AVERTISSEMENT

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Contact à la Bibliothèque universitaire de Médecine Pharmacie de Grenoble : bump-theses@univ-grenoble-alpes.fr [Données à caractère personnel]

Remerciements

Aux membres du Jury, M. le Professeur Denis Moro-Sibilot, merci de me faire l'honneur de présider mon jury. Merci de votre accompagnement, de votre enseignement et de votre bienveillance depuis le début de mon internat. Merci de me faire confiance pour la suite.

Mme le Professeur Anne Claire Toffart, ma directrice de thèse, merci infiniment de ton implication et de ta disponibilité tout au long de ce travail mais aussi au cours de mon internat à la fois sur le plan professionnel et humain.

Mme Le Docteur Chantal Decroisette, merci d'avoir accepté d'être là ce soir. Merci de la bonne humeur avec laquelle tu m'as transmis ta passion de l'oncologie thoracique et merci de rendre cette spécialité aussi glamour.

Mme Le Docteur De Fraipont Florence, merci chaleureusement de votre présence ce soir.

Aux docteurs qui m'ont insufflé la passion de l'oncologie thoracique :

Léonie, tu as été une grande source d'inspiration pour moi tant sur le plan de tes qualités humaines que professionnelles. Merci d'avoir pris autant soin de moi que des patients pendant notre semestre ensemble et d'avoir mis des paillettes dans le quotidien du 6èmeB.

Julian, merci de m'avoir transmis ton enthousiasme pour cette spécialité, merci pour ta bonne humeur et tes visites pédagogiques avec bonus chocolatés.

Matteo, merci infiniment pour ton enseignement, merci d'avoir cru en moi dès ce début de 2 ème semestre, merci de tes encouragements emplis de bienveillance. Tu as été un véritable mentor.

Thomas, merci pour ton accueil avant même le début du premier semestre, d'avoir pris soin de nous les petites nouvelles du 4D. Merci pour ta disponibilité, ta porte toujours ouverte pour une pause-café, ton envie de transmettre tes connaissances.

Sarah et Samy, parce que je peux vous mettre dans la case des docteurs tous les deux maintenant, c'est grâce à vous que j'ai adoré l'onco. Merci pour ce semestre tous les 3.

Aux onco de l'IDH et en particulier à Hélène et Sandrine qui auront presque réussi à me faire changer de bord. Merci pour m'avoir tant appris et fais confiance.

Aux purs pneumologues, parce qu'il n'y pas que l'oncologie qui soit passionnante :

Au professeur Pison pour sa bienveillance malgré les retards au colloque du jeudi.

Au professeur Degano pour son envie de nous transmettre son savoir.

Aux séniors qui m'ont tant appris et fais confiance : Sébastien, Christel, Boubou, Rebecca, Marie, Rita, Amandine. A toute l'équipe de pneumologie d'Annecy : Stéphane, Dorine, Marion, Michele.

A mes assistants au fil des semestres qui ont su rester patients et disponibles aussi bien pour la CV que pour les festivités : Johanna et Anne Laure, Victor, Hubert, Arnaud, Loïc, Sarah.

A Hélène, la plus merveilleuse des pharmaciennes devenu une amie.

A Pauline qui a été l'interne à qui je voulais ressembler en devenant grande.

A mes co internes, camarades de joie aussi bien que de galère : Romain confident masculin au milieu de ces dames, Marie qui est devenue une amie, Ami partenaire de rythme endiablé, Lucie, Perrine, Estelle, Camille, et les vieux de la vieilles : Geoffroy, Justin, Mickaël, Salomé, Héloïse.

Aux autres spé croisés au décours des années

Introduction

Over the last two decades, the survival of lung cancer patients has markedly improved for those with oncogenic addictions, particularly patients with epidermal growth factor receptor (EGFR) mutations treated with targeted therapies. EGFR mutations are present in 10% of patients with non-small-cell lung cancer (NSCLC) in France, more commonly in women and non-smokers [START_REF] Barlesi | Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT)[END_REF].

