Publications by authors named "Pernelle Lavaud"

29 Publications

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[Impact of the use of systemic corticosteroid therapy on the effectiveness of immune checkpoint inhibitors].

Bull Cancer 2021 Apr 19. Epub 2021 Apr 19.

Gustave-Roussy, hôpital de jour, département de médecine oncologique, 114, rue Édouard-Vaillant, 94805 Villejuif, France; Gustave-Roussy, département d'innovation thérapeutique et essais précoces (DITEP), 114, rue Édouard-Vaillant, 94805 Villejuif, France. Electronic address:

Immunotherapy, which consists in using molecules targeting the immune system, has existed for many years in oncology (vaccines, interleukins, monoclonal antibodies) but has recently expanded due to the development of immune checkpoint inhibitors. These monoclonal antibodies help to restore the immunity against cancer by specifically targeting some immune checkpoints such as CTLA-4, PD-1 and PD-L1. Furthermore, in oncology, it is common to use systemic corticosteroids in the management of symptoms linked to the natural history of the disease (pain, spinal cord compression, cerebral edema) and toxicities linked to anticancer treatment. The impact of corticosteroids on the efficacy of immune checkpoint inhibitors is still poorly understood and they should be used cautiously. According to previously published studies, there seems to be a deleterious effect of corticosteroid therapy on the efficacy of immune checkpoint inhibitors when administered before or at the initiation of immunotherapy, while this effect does not seem present when corticosteroids are administered to patients already undergoing immunotherapy. The aim of this work is to analyze the existing data evaluating the impact of corticosteroid use of on the efficacy of immune checkpoint inhibitors.
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http://dx.doi.org/10.1016/j.bulcan.2021.01.015DOI Listing
April 2021

Meningeal "Lazarus Response" to Lorlatinib in a ROS1-Positive NSCLC Patient Progressing to Entrectinib.

Cancer Manag Res 2021 26;13:2805-2810. Epub 2021 Mar 26.

Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France.

Background: ROS1 tyrosine kinase inhibitors (TKIs) have showed activity and efficacy in -rearranged non-small cell lung cancer (NSCLC). In the clinical practice, besides the utilization of crizotinib, less is known about the best treatment strategies involving additional, new-generation TKIs for the sequential treatment of ROS1-positive NSCLC patients.

Case Presentation: A patient suffering from a -rearranged lung adenocarcinoma, after receiving cisplatin-pemetrexed chemotherapy, was treated with entrectinib, a new-generation ALK/ROS1/NTRK inhibitor. After 16 months, central nervous system (CNS) metastases appeared, without extra-cerebral disease progression. Stereotactic brain radiotherapy was performed and entrectinib was maintained, due to the global systemic disease control. Approximately one month after radiotherapy, thoracic and meningeal progressions were detected, the latter highly symptomatic with neurocognitive disorders, visual hallucinations and worsening of psycho-motor impairment. A lumbar puncture was positive for tumor cells and for an fusion. The administration of lorlatinib (a third-generation ALK/ROS1 inhibitor) prompted an extremely rapid improvement of clinical conditions, anticipating the positive results observed at radiologic evaluation that confirmed the disease response still ongoing after nine months since treatment start.

Discussion: With the expanding availability of targeted agents with differential activity on resistance mechanism and on CNS disease, choosing wisely the best treatment strategies is pivotal to assure the best clinical outcomes in oncogene-addicted NSCLC patients. Here we have reported lorlatinib reverted an almost fatal meningeal carcinomatosis developing during entrectinib in a ROS1-positive NSCLC patient.
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http://dx.doi.org/10.2147/CMAR.S292730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009349PMC
March 2021

[Ipilimumab-nivolumab as first-line treatment in metastatic NSCLC].

Bull Cancer 2021 Mar 20;108(3):231-233. Epub 2021 Feb 20.

Université Paris-Saclay, département d'oncologie médicale, Gustave-Roussy Cancer Campus, Villejuif, France.

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http://dx.doi.org/10.1016/j.bulcan.2021.01.005DOI Listing
March 2021

Next-generation androgen receptor inhibitors in non-metastatic castration-resistant prostate cancer.

Ther Adv Med Oncol 2020 23;12:1758835920978134. Epub 2020 Dec 23.

Department of Cancer Medicine, University of Paris Saclay, Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif, 94805, France.

Until recently, continuing androgen deprivation therapy (ADT) and closely monitoring patients until evolution towards metastatic castration-resistant prostate cancer (CRPC) were recommended in men with non-metastatic CRPC (nmCRPC). Because delaying the development of metastases and symptoms in these patients is a major issue, several trials have investigated next-generation androgen receptor (AR) axis inhibitors such as apalutamide, darolutamide, and enzalutamide in this setting. This review summarizes the recent advances in the management of nmCRPC, highlighting the favourable impact of next-generation AR inhibitors on metastases-free survival, overall survival and other clinically meaningful endpoints.
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http://dx.doi.org/10.1177/1758835920978134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768840PMC
December 2020

Chronic Plasma Exposure to Kinase Inhibitors in Patients with Oncogene-Addicted Non-Small Cell Lung Cancer.

Cancers (Basel) 2020 Dec 14;12(12). Epub 2020 Dec 14.

