[EGFR molecular characterization in non-small cell bronchic cancer: comparative prospective study by NGS and Idylla platform technologies]. / Caractérisation moléculaire de l'EGFR dans les cancers bronchiques non à petites cellules : étude prospective comparative des technologies NGS et automate Idylla.

INTRODUCTION: Detection of genetic alterations in the EGFR tyrosine kinase domain is a major concern in the management of non-small cell lung cancer because it conditions access to tyrosine kinase inhibitors. In practice, it is possible to characterize only well-documented mutations or to sequence all relevant EGFR exons and also other targets of theranostic interest. This prospective study compares the targeted EGFR characterization on Idylla platform (Biocartis) and a more extensive one by next generation sequencing using Ion Torrent technology. MATERIAL AND METHODS: A total of 100 formalin-fixed paraffin-embedded tumour samples were tested simultaneously by both techniques under the conditions recommended by the suppliers. The comparison covered all technical and practical aspects of the laboratory. RESULTS: At least one EGFR mutation of interest for tyrosine kinase inhibitors for 9 and 7 samples was detected respectively by sequencing and by the Idylla system. For three samples, EGFR sensitive mutations to tyrosine kinase inhibitors were detected only by next-generation sequencing. In addition, for 37 samples, mutations of clinical interest outside EGFR were characterized by sequencing and communicated to the prescriber. CONCLUSION: Idylla technology allows the rapid characterization of a majority of EGFR variants. The result can be optimized by careful analysis of the amplification curves with the Idylla Explore tool or by increasing the amount of initial material. A complementary new generation sequencing analysis for non-contributory results by Idylla should also be recommended.

[News about targeted therapies in non-small-cell lung cancer in 2015 (except immuno-therapy)]. / Actualités sur les thérapies ciblées dans les cancers bronchiques non à petites cellules, hors immunothérapie.

Recently, developments of therapies that target abnormally activated signaling pathways are increasing for patients with non-small cell lung cancer. EGFR mutations are found in about 10% of lung cancers, especially in adenocarcinoma, women and non-smokers. Three EGFR inhibitors (erlotinib, gefitinib and afatinib) received a European marketing authorization for up to first line treatment of EGFR mutated NSCLC. Effectiveness of EGFR inhibitors is higher than conventional chemotherapy. Third generation EGFR inhibitors (rociletinib, AZD9291) are effective for patients who develop a resistance mutation such as T790M resistance mutation; they obtained temporary authorization for use in France in 2015. The EML4-ALK translocation is found in about 5% of NSCLC and more particularly in adenocarcinoma of young non-smoking patients. Crizotinib is a new therapeutic standard in ALK translocated NSCLC in second line. Ceritinib is a 2nd generation ALK inhibitor which received a European marketing authorization for up to treatment of ALK translocated NSCLC after progression with crizotinib. INCA supports ACSé program evaluating the efficacy of crizotinib in NSCLC amplified for MET or translocated for ROS1 and ACSé program evaluating the efficacy of vemurafenib in tumors non melanoma mutated V600E BRAF. The role of other biomarkers such as KRAS, BRAF, HER2 and PI3KCA mutations remains to be defined in NSCLC.

[First-line immunotherapy in non-small cell lung cancer diagnosed with brain metastases]. / CBNPC sans addictions oncogéniques métastatique cérébral d'emblée : place de l'immunothérapie.

INTRODUCTION: Up to 30% patients newly diagnosed with advanced non-small cell lung cancer (NSCLC) present with brain metastases. In the absence of oncogenic addiction, first-line immunotherapy, alone or in combination with chemotherapy, is the current standard of care. This review aims to synthesize the available data regarding the efficacy of immunotherapy in these patients, and to discuss the possibility of its being coordinated with local treatments such as radiotherapy. STATE OF THE ART: NSCLC patients with brain metastases appear to have survival benefits with immunotherapy similar to those of NSCLC patients without brain metastases. However, this finding is based on mainly prospective studies having included highly selected patients with pre-treated and stable brain metastases. Several retrospective studies and two prospective single-arm studies have confirmed the intracranial efficacy of immunotherapy, either alone or in combination with chemotherapy. PERSPECTIVES: The indications and optimal timing for cerebral radiotherapy remain subjects of debate. To date, there exists no randomized study assessing the addition of brain radiotherapy to first-line immunotherapy. That said, a recent meta-analysis showed increased intracerebral response when radiotherapy complemented immunotherapy. CONCLUSIONS: For NSCLC patients with brain metastases, the available data suggest a clear benefit of first-line immunotherapy, whether alone or combined with chemotherapy. However, most of these data are drawn from retrospective, non-randomized studies with small sample sizes.

