Osimertinib plus Chemotherapy versus Osimertinib for Patients with Advanced NSCLC Concomitant EGFR and TP53 Mutations: A Prospective Cohort Study

Osimertinib plus Chemotherapy versus Osimertinib for Patients with Advanced NSCLC Concomitant EGFR and TP53 Mutations: A Prospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Osimertinib plus Chemotherapy versus Osimertinib for Patients with Advanced NSCLC Concomitant EGFR and TP53 Mutations: A Prospective Cohort Study Jixian Li, Xiang Zhan, Mengqing Shao, Renya Zeng, Jianan Li, Hui Zhu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4467606/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Osimertinib is the standard first-line options for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). Co-mutations in TP53 results in poor survival for patients. However, the studies on treatment options and clinical outcomes of patients with EGFR-TP53 co- mutation are limited. Methods Patients with EGFR mutation-positive locally advanced or metastatic NSCLC carrying TP53 mutations were recruited from two institutions and allocated into two groups, either receiving osimertinib plus chemotherapy (Osi + Chemo group) or osimertinib monotherapy (Osi group). The progression-free survival (PFS) was evaluated as the primary endpoint and the response was also assessed. Results Between January 2020 and August 2023, Ninety-eight patients were enrolled with 47 and 51 patients receiving combination therapy and the monotherapy. After a median follow-up of 19.2 months, overall response rate (ORR) was 80.0% versus 71.7% ( p = 0.36), favoring Osi + Chemo group, as well as in disease control rate (DCR) (91.4% vs. 80.4%, p = 0.45). The median PFS in the Osi + Chemo group was 26.0 months versus 20.7 months in the Osi group, but without significant difference ( p = 0.34). The subgroup analysis indicated that for patients with L858R mutation, Osi + Chemo therapy significantly prolonged the median PFS (not reached [NR] versus 17.1 months, p = 0.03), but not in patients with 19Del (20.6 months versus NR, p = 0.31). Conclusion Osimertinib plus chemotherapy have a tendency to increase ORR and prolong PFS in NSCLC with EGFR and TP53 co-mutations, particularly in patients with L858R mutation. NSCLC Osimertinib EGFR TP53 Chemotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Lung cancer remains the leading cause of cancer-related death worldwide. The advent of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations( 1 ). EGFR-TKIs, either as monotherapy or in combination with chemotherapy, have become standard frontline treatment for these settings( 2 , 3 ). Osimertinib, the third-generation irreversible TKI, stands out as it effectively targets common EGFR mutations, including exon 21 L858R (L858R), exon 19 deletion (19Del), and the resistance mutation exon 20 T790M( 4 ). Additionally, osimertinib demonstrated a favorable response in the central nervous system (CNS) in contrast to other TKIs( 5 , 6 ). The FLAURA trial revealed that osimertinib extends progression-free survival (PFS) and overall survival (OS) compared to earlier TKIs without increasing adverse events( 7 , 8 ). Although the FLAURA trial showed a median PFS of 18.9 months and an overall response rate (ORR) of 80%, the subsequent decrease to 17.8 months in the FLAURA China trial suggests a pressing clinical requirement, highlighting an unmet therapeutic challenge( 9 ). Several factors serve as limitations to the efficacy of osimertinib. One prominent factor is the coexistence of concomitant TP53 mutations( 10 ). TP53 is a widely recognized tumor suppressor gene known for its vital role in preserving genomic stability and facilitating cellular stress response and a myriad of cellular response( 11 , 12 ). In the cases of advanced EGFR-driven NSCLC, TP53 mutations co-occur in approximately 50% − 60% of patients( 13 , 14 ). Existed studies have consistently indicated that the presence of TP53 mutations can lead to a reduction in the effectiveness of TKI treatment( 14 , 15 ). Nonetheless, the specific impact of concomitant TP53 and EGFR mutational status on the responsiveness to osimertinib has not been elucidated. The addition of chemotherapy has the potential to augment the efficacy of osimertinib. Our previous exploratory study with a small sample size also found similar results. Now, the phase 3 FLAURA2 trial provides compelling evidence that the first-line combination of chemotherapy with osimertinib significantly enhances median PFS, thereby affirming the necessity of including chemotherapy in the initial treatment regimen( 16 ). However, outcomes in patients with co-mutations, particularly those with TP53 mutations, were not reported in the FLAURA2 study. Integrating chemotherapy to osimertinib for all patients without selection is not aligned with the goal of precision medicine. Therefore, we report the results of our previously designed prospective study, evaluating the efficacy of first-line osimertinib in combination with chemotherapy for NSCLC patients with concomitant EGFR and TP53 co-mutations. Materials and Methods Study design and patients This prospective cohort study was conducted according to the principal of STROBE at the Shandong Provincial Hospital and Shandong Cancer Hospital between January 2020 and August 2023. Patients who received treatment in the two centers were enrolled with met the inclusion criteria: histologically diagnosed with adenocarcinoma, classified as locally advanced or advanced, adults had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0–2, EGFR and TP53 co-mutations, at least one measurable baseline lesion, and had no prior anti-cancer treatment before randomization. Patients were excluded according to the criteria: incomplete clinical and pathological data, concurrent malignant tumors, a history of confirmed substance abuse that cannot be discontinued, or a history of mental disorders. The patients were randomly allocated into two cohorts: one received osimertinib in combination with chemotherapy (Osi + Chemo group), and the other received osimertinib monotherapy (Osi group). Osimertinib is taken orally once daily at a dosage of 80 mg. Chemotherapy is administered intravenously, using a regimen that includes typical first-line treatment medications, pemetrexed, and platinum agents (carboplatin or cisplatin). The dosages of pemetrexed and cisplatin are calculated based on the patient's body surface area, with doses of 500 mg and 75 mg per square meter, respectively. The dosage of carboplatin is determined based on an area under the concentration-time curve of 5 mg. Chemotherapy drugs are supplied once every 3 weeks for a total of 4–6 cycles, then was followed-by osimertinib alone once daily until disease progression, death, intolerable toxic effects, or withdrawal of consent. Thoracic radiotherapy covering the residual primary tumor and local-regional lymph nodes during the maintenance of frontline treatment in patients without distant disease progression after chemotherapy completion was permitted. The radiotherapy involves a total dose of 50–60 Gy delivered in 25–30 fractions of 1.8 Gy − 2 Gy each. Assessments Systemic tumor responses were evaluated once every 6 weeks from the beginning of treatment by contrast-enhanced computed tomography and brain magnetic resonance imaging scans. After chemotherapy completed, patients were followed up every 3 months for the first year, and then every 6 months for the following 2 years, and annually thereafter. No scheduled brain imaging was necessary for patients without CNS metastases until radiographic evidence of progression or clinical symptoms of CNS metastases. Measurements were conducted according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). PFS was measured as the primary endpoint from the randomized time to the date of the disease progression, any caused death, or lost follow-up or withdrawal of consent, whichever occurs first. The ORR and disease control rate (DCR) was calculated as the secondary endpoints. The ORR refers to the proportion of patients with complete response (CR) and partial response (PR) among all evaluated patients. The DCR refers to the proportion of patients with CR, PR, and stable disease (SD). Sample Size Calculation This study was designed to verify whether combining first-line chemotherapy with osimertinib can prolong the PFS of EGFR and TP53 co-mutated NSCLC patients compared to using osimertinib alone. Based on previous reports, the median PFS of EGFR/TP53 co-mutated NSCLC patients receiving osimertinib as first-line treatment was 13.5 months, and the hazard ratio (HR) of PFS between the two patient cohorts was set at 0.5( 17 ). Considering an 80% power to reject the null hypothesis of equal survival time at a two-sided alpha of 0.05, we calculated a sample size of 92 patients using the method proposed by Schoenfeld ( 18 ). With an anticipated dropout rate of 5%, a total size of 97 patients was required in the study (48 in the Osi + Chemo group; and 49 in the Osi group). Statistical analysis Statistical analysis was conducted in the study to compare categorical variables using Fisher’s exact test or χ 2 test. Additionally, the independent t-test was employed to compare continuous variables such as age. Time-to-event variables such as the follow-up period and PFS were estimated using the Kaplan-Meier method, and comparisons of variation between curves were assessed using log-rank tests. The Cox proportional-hazards model was carried out to analyze the response and treatment-by-covariate interaction effects of pre-specified patient subgroups as well as for univariate and multivariate analysis to assess the influence of potentially independent prognosis factors on survival functions. Statistical analyses were performed using SPSS 27 (SPSS, Chicago, IL). HR with 95% confidence intervals (CI) was presented and a two-sided P -value < 0.05 was considered statistically significant. Results Patients’ baseline characteristics The process of patient enrollment is shown in the flowchart Fig. 1 . A total of 108 patients were enrolled according to the inclusion criteria. Within the cohort of patients