# Optimizing Treatment Strategies for Egfr-Mutated Non-Small-Cell Lung Cancer Treated with Osimertinib: Real-World Outcomes and Insights

Quentin Dominique Thomas, Nicolas Girard, Lise Bosquet, Sarah Cavaillon, Thomas Filleron, Siham Eltaief, Christos Chouaid, Hervé Lena, Didier Debieuvre, Maurice Perol, et al.

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Quentin Dominique Thomas, Nicolas Girard, Lise Bosquet, Sarah Cavaillon, Thomas Filleron, et al. Optimizing Treatment Strategies for Egfr-Mutated Non-Small-Cell Lung Cancer Treated with Osimertinib: Real-World Outcomes and Insights. Cancers, 2024, 16 (21), pp.3563. 10.3390/cancers16213563. inserm-04964054

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Article

# Optimizing Treatment Strategies for *Egfr*-Mutated Non-Small-Cell Lung Cancer Treated with Osimertinib: Real-World Outcomes and Insights

Quentin Dominique Thomas <fnref n="1" />,* ①, Nicolas Girard <fnref n="2" />, Lise Bosquet <fnref n="3" />①, Sarah Cavaillon <fnref n="1" />, Thomas Filleron <fnref n="4" />①, Siham Eltaief <fnref n="3" />, Christos Chouaid <fnref n="5" />①, Hervé Lena <fnref n="6" />, Didier Debieuvre <fnref n="7" />①, Maurice Perol <fnref n="8" /> and Xavier Quantin <fnref n="1" />①

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**Citation:** Thomas, Q.D.; Girard, N.; Bosquet, L.; Cavaillon, S.; Filleron, T.; Eltaief, S.; Chouaid, C.; Lena, H.; Debieuvre, D.; Perol, M.; et al.
Optimizing Treatment Strategies for *Egfr*-Mutated Non-Small-Cell Lung Cancer Treated with Osimertinib: Real-World Outcomes and Insights.
*Cancers* **2024**, *16*, 3563. https://doi.org/10.3390/cancers16213563

Academic Editor: Akiteru Goto

Received: 14 September 2024

Revised: 14 October 2024

Accepted: 17 October 2024

Published: 23 October 2024

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**Copyright:** © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
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4.0/).

**Simple Summary:** This study examined the real-world effectiveness of osimertinib, a third-generation tyrosine kinase inhibitor, on EGFR-mutated non-small-cell lung cancer. Osimertinib has shown promising results in clinical trials, but this research study looked at how it performs in real-world settings, where patients may have different characteristics than those typically included in trials. This study reviewed data from over 600 patients treated with osimertinib, either as their first (L1) or second metastatic line (L2) of treatment. The results showed that patients who took osimertinib as L1 experienced a median progression-free survival of 12.4 months, compared to 7.4 months for those treated in L2. The presence of brain metastases was associated with a poorer prognosis. Overall survival rates were lower than those reported in clinical trials, likely due to differences in patient conditions, such as older age and worse overall health. This study highlights the challenges of applying trial results to everyday medical practice and emphasizes the need for tailored treatment approaches for patients with advanced lung cancer.

**Abstract:** **Background:** Osimertinib, a third-generation *EGFR* tyrosine kinase inhibitor (TKI), demonstrated superior efficacy over first-generation TKIs in the FLAURA trial, resulting in its approval as first-line therapy for metastatic non-small-cell lung cancer (NSCLC). However, the real-world application of these trial results requires an evaluation of sequential therapeutic strategies. **Methods:** This retrospective, non-interventional study utilized data from the Epidemiological Strategy and Medical Economics (ESME) platform, which includes information on patients treated for lung cancer since 2015. Out of 39,974 patients in the database, 624 patients with *EGFR*-mutant advanced NSCLC treated with osimertinib as first-line (L1, n = 198) or second-line (L2, n = 426) treatment after first- or second-generation TKIs (n = 1262) were identified. Patient demographics, disease characteristics, treatment strategies, and disease progression were examined. Survival analyses were performed using Kaplan-Meier estimates and Cox proportional-hazards models. **Results:** In the study population (n = 624), 73.4% were female, with a median age of 70 years (range 28–93). Brain metastases at the start of osimertinib treatment were observed in 282 patients. ECOG PS-2 was reported in 29.4% of patients. The *T790M* mutation in exon 20 was identified in 257/426 patients (60.3%) receiving osimertinib in L2. Median progression-free survival (PFS) was 12.4 months (95% CI [10.7–14.7]) for L1 and 7.4 months (95% CI [6.2–8.7]) for L2. Median overall survival (OS) from advanced diagnosis was 28.5 months (95% CI [26.3–38.7]) for osimertinib L1 and 29.9 months (95%

<footnote n="1">¹ Department of Medical Oncology, Institut du Cancer de Montpellier, 34000 Montpellier, France; sarah.cavaillon@icm.unicancer.fr (S.C.); xavier.quantin@icm.unicancer.fr (X.Q.)</footnote>

<footnote n="2">² Department of Medical Oncology, Institut Curie, 75005 Paris, France; nicolas.girard2@curie.fr</footnote>

<footnote n="3">³ Unicancer, 75000 Paris, France; l-bosquet@unicancer.fr (L.B.); s-eltaief@unicancer.fr (S.E.)</footnote>

<footnote n="4">⁴ Biostatistics Unit, Oncopôle Claudius Régaud IUCT-O, 31100 Toulouse, France; filleron.thomas@iuct-oncopole.fr</footnote>