Cancer Medicine Department, Gustave Roussy, 94805 Villejuif, France.

Kinase inhibitors (KI) have dramatically improved the outcome of treatment in patients with non-small cell lung cancer (NSCLC), which harbors an oncogene addiction. This study assesses KI plasma levels and their clinical relevance in patients chronically exposed to KIs. Plasma samples were collected in NSCLC patients receiving erlotinib, gefitinib, osimertinib, crizotinib, or dabrafenib (with or without trametinib) for at least three months between November 2013 and February 2019 in a single institution. KI drug concentrations were measured by ultra-performance liquid chromatography coupled with tandem mass spectrometry and compared to published data defining optimal plasma concentration. The main outcome was the rate of samples with suboptimal KI plasma concentrations. Secondary outcomes included its impact on mutation emergence in patients receiving a first-generation epidermal growth factor receptor (EGFR) KI. Fifty-one samples were available from 41 patients with advanced NSCLC harboring driver genetic alterations, including , v-Raf murine sarcoma viral oncogene homolog B (), anaplastic lymphoma kinase () or ROS proto-oncogene 1 (), and who had an available evaluation of chronic KI plasma exposure. Suboptimal plasma concentrations were observed in 51% (26/51) of cases. In -mutant cases failing first-generation KIs, exon 20 p.T790M mutation emergence was detected in 31% (4/13) of samples in optimal vs. none in suboptimal concentration (0/5). Suboptimal plasma concentrations of KIs are frequent in advanced NSCLC patients treated with a KI for at least three months and might contribute to treatment failure.
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http://dx.doi.org/10.3390/cancers12123758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764991PMC
December 2020

Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations.

JAMA Netw Open 2020 10 1;3(10):e2021692. Epub 2020 Oct 1.

Department of Medical Oncology, Cantonal Hospital Winterthur, Winterthur, Switzerland.

Importance: DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown.

Objective: To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations.

Design, Setting, And Participants: In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations (ie, cohort 1, present; cohort 2, not detected; and cohort 3, not tested). Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019.

Exposure: Treatment with platinum-based compounds either as monotherapy or combination therapy.

Main Outcomes And Measures: The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations.

Results: A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients (14.7%; cohort 1), absent in 98 (19.3%; cohort 2), and not tested in 330 (65.0%; cohort 3). Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (P = .20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (P = .07). In the subgroup of 44 patients with BRCA2 gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively.

Conclusions And Relevance: In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.21692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593810PMC
October 2020

Impact of Intercurrent Introduction of Steroids on Clinical Outcomes in Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients under Immune-Checkpoint Inhibitors (ICI).

Cancers (Basel) 2020 Sep 30;12(10). Epub 2020 Sep 30.

Cancer Medicine Department, Gustave Roussy, 94805 Villejuif, France.

Background: Baseline steroids before ICI have been associated with poor outcomes, particularly when introduced due to cancer symptoms.

Methods: Retrospective analysis of advanced NSCLC patients treated with ICI. We collected the use of intercurrent steroids (≥10 mg of prednisone-equivalent) within the first eight weeks of ICI. We correlated steroid use with patient outcomes according to the indications.

Results: 413 patients received ICI, 299 were steroids-naïve at baseline. A total of 49 patients received intercurrent steroids (16%), of whom 38 for cancer-related symptoms and 11 for other indications, such as immune-related events. Overall, median (m) progression-free survival (PFS) was 1.9 months (mo.) [95% CI, 1.8-2.4] and overall survival (OS) 10 mo. [95% CI, 8.1-12.9]. Intercurrent steroids under ICI correlated with a shorter PFS/OS (1.3 and 2.3 mo. respectively, both < 0.0001). Intercurrent steroids for cancer-related symptoms correlated with poorest mPFS [1.1 mo.; 95% CI, 0.9-1.5] and mOS [1.9 mo.; 95%CI, 1.5-2.4; < 0.0001)]. No mOS and mPFS differences were found between cancer-unrelated-steroid group and no-steroid group. Steroid use for cancer-related symptoms was an independent prognostic factor for poor PFS [HR 2.64; 95% CI, 1.2-5.6] and OS [HR 4.53; 95% CI, 1.8-11.1], both < 0.0001.

Conclusion: Intercurrent steroids during ICI had no detrimental prognostic impact if the indication was unrelated to cancer symptoms.
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http://dx.doi.org/10.3390/cancers12102827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599488PMC
September 2020

Feasibility and first reports of the MATCH-R repeated biopsy trial at Gustave Roussy.

NPJ Precis Oncol 2020 8;4:27. Epub 2020 Sep 8.

Experimental and Translational Pathology Platform (PETRA), Genomic Platform - Molecular Biopathology unit (BMO) and Biological Resource Center, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.

