Publications by authors named "David Planchard"

147 Publications

Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study.

Lancet Respir Med 2021 Apr 6. Epub 2021 Apr 6.

University of Chicago, Chicago, IL, USA.

Background: Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study.

Methods: The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067.

Findings: Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation.

Interpretation: Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated.

Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(20)30515-4DOI 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/CMAR.S292730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009349PMC
March 2021

Pleural effusion is a negative prognostic factor for immunotherapy in patients with non-small cell lung cancer (NSCLC): The pluie study.

Lung Cancer 2021 Mar 24;155:114-119. Epub 2021 Mar 24.

Medical and Thoracic Oncology Department, Hôpital Européen Georges Pompidou AP-HP, Université de Paris, France. Electronic address:

Background: Pleural effusion (PE) is a common metastatic site of NSCLC, associated with poor outcomes. As very few data are available about immune checkpoint inhibitors (ICI) and PE, we aimed to assess the clinical outcome of PE in NSCLC treated with ICI.

Method: Multicenter international retrospective study of patients with metastatic NSCLC treated with ICI, between 2012 and 2019. Stratification according to the presence of PE at ICI baseline or appearance under ICI treatment (PE group) versus no history of PE (non-PE group). Primary endpoints were overall survival (OS) and early death rate (EDR, OS ≤ 3 months).

Results: A total of 538 patients were included: 196 in the PE group and 342 in the non-PE group. In the PE group, median age was 64, 31.6 % were female, 77.6 % had non-squamous histology, PD-L1 was ≥50 % in 38.6 % of cases (95 missing). PE was more likely associated with >2 metastatic sites (70.4 % vs. 50 %) and worse performance status (PS ≥ 2, 30.8 % vs 23.1 %). Globally, the overall median OS was 9.7 months [95 %CI: 8.1-11.8]; 6.3 [95 % CI: 4.0-8.6] in PE vs. 11.4 [95 %CI: 9.7-13.8] in the non-PE respectively, P = 0.002. Overall the EDR was 31.4 %; higher in the PE group (38.3 % vs. 27.5 %; OR 1.63, 95 %CI: 1.13-2.37, P = 0.01). In the PE PD-L1≥50 % group, EDR was 33.3 %. In multivariate analysis, after adjustment on PS, liver/intracranial/bone metastasis, ICI line and dNLR, PE remained an independent prognostic factor for OS [HR: 1.38, 95 %CI: 1.09-1.74, P = 0.007]. In the PE group, PE appeared under ICI for 31 patients (16.4 %). We observed lower EDR in this group compared to patients whom PE was already present (29.0 % vs 40.5 %, P = 0.2).

Conclusion: PE is associated with worse immunotherapy outcomes in NSCLC treated with ICI, including in patients with ≥50 % PD-L1 tumors. Thus, in these patients, combination strategies should be explored.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lungcan.2021.03.015DOI Listing
March 2021

Feasibility of a video-based cognitive behavioral therapy for insomnia in French adult cancer outpatients: results from the Sleep-4-All-1 study.

Support Care Cancer 2021 Mar 24. Epub 2021 Mar 24.

Gustave Roussy, Université Paris-Saclay, 114 Rue Edouard Vaillant, F-94805, Villejuif Cedex, France.

Background: Insomnia affects up to 63% of patients with cancer. Cognitive behavioral therapy for insomnia (CBT-I) is considered to be the non-pharmacological gold standard treatment, but it remains underutilized in France. Self-administered interventions offer new ways to overcome some of the barriers that restrict access to efficacious supportive care.

Objective: To assess the feasibility, among French adult cancer outpatients, of a validated Quebec video-based, self-administered, cognitive behavioral therapy for insomnia (VCBT-I).

Methods: A pre-post design with quantitative measures (Insomnia Severity Index, Edmonton Symptom Assessment System, Treatment Perception Questionnaire) and qualitative measures (semi-structured interviews) was used.