under investigation, a total of 6 patients were lost to follow-up, and an additional 4 patients withdrew their informed consent. Eventually, 47 patients received osimertinib in addition to chemotherapy, while 51 patients received osimertinib monotherapy. Detailed baseline clinicopathological characteristics are summarized in Table 1 . The median age of the entire cohort was 59.0 years with an interquartile range of 52.7–69.0 years. Most of the patients (65.3%) were females, and 76.5% of entire patients had no history of smoking. Additionally, a subset of patients (14.3%) with unresectable stage IIIb NSCLC were included in this study. In terms of the EGFR mutation status, 41 patients (41.8%) had an exon 19Del, while 50 patients (51.0%) had an exon 21 L858R mutation. In this study, 37 patients (37.8%) were diagnosed with CNS metastases, while 9 patients (9.2%) had liver metastases, 30 patients (30.6%) had pleural metastasis or malignant pleural effusion, and 39 patients (39.8%) had bone metastases. The median cycles of chemotherapy were 4 (range, 4–6). In addition, 20 patients (20.4%) who received thoracic radiotherapy were also included in this study during the maintenance of osimertinib treatment. All baseline characteristics were compared and well-balanced between the two groups. Table 1 Characteristics of baseline. n (%) Overall Osi + Chemo (n = 47) Osi Monotherapy (n = 51) P value Age, median (IQR) years 59(52.75-69) 59(54–68) 60(51–70) 0.83 > 65y 32(32.7) 15(31.9) 17(33.3) 0.88 ≤ 65y 66(67.3) 32(68.1) 34(66.7) Gender 0.58 Male 34(34.7) 15(31.9) 19(37.3) Female 64(65.3) 32(68.1) 32(62.7) Smoking Status 0.62 Never 75(76.5) 37(78.7) 38(74.5) Former 23(23.5) 10(21.3) 13(25.5) Stage at Diagnosed 0.06 IIIb 14(14.3) 10(21.3) 4(7.8) IV 84(85.7) 37(78.7) 47(92.2) EGFR Mutations 0.14 19Del 43(43.9) 17(36.2) 26(51) L858R 55(56.1) 30(63.8) 25(49) ECOG-PS 0.80 0 36(36.7) 16(34) 20(39.2) 1 55(56.1) 27(57.4) 28(54.9) 2 7(7.1) 4(8.5) 3(5.9) Thoracic Radiation 0.84 Yes 20(20.4) 10(21.3) 10(19.6) No 78(79.6) 37(78.7) 41(80.4) Pulmonary metastasis 0.80 Yes 28(28.6) 14(29.8) 14(27.5) No 70(71.4) 33(70.2) 37(72.5) CNS Metastases 0.86 Yes 30(37.8) 14(29.8) 16(31.4) No 68(62.2) 33(70.2) 35(68.6) Liver Metastases 0.10 Yes 9(9.2) 2(4.3) 7(13.7) No 89(90.8) 45(95.7) 44(86.3) Pleural Metastases or Effusion 1.00 Yes 30(30.6) 15(31.9) 15(29.4) No 68(69.4) 32(68.1) 36(70.6) Bone Metastases 0.05 Yes 39(39.8) 14(29.8) 25(49) No 59(60.2) 33(70.2) 26(51) Abbreviations: IQR: interquartile range; CNS: central nervous system Table 2 Univariate and multivariate analyses of clinical-pathological factors associated with PFS Univariate analysis Multivariate analysis OR (95%CI) P Value OR (95% CI) P Value Age (years) > 65y 1 0.75 ≤ 65y 0.90 (0.47–1.72) Gender Male 1 0.09 0.03 Female 0.54 (0.27–1.10) 0.45 (0.22–0.93) Smoking status Never 1 0.82 Former 0.92 (0.44–1.91) EGFR mutations 19Del 1 0.74 L858R 1.11 (0.60–2.02) ECOG-PS 0 1 0.62 1 0.75 (0.39–1.41) 2 1.03 (0.35–3.09) Treatment Osi monotherapy 1 0.35 Osi + Chemo 0.75 (0.41–1.37) Thoracic radiation No 1 0.61 Yes 1.21 (0.58–2.55) CNS Metastases 0.02 No 1 0.04 Yes 1.94 (1.05–3.59) 2.07 (1.11–3.86) Pleural Metastases or Effusion No 1 0.48 Yes 1.27 (0.65–2.48) Bone Metastases No 1 0.62 Yes 1.17 (0.63–2.15) Intrapulmonary metastasis No 1 0.03 0.01 Yes 2.00 (1.07–3.71) 2.31 (1.22–4.38) Efficacy The median duration follow-up period of the entire cohort was 20.0 months. In the Osi + Chemo group, the median follow-up was 18 months (95% CI, 13.5–22.5 months), whereas it was 21.5 months (95% CI, 16.0–24.2 months) in the Osi group. The ORR assessed in the whole cohort amounted to 76.5%, while the DCR reached a notable value of 92.9%. The best response rate was listed in supplementary Table 2. Higher ORR was observed in the Osi + Chemo group in contrast to the Osi group (78.7% vs. 74.5%, p = 0.64). The DCR was also higher in the Osi + Chemo group, with rates of 95.7% compared to 90.2% in the Osi group ( p = 0.44). At the time of the data cutoff, a total of 42 progress events (42.9%) were observed, with 19 patients (40.4%) in the Osi + Chemo group and 23 patients (45.1%) in the Osi group. The median PFS of the entire cohort was 23.1 months (95% CI, 13.7–32.5 months), whereas it was 26.0 months (95% CI, 10.8–41.3 months) in the Osi + Chemo group, compared to 20.7 months (95% CI, 18.4–25.5 months; p = 0.34) in the Osi group (Fig. 2 ). The 12-, 18-, and 24-months PFS rates were 81.3%, 62.0%, and 53.1%, retrospectively, in the Osi + Chemo group compared to 64.9%, 57.5%, and 40.8%, retrospectively, in the Osi group. The overall survival between the two groups was not reported, as they were immature. Since mutation subtype may impact treatment decisions due to the differential affinity of 19Del and L858R for osimertinib, we performed a subgroup analysis based on EGFR subtypes. For the entire group, the median PFS in patients with 19Del was similar compared to that in patients with L858R mutation (21.7 months versus 22.7 months, p = 0.74; Fig. 3 A). It appears that patients with L858R mutation benefit more from Osi + Chemo therapy, compared to that with 19Del (NR versus 20.6 months, p = 0.15; Fig. 3 B). Further analysis indicated the addition of chemotherapy to osimertinib significantly prolonged median PFS (NR versus 16.8 months, p = 0.02) among patients with L858R mutation (Fig. 3 C); however, this was no longer true for patients with 19Del (20.6 months versus NR, p = 0.31; Fig. 3 D). In addition, to eliminate the potential impact of thoracic radiation therapy on the efficacy, patients who received thoracic radiotherapy were excluded before the further analysis. However, the median PFS was still no statistical significance between the two groups, while it was 21.7 months vs. 20.6 months ( p = 0.94), respectively, favoring the osimertinib monotherapy (Supplementary Fig. 1). Multivariable and subgroup analysis To investigate the impact of confounding factors on treatment outcomes, we performed univariate and multivariate analyses using a Cox proportional hazards model (Table 2). The variables that displayed a P value below 0.1 in the univariate analysis were incorporated into the subsequent multivariate analysis. The multivariable Cox regression analysis revealed that female (OR = 0.45, 95% CI: 0.22–0.93, p = 0.03), CNS metastases (OR = 2.07, 95% CI: 1.11–3.86, p = 0.02), and intrapulmonary metastases (OR = 2.31, 95% CI: 1.22–4.38, p = 0.01) independently predicted PFS. Subgroup analyses were conducted using a Cox proportional-hazards model to assess the treatment-by-subgroup interaction, visually represented as a forest plot (Fig. 4 ). The results indicated that the proportional of Osi + Chemo on PFS was consistent across all pre-specified subgroups. Discussion To the best of our current knowledge, this study represents the primary exploring the effectiveness of combining osimertinib with chemotherapy for first-line therapy in patients with NSCLC who possess mutations in both EGFR and TP53 concurrently. Our study revealed that combination therapy had the potential to prolong the PFS in the whole cohort, particularly increasing PFS significantly in patients with the L858R mutation. Our research highlights the potential value of integrating chemotherapy with first-line osimertinib targeted therapy to mitigate the adverse impact of TP53 mutations. The results provide a more precise treatment option for patients with advanced NSCLC harboring co-mutations. TP53 is a common mutation in lung cancer, while the current research consensus is that co-mutations reduce patient survival( 19 , 20 ). The FLAURA study established osimertinib as first-line treatment in NSCLC due to its benefits in PFS and OS( 7 , 8 ). However, the presence of a TP53 mutation can impede the efficacy of osimertinib( 21 , 22 ). In Choudhury’s study, the median PFS was significantly reduced by 5 months, from 18.8 months in the wild-type patient group to 13.3 months in the group with the combined mutation ( p = 0.002), in patients receiving osimertinib as a first-line treatment( 23 ). For second- and further-line treatment, co-mutation of TP53 was also an independent risk that diminished the efficacy of osimertinib( 10 , 24 ). Consequently, alongside the development of TP53-targeted pharmaceuticals, the synergistic combination of existing therapeutic agents represents a pivotal strategy in the treatment paradigm. Emerging evidence suggests that osimertinib combined with chemotherapy has the potential to improve survival, especially in patients with co-mutation. The recently published FLAURA2 study provides confirmation that the PFS of patients receiving a combination of osimertinib with chemotherapy (25.5 months) was significantly extended compared to those receiving osimertinib monotherapy (16.7 months, p < 0.001)( 16 ). However, the survival outcomes for the subgroup of patients with co-mutations have not yet been reported in the FLAURA2 trial. Here, our study fills the research gap in this area, demonstrating that osimertinib plus chemotherapy improved PFS by 5.3 months compared to the osimertinib monotherapy group, although it did not reach statistical significance (26.0 months versus 20.7 months, p = 0.34). Yang and colleagues’ study also demonstrated the efficacy of combination therapy in patient with co-mutations, with PFS increasing from 11.4 months to 19.1 months in patients receiving first-generation TKI in combination with chemotherapy ( p = 0.001)( 25 ). Since patients with wild-type TP53 were not enrolled in the present study, comparing the efficacy and survival between TP53 wild-type and mutant populations is unfeasible. In EGFR-driven NSCLC, cases of approximately 50% − 60% were observed to harbor alterations of the TP53 gene in different exon( 13 , 14 ). Hence, despite the unknown TP53 mutational status in FLAURA2 study, our data remains comparable to theirs. Moreover, the median PFS of 26.0 months also surpasses the 17.5 months reported in another study( 26 ). On one hand, the disparate outcome observed in this study can be attributed to the heterogeneity of TP53 mutations and the admission bias among patients. Previous