Unravelling the biological processes driving tumour resistance is necessary to support the development of innovative treatment strategies. We report the design and feasibility of the MATCH-R prospective trial led by Gustave Roussy with the primary objective of characterizing the molecular mechanisms of resistance to cancer treatments. The primary clinical endpoints consist of analyzing the type and frequency of molecular alterations in resistant tumours and compare these to samples prior to treatment. Patients experiencing disease progression after an initial partial response or stable disease for at least 24 weeks underwent a tumour biopsy guided by CT or ultrasound. Molecular profiling of tumours was performed using whole exome sequencing, RNA sequencing and panel sequencing. At data cut-off for feasibility analysis, out of 333 inclusions, tumour biopsies were obtained in 303 cases (91%). From these biopsies, 278 (83%) had sufficient quality for analysis by high-throughput next generation sequencing (NGS). All 278 samples underwent targeted NGS, 215 (70.9%) RNA sequencing and 222 (73.2%) whole exome sequencing. In total, 163 tumours were implanted in NOD scid gamma (NSG) or nude mice and 54 patient-derived xenograft (PDX) models were established, with a success rate of 33%. Adverse events secondary to invasive tumour sampling occurred in 24 patients (7.6%). Study recruitment is still ongoing. Systematic molecular profiling of tumours and the development of patient-derived models of acquired resistance to targeted agents and immunotherapy is feasible and can drive the selection of the next therapeutic strategy.
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http://dx.doi.org/10.1038/s41698-020-00130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478969PMC
September 2020

Long-term Castration-related Outcomes in Patients With High-risk Localized Prostate Cancer Treated With Androgen Deprivation Therapy With or Without Docetaxel and Estramustine in the UNICANCER GETUG-12 Trial.

Clin Genitourin Cancer 2020 Dec 7;18(6):444-451. Epub 2020 Apr 7.

Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France. Electronic address:

Introduction: Neoadjuvant chemotherapy with docetaxel and estramustine (DE) significantly improved relapse-free survival in patients with high-risk localized prostate cancer treated with androgen deprivation therapy (ADT) for 3 years and a local treatment in the GETUG-12 phase III trial. We sought to explore whether the addition of DE impacts long-term treatment-related side effects.

Patients And Methods: Patients randomized within the UNICANCER GETUG-12 trial at Gustave Roussy who were alive when ADT was discontinued were followed-up prospectively. Serum testosterone levels and clinical data regarding body weight, libido, erection, and cardio-vascular events were collected.

Results: Seventy-eight patients were included: 36 patients had been treated with ADT plus a local treatment and 42 with ADT+DE plus a local treatment. With a median follow-up of 5.9 years after ADT discontinuation, serum testosterone levels returned to normal values (> 200 ng/mL) for 57 (78%) of 72 evaluable patients, and 29 (43%) of 68 evaluable patients reported erections allowing intercourse without medical assistance. No impact of DE on testosterone level recovery, libido, quality of erections, and changes in body weight after ADT discontinuation was detected. The incidence of cardiovascular events was low and similar in both treatment arms.

Conclusion: Treatment with DE was not associated with excess long-term castration-related toxicity in men with high-risk localized prostate cancer. The relapse-free survival improvement seen with DE in GETUG-12 is likely not related to differed testosterone recovery.
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http://dx.doi.org/10.1016/j.clgc.2020.03.017DOI Listing
December 2020

Association of metastatic pattern and molecular status in stage IV non-small cell lung cancer adenocarcinoma.

Eur Radiol 2020 Sep 23;30(9):5021-5028. Epub 2020 Apr 23.

Imaging Department, Gustave Roussy, Université Paris-Saclay, F-94805, Villejuif, France.

Objectives: The aim of our study was to investigate the association between driver oncogene alterations and metastatic patterns on imaging assessment, in a large cohort of metastatic lung adenocarcinoma patients.

Methods: From January 2010 to May 2017, 550 patients with stage IV lung adenocarcinoma with molecular analysis were studied retrospectively including 135 EGFR-mutated, 81 ALK-rearrangement, 47 BRAF-mutated, 141 KRAS-mutated, and 146 negative tumors for these 4 mutations (4N). After review of the complete imaging report by two radiologists (junior and senior) to identify metastatic sites, univariate correlation analyzes were performed.

Results: We found differences in metastatic tropism depending on the molecular alteration type when compared with the non-mutated 4N group: in the EGFR group, pleural metastases were more frequent (32% versus 20%; p = 0.021), and adrenal and node metastases less common (6% versus 23%; p < 0.001 and 11% versus 23%; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% versus 29%; p = 0.043 and 37% versus 24%; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (respectively 47% versus 20%; p < 0.001 and 11% versus 3%; p = 0.04) and bone metastases were rarer (21% versus 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK, and BRAF groups (respectively 6%, 7%, and 15% versus 1%); p = 0.016; p = 0.009; and p < 0.001.

Conclusion: The application of these correlations between molecular status and metastatic tropism in clinical practice may lead to earlier and more accurate identification of patients for targeted therapy.

Key Points: • Bone and brain metastasis are the most common organs involved in lung adenocarcinoma but the relative incidence of each metastatic site depends on the molecular alteration. • EGFR-mutated tumors preferentially spread to the pleura and less commonly to adrenals, ALK-rearrangement tumors usually spread to the brain and the lungs, whereas BRAF-mutated tumors are unlikely to spread to bones and have a serous (pericardial ad pleural) tropism. • These correlations could help in the clinical management of patients with metastatic lung adenocarcinoma.
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http://dx.doi.org/10.1007/s00330-020-06784-yDOI Listing
September 2020

Liver tests increase on abiraterone acetate in men with metastatic prostate cancer: Natural history, management and outcome.

Eur J Cancer 2020 04 6;129:117-122. Epub 2020 Mar 6.

