studies comparing osimertinib and other treatments were summarized in Table 1. A total of 4229 patients were included. However, 7 studies were from the FLAURA program and 4 studies were from the AURA3 program. The median age was 62 years old, while 62% were female, and 67% were never-smoking patients. FLAURA trial was mainly compared with osimertinib with other EGFR-TKI, AURA3, AURA, and IMPRESS were mainly compared with chemotherapy, and CAURAL study was mainly compared with combining the use of Durvalumab. The quality of the RCTs was evaluated as low risk The meta-analysis comparing OS and PFS was shown in Fig. 2. In terms of OS, the patients treating with osimertinib favors a higher survival rate compared with other treatments (HR 0.56,

Toxicities
The common AEs, including all grades and grades≥III, associated with osimertinib were listed in Table 3. The highest incidence of all-grade AEs was rash, occupying 42% patients (95% CI 34%-50%). The second common was diarrhea, occupying 35% of patients (95% CI 22%-49%). Besides, the incidence of all grade paronychia, dry skin, stomatitis was higher than 20%. The prevalence of headache, nausea, anorexia, headache, vomiting, anemia, pruritus, constipation, fatigue, and cough was between 10% and 20%. However, most of the results presented a higher heterogeneity (median I 2 = 64.9%, range from 0% to 99.0%). The increasing number of involved studies was related to a higher I 2 (r 2 = 0.566, P = .001).

Risk factors associated with survival outcome in treating with osimertinib
The risk factors associated with the survival outcome were presented in Figure 4 OS and Figure 5 PFS. Age and ECOG performance status were not the significant risk factor associated with survival outcomes in patients treating with osimertinib.