Radiotherapy in the management of synchronous metastatic lung cancer.

Metastatic lung cancer classically portends a poor prognosis. The management of metastatic lung cancer has dramatically changed with the emergence of immune checkpoint inhibitors, targeted therapy and due to a better understanding of the oligometastatic process. In metastatic lung cancers, radiation therapy which was only used with palliative intent for decades, represents today a promising way to treat primary and oligometastatic sites with a curative intent. Herein we present through a literature review the role of radiotherapy in the management of synchronous metastatic lung cancers.

[Serious adverse effects with immunotherapies for the treatment of melanoma, non-small cell lung cancer, and renal cell carcinoma: Real-world evidence study]. / Effets indésirables graves des immunothérapies dans le traitement du mélanome, du cancer bronchique non à petites cellules et du carcinome à cellules rénales : étude en vie réelle.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are a key component of standard anticancer systemic therapy. While their immune-related adverse effects (irAEs) have been widely described, there are few data on grade≥3 irAEs. The primary aim of our descriptive study was to evaluate their incidence and characteristics. METHODS: An observational, retrospective, monocentric study was conducted. It included patients with locally advanced or metastatic melanoma, non-small cell lung cancer or renal cell carcinoma who initiated ICI therapy between 2016-2021 and experienced at least one grade≥3 irAEs coded according to the MedDRA® system. RESULTS: All cancer types and ICIs combined, the incidence of grade≥3 irAEs was estimated at 11.7% [9.6-13.9]. These were mainly hepatobiliary (22%), gastrointestinal (17%), musculoskeletal (16%) and respiratory (16%) disorders. They occurred on average 6.2±6.2 months after the start of treatment, resulting in hospitalization or prolonged hospitalization in over 40 and 20% of cases, respectively. Resolution without sequelae was observed in 56% of cases, but four patients died. DISCUSSION: This real-world study investigated three cancers and several ICIs, unlike previously published studies that focused on a single cancer and/or one ICI. It provides a better understanding of grade≥3 irAEs, most of which are reversible, which an aim to optimize patient care.

[Stereotactic radiotherapy for operable stage I non-small cell lung cancer]. / Place de la radiothérapie stéréotaxique pour les cancers bronchiques non à petites cellules de stade I opérables.

Standard treatment stage of non-small cell lung cancer is currently surgery. For inoperable patients, stereotactic body radiotherapy is the reference treatment. This non-invasive technique has developed considerably and its excellent results in terms of carcinological control and tolerance raise the question of its indication for operable patients, especially for old patients and/or with comorbidities. This article reviews the available data in the literature of the place of stereotactic body radiotherapy for medically operable patients with stage I non-small cell lung cancer.

[Olimetastatic disease: Current status and perspectives in non-small cell lung cancer]. / Les maladies oligométastatiques : état actuel et perspectives dans les cancers bronchiques non à petites cellules.

The concept of oligometastatic disease was first introduced in the late 1990s to describe an situation more or less midway between locally advanced tumours and multifocal metastatic cancer. Four concepts are currently used: synchronous oligometastatic disease, metachronous oligometastatic disease (or oligo-recurrence), oligo-persistence and oligo-progression. Some phase II studies, randomised or not, have validated this concept in non-small cell lung cancer (NSCLC) and suggest the interest of adding local ablative therapy to systemic treatment. That said, numerous questions remain, and the impact of this therapeutic approach in the framework of immunotherapies and targeted therapies has yet to be assessed. Which of these new treatments offer hope of significantly improved long-term survival in stage IV NSCLC? This article appraises current knowledge and therapeutic regarding oligometastatic NSCLC.

[Interest of focal radiotherapy in case of oligoprogression under immunotherapy in the treatment of metastatic non-small cell lung cancer]. / Oligroprogression sous nivolumab du cancer bronchique non à petites cellules métastatiques traitées par radiothérapie.