Tyrosine kinase inhibitors (TKIs) are used in first-line in patients with metastatic disease [START_REF] Soria | Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer[END_REF] and in the adjuvant setting, as well [START_REF] Wu | Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer[END_REF].

In metastatic disease patients, first-generation (erlotinib and gefitinib) [START_REF] Rosell | Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial[END_REF][START_REF] Maemondo | Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR[END_REF] and secondgeneration (afatinib) [START_REF] Sequist | Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations[END_REF] TKIs have been available since the early 2000's, with median overall survival (OS) of 25.8 months (95% confidence interval [CI], 23.8-27.5) [START_REF] Lee | Gefitinib or Erlotinib vs Chemotherapy for EGFR Mutation-Positive Lung Cancer: Individual Patient Data Meta-Analysis of Overall Survival[END_REF]. However, acquired resistance to TKIs is very common. The most common resistance mutation is the EGFR exon 20 T790M missense mutation, which is detected in over 50% of patients displaying disease progression . [START_REF] Yu | Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers[END_REF]. Osimertinib is an irreversible third-generation EGFR-TKI that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M-resistance mutations. Initially, this compound was approved in second-line in refractory patients exhibiting EGFR T790M mutation [START_REF] Goss | Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study[END_REF].

Starting in 2019, osimertinib has been made available as frontline therapy, with a median OS of 38.6 months (95% CI, 34.5-41.8) [START_REF] Ramalingam | Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC[END_REF]. For patients treated with first-/second-generation EGFR-TKIs, osimertinib is still an alternative with consistent data, yet applicable only to patients developing T790M mutation [START_REF] Recondo | Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI?[END_REF]. These resistance mutations can be researched for on tumor tissues, using a tissue or liquid biopsy (circulating tumor DNA [ctDNA] on a blood sample) [START_REF] Debré | La biopsie liquide : alternative ou complément à la biopsie tissulaire ?[END_REF].

This work aimed to evaluate treatment strategies in a real-life setting for NSCLC patients harboring EGFR mutations.

Materials and methods

Design and setting

This retrospective study was conducted at Grenoble Alpes University Hospital, Grenoble Daniel Hollard Institute, Annecy Genevois Hospital, Alpes Leman Hospital, and Curie Institute in Paris, France.

Study ethics approval was obtained on 08 September (CECIC Rhône-Alpes-Auvergne, Clermont-Ferrand, IRB 5891). An information letter was sent to each living patient, providing the opportunity to refuse study participation.

The primary objective was to determine the proportion of patients having access to osimertinib in second-line following first-or second-line TKI generation. The secondary objectives were to describe the therapeutic sequences, resistance mutations identified by routine analyses, and survival according to the therapeutic sequence order.

Study population

Patients with metastatic NSCLC and EGFR mutations (exon 19 deletion, exon 21 L858R and L861Q, or exon 20 T790M missense mutation), treated in one of the five centers, having undergone a molecular biology analysis (at diagnosis or during the follow-up) between 2015 and 2019 were included.

Exclusion criteria were patients under 18 years of age at diagnosis, patient's opposition to using their data, exclusive presence of an EGFR TKI resistance mutation (exon 18, insertion / deletion / duplication of exon 20), and patients who exclusively benefited from palliative care.

Data collection

Patients were identified using the molecular biology platforms of Grenoble (that performs analyses for Grenoble, Annecy Genevois and Alpes Leman hospital) and Curie Institute. Clinical data were retrieved based on the patients' computerized medical charts from the different centers. Thereafter, data were anonymized, centralized, and analyzed at Grenoble Alpes University Hospital.

Demographic and clinical patient characteristics at diagnosis were collected, including gender, age, Charlson comorbidity score, smoking status, ECOG performance status (PS), as well as central nervous system (CNS) or hepatic metastases.

At diagnosis and each new biopsy, we recorded the following items: biopsy type, histological diagnosis, molecular analysis results (EGFR mutation and mutation identified as resistance mutation: T790M, C797S, HER2 or Met amplification, or PIK3CA), date of molecular analysis, ctDNA realization, as well as their impact on treatments (start, continuation, TKI stop or switch, another treatment start, as well as all treatment discontinuation). The first three treatment lines were recorded, along with beginning and end of the treatment dates, response, and reasons for treatment withdrawing. The vital status was recorded, as well.

