Search

Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown. Patients and Methods: SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS). Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Supplementary Figure 2. Forest plot with subgroup analysis for PFS in substudy 1.

Supplementary Table S1. Representativeness of Study Participants

Purpose:Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods:SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results:Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 n = 31; HR, 0.71; 95% CI, 0.31–1.60; Pinteraction = 0.036).Conclusions:Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Supplementary Figure legends 1-5

Supplementary materials - substudy 1 statistical report

Study protocol

Supplementary Figure from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Supplementary Data from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Purpose:Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods:SAFIR02-Lung was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results:Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 n = 31; HR, 0.71; 95% CI, 0.31–1.60; Pinteraction = 0.036).Conclusions:Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Supplementary Table from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

The high sensitivity of PET-CT can identify hypermetabolic mediastinal adenopathies during cancer management, but specificity is low and a biopsy is sometimes required to eliminate benign adenopathies.This prospective diagnostic accuracy study included patients with hypermetabolic mediastinal lymphadenopathies revealed on PET-CT during either the initial management of a cancer, treatment evaluation, or monitoring. All patients underwent EUS-FNA. Diagnoses of malignancy based on cytological analysis following EUS-FNA were compared with clinical and radiological follow-up information. The treatment strategy decided before the results of the EUS-FNA pathology reports (Multidisciplinary Team Meeting [MTM-1]) was recorded and compared to the treatment strategy decided once pathological data from EUS-FNA were available (MTM-2).Between 2013 and 2018, 75 patients were included with 47 eligible and evaluable patients. Sensitivity, specificity, and positive and negative predictive values of EUS-FNA were 93%, 100%, 100% and 90%, respectively. The concordance value between the therapeutic strategies determined for MTM-1 and MTM-2 was 44.7%. There were no significant differences in the intensity of fixation on PET-CT between malignant and benign lesions.The diagnostic accuracy of the minimally invasive EUS-FNA procedure is sufficiently robust to avoid the need for diagnostic surgery. The combination of PET-CT and EUS-FNA may alter the therapeutic strategy that would be considered after PET-CT alone.NCT01892501.

International audience; Non-small-cell lung carcinoma is a frequent type of lung cancer with a bad prognosis. Depending on the stage, genomics, several therapeutical approaches are used. Tyrosine Kinase Inhibitors (TKI) may be successful for a time in the treatment of EGFR-mutated non-small cells lung carcinoma. Our objective is here to propose a survival assessment as their efficacy in the long run is challenging to evaluate. The study includes 17 patients diagnosed as of EGFR-mutated non-small cell lung cancer and exposed to an EGFR-targeting TKI with 3 computed tomography (CT) scans of the primitive tumor (one before the TKI introduction and two after). An imaging biomarker based on the texture heterogeneity evolution between the first and the third exams is derived and computed from a mathematical model and patient data. Defining the overall survival as the time between the introduction of the TKI treatment and the patient death, we obtain a statistically significant correlation between the overall survival and our imaging marker (p = 0:009). Using the ROC curve, the patients are separated into two populations and the comparison of the survival curves is statistically significant (p = 0:025). The baseline exam seems to have a significant role in the prediction of response to TKI treatment. More precisely, our imaging biomarker defined using only the CT scan before the TKI introduction allows to determine a first classification of the population which is improved over time using the imaging marker as soon as more CT scans are available. This exploratory study leads us to think that it is possible to obtain a survival assessment using only few CT scans of the primary tumor.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer death; percutaneous thermal ablation (TA) has proven feasibility, good local control and good tolerance in stage I tumors for patients with medical comorbidities and who are ineligible for surgery. In this context, stereotactic body radiotherapy (SBRT) has demonstrated high efficacy in treating T1 NSCLC and will need to be compared with percutaneous ablation. TA is also indicated in oligoprogressive disease; and can be proposed as a salvage treatment option for tumor recurrence after radiotherapy. Besides more advanced NSCLC could be also an indication of TA in combination with systemic treatments. A large majority of diagnosed NSCLC do not exhibit specific targetable genetic aberration. Those tumors present poorer prognosis and have been treated with standard chemotherapy regimen until the recent development of immune checkpoint inhibitors (ICIs) based immunotherapy. Combining TA with immunotherapy is promising and still needs to be explored.

