Publications by authors named "Laurent Greillier"

86 Publications

Successful Lung Cryoablation for a Bulky Lung Carcinoma.

J Vasc Interv Radiol 2021 04;32(4):610

Department of Radiology, La Timone Hospital, Assistance Publique des Hôpitaux de Marseille, Aix Marseille Univ, LIIE, and Aix Marseille Univ, CERIMED, Marseille, France.

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http://dx.doi.org/10.1016/j.jvir.2020.10.025DOI Listing
April 2021

Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451.

J Clin Oncol 2021 Apr 8;39(12):1349-1359. Epub 2021 Mar 8.

Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.

Purpose: In extensive-disease small-cell lung cancer (ED-SCLC), response rates to first-line platinum-based chemotherapy are robust, but responses lack durability. CheckMate 451, a double-blind phase III trial, evaluated nivolumab plus ipilimumab and nivolumab monotherapy as maintenance therapy following first-line chemotherapy for ED-SCLC.

Methods: Patients with ED-SCLC, Eastern Cooperative Oncology Group performance status 0-1, and no progression after ≤ 4 cycles of first-line chemotherapy were randomly assigned (1:1:1) to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 12 weeks followed by nivolumab 240 mg once every 2 weeks, nivolumab 240 mg once every 2 weeks, or placebo for ≤ 2 years or until progression or unacceptable toxicity. Primary end point was overall survival (OS) with nivolumab plus ipilimumab versus placebo. Secondary end points were hierarchically tested.

Results: Overall, 834 patients were randomly assigned. The minimum follow-up was 8.9 months. OS was not significantly prolonged with nivolumab plus ipilimumab versus placebo (hazard ratio [HR], 0.92; 95% CI, 0.75 to 1.12; = .37; median, 9.2 9.6 months). The HR for OS with nivolumab versus placebo was 0.84 (95% CI, 0.69 to 1.02); the median OS for nivolumab was 10.4 months. Progression-free survival HRs versus placebo were 0.72 for nivolumab plus ipilimumab (95% CI, 0.60 to 0.87) and 0.67 for nivolumab (95% CI, 0.56 to 0.81). A trend toward OS benefit with nivolumab plus ipilimumab was observed in patients with tumor mutational burden ≥ 13 mutations per megabase. Rates of grade 3-4 treatment-related adverse events were nivolumab plus ipilimumab (52.2%), nivolumab (11.5%), and placebo (8.4%).

Conclusion: Maintenance therapy with nivolumab plus ipilimumab did not prolong OS for patients with ED-SCLC who did not progress on first-line chemotherapy. There were no new safety signals.
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http://dx.doi.org/10.1200/JCO.20.02212DOI Listing
April 2021

A Phase 1-2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC.

J Thorac Oncol 2021 Feb 27. Epub 2021 Feb 27.

Gustave Roussy, Villejuif, France; Espace Technologique, Paris-Saclay University, Saint-Aubin, France.

Introduction: This open-label, phase 1-2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC).

Methods: Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data.

Results: A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses.

Conclusions: Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.
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http://dx.doi.org/10.1016/j.jtho.2021.02.022DOI Listing
February 2021

Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study.

J Thorac Oncol 2021 Feb 16. Epub 2021 Feb 16.

Thoracic Oncology Department, Asklepios Fachkliniken München-Gauting, Gauting, Germany.

Introduction: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated.

Methods: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS).

Results: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6-7.3) in the Rova-T arm and 8.6 months (7.7-10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports.

Conclusions: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.
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http://dx.doi.org/10.1016/j.jtho.2021.02.009DOI Listing
February 2021

First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial.

Lancet 2021 01 21;397(10272):375-386. Epub 2021 Jan 21.

Bichat-Claude Bernard University Hospital, AP-HP, Université de Paris, Paris, France.

Background: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM.

Methods: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m intravenously] plus cisplatin [75 mg/m intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual.

Findings: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression).

Interpretation: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM.

Funding: Bristol Myers Squibb.
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http://dx.doi.org/10.1016/S0140-6736(20)32714-8DOI Listing
January 2021

Impact of care pathway for nursing home residents treated for cancer: ONCO-EHPAD study.

Support Care Cancer 2021 Jan 3. Epub 2021 Jan 3.

Division of Internal Medicine, Geriatric and Therapeutic, University Hospital of Marseille (AP-HM), Marseille, France.

Purpose: Few data are known about cancer management in frail nursing home residents.

Methods: Objective of our prospective, interventional study was to set up in the Marseille area, a care pathway for nursing homes residents with a suspected cancer. It combined cancer diagnosis procedures and comprehensive geriatric assessment (CGA), both made in our geriatric oncology outpatient unit, before oncologic advice for treatment decision. In standard care, CGA is carried out after therapeutic decision, to determine whether the planned treatment is compatible with the patient's frailties. CGA and quality of life were performed at enrolment and at 6 months. This study was registered in ClinicalTrials.gov (NCT03103659).

Results: Between April 2017 and March 2020, 48 residents from 38 nursing homes were included: 24 had the care pathway (PP), and 24 the standard care (NPP). Six were excluded (no cancer). PP had more frailties than NPP. All PP and 75% of NPP had outpatient care. Curative treatment was given to 77% of NPP (including chemotherapy in 10 cases), and 25% of PP (surgery, radiotherapy, hormone therapy). A majority of PP (75%) had supportive care. At 6 months, 16 patients died (11 NPP, 5 PP). Quality of life evolution was available for 11 PP and 7NPP: it showed stability in PP and degradation in NPP.