Statistical analysis

Continuous variables have been expressed as median (25-75% interquartile range [IQR]), and categorical variables as numbers (percentages). OS data were calculated from first-line or second-line treatment initiation to death. Time to treatment failure (TTF) was defined as the time separating treatment initiation to treatment stop. Survival curves were obtained using Kaplan-Meier methodology and compared using the log-rank testing. Patients lost to follow-up on March 2021 were considered censored. All statistical analyses were performed using SAS 4.0.

Results

Patient characteristics

Of the 433 patients that were screened between 2015 and 2019, 254 patients were included in the analysis (Fig. 1). Most patients were non-smokers (n=155, 64%), women (74%), and ECOG-PS 0-1 (n=185, 80%), with a median age of 70 years (IQR 25%-75%, 63-77) (Table 1). The most common comorbidity was prior cancer in 44 patients (17%). All patients displayed adenocarcinoma excepting four (1.5%) who exhibited squamous cell carcinoma, yet with exon 19 deletion. Overall, 10 patients displayed a co-mutation in the EGFR gene. Two patients exhibited cMet amplification at diagnosis, as well.

First-line treatment

A large majority of patients (n=228, 90%) received EGFR TKI as frontline treatment (Table 2).

A first-(1G) or second-generation (2G) TKI (1G/2G TKI) was used for 177 (70%) patients, including afatinib (n=41, 16%), erlotinib (n=72, 28%), and gefitinib (n=64, 25%), whereas a third-generation (3G) TKI was employed in 51 (20%) patients. Overall, 25 (10%) patients were treated with chemotherapy, as well as one patient with immunotherapy (immune checkpoint inhibitor [ICI]) in the first-line setting. In this patient group, molecular analysis was unavailable prior to treatment initiation in 21 patients (75%), while the treatment was switched to 1G/2G or 3G TKIs after receiving molecular analysis results, with a median duration of first-line treatment of 1.2 months (IQR 25%-75%, 0.3-2.5).

Responses were recorded only for TKI-treated patients. Among these, treatment response could not be assessed in 17 (7.5%) patients, including six who stopped treatment for toxicity reasons without undergoing their CT reassessment and three who started their treatment just prior to the end of data collection, whereas eight patients were lost to follow-up before the first reassessment.

At the follow-up's end, 60 (23.6%) patients were still on first-line treatment and 46 patients did not undergo any second-line treatment, owing to palliative care or death after first-line therapy.

Outcome after first-/second-generation tyrosine kinase inhibitors in first line

Of the 177 patients treated with 1G/2G TKIs in a first-line setting, the best response rate was 65%, disease control rate being 95%. The main reason of treatment discontinuation was disease progression (n=104; 84%). Following disease progression, a new biopsy was realized in 62 patients, representing 41% of the 150 patients who withdrew first-line treatment. This biopsy revealed the presence of EGFR T790M mutations in 29 patients (46%). A ctDNA analysis was performed in 62 (34%) patients, resulting in diagnosing T790M in 22/62 (35%) patients. Other resistance mutations were emergence of cMet amplification for two patients and HER 2 amplification for one. According to these results, 62 (55%) patients were treated in second-line with 3G TKIs, including osimertinib (n=61) and rociletinib (n=1). Twelve patients received osimertinib following 1G/2G TKIs without any T790M mutation identified. Fifteen patients (13%) underwent another 1G/2G TKI regimen in second-line, and these were mainly patients who discontinued first-line therapy for toxicity (n=11). Thirty-five patients (31%) underwent chemotherapy or ICI in second-line.

For patients treated with 3G TKI in second-line following 1G/2G TKI, the disease control rate was about 85%. After progression in second-line, a third biopsy was performed in 22 patients, (52% of the 42 patients who withdrew 3G TKIs in second-line). A resistance mechanism was identified in 8/22 patients, including six patients exhibiting a loss of T790M mutation, one patient with a cMet amplification, and another one with a C797S mutation. Twenty-seven patients underwent third-line treatment (40%), with chemotherapy provided to most of them (n=25, 93%).

the median OS exceeded 3 years. Only 19% of the studied patients received osimertinib in firstline, given that this agent was only made available in France in 2019.