studies have mainly concentrated on missense mutations primarily found between codons 100 and 300 and frequently located within the DNA-binding domain of the p53 protein( 10 , 21 , 25 ). Several hotspot mutations occurred inside the DNA-binding domain and account for only about 30% of the total mutated cases( 27 ). There is still a lack of in-depth understanding regarding the impact of different types and different site mutations of TP53. On the other hand, the disparities in study outcomes may also stem from differences in the clinical characteristics of the enrolled patients. Compared to FLAURA2 study, we observed a lower proportion of stage IV patients and fewer liver metastases, with a subset of patients receiving thoracic radiotherapy in our study. Those conditions suggest that our patient cohort might have a lower tumor burden compared to the FLAURA2 patients, potentially increasing sensitivity to treatment, which may have translated into a survival benefit further. Patients with different EGFR mutations who carry TP53 mutations may experience varying impacts when receiving treatment with osimertinib. Clinically, 19Del and L858R EGFR mutations, as common mutations, account for 90% of observed EGFR mutations( 28 ). However, they exhibit differing sensitivities to TKIs due to the varying affinities of different invariant types for TKI agents( 29 , 30 ). The prevailing consensus illustrated that patients with 19Del mutations catch greater benefits from TKIs than those with L858R mutations( 31 – 33 ). Consequently, patients with the 19Del mutation derive greater benefit from osimertinib monotherapy, thereby diminishing the advantage conferred by chemotherapy. In contrast, for patients with the L858R mutation, due to its lower affinity, the benefits of chemotherapy are amplified. Indeed, subgroup analysis in the present study confirmed these findings, with more pronounced benefits in L858R mutation patients and less so in those with 19Del. The median PFS in patients with the L858R mutation who underwent combination therapy was significantly prolonged compared to those who underwent osimertinib monotherapy (NR versus 16.8 months, p = 0.02). Therefore, combination therapy involving pemetrexed-based chemotherapy is considered the preferred treatment for patients with the L858R mutation. Although this is a prospective study from the two centers, there are still some limitations. First, the relatively small sample size may have hindered the effective investigation of differences between the two cohorts; therefore, larger samples are required for further analysis. Second, this study refrained from stratifying the analysis based on specific metastatic sites primarily to avoid the potential for inflated type I or type II statistical errors due to an insufficient sample size. In addition, toxic events occurring during the maintenance period are still being collected and therefore, have not been reported in this study. Last, the relatively short follow-up duration limited the assessment of the overall survival of first-line treatment, as the occurrence of death events was rare. Following the extended follow-up, the updated data will be reported in the near future. Conclusion In summary, this study provides evidence for the prolonged PFS benefits of addict chemotherapy to osimertinib in patients with EGFR mutant lung adenocarcinoma and concomitant TP53 co-mutations. Notably, those with the L858R mutation appear to derive more substantial benefits. Our research highlight the efficacy of integrating chemotherapy with osimertinib for this patient subset. This conclusion needs to be further validated through extensive prospective studies. Abbreviations NSCLC, Non-small cell lung cancer; EGFR, Epidermal Growth Factor Receptor； TKI, Tyrosine kinase inhibitor; CNS, Central nervous system; PFS, Progression-free survival; OS: Overall survival; ORR, Objective response rate; DCR: Disease control rate; CR, Complete response; PR, Partial response; SD, Stable disease. HR, Hazard ratio IQR, Interquartile range; CI, Confidence interval; NR, Not reached. OR, Odds ratio; RR, Relative risk. Declarations Ethics Ethics approval was obtained from the Ethical Review Committee of Shandong Provincial Hospital and Shandong Cancer Hospital for this study, and informed consent was obtained from all patients before conducting the treatment. The study was conducted in accordance with the principles of the Declaration of Helsinki. Data availability: The data that support the findings of this study are available on request from the corresponding author, Zhe Yang and Wang Jing, upon reasonable request. Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding This work was supported by the Cancer Research Funding of CSCO-Qilu (Y2019AZM-0522) and Cancer Research Funding of CSCO-Qilu(YQL2019-0149). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication Authors' Contributions Drs Z. Yang and W. Jing had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Z. Yang and W. Jing contributed equally to this work. Jixian Li: Formal analysis, Writing - Original Draft. Xiang Zhan: Investigation, Visualization. Mengqing Shao: Investigation. Jianan Li: Investigation. Hui Zhu: Supervision, Data curation. Alei Feng: Supervision, Zhe Yang: Project administration, Funding acquisition Conceptualization. Wang Jing: Conceptualization, Methodology. Acknowledgements We thank all the patients and their family members for their permission to participate in this study. References Singh S, Sadhukhan S, Sonawane A. 20 years since the approval of first EGFR-TKI, gefitinib: Insight and foresight. Biochim Biophys Acta Rev Cancer. 2023 Nov;1878(6):188967. Belani N, Liang K, Fradley M, Judd J, Borghaei H. How to Treat EGFR-Mutated Non-Small Cell Lung Cancer. JACC CardioOncol. 2023 Aug;5(4):542–5. Hendriks LE, Kerr KM, Menis J, Mok TS, Nestle U, Passaro A, et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023 Apr;34(4):339–57. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017 Feb 16;376(7):629–40. Jänne PA, Planchard D, Kobayashi K, Cheng Y, Lee CK, Valdiviezo N, et al. CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2023 Dec 2;JCO2302219. Colclough N, Chen K, Johnström P, Strittmatter N, Yan Y, Wrigley GL, et al. Preclinical Comparison of the Blood-brain barrier Permeability of Osimertinib with Other EGFR TKIs. Clin Cancer Res. 2021 Jan 1;27(1):189–201. Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113–25. Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41–50. Cheng Y, He Y, Li W, Zhang HL, Zhou Q, Wang B, et al. Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study. Target Oncol. 2021 Mar;16(2):165–76. Stockhammer P, Grant M, Wurtz A, Foggetti G, Expósito F, Gu J, et al. Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer. J Thorac Oncol. 2023 Oct 6;S1556-0864(23)02264-5. Levine AJ. p53: 800 million years of evolution and 40 years of discovery. Nat Rev Cancer. 2020 Aug;20(8):471–80. Soussi T, Béroud C. Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer. 2001 Dec;1(3):233–40. Liu SY, Zhou JY, Li WF, Sun H, Zhang YC, Yan HH, et al. Concomitant genetic alterations having greater impact on the clinical benefit of EGFR-TKIs in EGFR-mutant advanced NSCLC than BIM deletion polymorphism. Clin Transl Med. 2020 Jan;10(1):337–45. Passaro A, Attili I, Rappa A, Vacirca D, Ranghiero A, Fumagalli C, et al. Genomic Characterization of Concurrent Alterations in Non-Small Cell Lung Cancer (NSCLC) Harboring Actionable Mutations. Cancers (Basel). 2021 Apr 30;13(9):2172. Canale M, Petracci E, Delmonte A, Chiadini E, Dazzi C, Papi M, et al. Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors. Clin Cancer Res. 2017 May 1;23(9):2195–202. Planchard D, Jänne PA, Cheng Y, Yang JCH, Yanagitani N, Kim SW, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935–48. Choudhury NJ, Marra A, Sui JSY, Flynn J, Yang SR, Falcon CJ, et al. Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers. J Thorac Oncol. 2023 Apr;18(4):463–75. Schoenfeld DA. Sample-Size Formula for the Proportional-Hazards Regression Model. Biometrics. 1983;39(2):499–503. Tan J, Hu C, Deng P, Wan R, Cao L, Li M, et al. The Predictive Values of Advanced Non-Small Cell Lung Cancer Patients Harboring Uncommon EGFR Mutations-The Mutation Patterns, Use of Different Generations of EGFR-TKIs, and Concurrent Genetic Alterations. Front Oncol. 2021;11:646577. Kim Y, Lee B, Shim JH, Lee SH, Park WY, Choi YL, et al. Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC. J Thorac Oncol. 2019 Feb;14(2):193–202. van Veelen A, Veerman GDM, Verschueren MV, Gulikers JL, Steendam CMJ, Brouns AJWM, et al. Exploring the impact of patient-specific clinical features on osimertinib effectiveness in a real-world cohort of patients with EGFR mutated non-small cell lung cancer. Int J Cancer. 2024 Jan 15;154(2):332–42. Zhao J, Lin G, Zhuo M, Fan Z, Miao L, Chen L, et al. Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib. Lung Cancer. 2020 Mar;141:114–8. Choudhury NJ, Marra A, Sui JSY, Flynn J, Yang SR, Falcon CJ, et al. Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers. J Thorac Oncol. 2023 Apr;18(4):463–75. Roeper J, Christopoulos P, Falk M, Heukamp LC, Tiemann M, Stenzinger A, et al. TP53 co-mutations as an independent prognostic factor in 2nd and further line therapy—EGFR mutated non-small cell lung cancer IV patients treated with osimertinib. Transl Lung Cancer Res. 2022 Jan;11(1):4–13. Yang Z, Chen Y, Wang Y, Wang S, Hu M, Zhang B, et al. Efficacy of EGFR-TKI Plus Chemotherapy or Monotherapy as First-Line Treatment for Advanced EGFR-Mutant Lung Adenocarcinoma Patients With Co-Mutations. Front Oncol. 2021 Aug 16;11:681429. Liu X, Hong L, Nilsson M, Hubert SM, Wu S, Rinsurongkawong W, et al. Concurrent use of aspirin with osimertinib is associated with improved survival in advanced EGFR-mutant non-small cell lung cancer. Lung Cancer. 2020 Nov;149:33–40. Baugh EH, Ke H, Levine AJ, Bonneau RA, Chan CS. Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ. 2018 Jan;25(1):154–60. Hsu WH, Yang JCH, Mok TS, Loong HH. Overview of current systemic management of EGFR-mutant NSCLC. Annals of Oncology. 