<footnote n="5">⁵ Department of Pneumology, Centre Hospitalier Intercommunal, 94010 Créteil, France; christos.chouaid@chicreteil.fr</footnote>

<footnote n="6">⁶ Pneumology Department, CHU Pontchaillou, 35000 Rennes, France; herve.lena@chu-rennes.fr</footnote>

<footnote n="7">⁷ Respiratory Medicine Department, Groupe Hospitalier de la Région Mulhouse Sud-Alsace, 68100 Mulhouse, France; debieuvred@ghrmsa.fr</footnote>

<footnote n="8">⁸ Department of Medical Oncology Centre Léon Bérard, 69008 Lyon, France; maurice.perol@lyon.unicancer.fr</footnote>

<footnote>* Correspondence: quentin.thomas@icm.unicancer.fr</footnote>
CI [28.6–31.8]) for osimertinib L2 (HR = 0.93; 95% CI [0.75–1.16]; *p* = 0.50). For L1, median OS was 27.1 months (95% CI [22.0–30.2]) for patients with cerebral metastases and 38.7 months (95% CI [26.3–52.8]) for those without (HR = 0.73; 95% CI [0.48–1.11]; *p* = 0.15). **Discussion:** Patients in the real-world ESME database exhibited a poorer prognosis compared to those in the FLAURA trial. The presence of cerebral metastases at diagnosis worsens the prognosis.

**Keywords:** non-small-cell lung cancer; tyrosine kinase inhibitors; *EGFR* mutation; treatment sequencing; brain metastasis

**1. Introduction**

Lung cancer is the leading cause of cancer-related deaths worldwide [1]. Non-small-cell lung cancer (NSCLC) is the most common histological type, accounting for 80–85% of cases, and is often diagnosed at an advanced or metastatic stage [2]. In this context, comprehensive molecular genotyping aims to identify oncogene-addicted tumors [3]. One of the most frequent alterations is mutations in the epidermal growth factor receptor (*EGFR*), which confer sensitivity to *EGFR* tyrosine kinase inhibitors (TKIs). This represents a landmark application of precision medicine for NSCLC [4]. In over 85% of cases, these mutations are in-frame deletions in exon 19 or a single amino acid mutation, *L858R*, in exon 21 [5].

Osimertinib, a third-generation *EGFR* TKI, has been developed specifically to target the *EGFR T790M* mutation, which is associated with acquired resistance to first- and second-generation EGFR TKIs [6]. Osimertinib subsequently demonstrated progression-free survival (PFS) and overall survival (OS) benefits compared to first-generation *EGFR* TKIs in the first-line setting in the FLAURA trial, with a median OS of 38.6 months (95% CI [34.5 to 41.8]) vs. 31.8 months (95% CI [26.6 to 36.0]; *p* = 0.046), establishing the current standard of care upfront, particularly in the final FLAURA results [7].

Despite the central nervous system (CNS) efficacy observed with osimertinib, outcomes for patients with baseline CNS metastases remain poorer than for those without [8]. Ultimately, the application of therapeutic strategies from clinical trials to real-world practice remains uncertain, as outcomes may vary due to the significant impact of subsequent therapies and baseline clinical characteristics, which might not be accurately reflected in clinical trials [9]. Here, we utilized a large, nation-wide cohort of consecutive patients with advanced, metastatic *EGFR*-mutant NSCLC to report the therapeutic strategies and outcomes of patients treated in a real-world setting, with a focus on CNS metastases. This large database has already been used to describe clinical characteristics and survival outcomes of patients with advanced NSCLC with oncogenic alterations [10,11].

**2. Material and Methods**

2.1. *Study Design*

This non-interventional, retrospective, comparative study aimed to describe the treat-
ment strategies and outcomes of *EGFR*-mutant, advanced or metastatic NSCLC patients
included in the Epidemiological Strategy and Medical Economics (ESME) lung cancer (LC)
data platform [12]. The ESME LC database (ClinicalTrial.gov NCT03848052) is a centralized,
de-identified, structured database derived from the electronic health records of consecutive
patients treated for LC since 2015 at one of the 38 participating health facilities (18 private
non-profit Comprehensive Cancer Centers spread over 20 sites and 18 University or Gen-
eral Hospitals). Patient-related data, hospitalization-related data, and pharmacy-related
data are collected, including patient demographic characteristics, pathology, and disease
evolution. Treatment strategies are also recorded. Data are updated yearly and undergo a
data management process aimed at ensuring the quality of the data analyzed.
Unicancer manages the ESME LC data platform in accordance with current best practice guidelines. In compliance with French regulations, the ESME Data Warehouse was authorized by the French data protection authority (initial authorization no. DE-2017-397 and subsequent amendment dated 14 October 2019, in accordance with GDPR). All patients approved the use of their data.

## 2.2. *Patient Population*

In this study, patient selection focused on patients with the following inclusion criteria:

- Histologically confirmed advanced NSCLC;

- Common *EGFR*-activating mutations (i.e., exon 19 deletion or *L858R* mutation in exon 21);

- Patients treated with osimertinib in the first (L1) or second (L2, i.e., administered after first- or second-generation TKIs) line of treatment for advanced disease;

- Patients either newly diagnosed with or relapsed from early-stage disease.

Patients with one of the following exclusion criteria were excluded from this study:

- Uncommon *EGFR*-activating mutations identified;

- Patients treated with another regimen than *EGFR* TKIs in the first metastatic line;

- Patients who received first- or second-generation *EGFR* TKIs as first-line treatment for metastatic disease were excluded if they had not been treated with osimertinib monotherapy as second-line therapy.