The strengths of this study are the large number (n=254) of treated patients exhibiting EGFR mutations, along with its multicenter design. Due to its retrospective design, there are missing data, particularly for molecular testing and ctDNA (method and results). The period of identification of EGFR mutation was rather large (2015 to 2019), including accessibility to osimertinib in second-line (2017) and first-line (2019) settings in France. It is important to note that cancer diagnosis could have been made prior to 2015.

The characteristics of the studied patients are in accordance with the known characteristics of EGFR-mutated patients, including a majority of never-smokers, women, and patients without comorbidities [START_REF] Gahr | EGFR mutational status in a large series of Caucasian European NSCLC patients: data from daily practice[END_REF][START_REF] Shigematsu | Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers[END_REF][START_REF] Kosaka | Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications[END_REF]. The proportion of patients with CNS metastasis at diagnosis (43%) was higher than in other real-life studies such as 24.4% in the Rangachari's cohort [START_REF] Rangachari | Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers[END_REF] and 25% in the Hendriks' cohort from the Netherlands [START_REF] Hendriks | EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases?[END_REF]. Considering molecular biology characteristics at diagnosis, we have seen that 50% of patients displayed an exon 19 deletion, whereas Rosell et al.

[18] and Riely et al. [START_REF] Riely | Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib[END_REF] reported a higher number of exon 19 deletions (60%).

At progression after a first-line treatment with 1G/2G TKI, only 41% of patients benefited from a new biopsy, with ctDNA analysis performed in 41% of patients. In another real-life cohort of EGFR and ALK patients [START_REF] Bosc | Rebiopsy during disease progression in patients treated by TKI for oncogene-addicted NSCLC[END_REF], 46% of patients underwent re-biopsy at the time of acquired resistance. The low rate of tissue re-biopsy can be explained by a greater use of liquid biopsy.

Indeed, over the last 5 years, ctDNA has become one of the standards enabling to identify a resistance mutation.

At progression after first-line treatment with 1G/2G TKI, the T790M mutation was identified in 46% of patients who benefited from a biopsy. In 2011, Sequist et al. [START_REF] Sequist | Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors[END_REF] similarly reported a proportion of 49% of T790M mutations identified on tissue re-biopsy at progression, whereas this figure was even higher in the Yu et al. article [START_REF] Yu | Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers[END_REF], with 62.5% of patients benefiting from a new biopsy. The prescription of osimertinib concerned 55% (n=62) of patients eligible for a second-line regimen after stopping 1G/2G TKI. This proportion is similar to the comparator group of the FLAURA study in which 47% of patients received osimertinib after first-line 1G/2G TKI [START_REF] Ramalingam | Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC[END_REF]. In our cohort, for 12 out of 62 osimertinib-treated patients, osimertinib was prescribed in the absence of any T790M mutation. While the reasons for this prescription were not systematically recorded, this proportion appears to be consistent with that of another real-life study [START_REF] Mehlman | Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French study[END_REF].