2018 Jan 1;29:i3–9. Lee VHF, Tin VPC, Choy T shing, Lam K on, Choi C wai, Chung L ping, et al. Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first-line tyrosine kinase inhibitor in metastatic non-small-cell lung cancer. J Thorac Oncol. 2013 Sep;8(9):1148–55. Kumar A, Petri ET, Halmos B, Boggon TJ. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J Clin Oncol. 2008 Apr 1;26(10):1742–51. Lee CK, Wu YL, Ding PN, Lord SJ, Inoue A, Zhou C, et al. Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis. J Clin Oncol. 2015 Jun 10;33(17):1958–65. Sheng M, Wang F, Zhao Y, Li S, Wang X, Shou T, et al. Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations after tyrosine kinase inhibitors treatment: a meta-analysis. Eur J Clin Pharmacol. 2016 Jan;72(1):1–11. Zhao Y, Liu J, Cai X, Pan Z, Liu J, Yin W, et al. Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis. BMJ. 2019 Oct 7;367:l5460. Supplementary Table 1 Supplementary Table 1 is not available with this version Additional Declarations No competing interests reported. Supplementary Files Supplementaryfigure1.pdf Supplementarytable2.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4467606","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":309896916,"identity":"92f8e29b-d0a0-4912-bdac-1e6aea8627d1","order_by":0,"name":"Jixian Li","email":"","orcid":"","institution":"Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Jixian","middleName":"","lastName":"Li","suffix":""},{"id":309896917,"identity":"11ec2aed-6d1c-4265-a831-0b13eb396bce","order_by":1,"name":"Xiang Zhan","email":"","orcid":"","institution":"Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Xiang","middleName":"","lastName":"Zhan","suffix":""},{"id":309896918,"identity":"fd70894a-c3d1-4c0e-b1f7-92efdb4a5289","order_by":2,"name":"Mengqing Shao","email":"","orcid":"","institution":"Shandong Provincial Hospital Affiliated to Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mengqing","middleName":"","lastName":"Shao","suffix":""},{"id":309896919,"identity":"314eeb0f-e2e1-49e9-979b-deafefadedb7","order_by":3,"name":"Renya Zeng","email":"","orcid":"","institution":"Shandong Provincial Hospital Affiliated to Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Renya","middleName":"","lastName":"Zeng","suffix":""},{"id":309896920,"identity":"33c12aa3-b3ea-4a80-9927-2ef2b3092346","order_by":4,"name":"Jianan Li","email":"","orcid":"","institution":"Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Jianan","middleName":"","lastName":"Li","suffix":""},{"id":309896921,"identity":"05017466-1591-4fe6-9f45-e07241f67c9c","order_by":5,"name":"Hui Zhu","email":"","orcid":"","institution":"Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Zhu","suffix":""},{"id":309896922,"identity":"4e577cff-f4b8-403b-ac11-66b785054037","order_by":6,"name":"Alei Feng","email":"","orcid":"","institution":"Shandong Provincial Hospital Affiliated to Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Alei","middleName":"","lastName":"Feng","suffix":""},{"id":309896923,"identity":"6cd16d3c-0feb-408b-b627-09260234ae78","order_by":7,"name":"Zhe Yang","email":"","orcid":"","institution":"Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Zhe","middleName":"","lastName":"Yang","suffix":""},{"id":309896924,"identity":"fd24cbe2-d4c6-4674-a2c0-9d693d77c7b7","order_by":8,"name":"Wang Jing","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYBACxmYgkVABYjIfOPChglgtD86AmGyJB2ecIdamh20gisf4MG8LEcqZ23kPv0hgOyxvzr/mwwHeBgZ5frEDhBzGl2aRwHPYcOeMtxsOSO5gMJw5O4GQFh4zgwSJ24wbbpzdcMDwDEOCwW2itBjctt9w48yDA4ltxGkxfpCQcDtxw/kehgMHidRixpBw4H/yhhtsBgcbzkgQ9oth/xnjjz//pdluOH/48ec/FTby/NKEtDQwsEmAWRJglRL4lYOAPDBqPoBZ/AcIqx4Fo2AUjIKRCQCL21AUWQUznQAAAABJRU5ErkJggg==","orcid":"","institution":"Shandong Provincial Hospital Affiliated to Shandong First Medical University","correspondingAuthor":true,"prefix":"","firstName":"Wang","middleName":"","lastName":"Jing","suffix":""}],"badges":[],"createdAt":"2024-05-23 14:44:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4467606/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4467606/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58143724,"identity":"996397d8-6716-42e3-bc24-05ece84836fd","added_by":"auto","created_at":"2024-06-11 18:21:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":167521,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of patients’ enrollment. PD: progressive disease\u003c/p\u003e","description":"","filename":"figure18.5mm1.png","url":"https://assets-eu.researchsquare.com/files/rs-4467606/v1/36b35d232c30dab7c8c1105e.png"},{"id":58143726,"identity":"d67510ac-2034-4859-8b8a-b25b8dd3aa0a","added_by":"auto","created_at":"2024-06-11 18:21:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":149068,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves of PFS of patients for the entire group. HR: hazard ratio\u003c/p\u003e","description":"","filename":"figure2..png","url":"https://assets-eu.researchsquare.com/files/rs-4467606/v1/eb7704cb47d6ee855475dd48.png"},{"id":58145252,"identity":"fbdf3407-b181-453a-bd7a-6b9f757639f8","added_by":"auto","created_at":"2024-06-11 18:29:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":524429,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves of PFS of patients (A) stratified by EGFR subtypes for the entire group. (B) stratified by EGFR subtypes in subgroup of patients with Osi + Chemo (C) in subgroup of patients with L858R. (D) in subgroup of patients with 19Del. HR: hazard ratio; NR: not reached.\u003c/p\u003e","description":"","filename":"figure3..png","url":"https://assets-eu.researchsquare.com/files/rs-4467606/v1/54f91b84ec7624583229ef25.png"},{"id":58143727,"identity":"22170467-1cac-46bc-9f2d-ec857a284e4b","added_by":"auto","created_at":"2024-06-11 18:21:53","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":431906,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup Analysis of Progression-Free Survival.\u003c/p\u003e","description":"","filename":"figure4..png","url":"https://assets-eu.researchsquare.com/files/rs-4467606/v1/4042e84dc121841d9d0d9ba1.png"},{"id":58202975,"identity":"c031027e-e6fd-4222-8f7a-0ee0efc9b578","added_by":"auto","created_at":"2024-06-12 11:16:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1513889,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4467606/v1/9d9b25e7-9def-4007-956a-b015ea4677b7.pdf"},{"id":58143729,"identity":"1328b264-d56c-49a4-b5e3-cedd625f49f9","added_by":"auto","created_at":"2024-06-11 18:21:53","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":157685,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfigure1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4467606/v1/5ea36a813ea2b5ead5dd7c74.pdf"},{"id":58145251,"identity":"bc97b263-0e65-4190-821e-d2485350cc7e","added_by":"auto","created_at":"2024-06-11 18:29:53","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":14815,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarytable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4467606/v1/fcf22f010ba9cbc40d0a2878.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Osimertinib plus Chemotherapy versus Osimertinib for Patients with Advanced NSCLC Concomitant EGFR and TP53 Mutations: A Prospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLung cancer remains the leading cause of cancer-related death worldwide. The advent of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). EGFR-TKIs, either as monotherapy or in combination with chemotherapy, have become standard frontline treatment for these settings(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Osimertinib, the third-generation irreversible TKI, stands out as it effectively targets common EGFR mutations, including exon 21 L858R (L858R), exon 19 deletion (19Del), and the resistance mutation exon 20 T790M(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Additionally, osimertinib demonstrated a favorable response in the central nervous system (CNS) in contrast to other TKIs(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The FLAURA trial revealed that osimertinib extends progression-free survival (PFS) and overall survival (OS) compared to earlier TKIs without increasing adverse events(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Although the FLAURA trial showed a median PFS of 18.9 months and an overall response rate (ORR) of 80%, the subsequent decrease to 17.8 months in the FLAURA China trial suggests a pressing clinical requirement, highlighting an unmet therapeutic challenge(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSeveral factors serve as limitations to the efficacy of osimertinib. One prominent factor is the coexistence of concomitant TP53 mutations(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). TP53 is a widely recognized tumor suppressor gene known for its vital role in preserving genomic stability and facilitating cellular stress response and a myriad of cellular response(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In the cases of advanced EGFR-driven NSCLC, TP53 mutations co-occur in approximately 50% \u0026minus;\u0026thinsp;60% of patients(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Existed studies have consistently indicated that the presence of TP53 mutations can lead to a reduction in the effectiveness of TKI treatment(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Nonetheless, the specific impact of concomitant TP53 and EGFR mutational status on the responsiveness to osimertinib has not been elucidated.\u003c/p\u003e \u003cp\u003eThe addition of chemotherapy has the potential to augment the efficacy of osimertinib. Our previous exploratory study with a small sample size also found similar results. Now, the phase 3 FLAURA2 trial provides compelling evidence that the first-line combination of chemotherapy with osimertinib significantly enhances median PFS, thereby affirming the necessity of including chemotherapy in the initial treatment regimen(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). However, outcomes in patients with co-mutations, particularly those with TP53 mutations, were not reported in the FLAURA2 study. Integrating chemotherapy to osimertinib for all patients without selection is not aligned with the goal of precision medicine. Therefore, we report the results of our previously designed prospective study, evaluating the efficacy of first-line osimertinib in combination with chemotherapy for NSCLC patients with concomitant EGFR and TP53 co-mutations.