Data analyzed were those available in the ESME LC database as of the data cut-off of 1 October 2022. In France, it is recommended that CNS imaging be performed at baseline for all patients, irrespective of neurological symptoms.

## 2.3. *Data Collection*

The following data were collected: sociodemographic characteristics (gender, age, weight, height, body mass index, smoking status); clinical characteristics (medical history, history of other cancers, performance status); disease characteristics (date of primary tumor diagnosis, stage at primary tumor diagnosis, histological subtype of NSCLC, setting of advanced NSCLC (i.e., de novo or progression of regional disease or metastatic disease), time from primary tumor diagnosis to advanced NSCLC diagnosis, location of metastases, time from advanced NSCLC diagnosis to treatment initiation); *EGFR* mutation and other mutations (e.g., *ALK*, *KRAS*, *BRAF*, *ROS1*); treatment strategy (therapeutic agents, start and stop dates); disease evolution over time; survival status. Treatment lines were derived a posteriori based on treatment dates and progression events: a treatment line was defined as a given therapeutic strategy delivered for metastatic NSCLC until progression. The start date of the first-line therapy was defined as the date of the first systemic treatment initiated after diagnosis. Disease progression was defined as the occurrence of a new metastatic site or progression of existing metastases, regional tumor or lymph node progression, or discontinuation of systemic treatment due to progression or death from any cause. For the purpose of this study, the index date was defined as the start date of osimertinib.

## 2.4. *Statistical Analyses*

Data were summarized as medians and ranges for continuous variables and as frequencies and percentages for categorical variables. The number of missing data was presented for each variable but not considered in the percentage calculations. The Kaplan-Meier method was used to estimate survival endpoints (OS and PFS). OS was defined as the time from the locally advanced or metastatic diagnosis date to the date of death from any cause. OS(id) was defined as the time from the index date to the date of death from any cause. PFS was defined as the time from the start date of the line (=index date) to the date of the first progression of the disease or death from any cause; patients without progression reported after the index date or with death reported more than 9 months after the date of the last medical information were censored at the date of the last medical information.
Time to CNS metastases was defined as the time from the index date to the onset of CNS metastases in the osimertinib line. Patients with no onset of CNS metastases recorded were censored at the date of the last medical information or subsequent line, whichever occurred first. The HR and associated 95% CI were calculated using a Cox proportional-hazards model. Multivariable Cox proportional hazards models were constructed using a backward step-by-step manual selection procedure to identify time-independent prognostic factors of OS(id) in the whole cohort and for each treatment group. All factors significant at a conservative 2.5% level in univariable analysis were included in multivariable analysis. The variables included in the model were as follows: performance status; metastatic site (brain, liver, bone); age; gender; smoking status; EGFR mutation type; T790M mutation in exon 20; PD-L1 status; body mass index; radiotherapy at index date. The final model was reached when including only significant factors at a *p* < 0.05 significance level. Comparisons between survival at fixed points in time were conducted using the Cloglog method according to Klein [13]. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA) and R Core Team (2016, version 4.1.2).

## 3. Results

### 3.1. Characteristics of EGFR-Mutated Patients Treated with Osimertinib for Metastatic NSCLC

Of the 39,974 patients in the ESME LC database at the time of analysis, with a median follow-up of 49.7 months (95% CI [49.0–50.6 months]), 29,600 had confirmed advanced NSCLC. Overall, 16,759 NSCLC patients had EGFR testing at least once, 2569 of whom were EGFR-mutant (EGFRm) NSCLC (15.3%). Among these patients, 1764 presented with common EGFR mutations (deletion in exon 19 or L858R mutation in exon 21). Of these, 1262 patients were treated with first- or second-generation EGFR TKIs in the first line (L1), and 426 patients (33.8%) received osimertinib as monotherapy in the second line (L2). Finally, 624 patients received osimertinib as monotherapy in either L1 (198 patients) or L2 (426 patients) and were included in this study (Figure 1).

The majority of the study population were female (73.4%; n = 458); the median age was 70.0 years (range: 28–93). Current or former smokers (regardless of the number of pack-years, i.e., ≥1) accounted for 41.1% of the population, and 16.2% had a history of another cancer. The most common metastatic sites at the index date were bone (61.6%; n = 372), brain (46.7%; n = 282), including symptomatic brain metastasis (70.9%; n = 200/282), and contralateral lung (35.9%; n = 217). Notably, among patients treated with osimertinib in L1, 83 (44.6%) had brain metastasis, including 52/83 with symptomatic brain metastasis (62.7%). Among those who received osimertinib in L2, 199 (47.6%) had brain metastasis, including 148/199 with symptomatic brain metastasis (74.4%). The majority of patients (70.6%) had a good performance status (i.e., ECOG-PS 0 or 1) (Table 1). Focusing on CNS metastasis (i.e., brain metastasis plus leptomeningeal metastasis), patients with CNS lesions had a median age at the index date of 67.0 years (range: 28–89) versus 72.0 years (range: 36–93) for patients without CNS metastasis. Moreover, 20.5% of patients with CNS metastasis were over 75 years old versus 35.5% for those without CNS metastasis (Table 2). Regarding cerebral irradiation, 3/198 patients (1.51%) were treated with whole-brain radiation therapy (WBRT) before osimertinib in L1 versus 20/426 patients (4.7%) in L2.