TTF with 1G/2G TKI as frontline was 11.2 months. This is similar to the PFS obtained in a prior study with these molecules, being 13.1 months with erlotinib [START_REF] Zhou | Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study[END_REF], 10.8 months with gefitinib [START_REF] Maemondo | Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR[END_REF], and 11.1 months with afatinib [START_REF] Sequist | Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations[END_REF]. TTF observed following 3G TKI group in first-line was 20.6 months, which is also similar to the PFS obtained in the FLAURA study, namely 18.9 months [START_REF] Soria | Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer[END_REF]. OS of 1G/2G TKI-treated patients in first-line was 31.4 months, whereas for osimertinib-treated patients in first-line, OS was not reached after a median 12.3-month followup. Similarly, in the FLAURA study, OS was 31.8 months in the comparator group, whereas median OS was 38.6 months in the osimertinib arm with a median 35.8-month follow-up [START_REF] Goss | Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study[END_REF]. In the French early access program for osimertinib cohort, the median OS subsequently to osimertinib initiation was 20.5 months [START_REF] Auliac | Real-life efficacy of osimertinib in pretreated patients with advanced non-small cell lung cancer harboring EGFR T790M mutation[END_REF]. TTF with osimertinib in second-line after 1G/2G TKI was similar to the PFS obtained in the AURA trial, consisting of 8.9 months in our cohort and 10.1 months in AURA trial [START_REF] Mok | Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer[END_REF]. However, we have revealed a better OS with the osimertinib in second-line in our cohort, consisting of 41.3 months vs. 26.8 months in the AURA trial. This is in line with other studies, particularly concerning a post-hoc analysis of LUX-Lung 7 in which 23 patients who received sequentially gefitinib and osimertinib displayed a median OS of 46.0 months [START_REF] Paz-Ares | Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial[END_REF].

In our cohort, 75 patients had at least three treatment lines. In accordance with published realworld evidence studies, 24% of patients did not receive any subsequent systemic treatment [START_REF] Shah | Real-world (RW) treatment patterns and outcomes for second-line (2L) therapy and beyond in patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC receiving a first-line (1L) first-or second-generation (1G/2G) EGFR tyrosine kinase inhibitor (TKI)[END_REF].

After osimertinib in second-line, almost all the patients who received a third-line were, in fact, treated using chemotherapy. While a lot of resistance mechanisms have been well described to date, in about 40-50% of cases in first-or second-line settings, the resistance mechanism is unknown. The most common resistance mechanisms described are the loss of T790M mutation (49-68%), Met amplification (15-20%), C797S mutation (7% in first line up to 26% in second line), HER2 amplification (2-5%), PIK3CA mutation/amplification (4%), as well as BRAFV600E mutation (3%) [START_REF] Mehlman | Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French study[END_REF][START_REF] Oxnard | Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M-Positive Lung Cancer and Acquired Resistance to Osimertinib[END_REF][START_REF] Ramalingam | Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study[END_REF][START_REF] Papadimitrakopoulou | Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study[END_REF][START_REF] Leonetti | Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer[END_REF].

In addition, multiple co-existing molecular alterations have been observed in a considerable percentage of patients. Thus, developing an efficient treatment strategy to bypass resistance mechanisms proves to be a major challenge. Currently, many studies are evaluating drugs that could counteract tumor progression, especially concerning the Met amplification bypass pathway. To illustrate, savolitinib, which is a c-Met inhibitor, is being tested along with osimertinib in the TATTON study [START_REF] Oxnard | TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFRmutant lung cancer[END_REF]. An association of amivantanab (EGFR-MET bispecific antibody) and lazertinib (third-generation EGFR TKI that targets T790M mutation while activating EGFR mutations) is also being tested in the MARIPOSA study [START_REF] Shreeve | 76.73 MARIPOSA: Randomized Phase 3 Study of First-line Amivantamab + Lazertinib vs Osimertinib vs Lazertinib in EGFR-mutant NSCLC[END_REF]. There is also a renewed interest concerning the HER3 involvement in acquired resistance. Patritumumab and deruxtecan (antibody directed to HER3 attached to a topoisomerase I inhibitor) demonstrated antitumor activity across various EGFR TKI resistance mechanisms in pretreated patients in a phase I study, with a pivotal phase II study already initiated [START_REF] Esmo | Efficacy and Safety of Patritumab Deruxtecan in EGFR-mutated NSCLC Resistant to EGFR TKI Therapy[END_REF].

Conclusions

In a real-life setting, around half of EGFR mutated patients that had been 1G/2G TKI-pre-treated benefited from osimertinib in second-line, with a median OS of 3.5 years. TKI sequencing in the setting of EGFR mutant NSCLC is thus highly feasible. The challenge is to better understand resistance mechanism to osimertinib in second line and, even more so in first line, in order to develop new therapeutic options. 1G/2G: first-and second-generation; 3G: third generation; TKI: tyrosine kinase inhibitor.