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003e This prospective cohort study was conducted according to the principal of STROBE at the Shandong Provincial Hospital and Shandong Cancer Hospital between January 2020 and August 2023. Patients who received treatment in the two centers were enrolled with met the inclusion criteria: histologically diagnosed with adenocarcinoma, classified as locally advanced or advanced, adults had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0\u0026ndash;2, EGFR and TP53 co-mutations, at least one measurable baseline lesion, and had no prior anti-cancer treatment before randomization. Patients were excluded according to the criteria: incomplete clinical and pathological data, concurrent malignant tumors, a history of confirmed substance abuse that cannot be discontinued, or a history of mental disorders.\u003c/p\u003e \u003cp\u003eThe patients were randomly allocated into two cohorts: one received osimertinib in combination with chemotherapy (Osi\u0026thinsp;+\u0026thinsp;Chemo group), and the other received osimertinib monotherapy (Osi group). Osimertinib is taken orally once daily at a dosage of 80 mg. Chemotherapy is administered intravenously, using a regimen that includes typical first-line treatment medications, pemetrexed, and platinum agents (carboplatin or cisplatin). The dosages of pemetrexed and cisplatin are calculated based on the patient's body surface area, with doses of 500 mg and 75 mg per square meter, respectively. The dosage of carboplatin is determined based on an area under the concentration-time curve of 5 mg. Chemotherapy drugs are supplied once every 3 weeks for a total of 4\u0026ndash;6 cycles, then was followed-by osimertinib alone once daily until disease progression, death, intolerable toxic effects, or withdrawal of consent. Thoracic radiotherapy covering the residual primary tumor and local-regional lymph nodes during the maintenance of frontline treatment in patients without distant disease progression after chemotherapy completion was permitted. The radiotherapy involves a total dose of 50\u0026ndash;60 Gy delivered in 25\u0026ndash;30 fractions of 1.8 Gy \u0026minus;\u0026thinsp;2 Gy each.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAssessments\u003c/h2\u003e \u003cp\u003eSystemic tumor responses were evaluated once every 6 weeks from the beginning of treatment by contrast-enhanced computed tomography and brain magnetic resonance imaging scans. After chemotherapy completed, patients were followed up every 3 months for the first year, and then every 6 months for the following 2 years, and annually thereafter. No scheduled brain imaging was necessary for patients without CNS metastases until radiographic evidence of progression or clinical symptoms of CNS metastases. Measurements were conducted according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). PFS was measured as the primary endpoint from the randomized time to the date of the disease progression, any caused death, or lost follow-up or withdrawal of consent, whichever occurs first. The ORR and disease control rate (DCR) was calculated as the secondary endpoints. The ORR refers to the proportion of patients with complete response (CR) and partial response (PR) among all evaluated patients. The DCR refers to the proportion of patients with CR, PR, and stable disease (SD).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSample Size Calculation\u003c/h2\u003e \u003cp\u003eThis study was designed to verify whether combining first-line chemotherapy with osimertinib can prolong the PFS of EGFR and TP53 co-mutated NSCLC patients compared to using osimertinib alone. Based on previous reports, the median PFS of EGFR/TP53 co-mutated NSCLC patients receiving osimertinib as first-line treatment was 13.5 months, and the hazard ratio (HR) of PFS between the two patient cohorts was set at 0.5(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Considering an 80% power to reject the null hypothesis of equal survival time at a two-sided alpha of 0.05, we calculated a sample size of 92 patients using the method proposed by Schoenfeld (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). With an anticipated dropout rate of 5%, a total size of 97 patients was required in the study (48 in the Osi\u0026thinsp;+\u0026thinsp;Chemo group; and 49 in the Osi group).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was conducted in the study to compare categorical variables using Fisher\u0026rsquo;s exact test or χ\u003csup\u003e2\u003c/sup\u003e test. Additionally, the independent t-test was employed to compare continuous variables such as age. Time-to-event variables such as the follow-up period and PFS were estimated using the Kaplan-Meier method, and comparisons of variation between curves were assessed using log-rank tests. The Cox proportional-hazards model was carried out to analyze the response and treatment-by-covariate interaction effects of pre-specified patient subgroups as well as for univariate and multivariate analysis to assess the influence of potentially independent prognosis factors on survival functions. Statistical analyses were performed using SPSS 27 (SPSS, Chicago, IL). HR with 95% confidence intervals (CI) was presented and a two-sided \u003cem\u003eP\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003ePatients\u0026rsquo; baseline characteristics\u003c/h2\u003e\n \u003cp\u003eThe process of patient enrollment is shown in the flowchart Fig.\u0026nbsp;\u003cspan\u003e1\u003c/span\u003e. A total of 108 patients were enrolled according to the inclusion criteria. Within the cohort of patients under investigation, a total of 6 patients were lost to follow-up, and an additional 4 patients withdrew their informed consent. Eventually, 47 patients received osimertinib in addition to chemotherapy, while 51 patients received osimertinib monotherapy. Detailed baseline clinicopathological characteristics are summarized in Table\u0026nbsp;\u003cspan\u003e1\u003c/span\u003e. The median age of the entire cohort was 59.0 years with an interquartile range of 52.7\u0026ndash;69.0 years. Most of the patients (65.3%) were females, and 76.5% of entire patients had no history of smoking. Additionally, a subset of patients (14.3%) with unresectable stage IIIb NSCLC were included in this study. In terms of the EGFR mutation status, 41 patients (41.8%) had an exon 19Del, while 50 patients (51.0%) had an exon 21 L858R mutation. In this study, 37 patients (37.8%) were diagnosed with CNS metastases, while 9 patients (9.2%) had liver metastases, 30 patients (30.6%) had pleural metastasis or malignant pleural effusion, and 39 patients (39.8%) had bone metastases. The median cycles of chemotherapy were 4 (range, 4\u0026ndash;6). In addition, 20 patients (20.4%) who received thoracic radiotherapy were also included in this study during the maintenance of osimertinib treatment. All baseline characteristics were compared and well-balanced between the two groups.\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eCharacteristics of baseline.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOsi\u0026thinsp;+\u0026thinsp;Chemo\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;47)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOsi Monotherapy\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, median (IQR) years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59(52.75-69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59(54\u0026ndash;68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60(51\u0026ndash;70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;65y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32(32.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15(31.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17(33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;65y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e66(67.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32(68.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34(66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34(34.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15(31.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19(37.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64(65.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32(68.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32(62.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmoking Status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75(76.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37(78.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e38(74.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFormer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23(23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(21.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13(25.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage at Diagnosed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIIIb\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(21.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4(7.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84(85.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37(78.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47(92.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEGFR Mutations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19Del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43(43.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17(36.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26(51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL858R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55(56.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30(63.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25(49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG-PS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36(36.