EGFR-mutated non-small cells lung carcinoma are treated with Tyrosine Kinase Inhibitors (TKI). Very often, the disease is only responding for a while before relapsing. TKI efficacy in the long run is therefore challenging to evaluate. Our objective is to derive a new imaging biomarker that could offer better insights on the disease response to treatment. This study includes 17 patients diagnosed as EGFR-mutated non-small cell lung cancer and exposed to an EGFR-targeting TKI. The early response to treatment is evaluated with 3 computed tomography (CT) scans of the primitive tumor (one before the TKI introduction and two after). Using our knowledge of the disease, an imaging biomarker based on the tumor heterogeneity evolution between the first and the third exams is defined and computed using a novel mathematical model calibrated on patient data. Defining the overall survival as the time between the introduction of the TKI treatment and the patient death, we obtain a statistically significant correlation between the overall survival and our imaging marker (p = 0.009). Using the ROC curve, the patients are separated into two populations hence the comparison of the survival curves is statistically significant (p = 0.025). Initial state of the tumor seems to have a role for the prognosis of the response to TKI treatment. More precisely, the imaging marker - defined using only the CT scan before the TKI introduction - allows us to determine a first classification of the population which is refined over time using the imaging marker as more CT scans become available. This exploratory study leads us to think that it is possible to obtain a survival assessment using only few CT scans of the primary tumor.

A prospective multicenter phase II trial to evaluate the survival outcomes of percutaneous radiofrequency ablation (RFA) for patients with stage IA non-small cell lung cancer (NSCLC), ineligible for surgery. Patients with a biopsy-proven stage IA NSCLC, staging established by a positron emission tomography-computed tomography (PET-CT), were eligible. The primary objective was to evaluate the local control of RFA at 1-year. Secondary objectives were 1- and 3-year overall survival (OS), 3-year local control, lung function (prior to and 3 months after RFA) and quality of life (prior to and 1 month after RFA). Of the 42 patients (mean age 71.7 y) that were enrolled at six French cancer centers, 32 were eligible and assessable. Twenty-seven patients did not recur at 1 year corresponding to a local control rate of 84.38% (95% CI, [67.21–95.72]). The local control rate at 3 years was 81.25% (95% CI, [54.35–95.95]). The OS rate was 91.67% (95% CI, [77.53–98.25]) at 1 year and 58.33% (95% CI, [40.76–74.49]) at 3 years. The forced expiratory volume was stable in most patients apart from two, in whom we observed a 10% decrease. There was no significant change in the global health status or in the quality of life following RFA. RFA is an efficient treatment for medically inoperable stage IA NSCLC patients. RFA is well tolerated, does not adversely affect pulmonary function and the 3-year OS rate is comparable to that of stereotactic body radiotherapy, in similar patients. ClinicalTrials.gov Identifier NCT01841060 registered in November 2008.

To evaluate the survival outcomes of percutaneous thermal ablation (RFA + microwaves) for patients presenting N0 non-small-cell lung cancer (NSCLC) ineligible for surgery.Eighty-seven patients from two comprehensive cancer centers were included. Eighty-two patients were treated with RFA electrodes and five with microwave antenna. Overall survival (OS) and disease-free survival (DFS) were estimated and predictive factors of local tumor progression, OS and DFS identified and compared by univariate and multivariate analysesMedian follow-up was 30.5 months (interquartile range 16.7-51) and tumor size was 21 mm (range 10-54 mm). Treatment was incomplete for 14 patients with a local tumor progression of 11.5, 18.3, and 21.1 % at 1, 2, and 3 years, respectively. Two patients presented with neurological (grade III or IV) complications, and one died of respiratory and multivisceral failure as a result of the procedure at 29 days. In univariate analysis, increasing tumor size (P = 0.003) was the only predictive factor related to risk of local tumor progression. 5-year OS and DFS were 58.1 and 27.9 %, respectively. Sex (P = 0.044), pathology (P = 0.032), and tumor size2 cm (P = 0.046) were prognostic factors for DFS. In multivariate analysis, pathology (P = 0.033) and tumor size2 cm (P = 0.032) were independent prognostic factors for DFS.Oversized and overlapping ablation of N0 NSCLC was well tolerated, effective, with few local tumor progressions, even over long-term follow-up. Increasing tumor size was the main prognostic factor linked to OS, DFS, and local tumor progression.

Mediastinal lymphadenopathy may be detected by CT-scan or positron emission tomography. Malignant (e.g, lung cancer, metastatic cancer, lymphoma), infectious (e.g, tuberculosis, histoplasmosis), and systemic processes (e.g, sarcoidosis) can cause mediastinal adenopathy. In the posterior and inferior mediastinum, endoscopic ultrasound visualizes and directs transesophageal fine needle aspiration of adenopathy. In the anterior mediastinum, endobronchial ultrasound visualizes and directs transbronchial fine needle aspiration of adenopathy. We discuss the role of EUS and EBUS in the evaluation of mediastinal adenopathy according to their anatomical localization.