Gustave Roussy, Université Paris-Saclay, Oncology Medicine Department, Villejuif, F-94805, France. Electronic address:

Background: Abiraterone acetate (abiraterone) combined with prednisone is a standard of care in metastatic castration-resistant prostate cancer. Recently, benefit in overall survival was reported in metastatic castration-sensitive prostate cancer also, and an extension of indication has been granted. Abiraterone is seldom associated with liver toxicity. The clinical management and the outcome of patients with transaminase increase while on abiraterone have not been described.

Patients And Method: We identified 25 men with metastatic prostate cancer and liver function test disorders occurring while on abiraterone treatment from December 2009 to September 2017 in three oncology centres in France.

Results: Forty-six liver disorder events occurred in 25 patients while on abiraterone treatment. The median age at liver function test increase was 67 (55-85) years. The incidence of aspartate aminotransférase (AST) (24 events) and that of alanine aminotransférase (ALT) (22 events) increases were similar. Liver toxicity was of grade 1, 2 and 3 (Common Terminology Criteria for Adverse Events. version 4) in 7 (32%), 6 (27%) and 9 (41%) patients for ALT, and in 12 (50%), 6 (25%) and 6 (25%) for AST, respectively. The median time from abiraterone initiation to the detection of liver toxicity was 7.1 (4-95) weeks. The median time from highest ALT/AST increase to normalisation was 6.2 [2-14] weeks. In 13 patients (52%), liver tests spontaneously returned to baseline values, while abiraterone was continued at full dose.

Conclusion: Liver function test increase is a rare event that typically occurs within the first two months on abiraterone. Most patients experience normalisation of the tests, either spontaneously or after dose reduction/discontinuation.
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http://dx.doi.org/10.1016/j.ejca.2020.01.017DOI Listing
April 2020

Neuroendocrine Carcinoma of the Urinary Bladder: A Large, Retrospective Study From the French Genito-Urinary Tumor Group.

Clin Genitourin Cancer 2020 08 5;18(4):295-303.e3. Epub 2019 Dec 5.

Department of Pathology, Hôpital Foch, Suresnes, France; Department of Pathology, Institut Curie, Saint-Cloud, France.

Background: Neuroendocrine carcinoma of the urinary bladder (NCUB) is rare, accounting for < 1% of bladder cancer cases, with scarce reported data available.

Materials And Methods: We retrospectively reviewed the data from patients with NCUB treated at French institutions. The objectives were to describe the patient characteristics, treatments received, and outcomes (ie, disease-free survival [DFS], progression-free survival, overall survival [OS]) and investigate the prognostic factors.

Results: From 1997 to 2017, we included 236 patients, 173 with early-stage NCUB and 63 with advanced-stage NCUB. For those with early-stage disease, the median DFS was better for the patients who had received cisplatin-based chemotherapy compared with carboplatin (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.1-3.46), with no difference found between the neoadjuvant and adjuvant settings (HR, 1.1; 95% CI, 0.61-1.97). The median OS was 36 months (95% CI, 29-43 months) for stage I and II, 26 months (95% CI, 18 months to not reached) for stage IIIA, 16 months (95% CI, 12-21 months) for stage IIIB. The HR for stage IIIB compared with stage I/II was 2.6 (95% CI, 1.5-4.4). The DFS at 6 months was associated with OS (HR, 7.8; 95% CI, 4.1-15.0). For patients with metastases at diagnosis who had received chemotherapy, the median progression-free survival was 9 months (95% CI, 8-11) for first-line cisplatin and 6 months (95% CI, 4-13 months) for carboplatin; the median OS was 13 months (95% CI, 9-15 months). A high-risk Bajorin score (HR, 11.5; 95% CI, 1.2-112.6) and the use of carboplatin (HR, 2.26; 95% CI, 1.03-4.96) were associated with worse outcomes.

Conclusions: In early-stage disease, a shorter DFS was associated with worse OS, and the use of cisplatin was associated with better OS. For the patients with metastases at diagnosis, a high-risk Bajorin score and the use of carboplatin were associated with worse outcomes.
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http://dx.doi.org/10.1016/j.clgc.2019.11.014DOI Listing
August 2020

Circulating Tumor DNA Analysis for Patients with Oncogene-Addicted NSCLC With Isolated Central Nervous System Progression.

J Thorac Oncol 2020 03 13;15(3):383-391. Epub 2019 Dec 13.

Department of Cancer Medicine, Gustave Roussy Cancer Centre, Villejuif, France; Paris-Sud University, Orsay, France. Electronic address:

Introduction: In patients with oncogene-addicted NSCLC and isolated central nervous system progression (iCNS), tissue biopsy is challenging, and the clinical utility of plasma liquid biopsy (i.e., circulating tumor DNA [ctDNA]) is unknown.

Methods: Patients with advanced NSCLC with known baseline genomic alteration (GA) (EGFR, ALK, BRAF, KRAS, HER2, ROS1, MET, PIK3CA, STK11, TP53) on tissue were divided into three groups on the basis of their disease progression pattern: iCNS, extra-CNS only (noCNS), or both (cCNS). All patients with available plasma ctDNA were included and were analyzed by next-generation sequencing InVisionFirst-Lung. ctDNA was considered positive if at least one GA was detected. Cell-free tumor DNA was analyzed in cerebrospinal fluid when available.