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16(34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20(39.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55(56.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27(57.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28(54.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7(7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4(8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3(5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eThoracic Radiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20(20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(21.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10(19.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78(79.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37(78.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41(80.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePulmonary metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28(28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(27.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70(71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33(70.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37(72.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCNS Metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30(37.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16(31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68(62.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33(70.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35(68.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiver Metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9(9.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7(13.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e89(90.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45(95.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44(86.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePleural Metastases or Effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30(30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15(31.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15(29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68(69.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32(68.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36(70.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBone Metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39(39.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14(29.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25(49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59(60.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33(70.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26(51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eAbbreviations: IQR: interquartile range; CNS: central nervous system\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eUnivariate and multivariate analyses of clinical-pathological factors associated with PFS\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR (95%CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e Value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e Value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026gt;\u0026thinsp;65y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;65y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.90 (0.47\u0026ndash;1.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.54 (0.27\u0026ndash;1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.45 (0.22\u0026ndash;0.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSmoking status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFormer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.92 (0.44\u0026ndash;1.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEGFR mutations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19Del\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL858R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.11 (0.60\u0026ndash;2.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECOG-PS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.75 (0.39\u0026ndash;1.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.03 (0.35\u0026ndash;3.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOsi monotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOsi\u0026thinsp;+\u0026thinsp;Chemo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.75 (0.41\u0026ndash;1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eThoracic radiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.21 (0.58\u0026ndash;2.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCNS Metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.94 (1.05\u0026ndash;3.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.07 (1.11\u0026ndash;3.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003ePleural Metastases or Effusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.27 (0.65\u0026ndash;2.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBone Metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.17 (0.63\u0026ndash;2.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eIntrapulmonary metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.00 (1.07\u0026ndash;3.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.31 (1.22\u0026ndash;4.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"1\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\"\u003e\n \u003ch2\u003eEfficacy\u003c/h2\u003e\n \u003cp\u003eThe median duration follow-up period of the entire cohort was 20.0 months. In the Osi\u0026thinsp;+\u0026thinsp;Chemo group, the median follow-up was 18 months (95% CI, 13.5\u0026ndash;22.5 months), whereas it was 21.5 months (95% CI, 16.0\u0026ndash;24.2 months) in the Osi group. The ORR assessed in the whole cohort amounted to 76.5%, while the DCR reached a notable value of 92.9%. The best response rate was listed in supplementary Table\u0026nbsp;2. Higher ORR was observed in the Osi\u0026thinsp;+\u0026thinsp;Chemo group in contrast to the Osi group (78.7% vs. 74.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.64). The DCR was also higher in the Osi\u0026thinsp;+\u0026thinsp;Chemo group, with rates of 95.7% compared to 90.2% in the Osi group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.44). At the time of the data cutoff, a total of 42 progress events (42.9%) were observed, with 19 patients (40.4%) in the Osi\u0026thinsp;+\u0026thinsp;Chemo group and 23 patients (45.1%) in the Osi group. The median PFS of the entire cohort was 23.1 months (95% CI, 13.7\u0026ndash;32.5 months), whereas it was 26.0 months (95% CI, 10.8\u0026ndash;41.3 months) in the Osi\u0026thinsp;+\u0026thinsp;Chemo group, compared to 20.7 months (95% CI, 18.4\u0026ndash;25.5 months; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.34) in the Osi group (Fig.\u0026nbsp;\u003cspan\u003e2\u003c/span\u003e). The 12-, 18-, and 24-months PFS rates were 81.3%, 62.0%, and 53.1%, retrospectively, in the Osi\u0026thinsp;+\u0026thinsp;Chemo group compared to 64.9%, 57.5%, and 40.8%, retrospectively, in the Osi group. The overall survival between the two groups was not reported, as they were immature.\u003c/p\u003e\n \u003cp\u003eSince mutation subtype may impact treatment decisions due to the differential affinity of 19Del and L858R for osimertinib, we performed a subgroup analysis based on EGFR subtypes. For the entire group, the median PFS in patients with 19Del was similar compared to that in patients with L858R mutation (21.7 months versus 22.7 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.74; Fig.\u0026nbsp;\u003cspan\u003e3\u003c/span\u003eA). It appears that patients with L858R mutation benefit more from Osi\u0026thinsp;+\u0026thinsp;Chemo therapy, compared to that with 19Del (NR versus 20.6 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.15; Fig.\u0026nbsp;\u003cspan\u003e3\u003c/span\u003eB). Further analysis indicated the addition of chemotherapy to osimertinib significantly prolonged median PFS (NR versus 16.8 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) among patients with L858R mutation (Fig.\u0026nbsp;\u003cspan\u003e3\u003c/span\u003eC); however, this was no longer true for patients with 19Del (20.6 months versus NR, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.31; Fig.\u0026nbsp;\u003cspan\u003e3\u003c/span\u003eD). In addition, to eliminate the potential impact of thoracic radiation therapy on the efficacy, patients who received thoracic radiotherapy were excluded before the further analysis. However, the median PFS was still no statistical significance between the two groups, while it was 21.7 months vs. 20.6 months (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.94), respectively, favoring the osimertinib monotherapy (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e\n \u003cdiv id=\"Sec10\"\u003e\n \u003ch2\u003eMultivariable and subgroup analysis\u003c/h2\u003e\n \u003cp\u003eTo investigate the impact of confounding factors on treatment outcomes, we performed univariate and multivariate analyses using a Cox proportional hazards model (Table\u0026nbsp;2). The variables that displayed a \u003cem\u003eP\u003c/em\u003e value below 0.1 in the univariate analysis were incorporated into the subsequent multivariate analysis. The multivariable Cox regression analysis revealed that female (OR\u0026thinsp;=\u0026thinsp;0.45, 95% CI: 0.22\u0026ndash;0.93, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03), CNS metastases (OR\u0026thinsp;=\u0026thinsp;2.07, 95% CI: 1.11\u0026ndash;3.86, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02), and intrapulmonary metastases (OR\u0026thinsp;=\u0026thinsp;2.31, 95% CI: 1.22\u0026ndash;4.38, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01) independently predicted PFS. Subgroup analyses were conducted using a Cox proportional-hazards model to assess the treatment-by-subgroup interaction, visually represented as a forest plot (Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003e). The results indicated that the proportional of Osi\u0026thinsp;+\u0026thinsp;Chemo on PFS was consistent across all pre-specified subgroups.