INTRODUCTION: The prognosis of metastatic non-small cell lung cancer (NSCLC) has been improved by the use of immune checkpoint inhibitors (ICI). Unfortunately, in some cases, cancer cells will develop resistance mechanisms. In case of progression in a limited number of lesions (oligoprogression), focal treatment with radiotherapy is proposed while continuing the ICI therapy. METHODS: A cohort of 37 patients with metastatic NSCLC treated with nivolumab (anti-PD-1) in second or subsequent line and who received focal radiotherapy for oligoprogression with continuation of nivolumab was compared with a control cohort of 87 patients no oligoprogressor treated par immunotherapy. RESULTS: After a median follow-up of 37 months [18; 62], the median progression free survival (PFS) in the radiotherapy-treated cohort was 15.04 versus 5.04 months in the control cohort, with a statistically significant difference (P=0.048). The median PFS following focal radiotherapy in the oligoprogressor group was 7.5 months. In univariate analysis, the presence of lung metastasis was associated with increased PFS, in contrast to the presence of brain metastases, which were associated with decreased PFS in the radiotherapy group. The median overall survival was not reached in both groups, with no significant difference between the two cohorts. CONCLUSION: The combination of focal radiotherapy in case of oligoprogression and continued treatment with nivolumab in the treatment of metastatic NSCLC in the second or subsequent line of treatment seems to be with an increase in PFS.

[Impact of immunotherapy on the therapeutic strategy for the management of stage I non-small cell lung cancer: The radiation oncologist's point of view]. / Influence de l'immunothérapie sur le choix du traitement des cancers bronchiques non à petites cellules de stade I : point de vue de l'oncologue radiothérapeute.

Surgery is the standard treatment for operable patients with stage I non-small cell lung cancer (NSCLC) (T1-T2aN0M0). Stereotactic body radiotherapy (SBRT) is the treatment of choice for non-operable patients, and its positioning for operable patients remains to be clarified. The pattern of recurrence after management of stage I NSCLC is dominated by the risk of distant recurrence, this constituting the rationale for the adjunction of systemic treatment, and especially check point inhibitor (CPI), in combination with surgery or SBRT for patients with high risk features. While the benefit of postoperative CPI on the micro-metastatic disease is logically considered within the framework of a simply additive effect of both therapeutic modalities, it is reasonable to consider a synergistic effect of both CPI and SBRT. Given the role of tumor draining nodes in the development of an anti-tumor immune response, a "tumor-draining node sparing" strategy enabled by SBRT could therefore be of major interest in combination with CPI. Pending confirmation of the role of CPI in combination with RTS for the management of stage I NSCLC, we thus discuss in this review the theoretical advantages that this therapeutic strategy could have compared to a surgical strategy.

Impact of radiotherapy schedule on survival of patients treated with immune-checkpoint inhibitors for advanced melanoma and non-small cell lung cancer.

PURPOSE: Preclinical and clinical data suggest a potential benefit in the addition of radiotherapy (RT) to immune-checkpoint inhibitors (ICI) during the treatment of advanced cancers. Nevertheless, the ideal patients for this approach and the optimal RT regimen is still debated. MATERIAL AND METHODS: The aim of this study was to determine the effect RT schedule has on survival for advanced non-small cell lung cancer and melanoma patients (pts) treated with ICI (anti-PD1 or anti-CTLA4) and concomitant RT. RESULTS: A total of 58 pts were identified, of which 26 received RT concomitantly with ICI while the remaining 32 pts were treated with RT at the time of progression under ICI. The RT parameters associated with outcome include dose per fraction, biological effective dose, RT to all targets and lung irradiation. Independent predictors of improved progression-free survival were lung irradiation, melanoma histology, oligometastatic status (<6 metastasis), presence of liver metastasis, PNN<7000/mm3 and normal LDH. Independent predictors of improved overall survival were melanoma histology and normal LDH. Among pts who were irradiated at progression, 68.7% had an overall clinical benefit and had a median extension of ICI use by 2.3 months (range: 0-29.1), among which 2 presented with an abscopal effect. CONCLUSIONS: The irradiation of lung metastases may increase survival in patients under ICI. RT at progression could prolong the use of ICI, and neutrophilia and LDH should be considered during patient selection of this combined RT/ICI approach.

[Management of EGFR mutated non-small cell lung carcinoma patients]. / Analyse de la prise en charge des cancers bronchiques avec mutation du gène de l'EGFR.

INTRODUCTION: Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC). Over the past decade, the management of NSCLC-carrying EGFR mutation has evolved considerably with the use of tyrosine kinase inhibitors (TKIs). The main objective of this retrospective study was to analyze the evolution of therapeutic strategies in a cohort of patients with metastatic or locally advanced EGFR- mutated NSCLC. METHODS: Data on patients with EGFR-mutated NSCLC, eligible for TKIs, and treated between 2010 to 2019 were collected. The main therapeutic strategies adopted following progression under TKIs and the prognostic factors for survival were analyzed. RESULTS: The median age of the 177 patients was included in the cohort was 70years. The majority of patients (77.4%) received TKIs as first-line treatment, while 16.4% received chemotherapy. Osimertinib initiation as second-line treatment was a factor for better prognosis (OR=0.5). Finally, change of chemotherapy line was the main therapeutic strategy adopted for 41.3% of the patients having relapsed under TKIs. DISCUSSION: Therapeutic management of EGFR-mutated NSCLC patients was in accordance with regional, national and international recommendations. The characterization of progression under TKI therapy has become systematic, allowing better adaption of therapeutic strategies.