Results: Out of 517 patients screened, 247 were included: 54 had iCNS, 99 had noCNS, and 94 had cCNS progressive disease (64, 128, and 110 ctDNA samples, respectively). CtDNA was positive in 52% iCNS versus 84% in noCNS and 92% in cCNS (p < 0.00001), with lower detection of driver (37% versus 77% and 73%, respectively) and resistance alterations (6% versus 45% and 44%). Patients with iCNS and positive ctDNA were more at risk of extra-CNS progression (32% versus 7%, p = 0.026). In 12 patients with iCNS, ctDNA was positive in six (50%) plasma and in 10 (83%) paired cerebrospinal fluid (p = 0.193).

Conclusions: Although tagged amplicon-based next-generation sequencing has high detection rates of GA in plasma ctDNA in patients with NSCLC with extra-CNS disease, detection rate of GAs (52%) is lower in the subset of patients with iCNS disease. Complementary tests such as cerebrospinal fluid cell-free DNA may be useful. Further evidence would be beneficial to understand the genomic landscape in patients with NSCLC and iCNS.
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http://dx.doi.org/10.1016/j.jtho.2019.11.024DOI Listing
March 2020

Studying Rarity in Bladder Cancer.

Eur Urol 2020 04 5;77(4):447-448. Epub 2019 Dec 5.

Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, Université Paris-Sud, Université Paris-Saclay, Villejuif, France. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2019.11.018DOI Listing
April 2020

Clinical outcome after progressing to frontline and second-line Anti-PD-1/PD-L1 in advanced urothelial cancer.

Eur Urol 2020 02 5;77(2):269-276. Epub 2019 Nov 5.

Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Immune checkpoint inhibitors (ICIs) are approved for first-line (cisplatin unfit, PD-L1+) and platinum-refractory urothelial carcinoma (UC). Still, most patients experience progressive disease (PD) as the best response. Although higher response rates to subsequent systemic treatment (SST) have been described, post-PD outcome data are scarce.

Objective: To examine the outcome of UC patients who received SST and no SST after progressing to ICIs.

Design, Setting, And Participants: A retrospective analysis of UC patients progressing to frontline or later-line anti-PD-1/PD-L1 therapy in 10 European institutions was conducted between March 2013 and September 2017.

Intervention: Post-PD management as per standard practice.

Outcome Measurements And Statistical Analysis: Overall survival (OS) was analyzed with a Kaplan-Meier model. Cox regression was used for multivariate analysis (MV). Impact of SST on OS was examined with a time-varying covariate model.

Results And Limitations: A total of 270 UC patients with PD to ICIs (69 frontline, 201 later line) were analyzed. Of the patients, 57% of frontline-ICI-PD and 34% of later-line-ICI-PD patients received SST, and SST had an impact on OS in MV (frontline: hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.10-0.51, p <  0.001; later line: HR 0.22, 95% CI 0.13-0.36, p <  0.001). In the frontline-ICI-PD group, median OS with and without SST was 6.8 mo (95% CI 5.0-8.6) and 1.9 mo (95% CI 0.9-3.0), respectively. High disease burden (three or more metastatic sites: HR 2.49, p =  0.03; simultaneous liver/bone metastases: HR 3.93, p =  0.03) predicted worse survival. In later-line-ICI-PD group, response to ICIs (HR 0.37, p =  0.03), longer exposure to ICIs (HR 0.89, p =  0.002), and bone metastasis (HR 2.42, p <  0.001) predicted survival. The retrospective nature of this study and a lack of certain parameters limit the interpretation of our analysis.

Conclusions: Patients progressing to frontline ICIs are at risk of early death, excluding them from experiencing potential benefit from chemotherapy PATIENT SUMMARY: Our analysis suggests that outcomes after failing immunotherapy are poor, particularly in UC patients who received no prior chemotherapy.
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http://dx.doi.org/10.1016/j.eururo.2019.10.004DOI Listing
February 2020

Correction to: Focus on Recommendations for the Management of Non-small Cell Lung Cancer.

Cardiovasc Intervent Radiol 2020 Jan;43(1):168

Interventional Radiology, Gustave Roussy, Villejuif, France.

The authors would like to apologize for the misspelling of one of the co-authors names.
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http://dx.doi.org/10.1007/s00270-019-02370-yDOI Listing
January 2020

Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer.

Clin Cancer Res 2020 01 4;26(1):242-255. Epub 2019 Oct 4.

Department of Medical Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif, France.

Purpose: Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with -rearranged lung cancer and design new therapeutic strategies in this setting.

Experimental Design: Resistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel compound mutations. Drug combinatory strategies were evaluated and to overcome lorlatinib resistance.

Results: Diverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial-mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors.

Conclusions: This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942925PMC
January 2020

[Management of metastatic testicular germ cell tumors].

Bull Cancer 2019 Oct 26;106(10):896-902. Epub 2019 Aug 26.

Université Paris-Saclay, Gustave-Roussy, Department of Cancer Medicine, 114, rue Edouard-Vaillant, Villejuif, France.