Results: One hundred and seventy-three cancer outpatients were self-screened for insomnia, and 57% (n=99) reported significant symptoms. Among them, 80% (n=79) agreed to participate in the VCBT-I. The download rate of the VCBT-I was 78% (n=62/79). Several technical and contextual barriers to the delivery and the applicability of the VCBT-I emerged. However, participants reported a high level of satisfaction, and some valuable benefits at post-immediate intervention (increased knowledge about sleep, better quality of sleep, and higher acceptance of the burden of insomnia), regardless of whether or not they still had insomnia.

Discussion: This study confirms that there is a demand for a VCBT-I, which was perceived as appropriate by a sample of French cancer outpatients with insomnia, but it also highlights some limitations in terms of implementation and practicality. Remote professional support appears to be a core need in order to address these issues and personalize the guidance process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00520-021-06151-7DOI Listing
March 2021

An overview of osimertinib as a treatment of non-small cell lung cancer (NSCLC): an update.

Expert Opin Pharmacother 2021 Feb 24:1-12. Epub 2021 Feb 24.

Clinica Di Oncologia Medica, IRCCSO spedale Policlinico San Martino, Genova, Italy.

Osimertinib is a third-generation anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), that irreversibly binds to mutant EGFR, specifically to the T790M  mutant non-small cell lung cancer (NSCLC). Since its approval, osimertinib has been tested in multiple scenarios, including the first-line and adjuvant setting of -mutant disease. The authors summarize the most recent evidence about osimertinib in NSCLC, covering its use as a first-line therapy, its activity on central nervous system metastatic disease, and in elderly patients. Moreover, the authors focus on resistance to this drug and on the therapeutic strategies that may be used to overcome this issue. Osimertinib is a key player in the treatment of mutant NSCLC and will probably be used in earlier clinical settings in the future, giving rise to an emerging variety of resistance mechanisms. These could be potentially overcome in several ways: e.g. as an oligo-progressive disease local therapy, maintaining osimertinib might be a reasonable option; however, for widespread progressive disease, a switch to chemotherapy should be considered. Finally, either liquid biopsy or tissue biopsy might be considered in patients progressing to osimertinib, as they can lead to the identification of potentially targetable resistance mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14656566.2021.1888928DOI Listing
February 2021

Patient-reported outcomes with durvalumab by PD-L1 expression and prior chemoradiotherapy-related variables in unresectable stage III non-small-cell lung cancer.

Future Oncol 2021 Apr 15;17(10):1165-1184. Epub 2021 Feb 15.

H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.

We retrospectively investigated the impact of tumor PD-L1 expression and prior chemoradiotherapy (CRT)-related variables on patient-reported outcomes (PROs) from PACIFIC. PACIFIC was a Phase III study of durvalumab versus placebo after CRT in patients with unresectable, stage III non-small-cell lung cancer. If available, pre-CRT tumor tissue was tested for PD-L1 tumor-cell expression, scored at prespecified (25%) and (1%) cut-offs. PROs were assessed using EORTC QLQ C30/-LC13. Similar to the intent-to-treat (ITT) population, most PROs remained stable over time across PD-L1 and CRT subgroups, with few clinically relevant differences between treatment arms. Time to deterioration was generally similar to the ITT population. Neither PD-L1 expression nor prior CRT-related variables influenced PROs with durvalumab therapy. NCT02125461 (ClinicalTrials.gov).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2020-1102DOI Listing
April 2021

Tumour-infiltrating lymphocyte density is associated with favourable outcome in patients with advanced non-small cell lung cancer treated with immunotherapy.

Eur J Cancer 2021 Mar 27;145:221-229. Epub 2021 Jan 27.

Pathology Department, Gustave Roussy, Villejuif, France. Electronic address:

Background: The established role of morphological evaluation of tumour-infiltrating lymphocytes (TILs) with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. We aimed to determine TIL association with the outcome for ICIs and for chemotherapy in advanced NSCLC.

Methods: This is a multicenter retrospective study of a nivolumab cohort of 221 patients treated between November 2012 and February 2017 and a chemotherapy cohort of 189 patients treated between June 2009 and October 2016. Patients with available tissue for stromal TIL evaluation were analysed. The presence of a high TIL count (high-TIL) was defined as ≥10% density. The primary end-point was overall survival (OS).