Lung cancer is the leading cause of cancer death in France. In above 75% of cases, disease is too advanced to permit curative treatments. Adenocarcinomas are the principal histologic type, with above 10% of epidermal growth factor (EGFR) mutations. These mutations lead to constitutive activation of this receptor. Tumors presenting EGFR mutations have a dramatically response rate to tyrosine kinase inhibitors (TKI). Responses occur during 10 to 12 months in median. After this period, all patients improve relapses because of emergence of tumor resistance. Several therapeutics strategies are proposed but there are not therapeutics standards for treatment of these resistances. The aim of this study was to analyze clinical and molecular characteristics of relapses of 69 patients treated at Bergonie Institute (Bordeaux) and to evaluate therapeutics strategies used. We have shown that oligometastatic patients might benefit of local treatments, with TKI continuation. For others relapses, a biopsy must be realized. Molecule assessment of these biopsies can guide treatments. Slow and asymptomatic progressions are often due to EGFR-dependant progressions, and can be treated with TKI continuation or chemotherapy and rechallenge. EGFR-independent relapses lead to rapid or symptomatic progressions and must be treated with chemotherapies. New treatments like new generation TKI or immunotherapies will change these strategies and might be considered in future trials., Environ 10% des adénocarcinomes bronchiques sont porteurs d’une mutation du gène du récepteur de l’epidermal growth factor (EGFR). Cette mutation rend le récepteur constitutivement actif et sensibilise la tumeur aux inhibiteurs de tyrosine kinase (ITK) visant à bloquer l’activation du récepteur. Les patients répondent en médiane pendant 10 à 12 mois à ces traitements, avant de présenter une progression tumorale liée à l’apparition de phénomènes de résistances moléculaires. Il n’existe actuellement aucun standard pour la prise en charge de ces progressions sous ITK. Ce travail de thèse a donc porté sur l’analyse des modalités de rechute de 69 patients suivis à l’Institut Bergonié (Bordeaux) et sur les stratégies qui ont été mises en œuvre au décours de la progression. Nous avons ainsi montré avec les données de la cohorte et de la littérature que les patients présentant une rechute oligo-métastatique doivent bénéficier d’un traitement local permettant la poursuite de l’ITK. Les progressions disséminées doivent faire l’objet d’une rebiopsie chaque fois que possible. Les résultats de l’analyse moléculaire de ces biopsies guideront ainsi le traitement. Les progressions disséminées, lentes et asymptomatiques, sont souvent liées à une résistance dépendante de l’EGFR, et peuvent être traitées par la poursuite de l’ITK ou l’initiation d’une chimiothérapie avec rechallenge ensuite par ITK. Enfin, les progressions rapides sont plutôt le fait de résistances indépendantes de la voie EGFR, et ont été majoritairement traitées par chimiothérapie dans notre étude. Actuellement, ces données sont remises en cause. En effet, les patients présentant une mutation T790M pourront bénéficier d’un traitement par ITK de 3e génération. Il faudra maintenant définir la stratégie thérapeutique des patients mutés EGFR avec l’arrivée de ces molécules. De plus, les immunothérapies vont également modifier les conduites thérapeutiques dans les prochaines années, et il faudra définir leur place par rapport aux ITK.

Purpose: To describe efficacy of radiofrequency and thoracic radiotherapy combination therapy for the treatment of all stage lung cancer non-small cell (NSCL). Materials and Methods: We retrospectively describe the overall and disease-free survivals of 29 NSCLC patients treated with radiofrequency and thoracic radiotherapy for all stage neoplasms either during treatment of two distinct lung carcinoma or during multimodal treatment for advanced NSCLC. We also assess local control provided by radiofrequency and complications of this treatment. Results: The median follow-up of our series was 29.4 months (19.1 to 56.5). Progression-free survival at 12, 24, and 36 months respectively was 82%, 40.5% and 34.7%. Overall survival was 85.94%, 74.0% and 74% at 12, 24 and 36 months. Local control of radiofrequency ablation during follow-up was 86.2%, with a complication rate of 65.5%. Conclusion: Radiofrequency associated with thoracic radiotherapy appears useful in many situations in the treatment of NSCLC and is not confined to the treatment of stage I and II., Objectifs : Décrire l’efficacité, en termes de survie globale et sans progression, d’un traitement combiné par radiofréquence et radiothérapie thoracique dans la prise en charge des cancers bronchiques non à petites cellules tous stades confondus. Matériels et méthodes : Nous décrivons rétrospectivement les survies globales et sans progression d’une série de 29 patients atteints de CBNPC et traités par radiofréquence et radiothérapie thoracique tous stades confondus : lors de la prise en charge de 2 néoplasies distinctes ou dans le cadre du traitement multimodal d’un CBNPC à un stade avancé. Nous évaluons aussi le contrôle local apporté par la radiofréquence ainsi que les complications de ce traitement. Résultats : Le suivi médian de notre série est de 29.4 mois. La survie sans progression à 12, 24, et 36 mois est estimée respectivement à 82%, 40.5%, et 34.7%. La survie globale était de 85.94%, 74.0%, et 74% à 12, 24 et 36 mois. Le contrôle local de la radiofréquence au cours de notre suivi est de 86.2% avec un taux de complication de 65.5%. Conclusion : La radiofréquence associée à la radiothérapie thoracique semble donc avoir un intérêt dans plusieurs situations au cours de la prise en charge des CBNPC et ne pas se cantonner au traitement des stades I et II.