Discussion
This is the largest-scale systematic review to evaluate the efficacy and safety of osimertinib in treating EGFR-mutated NSCLC patients. Our meta-analysis suggested that osimertinib presented a better long-term survival outcome compared with other EGFR-TKI treatments and chemotherapy, with an acceptable AE. The EGFR mutation and smoking status were the risk factors associated with outcome in patients treating with osimertinib. More RCTs and real-world data analysis need to be performed to demonstrate its efficacy in different regions and populations. Osimertinib, also named as AZD9291, has a distinctive and unique chemical structure. Compared with wild-type EGFR, osimertinib has a nearly 200-fold potency in resistance to L858R/ T790 M, which confirm its selectivity to the mutant EGFR NSCLC. [69] In establishing in vitro models to evaluate the specificity of different EGFR TKI mutations, osimertinib has shown a full therapeutic window of resistance to EGFR T790 M mutations. [70] It has also demonstrated minimal off-target kinase activity when studying a variety of other kinases, thus demonstrating the overall selectivity of osimertinib. Interestingly, osimertinib did not show activity on insulin-like growth factor receptor 1, and insulin receptors in vitro and this observation was confirmed in vivo studies, indicating that osimertinib was associated with low risk of hyperglycemia-related dose-limiting toxicity. [69] Unlike the first-generation TKI, osimertinib is more effective to inhibit phosphorylation in T790 M mutant cell lines (H1975 and PC À9), can also more effectively inhibit downstream signal transduction substrates (pAKT, pERK). Based on the encouraging results of preclinical studies, osimertinib has mostly demonstrated its continued antitumor activity as a selective inhibitor of EGFR mutations. [69,70] In terms of clinical trials, the phase I/II AURA trials were designed to determine the safety and effectiveness of osimertinib in the progression of disease after receiving EGFR TKI in patients  Table 3 Meta-analysis of the common adverse events. with advanced NSCLC. [16] In this study, a total of 253 patients with known EGFR sensitization mutations or those who have benefited from the clinical treatment of EGFR-TKI and have significant disease progression during treatment were included: a total of 31 patients in a dose-escalation cohort. [5] There were 222 patients in the extended queue. In the expanded cohort, tumor biopsies were performed on all patients to determine the mutation status of EGFR T790 M, of which 138 (62%) were mutationpositive. Of the 239 evaluable patients, 123 (51%) had a clear objective response, including 122 patients with PR and 1 CR with a DCR of 84%, and the median PFS duration was 8.2 months. The results and safety of the AURA I/II were encouraging, and the subsequent phase II AURA also presented an inspiring result in multicenter, single-course analysis. A total of 210 patients with EGFR T790 M mutation-positive locally advanced or metastatic NSCLC were enrolled and received 80 mg orally daily osimertinib treatment. [68] As of the data deadline (January 1, 2015), the median follow-up time was 13 months, and 58% of patients were still receiving treatment. Of the 199 evaluable patients, the ORR was 70%, of which CR was 3% and, DCR was 92%. The high proportion of objective responses was consistent across all subgroups, including patients with CNS metastases. Subsequent phase II AURA extended studies also confirmed that after EGFR TKI treatment, patients with EGFR-sensitive and T790Mpositive NSCLC benefited from osimertinib treatment. [21] Afterward, a randomized phase III clinical trial (AURA3) was designed to demonstrate that osimertinib is superior to platinum in patients with EGFR mutations and T790M-positive NSCLC who have disease progression after first-line EGFR-TKI and chemotherapy with Pemetrexed. Patients with EGFR mutations and T790M-positive NSCLC after disease progression after TKI treatment are superior to standard chemotherapy with platinum and Pemetrexed. [19] Compared with the control group, the median PFS and ORR in the osimertinib group were significantly improved. FLAURA is a phase III, double-blind, international multicenter study that assessed the safety and efficacy of first-line treatment of osimertinib and early EGFR TKI in locally advanced or metastatic EGFR-positive NSCLC. The risk of disease progression or death was significantly reduced by 54% in the osimertinib group (HR = 0.46), and this advantage was observed in all subgroups, includes patients with CNS metastases at baseline. [20] These were the most extensive and analytical studies comparing osimertinib and other treatments up to now. After combining the results of the clinical studies, our meta-analysis still demonstrated that osimertinib has superior efficacy than other treatments in treating with EGFR mutation NSCLC patients. Rash and diarrhea were the most common AEs in patients treating with osimertinib, among which only 1% patients will have severe toxicity. Interstitial pneumonia is one of the severe AEs that causes discontinuation of treatment with osimertinib.
Our meta-analysis summarized 22 patients had severe pneumonia occupying 3% of the patients. Some clinical trials also stated that the incidence of these AEs is 3.3%, of which 0.5% is lifethreatening. [59] The results of the geographical distribution study showed that the impact of pneumonia in the Japanese population was relatively high, reaching 9%, while the impact in the non-Japanese Asian population was comparable to that of Whites, approximately 4%. [21] Also, some studies have pointed out the use of programmed death receptor-1 (PD-1) inhibitors or both at the same time as the risk factors for interstitial pneumonia. [71] Ahn et al [72] reported that the incidence of interstitial pneumonia was as high as 38% in patients who used both osimertinib and duvazumab, which may be related to the enhanced immunological activity of lymphocyte T cells CD8 + by PD-1 inhibitors. The median time to interstitial pneumonia after using osimertinib was 34.5 days (4-114 days). After the occurrence of interstitial pneumonia, it is generally necessary to discontinue osimertinib and receive supportive care, including glucocorticoids. [21] In our meta-analysis, the heterogeneity remained higher, which was related to the increasing number of involved studies. There were some limitations to our study. First, almost all the RCTs were from the AURA3 or FLAURA studies, and most of the studies were not controlled studies, which may decrease the quality of the meta-analysis. Therefore, more RCTs comparing osimertinib and other therapy are needed to validate the current result. Second, the subgroup analysis of T790 positive and negative, firstline use, and second use of osimertinib was not performed due to the insufficient data. Third, although we included a large scale of NSCLC patients treated with osimertinib, this study was not a meta-analysis based on the "individual patients," thus much of essential data were lost when reviewing from each manuscript. While due to the lower incidence of the AEs, the rate remains heterogeneity, which could not be avoided in our current metaanalysis. Further efforts need to be made in individual patient metaanalyses and regressions to discuss the efficacy and safety in patients treating with osimertinib.

Conclusion
Our systematic review and meta-analysis indicated that osimertinib has an impressive antitumor activity compared with prior EGFR-TKI and chemotherapy. The sequential use of osimertinib could achieve an acceptable response with tolerable AEs. EGFR mutation type and smoking status were the risk factors for mortality and progression in NSCLC patients. Further clinical trials, real-world data are needed to update this meta-analysis and investigate the role of osimertinib in treating NSCLC patients.