Results: Among the nivolumab cohort, 64% were male, with median age of 63 years, 82.3% were smokers, 77% had performance status ≤1 and 63% had adenocarcinoma histology. High-TIL was observed in 22% patients and associated with OS (hazard ratio [HR] 0.48; 95% confidence interval [95% CI]: 0.28-0.81) and progression-free survival [PFS] (HR = 0.40; 95% CI: 0.25-0.64). Median PFS was 13.0 months (95% CI: 5.0-not reached) with high-TIL versus 2.2 months (95% CI: 1.7-3.0) with the presence of a low TIL count (low-TIL). Median OS for high-TIL was not reached (95% CI: 12.2-not reached) versus 8.4 months (95% CI: 5.0-11.6) in the low-TIL group. High-TIL was associated with the overall response rate (ORR) and disease control rate (DCR) (both, P < .0001). Among the chemotherapy cohort, 69% were male, 89% were smokers, 86% had performance status ≤1 and 90% had adenocarcinoma histology. High-TIL was seen in 37%. Median PFS and OS were 5.7 months (95% CI: 4.9-6.7) and 11.7 months (95% CI: 9.3-13.0), respectively, with no association with TILs.

Conclusions: High-TIL was associated with favourable outcomes in a real-world immunotherapy cohort of patients with NSCLC, but not with chemotherapy, suggesting that TILs may be useful in selecting patients for immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.10.017DOI Listing
March 2021

Cannabis use and lung cancer: time to stop overlooking the problem?

Eur Respir J 2021 Jan 28. Epub 2021 Jan 28.

Thoracic Surgery and Pneumology department, Marie Lannelongue Hospital, Paris Saint Joseph Hospital and Paris Saclay University, Le Plessis-Robinson, France

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.04132-2020DOI Listing
January 2021

Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC-an Update From the PACIFIC Trial.

J Thorac Oncol 2021 Jan 19. Epub 2021 Jan 19.

Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Introduction: In the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53-0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42-65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized.

Methods: Patients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan-Meier method.

Results: Overall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2-64.9), updated OS (HR = 0.71; 95% CI: 0.57-0.88) and PFS (HR = 0.55; 95% CI: 0.44-0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively.

Conclusion: These updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2020.12.015DOI Listing
January 2021

Safety of current immune checkpoint inhibitors in non-small cell lung cancer.

Expert Opin Drug Saf 2021 Mar 25:1-17. Epub 2021 Mar 25.

Department of Cancer Medicine, Thoracic Oncology Unit, Gustave Roussy Cancer Campus, Villejuif, France.

: Immune checkpoint inhibitors (ICIs) achieved response rates around 20% in advanced non-small cell lung cancer (NSCLC) with 8% of patients becoming long-term survivors. Outcomes have improved with the addition of chemotherapy to immunotherapy or the combination of anti-PD(L)1 with anti-CTLA-4 agents.: The incidence of immune-related adverse events (irAEs) in patients with NSCLC treated with ICIs varied across clinical trials and real-life studies. The onset of irAEs was 10 weeks. Toxic deaths from irAEs following anti-PD(L)1 administration resulted mainly from pneumonitis. Some irAEs such as rash and thyroiditis were probably associated with better clinical outcomes, though confounding biases exist. Investigations are on-going to determine ideal biomarkers to predict the occurrence, to screen for and to diagnose irAEs.: Prevention, anticipation, detection, treatment and careful monitoring are the five principles that characterize our management of irAEs. Distinguishing immune-induced pneumonitis from progression, pseudo progression, hyper progression, or other etiologies (COVID-19) can be particularly challenging in lung cancer due to the baseline vulnerable pulmonary function and thus requires caution and teamwork. We treat patients according to institutional and international guidelines and we only rechallenge them with ICIs after resolution of the AE and corticosteroid tapering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14740338.2021.1867100DOI Listing
March 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12123758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764991PMC
December 2020

Oncogene addiction and immune escape: friends or foes?

Ann Transl Med 2020 Sep;8(18):1194

Department of Medical Oncology, Gustave Roussy, Villejuif, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm-20-3036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576068PMC
September 2020

FLAURA strikes again: efficacy of osimertinib is independent of PD-L1 expression.