[Perioperative treatment for resected non-small cell lung cancer: Which option in 2020?] / Les traitements périopératoires des cancers bronchiques non à petites cellules : quelles options en 2020 ?

Surgery is the ultimate curative treatment for resectable non-small cell lung cancer (NSCLC). However, the prognosis for operated patients remains disappointing. Multiple randomized studies have shown that administering perioperative chemotherapy improves the prognosis and increases the cure rate by around 3-5%. The purpose of this article is to take stock of the role of perioperative treatments for NSCLC, which can be completely resected. Six questions were evaluated: 1) What is the place of (neo) adjuvant chemotherapy in 2020, among others in the early stages (IB)? 2) Can new chemotherapy agents be combined with a platinum derivative? 3) What is the place of radiochemotherapy for resectable NSCLC? 4) Is there a place for postoperative radiotherapy (PORT)? 5) Is there a place for targeted therapies for resectable NSCLC? 6) What is the place of immunotherapies in the perioperative period?

[Management of a patient with a double EGFR and MET anomaly by combined treatment]. / Prise en charge d'un patient par traitement combiné d'une double anomalie EGFR et MET.

INTRODUCTION: Lung cancer displays molecular anomalies for which targeted therapies are the standard first line treatment. The EGFR mutation is present in 10% of cases of non-small cell lung cancer in Caucasians. MET amplification associated with an exon 19 EGFR mutation has been identified though it is usually regarded as a mechanism of resistance. CASE REPORT: We report the case of a 74-year-old never-smoking woman who was diagnosed with stage IV bronchial adenocarcinoma showing both EGFR mutation and MET amplification. Initial treatment with gefitinib did not control the disease. Platinum-based chemotherapy with pemetrexed maintenance allowed a temporary response. Treatment with durvalumab for 27 months was associated with disease stability. Single agent crizotinib was associated with a slight response followed by progression. The concomitant introduction of crizotinib and gefitinib led to a spectacular and durable response with no safety issues. CONCLUSIONS: This case highlights the efficacy of concomitant treatment in a patient with two oncogenic drivers.

Management of CNS disease in ALK-positive non-small cell lung cancer: Is whole brain radiotherapy still needed?

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.

[Stereotactic radiotherapy of stage I non-small cell lung cancer. State of the art in 2019 and recommendations: Stereotaxy as an alternative to surgery?] / Radiothérapie stéréotaxique du cancer bronchique non à petites cellules de stade I. État de l'art en 2019 et recommandations : la stéréotaxie comme alternative à la chirurgie ?

Stereotactic radiotherapy (or Stereotactic body radiotherapy [SBRT]) is a technique currently well established in the therapeutic arsenal for the management of bronchial cancers. It represents the standard treatment for inoperable patients or who refuses surgery. It is well tolerated, especially in elderly and frail patients, and the current issue is to define its indications in operated patients, based on retrospective and randomized trials comparing stereotactic radiotherapy and surgery, with results equivalents. This work analyzes in detail the different aspects of pulmonary stereotactic radiotherapy and suggests arguments that help in the therapeutic choice between surgery and stereotaxic irradiation. In all cases, the therapeutic decision must be discussed in a multidisciplinary consultation meeting, while informing the patient of the possible therapeutic options.

[Search for the T790M mutation: The need to persevere]. / Recherche de la mutation T790M : savoir persévérer.

In cases of advanced EGFR mutation-positive non-small cell lung cancer, first or second generation EGFR-tyrosine kinase inhibitors (TKI-EGFR 1G or TKI-EGFR 2G) are recommended as first line treatment. Inexorably, progressive disease occurs and, in 50-60% of the cases, is secondary to a T790M resistant mutation. The prescription of osimertinib (TKI-EGFR3G) in second line is dependent on identification of the T790M mutation. We report 7 cases in which the identification of the T790M mutation required repeated analyses of cell free DNA and/or biopsies over a period of time. In some cases, a positive result was obtained a long time after progressive disease had been diagnosed during treatment with first or second generation EGFR-TKI. We discuss here the different modalities of screening for the T790M mutation and we encourage persevering in this search when no alternative mechanism of resistance has been identified.