<table><caption>**Table 1.** Patient characteristics according to line of initiation of osimertinib.</caption><thead><tr><th></th><th>Study Population<br>Overall (n = 624)</th><th>Osimertinib in L1<br>(n = 198)</th><th>Osimertinib in L2<br>(n = 426)</th></tr></thead><tbody><tr><td><strong>Age at index date (yr)</strong></td><td></td><td></td><td></td></tr><tr><td>Median (range)</td><td>70.0 (28.0; 93.0)</td><td>71.0 (34.0; 93.0)</td><td>69.0 (28.0; 92.0)</td></tr><tr><td>&gt;75 yr—no (%)</td><td>177 (28.4)</td><td>58 (29.3)</td><td>119 (27.9)</td></tr><tr><td><strong>Female sex—no. (%)</strong></td><td>458 (73.4)</td><td>151 (76.3)</td><td>307 (72.2)</td></tr></tbody></table>
<table><caption>Table 1. *Cont.*</caption><thead><tr><th></th><th>Study Population<br>Overall (n = 624)</th><th>Osimertinib in L1<br>(n = 198)</th><th>Osimertinib in L2<br>(n = 426)</th></tr></thead><tbody><tr><td><strong>Smoking status—no. (%);<br>(n = 577)</strong></td><td></td><td></td><td></td></tr><tr><td>Current smoker</td><td>48 (8.3)</td><td>11 (6.2)</td><td>37 (9.3)</td></tr><tr><td>Former smoker</td><td>189 (32.8)</td><td>63 (35.4)</td><td>126 (31.6)</td></tr><tr><td>Never</td><td>340 (58.9)</td><td>104 (58.4)</td><td>236 (59.1)</td></tr><tr><td><strong>Number of<br>pack-years—Median (Q1–Q3)</strong></td><td></td><td></td><td></td></tr><tr><td>Current smoker</td><td>24.5 (15.0; 30.0)</td><td>30.0 (20.0; 40.0)</td><td>22.0 (13.0; 30.0)</td></tr><tr><td>Former smoker</td><td>15.0 (6.0; 30.0)</td><td>15.0 (6.0; 30.0)</td><td>15.0 (6.0; 25.0)</td></tr><tr><td><strong>ECOG performance status<br>score—no. (%); (n = 289)</strong></td><td></td><td></td><td></td></tr><tr><td>0–1</td><td>204 (70.6)</td><td>75 (65.2)</td><td>129 (74.1)</td></tr><tr><td>≥2</td><td>85 (29.4)</td><td>40 (34.8)</td><td>45 (25.9)</td></tr><tr><td><strong>Histologic type—no (%)</strong></td><td></td><td></td><td></td></tr><tr><td>Adenocarcinoma</td><td>589 (94.4)</td><td>187 (94.4)</td><td>402 (94.4)</td></tr><tr><td>Squamous carcinoma</td><td>15 (2.4)</td><td>3 (1.5)</td><td>12 (2.8)</td></tr><tr><td>Other °</td><td>20 (3.2)</td><td>8 (4.0)</td><td>12 (2.8)</td></tr><tr><td><strong>PD-L1 tumor proportion<br>score—no (%); (n = 416)</strong></td><td></td><td></td><td></td></tr><tr><td>&lt;1%</td><td>190 (45.7)</td><td>72 (45.3)</td><td>118 (45.9)</td></tr><tr><td>1–49%</td><td>140 (33.6)</td><td>61 (38.4)</td><td>79 (30.7)</td></tr><tr><td>≥50%</td><td>74 (17.8)</td><td>22 (13.8)</td><td>52 (20.3)</td></tr><tr><td>Not contributive</td><td>12 (2.9)</td><td>4 (2.5)</td><td>8 (3.1)</td></tr><tr><td><strong>EGFR mutation type—no (%)</strong></td><td></td><td></td><td></td></tr><tr><td>Exon 19 deletion</td><td>364 (58.3)</td><td>104 (52.5)</td><td>260 (61.0)</td></tr><tr><td>L858R</td><td>260 (41.7)</td><td>94 (47.5)</td><td>166 (39.0)</td></tr><tr><td><strong>Metastases status—no (%)</strong></td><td></td><td></td><td></td></tr><tr><td>Brain<br>(asymptomatic/symptomatic)</td><td>282 (46.7): 82/200</td><td>83 (44.6): 31/52</td><td>199 (47.6): 51/148</td></tr><tr><td>Meninges</td><td>32 (5.3)</td><td>6 (3.2)</td><td>26 (6.2)</td></tr><tr><td>Contralateral lung</td><td>217 (35.9)</td><td>57 (30.6)</td><td>160 (38.3)</td></tr><tr><td>Bone</td><td>372 (61.6)</td><td>106 (57.0)</td><td>266 (63.6)</td></tr><tr><td>Liver</td><td>143 (23.7)</td><td>33 (17.7)</td><td>110 (26.3)</td></tr><tr><td>Pleura</td><td>114 (18.9)</td><td>32 (17.2)</td><td>82 (19.6)</td></tr><tr><td>Adrenal gland</td><td>81 (13.4)</td><td>29 (15.6)</td><td>52 (12.4)</td></tr><tr><td>Other</td><td>166 (27.5)</td><td>42 (22.6)</td><td>124 (29.7)</td></tr><tr><td><strong>EGFR-TKI previously<br>administered—no (%)</strong></td><td></td><td></td><td></td></tr><tr><td>Gefitinib</td><td>145 (23.2)</td><td>0</td><td>145 (34.0)</td></tr><tr><td>Erlotinib</td><td>168 (26.9)</td><td>0</td><td>168 (39.4)</td></tr><tr><td>Afatinib</td><td>71 (11.4)</td><td>0</td><td>71 (16.7)</td></tr></tbody></table>