Metastatic testicular germ cell tumors are rare entities with a high cure rate owing to their major chemosensitivity. Current guidelines should be strictly followed to ensure maximal cure rate. Germ cell tumor treatment requires multidisciplinary skills and is based on cisplatin-based chemotherapy. The current challenge for these patients with favorable prognosis is to limit over- or under-treatment. Centralization of care for patients with these rare cancers is a key point to achieve the best chance of cure.
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http://dx.doi.org/10.1016/j.bulcan.2019.05.004DOI Listing
October 2019

Activity of EGFR Tyrosine Kinase Inhibitors in NSCLC With Refractory Leptomeningeal Metastases.

J Thorac Oncol 2019 08 18;14(8):1400-1407. Epub 2019 May 18.

Department of Medical Oncology, Gustave Roussy, Villejuif, France; Paris-Sud University, Orsay, France. Electronic address:

Introduction: Leptomeningeal metastases (LMs) are associated with dismal prognosis in NSCLC. Optimal management remains unknown in patients with EGFR-mutated NSCLC after initial tyrosine kinase inhibitor (TKI) failure.

Methods: We conducted a multicenter retrospective study including patients with EGFR-mutated NSCLC and LM. TKI failure was defined as diagnosis of LM on TKI, or progression of known LM on TKI.

Results: Ninety-two patients were included, median age of 60 years, predominantly female (68%), never-smokers (74%). EGFR mutations included L858R (45%), exon 19 deletions (28%), or other mutations (14%). Median time to LM diagnosis was 18.5 months after initial diagnosis of advanced NSCLC. LM was diagnosed after a median of 2 (range: 0-9) systemic therapies. Median overall survival from LM diagnosis was 6.1 months (95% confidence interval [CI]: 4.2-7.6 months). Among 87 patients with TKI failure, patients rechallenged with TKI (n = 50) had a median LM overall survival of 7.6 months (95% CI: 5.7-10.9) compared to 4.2 months (95% CI: 1.6-6.7) in patients without further therapy. Overall, 60% of patients rechallenged with TKI experienced clinical benefit (clinical response or stable disease >2 months), and 23% were treatment failure-free at 6 months. Clinical benefit was reported in 11 of 20 (55%) patients treated with erlotinib after afatinib or gefitinib. Strategies based on increasing dose intensity (n = 17) yielded clinical benefit in 59% of patients. All four patients who received osimertinib after first- and second-generation TKI experienced clinical benefit.

Conclusions: TKI rechallenge strategies, including dosing intensification, may improve clinical outcomes of patients with LM from EGFR-mutated NSCLC after initial TKI failure.
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http://dx.doi.org/10.1016/j.jtho.2019.05.007DOI Listing
August 2019

Low risk of invasive lobular carcinoma of the breast in carriers of BRCA1 (hereditary breast and ovarian cancer) and TP53 (Li-Fraumeni syndrome) germline mutations.

Breast J 2019 01 9;25(1):16-19. Epub 2018 Nov 9.

Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Background: Invasive lobular carcinoma (ILC) of the breast has epidemiological, molecular and clinical specificities, and should likely be considered a unique entity. As for genetic susceptibility, CDH1 germline mutations predispose exclusively to ILC. Data are however scarce regarding ILC in women with BRCA1/2 (Hereditary Breast and Ovarian Cancer) and TP53 (Li-Fraumeni syndrome) germline mutations.

Methods: We included all breast cancers from female patients tested at our institute between 1992 and 2016 (n = 3469) for which pathology data were available. ILC proportion comparison according to mutational status was performed by a chi-squared test. The impact of susceptibility genes on ILC proportion was investigated by univariate logistic regression with wild-type patients as reference.

Results And Discussion: There were 265 (7.64%) ILC: 2/342 (0.58%) in BRCA1 patients, 24/238 (10%) in BRCA2 patients, 1/57 (1.75%) in TP53 patients and 238/2832 (8.4%) in non-carriers. The majority of breast cancers in all groups were invasive ductal and ductal in situ carcinomas. The difference in ILC proportion was highly significant (P < 0.001). Compared to wild-type patients, BRCA1 was associated with a lower ILC proportion (OR 0.064 [95% CI 0.016;0.259], P < 0.0001). BRCA2 OR was 1.222 [95%CI 0.785;1.902] (P = 0.374), TP53 OR was 0.195 [95%CI 0.027;1.412] (P = 0.105). ILC are therefore underrepresented in BRCA1 and TP53 mutation carriers. Formal significance (P = 0.05) was not reached for TP53, but statistical power was only 38%. Based on ILC incidence in the general population, we make the hypothesis that BRCA1 and TP53 do not predispose to ILC, as the few occurrences of ILC in mutation carriers could be attributed to chance and not to germline mutations. Our observations will be useful to clinical cancer geneticists managing patients with ILC, as a BRCA1 or TP53 mutation in these patients would be unlikely. Genetic counseling should be adapted accordingly.
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http://dx.doi.org/10.1111/tbj.13154DOI Listing
January 2019

Durvalumab in urothelial cancers.

Expert Rev Anticancer Ther 2018 04 5;18(4):311-318. Epub 2018 Mar 5.

b Drug Development Department (DITEP), Gustave Roussy , Université Paris-Sud, Université Paris-Saclay , Villejuif , France.