Transl Lung Cancer Res 2020 Oct;9(5):2165-2172

Department of Medical Oncology, Gustave Roussy, Villejuif, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tlcr-20-628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653102PMC
October 2020

CD103CD8 T Cells Accumulate in Tumors of Anti-PD-1-Responder Lung Cancer Patients and Are Tumor-Reactive Lymphocytes Enriched with Tc17.

Cell Rep Med 2020 Oct 20;1(7):100127. Epub 2020 Oct 20.

INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Faculté de Médecine, Université Paris-Sud, Université Paris-Saclay, 94805 Villejuif, France.

Accumulation of CD103CD8 resident memory T (T) cells in human lung tumors has been associated with a favorable prognosis. However, the contribution of T to anti-tumor immunity and to the response to immune checkpoint blockade has not been clearly established. Using quantitative multiplex immunofluorescence on cohorts of non-small cell lung cancer patients treated with anti-PD-(L)1, we show that an increased density of CD103CD8 lymphocytes in immunotherapy-naive tumors is associated with greatly improved outcomes. The density of CD103CD8 cells increases during immunotherapy in most responder, but not in non-responder, patients. CD103CD8 cells co-express CD49a and CD69 and display a molecular profile characterized by the expression of PD-1 and CD39. CD103CD8 tumor T, but not CD103CD8 tumor-infiltrating counterparts, express Aiolos, phosphorylated STAT-3, and IL-17; demonstrate enhanced proliferation and cytotoxicity toward autologous cancer cells; and frequently display oligoclonal expansion of TCR-β clonotypes. These results explain why CD103CD8 T are associated with better outcomes in anti-PD-(L)1-treated patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xcrm.2020.100127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659589PMC
October 2020

Adjuvant Osimertinib in -Mutated Non-Small-Cell Lung Cancer.

Authors:
David Planchard

N Engl J Med 2020 10;383(18):1780-1782

From the Department of Medical Oncology, Thoracic Oncology Unit, Institut Gustave Roussy, Villejuif, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMe2029532DOI Listing
October 2020

Phase I Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-positive -mutant Non-small Cell Lung Cancer.

Clin Cancer Res 2021 Feb 12;27(4):992-1002. Epub 2020 Oct 12.

Department of Medical Oncology, Thoracic Unit, Gustave Roussy, Villejuif, France.

Purpose: We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive -mutant non-small cell lung cancer (NSCLC).

Patients And Methods: This open-label, single-arm phase I study enrolled patients with T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation.

Results: Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with ( = 10) and without central nervous system (CNS) metastasis ( = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6-21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification.

Conclusions: Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive -mutant NSCLC..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1690DOI Listing
February 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.

Université Paris-Saclay, Institut Gustave Roussy, Inserm U981, Biomarqueurs prédictifs et nouvelles stratégies thérapeutiques en oncologie, 94800 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41698-020-00130-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478969PMC
September 2020

Clinical Relevance of an Amplicon-Based Liquid Biopsy for Detecting and Fusion and Resistance Mutations in Patients With Non-Small-Cell Lung Cancer.

JCO Precis Oncol 2020 2;4. Epub 2020 Apr 2.

Department of Medical Oncology, Centre Léon Bérard Lyon, France.

Purpose: Liquid biopsy specimen genomic profiling is integrated in non-small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with -positive NSCLC and its impact on outcomes.

Patients And Methods: Patients with advanced -positive NSCLC were prospectively enrolled in the study by researchers at eight French institutions. Plasma samples were analyzed using InVisionFirst-Lung and correlated with clinical outcomes.

Results: Of the 128 patients included in the study, 101 were positive for and 27 for alterations. Blood samples (N = 405) were collected from 29 patients naïve for treatment with tyrosine kinase inhibitors (TKI) or from 375 patients under treatment, including 105 samples collected at disease progression (PD). Sensitivity was 67% (n = 18 of 27) for fusion detection. Higher detection was observed for fusions at TKI failure (n = 33 of 74; 46%) versus in patients with therapeutic response (n = 12 of 109; 11%). -resistance mutations were detected in 22% patients (n = 16 of 74) overall; 43% of the total -resistance mutations identified occurred after next-generation TKI therapy. was the most common mutation detected (n = 7 of 16). Heterogeneity of resistance was observed. resistance was detected in 30% (n = 3 of 10). The absence of circulating tumor DNA mutations at TKI failure was associated with prolonged median overall survival (105.7 months). Complex -resistance mutations correlated with poor overall survival (median, 26.9 months NR for single mutation; = .003) and progression-free survival to subsequent therapy (median 1.7 6.3 months; = .003).