<footnote>° Undifferentiated carcinoma; neuroendocrine large cell carcinoma; others.</footnote>
<figure><img src="image_6.png" /><figcaption>**Figure 1.** Flow-chart. AMLC = advanced or metastatic lung cancer; SCLC = small-cell lung cancer; TKI = tyrosine kinase inhibitor.</figcaption></figure>

<table><caption>**Table 2.** Patient characteristics according to CNS metastasis status.</caption><thead><tr><th></th><th>Patient Without CNS<br>Metastasis<br>(n = 327)</th><th>Patient With CNS<br>Metastasis<br>(n = 297)</th></tr></thead><tbody><tr><td><strong>Age at index date (yr)</strong></td><td></td><td></td></tr><tr><td>Median (range)</td><td>72.0 (36.0; 93.0)</td><td>67.0 (28.0; 89.0)</td></tr><tr><td>&gt;75 yr—no (%)</td><td>116 (35.5)</td><td>61 (20.5)</td></tr><tr><td><strong>Female sex—no. (%)</strong></td><td>234 (71.6)</td><td>224 (75.4)</td></tr><tr><td><strong>Smoking status—no. (%); (n = 577)</strong></td><td></td><td></td></tr><tr><td>Current smoker</td><td>24 (7.9)</td><td>24 (8.8)</td></tr><tr><td>Former smoker</td><td>95 (31.3)</td><td>94 (34.4)</td></tr><tr><td>Never</td><td>185 (60.9)</td><td>155 (56.8)</td></tr></tbody></table>
<table><caption>**Table 2.** *Cont.*</caption><thead><tr><th></th><th>Patient Without CNS<br>Metastasis<br>(n = 327)</th><th>Patient With CNS<br>Metastasis<br>(n = 297)</th></tr></thead><tbody><tr><td><strong>Number of pack-years—Median<br>(Q1–Q3)</strong></td><td></td><td></td></tr><tr><td>Current smoker</td><td>30.0 (20.0; 35.0)</td><td>20.0 (15.0; 30.0)</td></tr><tr><td>Former smoker</td><td>15.5 (7.0; 30.0)</td><td>10.0 (6.0; 20.0)</td></tr><tr><td><strong>ECOG performance-status score—no.<br>(%);</strong></td><td>n = 55</td><td>n = 53</td></tr><tr><td>0–1</td><td>43 (78.2)</td><td>43 (81.1)</td></tr><tr><td>≥2</td><td>12 (21.8)</td><td>10 (18.9)</td></tr><tr><td><strong>Histologic type—no (%)</strong></td><td></td><td></td></tr><tr><td>Adenocarcinoma</td><td>306 (93.6)</td><td>283 (95.3)</td></tr><tr><td>Squamous carcinoma</td><td>11 (3.4)</td><td>4 (1.3)</td></tr><tr><td>Other °</td><td>10 (3.1)</td><td>10 (3.4)</td></tr><tr><td><strong>PD-L1 tumor proportion score—no (%);<br>(n = 416)</strong></td><td></td><td></td></tr><tr><td>&lt;1%</td><td>190 (45.7)</td><td>72 (45.3)</td></tr><tr><td>1–49%</td><td>140 (33.6)</td><td>61 (38.4)</td></tr><tr><td>≥50%</td><td>74 (17.8)</td><td>22 (13.8)</td></tr><tr><td>Not contributive</td><td>12 (2.9)</td><td>4 (2.5)</td></tr><tr><td><strong>EGFR mutation type—no (%)</strong></td><td></td><td></td></tr><tr><td>Exon 19 deletion</td><td>186 (56.9)</td><td>178 (59.9)</td></tr><tr><td>L858R</td><td>141 (43.1)</td><td>119 (40.1)</td></tr><tr><td><strong>EGFR-TKI previously<br>administered—no (%) *</strong></td><td>n = 216</td><td>n = 210</td></tr><tr><td>Gefitinib</td><td>81 (37.5)</td><td>87 (41.4)</td></tr><tr><td>Erlotinib</td><td>30 (13.9)</td><td>54 (25.7)</td></tr><tr><td>Afatinib</td><td>105 (48.6)</td><td>79 (37.6)</td></tr></tbody></table>

EGFR mutations were distributed as follows: EGFR-L858R = 260/624 patients (41.7%); EGFR-DEL19 = 364/624 patients (58.3%). The gatekeeper T790M mutation in exon 20 was identified in 257/426 patients (60.3%) receiving osimertinib in L2.

## 3.2. Progression-Free Survival and Overall Survival According to the Line of Osimertinib Adminisitration

Median PFS according to the line of osimertinib initiation was 12.4 months (95% CI [10.7–14.7 months]) for L1 and 7.4 months (95% CI [6.2–8.7 months]) for L2. Regarding the prognostic impact of CNS metastases in patients treated with osimertinib in L1, unadjusted median PFS was 11.3 months (95% CI [10.1–15.7 months]) for patients with cerebral metastases and 12.7 months (95% CI [9.0–16.9 months]) for patients without cerebral metastases (HR = 0.88; 95% CI [0.63–1.22]; *p* = 0.4). For patients receiving osimertinib in L2, median PFS was 6.3 months (95% CI [5.4–7.9 months]) and 8.7 months (95% CI [6.8–9.9 months]) (HR = 0.89; 95% CI [0.73–1.09]; *p* = 0.3) for patients with and without cerebral metastases, respectively (Figure 2). Median OS from the advanced diagnosis date was 28.5 months (95% CI [26.3–38.7 months]) for osimertinib in L1 and 29.9 months (95% CI [28.6–31.8 months])