Figures and Table

Table 1

Demographic and clinical patient characteristics at diagnosis.

Patient characteristics N=254

Male gender 65 (26)

Age

  VRAIE VIE DES PATIENTS PRESENTANT UN CARCINOME BRONCHIQUE NON A PETITES CELLULES AVEC MUTATION ACTIVATRICE DE L'EGFRTHÈSE POUR LE DIPLÔME D'ÉTAT DE DOCTEUR EN MÉDECINE SPÉCIALITÉ : PNEUMOLOGIE FST ONCOLOGIE Par Mme Giulia BERARDI THÈSE SOUTENUE PUBLIQUEMENT À LA FACULTÉ DE MÉDECINE DE GRENOBLE Le 24/09/2021 DEVANT LE JURY COMPOSÉ DE : Président du jury : M. le Pr Denis MORO-SIBILOT Membres : Mme le Pr Anne Claire TOFFART (directrice de thèse) Mme le Dr Chantal DECROISETTE Mme le Dr Florence DE FRAIPONT L'UFR de Médecine de Grenoble n'entend donner aucune approbation ni improbation aux opinions émises dans les thèses ; ces opinions sont considérées comme propres à leurs auteurs.

  Figures and Table ..........................................................................................................................

Fig

  Fig. 1. Study population: flow-chart.

. 1 .

 1 Fig. 1. Study population: flow-chart.

Fig. 2 .

 2 Fig. 2. Time to treatment failure according to first-line tyrosine kinase inhibitor.

Fig. 3 .

 3 Fig. 3. Overall survival according to first-line tyrosine kinase inhibitor.

  expressed as n (%) and quantitative variables as median (IQR, 25%-75%). * Co-mutation in EGFR gene in 10 patients. MD: missing data; WHO: World Health Organization; CNS: central nervous system; EGFR: epidermal growth factor receptor; SCC: squamous cell carcinoma.

A tous les para-médicaux, sans qui ce métier ne serait pas réalisable

  , merci pour votre soutien et votre folie. Je vous suis tellement reconnaissante. A Zoé qui est venue agrandir la famille des paillettes et qu'on aime toutes déjà tant. A Guillaume, pour avoir rendu ces 9 dernières années aussi belles. Merci pour tous ces merveilleux souvenirs. Merci d'être toujours là.

	A mes colocataires malgré eux, Bastien, Bénédicte, Fiona, Moïse, Minou et Minette merci
	A toutes celles et ceux avec qui j'ai eu le plaisir de travailler et en particulier le superbe comité d'avoir fait de l'appartement mon chez moi.
	d'animation de la pneumologie du 4D et les filles du 6B. Vous avez été d'un soutien précieux A mes co-internes devenues mes plus proches amies : Wassila, Orlane, Juliette et Cécile. Merci
	lors de ces longues journées et nuits difficiles. Vous croisez au détour d'un couloir redonne le d'être là
	sourire même au début d'un VD.
	A ma famille
	A mes parents, c'est grâce à vous et votre amour inconditionnel que j'ai l'honneur de devenir
	docteur aujourd'hui. Merci de toujours croire en moi et d'être toujours là, à n'importe quelle
	heure du jour et de la nuit. Je vous aime et je suis fière d'être votre fille.
	A ma belle-famille devenue famille tout court, Nunzia, Barbara, Christel, Nico, Olivier, merci de
	m'avoir aussi bien accueillie parmi vous dès le premier jour.
	A ma famille d'adoption savoyarde Marie Thé, Pascale, Christine, merci de votre présence.
	A Axelle, avec qui j'ai grandi comme une soeur, partenaire rêvée de toutes les péripéties
	d'adolescence et bien plus. Je t'a.
	A Estelle et Pauline, parce que le CCK est une famille.
	A mes amis
	Aux carabins grenoblois qui ont rendu l'aventure des bancs de la fac fantastique : Fanny et
	Romain qui resteront toujours Les colocataires, Amandine, Claire, Geoffrey, Baptise, Bubu,
	Marion, Aude, Lolo, Pétra, Axelle, Astrid, Cédric, Manu, Justine, Alizée, Dani. Merci pour tout.
	A Sophie notre interniste du premier semestre, Mickael et Fanny les rhumato, Thibaud
	nucléariste, Ondine et Marine les généralistes. A Shirin, doux hasard des noms de famille, amitié née en APP et qui perdure depuis 10 ans
	maintenant.
	A l'équipe de radiothérapie d'Annecy et en particulier à Alex qui aura officiellement été le chef
	le plus sympa de tout mon internat. A Juliette, la meilleure des futures obstétriciennes, quelle chance de m'être assise à côté de toi en
	ce premier jour d'internat. A Nico, qui a su supporter tous nos débats médicaux.