Conclusion: Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.19.00281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448797PMC
April 2020

Successful Switch to Vemurafenib Plus Cobimetinib After Dabrafenib Plus Trametinib Toxicity in BRAF-Mutant Metastatic Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2021 Jan 5;22(1):e54-e56. Epub 2020 Aug 5.

Medical Oncology Department, Gustave Roussy, Villejuif, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2020.07.013DOI Listing
January 2021

Circulating T-cell Immunosenescence in Patients with Advanced Non-small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy.

Clin Cancer Res 2021 Jan 4;27(2):492-503. Epub 2020 Sep 4.

Gustave Roussy Cancer Campus, Laboratory of Immunomonitoring in Oncology, CNRS-UMS 3655 and INSERM-US23, Villejuif, France.

Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non-small cell lung cancer (aNSCLC) is unknown.

Experimental Design: The percentage of CD28, CD57, KLRG1 among CD8 T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP CD8 T cells were assessed .

Results: In the ICI discovery cohort ( = 37), SIP cut-off was 39.5%, 27% of patients were SIP. In the ICI validation cohort ( = 46), SIP status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, = 0.02]. SIP status was significantly associated with circulating specific immunephenotypes, lower CD8 T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population ( = 83), SIP status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort ( = 61), 11% of patients were SIP. SIP status did not correlate with outcomes upon PCT.

Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1420DOI Listing
January 2021

Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with -Mutant Metastatic Non-Small Cell Lung Cancer.

Clin Cancer Res 2020 Dec 28;26(23):6242-6253. Epub 2020 Aug 28.

Department of Cancer Medicine, Gustave Roussy Cancer Campus, Villejuif, France.

Purpose: The limited knowledge on the molecular profile of patients with -mutant non-small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with -mutant NSCLC.

Experimental Design: This was a prospective study of 78 patients with advanced -mutant NSCLC, enrolled in 27 centers across France. Blood samples ( = 208) were collected from BRAF-TT-naïve patients ( = 47), patients nonprogressive under treatment ( = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.

Results: ctDNA was detected in 74% of BRAF-TT-naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as -mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in , and .

Conclusions: ctDNA sequencing is clinically relevant for the detection of -activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in -mutant NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-1037DOI Listing
December 2020

F-FDG PET and DCE kinetic modeling and their correlations in primary NSCLC: first voxel-wise correlative analysis of human simultaneous [18F]FDG PET-MRI data.

EJNMMI Res 2020 Jul 30;10(1):88. Epub 2020 Jul 30.

Université Paris-Saclay, CEA, CNRS, Inserm, BioMAPs, 91401, Orsay, France.

Objectives: To decipher the correlations between PET and DCE kinetic parameters in non-small-cell lung cancer (NSCLC), by using voxel-wise analysis of dynamic simultaneous [18F]FDG PET-MRI.

Material And Methods: Fourteen treatment-naïve patients with biopsy-proven NSCLC prospectively underwent a 1-h dynamic [18F]FDG thoracic PET-MRI scan including DCE. The PET and DCE data were normalized to their corresponding T-weighted MR morphological space, and tumors were masked semi-automatically. Voxel-wise parametric maps of PET and DCE kinetic parameters were computed by fitting the dynamic PET and DCE tumor data to the Sokoloff and Extended Tofts models respectively, by using in-house developed procedures. Curve-fitting errors were assessed by computing the relative root mean square error (rRMSE) of the estimated PET and DCE signals at the voxel level. For each tumor, Spearman correlation coefficients (r) between all the pairs of PET and DCE kinetic parameters were estimated on a voxel-wise basis, along with their respective bootstrapped 95% confidence intervals (n = 1000 iterations).