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our current knowledge, this study represents the primary exploring the effectiveness of combining osimertinib with chemotherapy for first-line therapy in patients with NSCLC who possess mutations in both EGFR and TP53 concurrently. Our study revealed that combination therapy had the potential to prolong the PFS in the whole cohort, particularly increasing PFS significantly in patients with the L858R mutation. Our research highlights the potential value of integrating chemotherapy with first-line osimertinib targeted therapy to mitigate the adverse impact of TP53 mutations. The results provide a more precise treatment option for patients with advanced NSCLC harboring co-mutations.\u003c/p\u003e \u003cp\u003eTP53 is a common mutation in lung cancer, while the current research consensus is that co-mutations reduce patient survival(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The FLAURA study established osimertinib as first-line treatment in NSCLC due to its benefits in PFS and OS(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). However, the presence of a TP53 mutation can impede the efficacy of osimertinib(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In Choudhury\u0026rsquo;s study, the median PFS was significantly reduced by 5 months, from 18.8 months in the wild-type patient group to 13.3 months in the group with the combined mutation (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), in patients receiving osimertinib as a first-line treatment(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). For second- and further-line treatment, co-mutation of TP53 was also an independent risk that diminished the efficacy of osimertinib(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Consequently, alongside the development of TP53-targeted pharmaceuticals, the synergistic combination of existing therapeutic agents represents a pivotal strategy in the treatment paradigm.\u003c/p\u003e \u003cp\u003eEmerging evidence suggests that osimertinib combined with chemotherapy has the potential to improve survival, especially in patients with co-mutation. The recently published FLAURA2 study provides confirmation that the PFS of patients receiving a combination of osimertinib with chemotherapy (25.5 months) was significantly extended compared to those receiving osimertinib monotherapy (16.7 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001)(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). However, the survival outcomes for the subgroup of patients with co-mutations have not yet been reported in the FLAURA2 trial. Here, our study fills the research gap in this area, demonstrating that osimertinib plus chemotherapy improved PFS by 5.3 months compared to the osimertinib monotherapy group, although it did not reach statistical significance (26.0 months versus 20.7 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.34). Yang and colleagues\u0026rsquo; study also demonstrated the efficacy of combination therapy in patient with co-mutations, with PFS increasing from 11.4 months to 19.1 months in patients receiving first-generation TKI in combination with chemotherapy (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001)(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSince patients with wild-type TP53 were not enrolled in the present study, comparing the efficacy and survival between TP53 wild-type and mutant populations is unfeasible. In EGFR-driven NSCLC, cases of approximately 50% \u0026minus;\u0026thinsp;60% were observed to harbor alterations of the TP53 gene in different exon(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Hence, despite the unknown TP53 mutational status in FLAURA2 study, our data remains comparable to theirs. Moreover, the median PFS of 26.0 months also surpasses the 17.5 months reported in another study(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). On one hand, the disparate outcome observed in this study can be attributed to the heterogeneity of TP53 mutations and the admission bias among patients. Previous studies have mainly concentrated on missense mutations primarily found between codons 100 and 300 and frequently located within the DNA-binding domain of the p53 protein(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Several hotspot mutations occurred inside the DNA-binding domain and account for only about 30% of the total mutated cases(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). There is still a lack of in-depth understanding regarding the impact of different types and different site mutations of TP53. On the other hand, the disparities in study outcomes may also stem from differences in the clinical characteristics of the enrolled patients. Compared to FLAURA2 study, we observed a lower proportion of stage IV patients and fewer liver metastases, with a subset of patients receiving thoracic radiotherapy in our study. Those conditions suggest that our patient cohort might have a lower tumor burden compared to the FLAURA2 patients, potentially increasing sensitivity to treatment, which may have translated into a survival benefit further.\u003c/p\u003e \u003cp\u003ePatients with different EGFR mutations who carry TP53 mutations may experience varying impacts when receiving treatment with osimertinib. Clinically, 19Del and L858R EGFR mutations, as common mutations, account for 90% of observed EGFR mutations(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). However, they exhibit differing sensitivities to TKIs due to the varying affinities of different invariant types for TKI agents(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). The prevailing consensus illustrated that patients with 19Del mutations catch greater benefits from TKIs than those with L858R mutations(\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Consequently, patients with the 19Del mutation derive greater benefit from osimertinib monotherapy, thereby diminishing the advantage conferred by chemotherapy. In contrast, for patients with the L858R mutation, due to its lower affinity, the benefits of chemotherapy are amplified. Indeed, subgroup analysis in the present study confirmed these findings, with more pronounced benefits in L858R mutation patients and less so in those with 19Del. The median PFS in patients with the L858R mutation who underwent combination therapy was significantly prolonged compared to those who underwent osimertinib monotherapy (NR versus 16.8 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02). Therefore, combination therapy involving pemetrexed-based chemotherapy is considered the preferred treatment for patients with the L858R mutation.\u003c/p\u003e \u003cp\u003eAlthough this is a prospective study from the two centers, there are still some limitations. First, the relatively small sample size may have hindered the effective investigation of differences between the two cohorts; therefore, larger samples are required for further analysis. Second, this study refrained from stratifying the analysis based on specific metastatic sites primarily to avoid the potential for inflated type I or type II statistical errors due to an insufficient sample size. In addition, toxic events occurring during the maintenance period are still being collected and therefore, have not been reported in this study. Last, the relatively short follow-up duration limited the assessment of the overall survival of first-line treatment, as the occurrence of death events was rare. Following the extended follow-up, the updated data will be reported in the near future.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, this study provides evidence for the prolonged PFS benefits of addict chemotherapy to osimertinib in patients with EGFR mutant lung adenocarcinoma and concomitant TP53 co-mutations. Notably, those with the L858R mutation appear to derive more substantial benefits. Our research highlight the efficacy of integrating chemotherapy with osimertinib for this patient subset. This conclusion needs to be further validated through extensive prospective studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNSCLC, Non-small cell lung cancer; EGFR, Epidermal Growth Factor Receptor；\u0026nbsp;TKI, Tyrosine kinase inhibitor; CNS, Central nervous system; PFS, Progression-free survival; OS: Overall survival; ORR, Objective response rate; DCR: Disease control rate; CR, Complete response; PR, Partial response; SD, Stable disease. HR, Hazard ratio IQR, Interquartile range; CI, Confidence interval; NR, Not reached. OR, Odds ratio; RR, Relative risk.\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was obtained from the Ethical Review Committee of Shandong Provincial Hospital and Shandong Cancer Hospital for this study, and informed consent was obtained from all patients before conducting the treatment. The study was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author, Zhe Yang and Wang Jing, upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Cancer Research Funding of CSCO-Qilu (Y2019AZM-0522) and Cancer Research Funding of CSCO-Qilu(YQL2019-0149). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDrs Z. Yang and W. Jing had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Z. Yang and W. Jing contributed equally to this work.\u003c/p\u003e\n\u003cp\u003eJixian Li: Formal analysis, Writing - Original Draft. Xiang Zhan: Investigation, Visualization. Mengqing Shao: Investigation. Jianan Li: Investigation. Hui Zhu: Supervision, Data curation. Alei Feng: Supervision, Zhe Yang: Project administration, Funding acquisition Conceptualization. Wang Jing: Conceptualization, Methodology.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the patients and their family members for their permission to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSingh S, Sadhukhan S, Sonawane A. 20 years since the approval of first EGFR-TKI, gefitinib: Insight and foresight. Biochim Biophys Acta Rev Cancer. 