Introduction: Urothelial bladder cancer is one of the most predominant malignancies worldwide with a poor prognosis when presented at an advanced or metastatic stage. Improving the therapeutic landscape in this setting has been an unmet medical need. Palliative cisplatin-based chemotherapy is currently the standard of care in first line therapies, but many patients are ineligible and few alternative therapies exist. Moreover second-line chemotherapy has minimal activity. Recently, immune-checkpoint inhibitors have shifted the therapeutic armamentarium of bladder cancer and it is now necessary to redesign the therapeutic paradigm. Areas covered: In this article, we focus on the development of durvalumab and provide an overview of the safety, activity, efficacy and future perspectives of this drug in urothelial carcinoma. Expert commentary: Durvalumab is a well-tolerated drug and demonstrated major and durable response in advanced bladder cancer. Combinations with durvalumab will probably emerge as promising therapeutic strategies for the treatment of urothelial carcinoma. Further research efforts are needed to identify predictive biomarkers of response to immune-oncology agents.
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http://dx.doi.org/10.1080/14737140.2018.1443812DOI Listing
April 2018

[Atezolizumab (Tecentriq): Activity, indication and modality of use in advanced or metastatic urinary bladder carcinoma].

Bull Cancer 2018 Feb 28;105(2):140-145. Epub 2017 Dec 28.

University of Paris Sud, Gustave Roussy cancer campus, drug development department, 94805 Villejuif cedex, France; University of Paris Sud, Gustave Roussy cancer campus, department of medical oncology, 94805 Villejuif cedex, France. Electronic address:

Treatments for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin are currently limited. Atezolizumab (Tecentriq) is a monoclonal antibody targeting PD-L1. The first of IMVIGOR 210 phase II trial (NCT02951767) investigated atezolizumab as front line treatment among 119 patients with metastatic urothelial cancer unfit for cisplatin. Response rate was 23% and median overall survival 15.9 months. The second cohort (NCT02108652) included 310 patients whose tumors were progressing after first line platinum-based chemotherapy. Response rate was 15% and median overall survival 7.9 months. Among patients with high PD-L1 expression on infiltrating immune cells (ICs), response rate was 26% and median overall survival 11 months. Atezolizumab was well-tolerated in both cohorts with 66% of treatment-related toxicities including 12% (cohort 1) and 7% (cohort 2) of grade 3-4 adverse events. These results led to an approval by the FDA in United States and the EMA in Europe. In France, atezolizumab was available through an early access agreement by the French National Agency for Medicines and Health Products (ANSM) for patients with metastatic or advanced urothelial carcinomas on progression after first line chemotherapy or unfit for cisplatin. So far, its avaibility in France within the EMA approval is pending its pricing.
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http://dx.doi.org/10.1016/j.bulcan.2017.10.030DOI Listing
February 2018

Atezolizumab in urothelial bladder carcinoma.

Future Oncol 2018 Feb 14;14(4):331-341. Epub 2017 Nov 14.

Department de Médecine Oncologique & INSERM U981, Gustave Roussy, Université Paris-Saclay, 94805, Villejuif, France.

Metastatic bladder cancer is an aggressive malignancy with a poor prognosis when presenting with advanced stage. Cisplatin-based therapy has been the mainstay of first-line treatment but therapy in second-line setting has been an unmet medical need for decades. Moreover, many patients are unable to receive cisplatin-based therapy. Recently, immune-checkpoint inhibitors transformed the management and prognosis of many malignancies and will certainly redefine the standard of care for bladder cancer. Atezolizumab, an anti-PD-L1 antibody, was the first immune-checkpoint inhibitor to be approved by the US FDA in May 2016 for patients with urothelial carcinoma. In this review, we discuss the evidence behind this promising drug.
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http://dx.doi.org/10.2217/fon-2017-0433DOI Listing
February 2018

Anticancer Activity and Tolerance of Treatments Received Beyond Progression in Men Treated Upfront with Androgen Deprivation Therapy With or Without Docetaxel for Metastatic Castration-naïve Prostate Cancer in the GETUG-AFU 15 Phase 3 Trial.

Eur Urol 2018 05 23;73(5):696-703. Epub 2017 Oct 23.

Medical Oncology Department, Clinique Saint-Jean Languedoc, Toulouse, France.

Background: Androgen deprivation therapy (ADT) plus docetaxel is the standard of care in fit men with metastatic castration-naive prostate cancer (mCNPC) following results from GETUG-AFU 15, CHAARTED, and STAMPEDE. No data are available on the efficacy of treatments used for metastatic castration-resistant prostate cancer (mCRPC) in men treated upfront with ADT plus docetaxel for mCNPC.

Objective: To investigate the efficacy and tolerance of subsequent treatments in patients treated upfront with chemo-hormonal therapy for mCNPC.

Design, Setting, And Participants: Retrospective data from the GETUG-AFU 15 phase 3 trial were collected for treatments received for mCRPC.

Outcome Measurements And Statistical Analysis: For the first three lines of salvage treatment for mCRPC we investigated the biochemical progression-free survival, maximum prostate-specific antigen (PSA) decline, overall survival, and tolerance.