Results: Curve-fitting metrics provided fit errors under 20% for almost 90% of the PET voxels (median rRMSE = 10.3, interquartile ranges IQR = 8.1; 14.3), whereas 73.3% of the DCE voxels showed fit errors under 45% (median rRMSE = 31.8%, IQR = 22.4; 46.6). The PET-PET, DCE-DCE, and PET-DCE voxel-wise correlations varied according to individual tumor behaviors. Beyond this wide variability, the PET-PET and DCE-DCE correlations were mainly high (absolute r values > 0.7), whereas the PET-DCE correlations were mainly low to moderate (absolute r values < 0.7). Half the tumors showed a hypometabolism with low perfused/vascularized profile, a hallmark of hypoxia, and tumor aggressiveness.

Conclusion: A dynamic "one-stop shop" procedure applied to NSCLC is technically feasible in clinical practice. PET and DCE kinetic parameters assessed simultaneously are not highly correlated in NSCLC, and these correlations showed a wide variability among tumors and patients. These results tend to suggest that PET and DCE kinetic parameters might provide complementary information. In the future, this might make PET-MRI a unique tool to characterize the individual tumor biological behavior in NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13550-020-00671-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392998PMC
July 2020

ESMO Management and treatment adapted recommendations in the COVID-19 era: Lung cancer.

ESMO Open 2020 06;5(Suppl 3)

Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

The COVID-19 pandemic, characterised by a fast and global spread during the first months of 2020, has prompted the development of a structured set of recommendations for cancer care management, to maintain the highest possible standards. Within this framework, it is crucial to ensure no disruption to essential oncological services and guarantee the optimal care.This is a structured proposal for the management of lung cancer, comprising three levels of priorities, namely: tier 1 (high priority), tier 2 (medium priority) and tier 3 (low priority)-defined according to the criteria of the Cancer Care Ontario, Huntsman Cancer Institute and Magnitude of Clinical Benefit Scale.The manuscript emphasises the impact of the COVID-19 pandemic on lung cancer care and reconsiders all steps from diagnosis, staging and treatment.These recommendations should, therefore, serve as guidance for prioritising the different aspects of cancer care to mitigate the possible negative impact of the COVID-19 pandemic on the management of our patients.As the situation is rapidly evolving, practical actions are required to guarantee the best patients' treatment while protecting and respecting their rights, safety and well-being. In this environment, cancer practitioners have great responsibilities: provide timely, appropriate, compassionate and justified cancer care, while protecting themselves and their patients from being infected with COVID-19. In case of shortages, resources must be distributed fairly. Consequently, the following recommendations can be applied with significant nuances, depending on the time and location for their use, considering variable constraints imposed to the health systems. An exceptional flexibility is required from cancer caregivers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2020-000820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319703PMC
June 2020

Outcomes in oncogenic-addicted advanced NSCLC patients with actionable mutations identified by liquid biopsy genomic profiling using a tagged amplicon-based NGS assay.

PLoS One 2020 11;15(6):e0234302. Epub 2020 Jun 11.

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

Circulating tumor DNA (ctDNA)-based molecular profiling is rapidly gaining traction in clinical practice of advanced cancer patients with multi-gene next-generation sequencing (NGS) panels. However, clinical outcomes remain poorly described and deserve further validation with personalized treatment of patients with genomic alterations detected in plasma ctDNA. Here, we describe the outcomes, disease control rate (DCR) at 3 months and progression-free survival (PFS) in oncogenic-addicted advanced NSCLC patients with actionable alterations identified in plasma by ctDNA liquid biopsy assay, InVisionFirst®-Lung. A pooled retrospective analysis was completed of 81 advanced NSCLC patients with all classes of alterations predicting response to current FDA approved drugs: sensitizing common EGFR mutations (78%, n = 63) with T790M (73%, 46/63), ALK / ROS1 gene fusions (17%, n = 14) and BRAF V600E mutations (5%, n = 4). Actionable driver alterations detected in liquid biopsy were confirmed by prior tissue genomic profiling in all patients, and all patients received personalized treatment. Of 82 patients treated with matched targeted therapies, 10% were at first-line, 41% at second-line, and 49% beyond second-line. Acquired T790M at TKI relapse was detected in 73% (46/63) of patients, and all prospective patients (34/46) initiated osimertinib treatment based on ctDNA results. The 3-month DCR was 86% in 81 evaluable patients. The median PFS was of 14.8 months (12.1-22.9m). Baseline ctDNA allelic fraction of genomic driver did not correlate with the response rate of personalized treatment (p = 0.29). ctDNA molecular profiling is an accurate and reliable tool for the detection of clinically relevant molecular alterations in advanced NSCLC patients. Clinical outcomes with targeted therapies endorse the use of liquid biopsy by amplicon-based NGS ctDNA analysis in first line and relapse testing for advanced NSCLC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234302PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289417PMC
August 2020