2023 Nov;1878(6):188967. \u003c/li\u003e\n\u003cli\u003eBelani N, Liang K, Fradley M, Judd J, Borghaei H. How to Treat EGFR-Mutated Non-Small Cell Lung Cancer. JACC CardioOncol. 2023 Aug;5(4):542\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eHendriks LE, Kerr KM, Menis J, Mok TS, Nestle U, Passaro A, et al. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023 Apr;34(4):339\u0026ndash;57. \u003c/li\u003e\n\u003cli\u003eMok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med. 2017 Feb 16;376(7):629\u0026ndash;40. \u003c/li\u003e\n\u003cli\u003eJ\u0026auml;nne PA, Planchard D, Kobayashi K, Cheng Y, Lee CK, Valdiviezo N, et al. CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2023 Dec 2;JCO2302219. \u003c/li\u003e\n\u003cli\u003eColclough N, Chen K, Johnstr\u0026ouml;m P, Strittmatter N, Yan Y, Wrigley GL, et al. Preclinical Comparison of the Blood-brain barrier Permeability of Osimertinib with Other EGFR TKIs. Clin Cancer Res. 2021 Jan 1;27(1):189\u0026ndash;201. \u003c/li\u003e\n\u003cli\u003eSoria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113\u0026ndash;25. \u003c/li\u003e\n\u003cli\u003eRamalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020 Jan 2;382(1):41\u0026ndash;50. \u003c/li\u003e\n\u003cli\u003eCheng Y, He Y, Li W, Zhang HL, Zhou Q, Wang B, et al. Osimertinib Versus Comparator EGFR TKI as First-Line Treatment for EGFR-Mutated Advanced NSCLC: FLAURA China, A Randomized Study. Target Oncol. 2021 Mar;16(2):165\u0026ndash;76. \u003c/li\u003e\n\u003cli\u003eStockhammer P, Grant M, Wurtz A, Foggetti G, Exp\u0026oacute;sito F, Gu J, et al. Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer. J Thorac Oncol. 2023 Oct 6;S1556-0864(23)02264-5. \u003c/li\u003e\n\u003cli\u003eLevine AJ. p53: 800 million years of evolution and 40 years of discovery. Nat Rev Cancer. 2020 Aug;20(8):471\u0026ndash;80. \u003c/li\u003e\n\u003cli\u003eSoussi T, B\u0026eacute;roud C. Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer. 2001 Dec;1(3):233\u0026ndash;40. \u003c/li\u003e\n\u003cli\u003eLiu SY, Zhou JY, Li WF, Sun H, Zhang YC, Yan HH, et al. Concomitant genetic alterations having greater impact on the clinical benefit of EGFR-TKIs in EGFR-mutant advanced NSCLC than BIM deletion polymorphism. Clin Transl Med. 2020 Jan;10(1):337\u0026ndash;45. \u003c/li\u003e\n\u003cli\u003ePassaro A, Attili I, Rappa A, Vacirca D, Ranghiero A, Fumagalli C, et al. Genomic Characterization of Concurrent Alterations in Non-Small Cell Lung Cancer (NSCLC) Harboring Actionable Mutations. Cancers (Basel). 2021 Apr 30;13(9):2172. \u003c/li\u003e\n\u003cli\u003eCanale M, Petracci E, Delmonte A, Chiadini E, Dazzi C, Papi M, et al. Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors. Clin Cancer Res. 2017 May 1;23(9):2195\u0026ndash;202. \u003c/li\u003e\n\u003cli\u003ePlanchard D, J\u0026auml;nne PA, Cheng Y, Yang JCH, Yanagitani N, Kim SW, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med. 2023 Nov 23;389(21):1935\u0026ndash;48. \u003c/li\u003e\n\u003cli\u003eChoudhury NJ, Marra A, Sui JSY, Flynn J, Yang SR, Falcon CJ, et al. Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers. J Thorac Oncol. 2023 Apr;18(4):463\u0026ndash;75. \u003c/li\u003e\n\u003cli\u003eSchoenfeld DA. Sample-Size Formula for the Proportional-Hazards Regression Model. Biometrics. 1983;39(2):499\u0026ndash;503. \u003c/li\u003e\n\u003cli\u003eTan J, Hu C, Deng P, Wan R, Cao L, Li M, et al. The Predictive Values of Advanced Non-Small Cell Lung Cancer Patients Harboring Uncommon EGFR Mutations-The Mutation Patterns, Use of Different Generations of EGFR-TKIs, and Concurrent Genetic Alterations. Front Oncol. 2021;11:646577. \u003c/li\u003e\n\u003cli\u003eKim Y, Lee B, Shim JH, Lee SH, Park WY, Choi YL, et al. Concurrent Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC. J Thorac Oncol. 2019 Feb;14(2):193\u0026ndash;202. \u003c/li\u003e\n\u003cli\u003evan Veelen A, Veerman GDM, Verschueren MV, Gulikers JL, Steendam CMJ, Brouns AJWM, et al. Exploring the impact of patient-specific clinical features on osimertinib effectiveness in a real-world cohort of patients with EGFR mutated non-small cell lung cancer. Int J Cancer. 2024 Jan 15;154(2):332\u0026ndash;42. \u003c/li\u003e\n\u003cli\u003eZhao J, Lin G, Zhuo M, Fan Z, Miao L, Chen L, et al. Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib. Lung Cancer. 2020 Mar;141:114\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eChoudhury NJ, Marra A, Sui JSY, Flynn J, Yang SR, Falcon CJ, et al. Molecular Biomarkers of Disease Outcomes and Mechanisms of Acquired Resistance to First-Line Osimertinib in Advanced EGFR-Mutant Lung Cancers. J Thorac Oncol. 2023 Apr;18(4):463\u0026ndash;75. \u003c/li\u003e\n\u003cli\u003eRoeper J, Christopoulos P, Falk M, Heukamp LC, Tiemann M, Stenzinger A, et al. TP53 co-mutations as an independent prognostic factor in 2nd and further line therapy\u0026mdash;EGFR mutated non-small cell lung cancer IV patients treated with osimertinib. Transl Lung Cancer Res. 2022 Jan;11(1):4\u0026ndash;13. \u003c/li\u003e\n\u003cli\u003eYang Z, Chen Y, Wang Y, Wang S, Hu M, Zhang B, et al. Efficacy of EGFR-TKI Plus Chemotherapy or Monotherapy as First-Line Treatment for Advanced EGFR-Mutant Lung Adenocarcinoma Patients With Co-Mutations. Front Oncol. 2021 Aug 16;11:681429. \u003c/li\u003e\n\u003cli\u003eLiu X, Hong L, Nilsson M, Hubert SM, Wu S, Rinsurongkawong W, et al. Concurrent use of aspirin with osimertinib is associated with improved survival in advanced EGFR-mutant non-small cell lung cancer. Lung Cancer. 2020 Nov;149:33\u0026ndash;40. \u003c/li\u003e\n\u003cli\u003eBaugh EH, Ke H, Levine AJ, Bonneau RA, Chan CS. Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ. 2018 Jan;25(1):154\u0026ndash;60. \u003c/li\u003e\n\u003cli\u003eHsu WH, Yang JCH, Mok TS, Loong HH. Overview of current systemic management of EGFR-mutant NSCLC. Annals of Oncology. 2018 Jan 1;29:i3\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eLee VHF, Tin VPC, Choy T shing, Lam K on, Choi C wai, Chung L ping, et al. Association of exon 19 and 21 EGFR mutation patterns with treatment outcome after first-line tyrosine kinase inhibitor in metastatic non-small-cell lung cancer. J Thorac Oncol. 2013 Sep;8(9):1148\u0026ndash;55. \u003c/li\u003e\n\u003cli\u003eKumar A, Petri ET, Halmos B, Boggon TJ. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J Clin Oncol. 2008 Apr 1;26(10):1742\u0026ndash;51. \u003c/li\u003e\n\u003cli\u003eLee CK, Wu YL, Ding PN, Lord SJ, Inoue A, Zhou C, et al. Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis. J Clin Oncol. 2015 Jun 10;33(17):1958\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eSheng M, Wang F, Zhao Y, Li S, Wang X, Shou T, et al. Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations after tyrosine kinase inhibitors treatment: a meta-analysis. Eur J Clin Pharmacol. 2016 Jan;72(1):1\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eZhao Y, Liu J, Cai X, Pan Z, Liu J, Yin W, et al. Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis. BMJ. 2019 Oct 7;367:l5460. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Supplementary Table 1","content":"\u003cp\u003eSupplementary Table 1 is not available with this version\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"NSCLC, Osimertinib, EGFR, TP53, Chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-4467606/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4467606/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eOsimertinib is the standard first-line options for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). Co-mutations in TP53 results in poor survival for patients. However, the studies on treatment options and clinical outcomes of patients with EGFR-TP53 co- mutation are limited.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003ePatients with EGFR mutation-positive locally advanced or metastatic NSCLC carrying TP53 mutations were recruited from two institutions and allocated into two groups, either receiving osimertinib plus chemotherapy (Osi\u0026thinsp;+\u0026thinsp;Chemo group) or osimertinib monotherapy (Osi group). The progression-free survival (PFS) was evaluated as the primary endpoint and the response was also assessed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBetween January 2020 and August 2023, Ninety-eight patients were enrolled with 47 and 51 patients receiving combination therapy and the monotherapy. After a median follow-up of 19.2 months, overall response rate (ORR) was 80.0% versus 71.7% (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.36), favoring Osi\u0026thinsp;+\u0026thinsp;Chemo group, as well as in disease control rate (DCR) (91.4% vs. 80.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.45). The median PFS in the Osi\u0026thinsp;+\u0026thinsp;Chemo group was 26.0 months versus 20.7 months in the Osi group, but without significant difference (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.34). The subgroup analysis indicated that for patients with L858R mutation, Osi\u0026thinsp;+\u0026thinsp;Chemo therapy significantly prolonged the median PFS (not reached [NR] versus 17.1 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.03), but not in patients with 19Del (20.6 months versus NR, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.31).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOsimertinib plus chemotherapy have a tendency to increase ORR and prolong PFS in NSCLC with EGFR and TP53 co-mutations, particularly in patients with L858R mutation.\u003c/p\u003e","manuscriptTitle":"Osimertinib plus Chemotherapy versus Osimertinib for Patients with Advanced NSCLC Concomitant EGFR and TP53 Mutations: A Prospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-11 18:21:48","doi":"10.21203/rs.3.rs-4467606/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1595435f-77b1-4fdf-933e-c7d9e48f3a1d","owner":[],"postedDate":"June 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-08T03:59:18+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-11 18:21:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4467606","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4467606","identity":"rs-4467606","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}