<footnote>° Undifferentiated carcinoma; neuroendocrine large cell carcinoma; others. * Only for patients receiving osimertinib in L2.</footnote>
for patients treated with first- or second-generation TKIs in L1 (n = 1262) (HR = 0.93; 95% CI [0.75–1.16]; *p* = 0.50). In patients treated with osimertinib in L1, unadjusted median OS was 27.1 months (95% CI [22.0–30.2 months]) for patients with cerebral metastases and 38.7 months (95% CI [26.3–52.8 months]) for patients without cerebral metastases (HR = 0.73; 95% CI [0.48–1.11]; *p* = 0.15) (Figure 3). Of the 327 patients without CNS metastases at the index date (i.e., the date of osimertinib initiation), the estimated probability of being cerebral metastasis-free at 18 months was 86.9% (95% CI [79.4–94.4%]) for osimertinib in L1 and 75.7% (95% CI [68.4–83.0%]) for osimertinib in L2. Median time to CNS progression was not reached (NR) (95% CI [NR–NR]) for osimertinib in L1 and 45.2 months (95% CI [34.6–NR]) for osimertinib in L2 (HR = 1.66; 95% CI [0.94–2.92]; Figure 4).

<figure><img src="image_7.png" /><figcaption>**Figure 2.** Progression-free survival: (A) according to osimertinib administration line; (B) according to central nervous system metastasis status at index date (i.e., start date of osimertinib) in L1; (C) according to central nervous system metastasis status at index (i.e., start date of osimertinib) date in L2.</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**Figure 3.** Overall survival: (A) OS: from the locally advanced or metastatic diagnosis date, whether patients were treated with osimertinib or first- or second-generation TKIs in L1. (B) OSid: according to central nervous system metastasis status at index date (i.e., start date of osimertinib) in L1. (C) OSid: according to central nervous system metastasis status at index (i.e., start date of osimertinib) date in L2.</figcaption></figure>
<figure><img src="image_9.png" /><figcaption>**Figure 4.** Time to central nervous system metastasis for patients treated with osimertinib.</figcaption></figure>

### 3.3. *Subsequent Treatment Received after Osimertinib*

Of note, 356/624 patients (57.1%) did not receive a subsequent treatment line after osimertinib administration. When osimertinib was administered in L1, 131/198 (66.2%) did not receive a subsequent treatment line, which was the case for 225/426 (52.8%) when osimertinib was given in L2. For patients receiving subsequent treatment after osimertinib, 75.4% received a platinum-based chemotherapy regimen; 19.1% received an *EGFR*-TKI or *MET*-TKI alone or in combination; 23.8% received a combination containing a vascular endothelial growth factor (VEGF) inhibitor; 9.3% received a regimen including an immune checkpoint inhibitor; and 4.5% a non-platinum-based chemotherapy.

### 3.4. *Prognostic Factors Associated with Overall Survival*

Focusing on the prognostic factors associated with OS(id) in independent multivariable analysis according to the line of osimertinib administration (L1 and L2), a good ECOG status (i.e., 0–1 versus ≥2) in L1 (*p* = 0.016) and L2 (*p* < 0.001) and an exon 19 deletion (versus L858R mutation in exon 21) in L1 (*p* = 0.019) and L2 (*p* < 0.001) were identified as good prognostic factors. Additionally, the female gender was associated with better prognosis for osimertinib administered in L1 (*p* = 0.03); the presence of liver metastasis (*p* = 0.004) and PD-L1 positive testing (*p* = 0.018) were associated with worse prognosis for osimertinib administered in L2 (Supplementary Tables S1 and S2).

## 4. Discussion

This real-world multicenter retrospective study focused on the treatment sequences and outcomes of 624 patients treated for *EGFR*-mutated advanced NSCLC. The median OS was 28.5 months (95% CI [26.3–38.7 months]) for 198 patients treated with osimertinib monotherapy in the first line (L1) and 29.9 months (95% CI [28.6–31.8 months]) for 1262 patients treated with first- or second-generation TKIs in L1, among whom 426 patients received osimertinib in the second line (L2) (HR = 0.93; 95% CI [0.75–1.16]; *p* = 0.50). The median OS of patients receiving osimertinib in L1 in our real-world cohort was shorter than in the FLAURA trial (38.6 months (95% CI [34.5–41.8 months] [7]. This discrepancy is probably linked to different patient baseline characteristics: in the FLAURA trial, patients were younger (median age= 64 years (26–85) vs. 70.0 (28–93)), had better general status (ECOG PS 2 = 0% vs. ECOG PS 2 = 29.4%) than in our real-world cohort. More importantly, 52/198 (26.3%) patients treated with osimertinib in L1 in this real-world cohort had symp-
tomatic brain metastases, whereas these patients were excluded from the FLAURA study. Recent data confirms this assessment. Indeed, from a cohort of 311 patients treated with L1 osimertinib in Canada, Connor Wells et al. classified patients according to whether or not they met the inclusion criteria of the FLAURA study. The median OS for the entire cohort was 27.4 months (95% CI [23.8–30.1]). The median OS for the 137 (44%) patients deemed ineligible for the FLAURA trial was 18.4 months shorter than that of eligible patients (15.8 vs. 34.2 months; *p* < 0.001) [14].