Clarification of Definitions of Hyperprogressive Disease During Immunotherapy for Non-Small Cell Lung Cancer.

JAMA Oncol 2020 07;6(7):1039-1046

UMR (Unité Mixte de Recherche) 1281, Université Paris-Saclay, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Commissariat à l'énergie Atomique et Aux Énergies Alternatives, Laboratoire d'Imagerie Biomédicale Multimodale Paris-Saclay, Villejuif, France.

Importance: Hyperprogressive disease (HPD) is an aggressive pattern of progression reported for patients treated with programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1) inhibitors as a single agent in several studies. However, the use of different definitions of HPD introduces the risk of describing different tumoral behaviors.

Objective: To assess the accuracy of each HPD definition to identify the frequency of HPD and the association with poorer outcomes of immune-checkpoint inhibitor (ICI) treatment in patients with advanced non-small cell lung cancer (NSCLC) and to provide an optimized and homogenized definition based on all previous criteria for identifying HPD.

Design, Setting, And Participants: This retrospective cohort study included 406 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors from November 1, 2012, to April 5, 2017, in 8 French institutions. Measurable lesions were defined using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria on at least 2 computed tomographic scans before the initiation of ICI therapy and 1 computed tomographic scan during treatment. Data were analyzed from November 1, 2012, to August 1, 2019.

Exposures: Advanced NSCLC and treatment with PD-1/PD-L1 inhibitors.

Main Outcomes And Measures: Association of the definition with the related incidence and the HPD subset constitution and the association between each HPD definition and overall survival. All dynamic indexes used in the previous proposed definitions, such as the tumor growth rate (TGR) or tumor growth kinetics (TGK), were calculated before and during treatment.

Results: Among the 406 patients with NSCLC included in the analysis (259 male [63.8%]; median age at start of ICI treatment, 64 [range, 30-91] years), the different definitions resulted in incidences of the HPD phenomenon varying from 5.4% (n = 22; definition based on a progression pace >2-fold and a time to treatment failure of <2 months) to 18.5% (n = 75; definition based on the TGR ratio). The concordance between these different definitions (using the Jaccard similarity index) varied from 33.3% to 69.3%. For every definition, HPD was associated with poorer survival (range of median overall survival, 3.4 [95% CI, 1.9-8.4] to 6.0 [95% CI, 3.7-9.4] months). The difference between TGR before and during therapy (ΔTGR) was the most correlated with poor overall survival with an initial plateau for a larger number of patients and a slower increase, and it had the highest ability to distinguish patients with HPD from those with progressive disease not classified as HPD. In addition, an optimal threshold of ΔTGR of greater than 100 was identified for this distinction.

Conclusions And Relevance: The findings of this retrospective cohort study of patients with NSCLC suggest that the previous 5 definitions of HPD were not associated with the same tumor behavior. A new definition, based on ΔTGR of greater than 100, appeared to be associated with the characteristics expected with HPD (increase of the tumor kinetics and poor survival). Additional studies on larger groups of patients are necessary to confirm the accuracy and validate this proposed definition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2020.1634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290708PMC
July 2020

Non-small cell lung carcinomas with CTNNB1 (beta-catenin) mutations: A clinicopathological study of 26 cases.

Ann Diagn Pathol 2020 Jun 20;46:151522. Epub 2020 Apr 20.