Table des matières

 des Materials and methods .................................................................................................................. Results ..........................................................................................................................................

Abréviations .................................................................................................................................. Abstract ......................................................................................................................................... Introduction ................................................................................................................................... Discussion ..................................................................................................................................... Conclusions ................................................................................................................................... References ..................................................................................................................................... Figures and Table .

Keywords: non-small-cell lung cancer; tyrosine kinase inhibitor; EGFR mutation; osimertinib; treatment sequence When a 1G/2G TKI was employed as frontline treatment, after a median follow-up of 21.9 months [IQR 25%-75%, 10-30.5], median TTF was 11.2 months (IQR 25%-75%, 5.5-20.8) with an OS of 31.4 months (IQR 25%-75%, 17.3-69.2).

When osimertinib was used as second-line therapy following 1G/2G TKI, after a median followup of 12.8 months (IQR 25%-75%, 6.6-18), median TTF was 8.9 months (IQR 25%-75%, 4. [START_REF] Barlesi | Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT)[END_REF][START_REF] Soria | Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer[END_REF][START_REF] Wu | Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer[END_REF][START_REF] Rosell | Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial[END_REF][START_REF] Maemondo | Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR[END_REF][START_REF] Sequist | Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations[END_REF][START_REF] Lee | Gefitinib or Erlotinib vs Chemotherapy for EGFR Mutation-Positive Lung Cancer: Individual Patient Data Meta-Analysis of Overall Survival[END_REF][START_REF] Yu | Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers[END_REF][START_REF] Goss | Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study[END_REF][START_REF] Ramalingam | Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC[END_REF][START_REF] Recondo | Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI?[END_REF][START_REF] Debré | La biopsie liquide : alternative ou complément à la biopsie tissulaire ?[END_REF][START_REF] Gahr | EGFR mutational status in a large series of Caucasian European NSCLC patients: data from daily practice[END_REF][START_REF] Shigematsu | Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers[END_REF][START_REF] Kosaka | Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications[END_REF]. OS from osimertinib initiation was 19.7 months (IQR 25%-75%, 12.8-NR) and OS was 41.3 months (IQR 25%-75%, 25.5-NR).

Outcome after third-generation tyrosine kinase inhibitors in first line

Among the 51 patients treated with 3G TKI in first-line, best response rate was 78%, and disease control rate was 100%. At the follow-up's end, 33 patients were still on treatment. The main reason of treatment discontinuation was disease progression (n=10/13; 77%).

After disease progression, a new biopsy was realized in 12 patients, involving 66% of the 18 patients who withdrew first-line treatment. A ctDNA was performed in two patients. The resistance mutations in this group were amplification of cMet for two patients, whereas C797S and PIK3CA mutations were present in one patient each. For these patients, second-line therapy mainly consisted of chemotherapy with or without ICI therapy (n=7, 70%).

When osimertinib was used in frontline, after a median follow up of 12.3 months (IQR 25%-75%, 9.2-18.5), TTF was 20.6 months (IQR 25%-75%, 13-NR), whereas the median OS was not reached. For first-line TKI, median TTF was significantly longer in patients with osimertinib than in those with 1G/2G TKI regimens (P-value=2.10-3). There was no statistically significant difference between both groups in terms of OS (P-value=0.6) (Fig. 2 and3).

Discussion

In this large multicenter retrospective study, we have revealed that 55% of patients who received a second-line treatment following 1G/2G TKI were treated with osimertinib. For this population,

Conclusion