Moreover, OS from the APPLE trial of osimertinib versus gefitinib followed by osimertinib in advanced EGFR-mutant NSCLC is almost the same in both strategies (HR = 1.01; 90% CI [0.61–1.68]), with a 18-month survival probability of 84% and 82.3%, respectively [15]. One main explanation for the discrepancies observed between the control arm of FLAURA and that of the APPLE trial is the proportion of patients treated with osimertinib in L2 after disease progression under first- or second-generation TKIs. In the FLAURA trial, 47% of patients benefiting from the first subsequent therapy were treated with osimertinib after progression with gefitinib or erlotinib. This rate is much lower than in the APPLE trial (73%), which is in line with what is expected in the real-world setting, where patients may be monitored more closely, leading to a higher rate of rebiopsy and detection of the EGFR T790M mutation in patients receiving first- or second-generation TKIs, which appears to be present in up to 50–75% of cases [16–18]. Therefore, the control arm of the FLAURA trial may underestimate the benefit of an appropriate TKI sequencing approach in this population. Of note, in our real-world cohort, 66.2% of the patients receiving osimertinib in L1 and 29.9% of patients treated with first- or second-generation TKIs in L1 did not receive subsequent therapy after progression. These results are in line with those of the FLAURA trial, where 146/279 patients (52%) did not receive subsequent therapy after frontline osimertinib versus 97/277 patients (35%) treated with gefitinib or erlotinib. Otherwise, osimertinib presents many advantages compared to first- and second-generation EGFR-TKIs. First of all, osimertinib has higher CNS penetration [19]. Preventing or delaying the onset of CNS metastasis is particularly important as it clearly impairs the patients’ quality of life and cognition [20]. Moreover, the safety profile of osimertinib is better than that of gefitinib or erlotinib. In the FLAURA trial, adverse events of grade 3 or higher were less frequent with osimertinib than with other EGFR-TKIs (34% vs. 45%) [8].

The next step for the treatment of EGFR-mutated patients will be the implementation of chemotherapy in combination with osimertinib in the first metastatic line, according to the results of the FLAURA-2 trial [21]. Indeed, the combination of platinum-pemetrexed chemotherapy plus osimertinib significantly extended PFS as assessed by the investigators, by 8.8 months compared with osimertinib monotherapy (HR = 0.62; 95% CI [0.49–0.79]; *p* < 0.001) [21]. The addition of chemotherapy in combination with osimertinib seems particularly valuable for patients with CNS metastases. This combination delays intracranial disease progression, irrespective of baseline CNS metastasis status. In the full CNS analysis set of the FLAURA-2 trial, the HR for CNS progression or death was 0.58, 95% CI [0.33–1.01], in patients with baseline CNS metastases and 0.67, 95% CI [0.43–1.04], in patients without baseline CNS metastases, both favoring chemo-osimertinib treatment. The CNS objective response rates were 73% (64 to 81%) in the combination arm versus 69% (59 to 78%) in the osimertinib monotherapy arm; 59% versus 43% had CNS complete response [22]. Some other considerations could be of interest as co-mutation profile (TP53 mutant vs. TP53 wild-type) to propose therapeutic intensification to patients.

Our study has some limitations. (1) According to the inclusion period, most patient were treated with osimertinib in L2; (2) due to the low search rate for associated mutations, we could not evaluate their prognostic and predictive impact, particularly for TP53 status; (3) the ESME database is not appropriate to evaluate the resistance mechanisms induced by osimertinib. Currently, the mechanisms of resistance to osimertinib are mainly the occurrence of MET amplification (15–20%), the occurrence of a new mutation in the EGFR gene (10%), the acquisition of resistance mutations in the MAPKinase and PIK3 signaling pathways (10–15%), and a possible histological switch (10–15%) of cases towards
small-cell lung cancer or a squamous NSCLC profile [23,24]. There are also other resistance mechanisms that are being extensively studied in basic and translational research. These include drug-tolerant persister cells, which can survive under therapeutic pressure by having a slow proliferative rate with an altered cellular metabolism [25,26]. These cell subtypes may serve as a reservoir from which various resistance mechanisms can emerge [27]. Moreover, growing evidence suggests that the tumor microenvironment may play a role in the acquired resistance to osimertinib. Specifically, an immunosuppressive environment may contribute to resistance against third-generation EGFR tyrosine kinase inhibitors (TKIs) [28].

**5. Conclusions**

This large real-world cohort indicates that advanced *EGFR*-mutant NSCLC patients have a poorer prognosis than patients included in clinical trials. Median PFS was 12.4 months (95% CI [10.7–14.7]) for osimertinib administred in L1 in our cohort. It also confirms the poor prognosis of patients with cerebral metastases. The optimization of treatment strategies for these patients remains a major challenge in *EGFR*-mutated NSCLC.

**Supplementary Materials:** The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/cancers16213563/s1, Table S1: Prognostic factors associated with osimertinib OS in L1—multivariable analysis with Cox model; Table S2: Prognostic factors associated with osimertinib OS in L2—Multivariable analysis with Cox model.

**Author Contributions:** Conceptualization, Q.D.T., S.C., M.P. and X.Q.; methodology, Q.D.T., L.B., T.F., S.E., M.P. and X.Q.; formal analysis, L.B.; investigation, Q.D.T. and S.E.; writing—original draft preparation, Q.D.T.; writing—review and editing, N.G., L.B., S.C., T.F., C.C., H.L., D.D., M.P. and X.Q.; visualization, Q.D.T., L.B. and S.E.; supervision, N.G., T.F., C.C., H.L., D.D., M.P. and X.Q. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by Unicancer. Unicancer independently manages ESME databases (i.e., data collection, analysis, and publication) and is the sole data controller for data processing. The ESME LC database receives financial support from industrial partners (AstraZeneca, Pfizer, Janssen, Amgen, Roche, Merck Sharp & Dohme, Bristol-Meyers Squibb, and Daiichi Sankyo). Janssen specifically funded this work.