Department of Pathology, Marie Lannelongue Hospital, 133 avenue de la Résistance, 92350 Le Plessis Robinson, France.

Beta-catenin, encoded by the CTNNB1 gene, plays an important role in cell proliferation. Mutations of CTNNB1 are oncogenic in several tumor types and are often associated with a nuclear abnormal expression. However, such mutations have only rarely been reported in non-small cell lung carcinomas and their clinical signification is not well described. Our study was conducted on 26 CTNNB1-mutated non-small cell lung carcinomas. Tumors were routinely tested by next generation sequencing for mutations in exon 3 of CTNNB1 gene. Twenty three cases were from a series of 925 tumors (2.48%). The hospital files and pathological data, from surgical samples (n = 16), small biopsies (n = 5) and trans-bronchial fine needle aspirations (n = 5), were reviewed. Immunohistochemistry was performed with an anti-beta-catenin antibody. There were 10 female and 16 male patients aged 52 to 83. Eleven of 25 patients were no-smoking or light smokers. Three cases were diagnosed while under treatment with EGFR tyrosine kinase inhibitor. There were 25 adenocarcinomas and 1 squamous cell carcinoma. Most adenocarcinomas had a papillary component and were TTF1-positive. One case was a well-differentiated fetal adenocarcinoma. Eleven cases (42%) with CTNNB1 mutations showed associated EGFR mutations. The frequency of CTNNB1 mutations was higher among EGFR mutated carcinomas. Immunohistochemistry showed heterogeneous nuclear or cytoplasmic abnormal expression. Our study shows that CTNNB1 mutations mostly occur in TTF1-positive adenocarcinomas with a papillary pattern. These mutations are often associated with EGFR mutations and possibly interfer in the mechanism of resistance to tyrosine kinase inhibitors. Our experience suggests that immuno-histochemistry cannot be used for screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anndiagpath.2020.151522DOI Listing
June 2020

Molecular mechanisms of resistance to BRAF and MEK inhibitors in BRAF non-small cell lung cancer.

Eur J Cancer 2020 06 6;132:211-223. Epub 2020 May 6.

Department of Cancer Medicine, Gustave Roussy Cancer Centre, Villejuif, France.

Introduction: BRAF is a confirmed therapeutic target in non-small cell lung cancer (NSCLC), as the BRAF inhibitor dabrafenib, in combination with the MEK inhibitor trametinib, is approved for the treatment of NSCLC harbouring BRAF V600E mutation. Scant evidence is available concerning the mechanisms of resistance to BRAF/MEK inhibitors in BRAF NSCLC.

Patients And Methods: Patients with BRAF NSCLC with acquired resistance to BRAF/MEK inhibitors were included in the institutional, prospective MATCH-R (from "Matching Resistance") trial and underwent tumour and liquid biopsies at the moment of radiological progression. Extensive molecular analyses were performed, including targeted next-generation sequencing (NGS), whole-exome sequencing (WES), RNA sequencing and comparative genomic hybridisation (CGH) array.

Results: Of the 11 patients included, eight had progressed on dabrafenib-trametinib combination, two on dabrafenib monotherapy and one on vemurafenib (BRAF inhibitor). Complete molecular analyses were available for seven patients, whereas an additional case had only targeted NGS and CGH array data. Among these eight patients, acquired molecular events potentially responsible for resistance were detected in three who progressed on dabrafenib-trametinib combination, that is, MEK1 K57N, RAS viral (v-ras) oncogene homolog (NRAS) Q61R and rat sarcoma viral oncogene homolog (KRAS) Q61R mutations. One patient progressing on dabrafenib monotherapy developed a PTEN frameshift mutation. No molecular hints addressing resistance emerged in the remaining four patients with analyses performed. Tumour mutational burden, evaluated by WES in seven patients, was low (median = 2.06 mutations/megabase, range = 1.57-3.75 mut/Mb).

Conclusions: Novel resistance mechanisms to BRAF/MEK inhibitors in BRAF NSCLC were identified, pointing out the recurring involvement of the MAPK pathway and guiding the development of new treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.03.025DOI Listing
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00330-020-06784-yDOI Listing
September 2020