Results And Limitations: Overall, 245 patients received at least one treatment for mCRPC. For docetaxel used in first-line, a PSA decline ≥50% was observed in 25/66 (38%) and in 4/20 patients (20%) who had received upfront ADT alone and ADT plus docetaxel (p=0.14). The median biochemical progression-free survival was 6.0 mo (95% confidence interval: 3.6-7.7) and 4.1 mo (95% confidence interval: 1.3-4.9), respectively. For docetaxel used in first- or second-line, a PSA decline ≥50% was observed in 36/80 (45%) and in 4/29 patients (14%) who had received upfront ADT alone and ADT plus docetaxel (p=0.07). PSA declines ≥50% were observed with bicalutamide in 12/28 (43%) and 4/23 patients (17%) who had received upfront ADT alone and ADT plus docetaxel. Among men treated upfront with ADT plus docetaxel who received abiraterone or enzalutamide for mCRPC, 10/19 patients (53%) achieved a PSA decline ≥50%. Few grade 3-4 events occurred. Study limitations include the observational design and retrospective characteristics of this analysis, without standardized therapeutic salvage protocols, and the limited number of patients in some of the treatment subgroups.

Conclusions: Docetaxel rechallenge following progression to mCRPC after upfront ADT plus docetaxel for mCNPC was active only in a limited number of patients. Available data on abiraterone and enzalutamide support maintained efficacy in this setting. The lack of standardized therapeutic protocols for men developing mCRPC limits the comparability between patients.

Patient Summary: Rechallenging docetaxel at castration-resistance was active only in a limited number of patients treated upfront with chemo-hormonal therapy for metastatic castration-naive prostate cancer. Anticancer activity was suggested with abiraterone or enzalutamide in this setting.
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http://dx.doi.org/10.1016/j.eururo.2017.09.022DOI Listing
May 2018

Long-term complete remission with Ipilimumab in metastatic castrate-resistant prostate cancer: case report of two patients.

J Immunother Cancer 2017 18;5:31. Epub 2017 Apr 18.

Institut Gustave Roussy, University of Paris-Sud, Department of Cancer Medicine, 114 Rue Edouard Vaillant, 94800 Villejuif, France.

Background: Prostate cancer is one of the most common cancers in men and the fourth leading cause of cancer mortality worldwide. Although major progress has been achieved in the last years for patients with metastatic castrate-resistant prostate cancer (mCRPC), thanks to next-generation androgen receptor axis targeted drugs, taxanes, and bone-targeted agents, immunotherapy has not been widely approved and used for the treatment of prostate cancer. Two large studies with ipilimumab, an anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) antibody reported improved progression-free survival, but not statistically improved overall survival at the primary analysis (CA184 043 and CA184 095).

Case Presentation: Here, we report on two patients who received ipilimumab in these trials and are still in long-term complete remission with a follow-up of 64 and 52 months respectively after the initiation of ipilimumab. Immunohistochemical staining for hMLH1, hMSH2, hMSH6 and PMS2 was performed on archival prostate biopsy samples from one of the two patients; they exhibited normal protein expression. Interestingly for this patient, a high CD3+ and CD8+ T cell infiltration was observed on archival prostate biopsies as well as Treg FoxP3+ T cells.

Conclusion: Ipilimumab produces clinical activity in patients with CRPC, including very long responders with no detectable residual disease.
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http://dx.doi.org/10.1186/s40425-017-0232-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394619PMC
June 2018

[ESMO ECCO 2015: The highlights of immunotherapy and targeted therapies].

Bull Cancer 2016 Jun 24;103(6):594-603. Epub 2016 May 24.

AERIO, 149, avenue du Maine, 75014 Paris, France; DITEP, Gustave-Roussy, 94805 Villejuif, France. Electronic address:

The ESMO/ECC congress (European Society for Medical Oncology/European Cancer Congress) took place in Vienna, Austria, September 25-29. The main topic of the conference was immunotherapies especially in advanced kidney cancer with nivolumab in phase III and in metastatic lung cancer with atezolizumab in phase II. Targeted therapies were also highlighted with cabozantinib proposed in advanced renal cancer or everolimus in differenciated neuroendocrine tumors grade 1 or 2. Furthermore the current challenges remain unchanged: improving patients' care through better selection and finding biomarkers using simple samples (blood or urine). Also early phases and personalized medicine found their place in the different presentations and were highlighted largely bringing new approaches in the treatment of metastatic patients.
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http://dx.doi.org/10.1016/j.bulcan.2016.04.001DOI Listing
June 2016

Strategies to overcome trastuzumab resistance in HER2-overexpressing breast cancers: focus on new data from clinical trials.

BMC Med 2014 Aug 12;12:132. Epub 2014 Aug 12.

Breast cancers over-express the human epidermal growth factor receptor 2 (HER2) in about 15% of patients. This transmembrane tyrosine kinase receptor activates downstream signaling pathways and leads to proliferation of cancer cells. Trastuzumab, an anti-HER2 monoclonal antibody, improves outcome in women with early and metastatic breast cancer. Resistance to trastuzumab involves the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway, truncation of the Her2 receptor or lack of immune response. The last decade has seen major advances in strategies to overcome resistance to trastuzumab. This includes the development of antibody-drug conjugates, dual HER2 inhibition strategies, inhibition of PI3K/mTOR pathway and development of modulators of immune checkpoints.
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http://dx.doi.org/10.1186/s12916-014-0132-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243818PMC
August 2014