**Institutional Review Board Statement:** Unicancer manages the ESME AMLC data platform in accordance with the current best practice guidelines. In compliance with French regulations, the ESME Data platform was authorized by the French data protection authority (initial authorization no. DE-2017-397 and subsequent amendment dated 14 October 2019, in accordance with GDPR).

**Informed Consent Statement:** In accordance with the authorizations issued by the French authorities for the ESME AMLC data platform and in compliance with the regulation in force for such retrospective registries, no formal dedicated informed consent is required, but all patients have approved the analysis of their electronically recorded data.

**Data Availability Statement:** The datasets analyzed in the current study were extracted from the ESME LC Data Platform. In accordance with the ethical and legal requirements related to the ESME data warehouse, individual data from the ESME databases cannot be made available. For any specific request, please contact the corresponding author. Each request will be examined on a case-by-case basis by the scientific committee. During the preparation of this work, the author(s) used open AI Chat GPT in order to improve language and readability. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.

**Acknowledgments:** We deeply thank all patients who participate in the ESME LC database for granting access to their data and allowing for the creation of this work. We thank the participating sites and each ESME local coordinator for managing the project at the local level (alphabetical order): Institut de Cancérologie de l'Ouest, Angers/Nantes; CHU, Angers; CH Annecy-Genevois, Annecy; Institut Ste Catherine, Avignon; CH Côte Basque, Bayonne; Institut Bergonié, Bordeaux; Centre François Baclesse, Caen; CH Métropole Savoie, Chambéry; Centre Jean Perrin, Clermont-Ferrand; Hôpital Intercommunal de Créteil; Centre Georges-François Leclerc, Dijon; CH Départemental de
Vendée, La Roche-sur-Yon; Centre Oscar Lambret, Lille; CHU Dupuytren, Limoges; Centre Léon Bérard, Lyon; CH Est francilien, Marne la Vallée; Hôpital Européen, Marseille; Institut Paoli-Calmettes, Marseille; CH Est francilien, Meaux; Institut de Cancérologie de Montpellier; GHRMSA/Hôpital Emile Muller, Mulhouse; Institut de Cancérologie de Lorraine, Nancy; Centre Antoine Lacassagne, Nice; Institut Jean Godinot, Reims; CHU Pontchaillou, Rennes; Centre Eugène Marquis, Rennes; Centre Henri Becquerel, Rouen; CH Saint-Quentin; Centre Paul Strauss ICANS, Strasbourg; CH Sainte-Musse, Toulon; Institut Claudius Regaud IUCT-O, Toulouse; CHRU Tours; CHU, Rouen; Hôpital Intercommunal de Toulon, Toulon La Seyne sur Mer; Hôpital d'instruction des Armée Ste Anne, Toulon; CH Nord-Ouest, Villefranche-sur-Saône; Institut Curie, Paris/Saint-Cloud, Gustave Roussy, Villejuif. We also thank the ESME central coordinating staff, the LC Scientific Group, and the ESME Strategic Committee for their ongoing support.

**Conflicts of Interest:** Quentin Dominique Thomas reports personal fees from Amgen, AstraZeneca Roche, and Sanofi, outside the submitted work. Nicolas Girard reports grants and personal fees from AstraZeneca; personal fees from Daiichi; grants and personal fees from Roche; grants and personal fees from MSD; grants and personal fees from BMS; grants and personal fees from Pfizer; grants and personal fees from Janssen; grants and personal fees from Boehringer Ingelheim; grants and personal fees from Takeda; grants and personal fees from Novartis; and grants and personal fees from Sanofi, outside the submitted work, as well as being a Family Member employee of AstraZeneca. Lise Bosquet, Sarah Cavaillon, Thomas Filleron, Siham Eltaief, Didier Debrieuve and Xavier Quantin have nothing to disclose. Christos Chouaid reports grants, personal fees, and non-financial support from AstraZeneca; grants, personal fees, and non-financial support from Boehringer Ingelheim; grants, personal fees, and non-financial support from GSK; grants, personal fees, and non-financial support from Roche; grants, personal fees, and non-financial support from Sanofi Aventis; grants, personal fees, and non-financial support from BMS; grants, personal fees, and non-financial support from MSD; grants, personal fees, and non-financial support from Lilly; grants, personal fees, and non-financial support from Novartis; grants, personal fees, and non-financial support from Pfizer; grants, personal fees, and non-financial support from Takeda; grants, personal fees, and non-financial support from Bayer; grants, personal fees, and non-financial support from Janssen; grants, personal fees, and non-financial support from Viatris; grants, personal fees, and non-financial support from Chugai; grants, personal fees, and non-financial support from Pierre Fabre; and grants, personal fees, and non-financial support from Amgen, outside the submitted work. Herve Lena reports personal fees and non-financial support from Roche; personal fees from AstraZeneca; personal fees and non-financial support from MSD; personal fees and non-financial support from Novartis; personal fees and non-financial support from Takeda; personal fees from BMS; personal fees and non-financial support from Pfizer; non-financial support from Lilly; and personal fees and non-financial support from Amgen, outside the submitted work. Maurice Perol reports personal fees and non-financial support from Takeda; personal fees from Janssen; and personal fees and non-financial support from AstraZeneca, outside the submitted work.

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