Conclusion: Even if part of residents were too frail to get curative treatment, the care pathway enabled them to benefit from oncologic advice and appropriate supportive care while preserving their quality of life. Further investigations are needed to confirm these findings.
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http://dx.doi.org/10.1007/s00520-020-05973-1DOI Listing
January 2021

Early-stage non-small cell lung cancer beyond life expectancy: Still not too old for surgery?

Lung Cancer 2021 02 14;152:86-93. Epub 2020 Dec 14.

Public Health Department Research, Unit EA3279, Aix-Marseille University, 27 Bd Jean Moulin, 13385, Marseille, France.

Objective: We investigated on the benefit/risk ratio of surgery in octogenarians with early-stage non-small cell lung cancer (NSCLC).

Material And Methods: From 2005-2020, 100 octogenarians were operated on for a clinical stage IA to IIA NSCLC. All patients had undergone whole body PET -scan and brain imaging. Operability was assessed according to current guidelines regarding the cardiopulmonary function. Since 2015, patients followed a dedicated geriatric evaluation pathway. Minimally invasive approaches were used in 66 patients, and a thoracotomy in 34.

Results: Clavien-Dindo grade ≥ 4 complications occurred in 15 patients within 90 days, including 7 fatalities. At multivariable analysis, the number of co-morbidities was their single independent prognosticator. Following resection, 24 patients met pathological criteria for adjuvant therapy among whom 3 (12.5 %) received platinum-based chemotherapy. Five-year survival rates were overall (OS) 47 ± 6.3 %, disease-free (DFS) 77.6 ± 5.1 %, and lung cancer-specific (CSS) 74.7 ± 6.3 %. Diabetes mellitus impaired significantly long-term outcomes in these 3 dimensions. OS was improved since the introduction of a dedicated geriatric assessment pathway (72.3 % vs. 6.4 %, P = 0.00002), and when minimally invasive techniques were used (42.3 % vs. 11.3 %; P = 0.02). CSS was improved by the performance of systematic lymphadenectomy (55.3 % vs. 26.9 %; P = 0.04). Multivariable and recursive partitioning analyses showed that a decision tree could be built to predict overall survival on the basis of diabetes mellitus, high co-morbidity index and low ppoDLCO values.

Conclusions: The introduction of a dedicated geriatric assessment pathway to select octogenarians for lung cancer surgery was associated with OS values that are similar to outcomes in younger patients. The use of minimally invasive surgery and the performance of systematic lymphadenectomy were also associated with improved long-term survival. Octogenarians with multiple co-morbid conditions, diabetes mellitus, or low ppo DLCO values may be more appropriately treated with SBRT.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.009DOI Listing
February 2021

Circulating Tumor DNA as a Prognostic Determinant in Small Cell Lung Cancer Patients Receiving Atezolizumab.

J Clin Med 2020 Nov 27;9(12). Epub 2020 Nov 27.

Department of Thoracic Oncology, Montpellier Regional University Hospital, 34090 Montpellier, France.

Background: The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients who benefited from atezolizumab.

Methods: 68 patients were included in this study: 46 patients were treated with atezolizumab and 22 with conventional chemotherapy. Circulating DNA was extracted from plasma and NGS (Next Generation Sequencing) looked for mutations in the , and genes. ctDNA was detectable when at least one somatic mutation was identified, and its relative abundance was quantified by the variant allele fraction (VAF) of the most represented mutation.

Results: We found that 49/68 patients (70.6%) had detectable baseline ctDNA. The most frequently identified mutations were TP53 (32/49; 65.3%) and RB1 (25/49; 51.0%). Patients with detectable ctDNA had a significantly lower disease control rate at week 6 compared with patients with no detectable ctDNA, regardless of the nature of the treatment. Detection of ctDNA was associated with a poor OS prognosis. The detection of ctDNA at a relative abundance greater than the median value was significantly associated with poor overall survival (OS) and progression free survival (PFS). Interestingly, the benefit in overall survival (OS) associated with low ctDNA was more pronounced in patients treated with atezolizumab than in patients receiving chemotherapy. Among patients whose relative ctDNA abundance was below the median, those treated with atezolizumab tended to have higher OS than those in the chemotherapy arm.

Conclusion: ctDNA is strongly associated with the prognosis of SCLC patients treated with second-line immunotherapy. Its analysis seems justified for future SCLC clinical trials.
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http://dx.doi.org/10.3390/jcm9123861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760916PMC
November 2020

Octogenarians treated for thoracic and lung cancers: Impact of comprehensive geriatric assessment.

J Geriatr Oncol 2021 Apr 21;12(3):402-409. Epub 2020 Oct 21.

Multidisciplinary Oncology and Therapeutic Innovations Department, AP-HM, Marseille, France; Aix-Marseille Univ, CNRS, INSERM, CRCM, Marseille, France.

Background: Lung cancer affects older and older old adults and is the leading cause of death by cancer. Comprehensive Geriatric Assessment (CGA) is recommended before and during cancer treatment to guide therapy management in this population.

Methods: This study was conducted between September 2015 and January 2019 at Marseille University Hospital (AP-HM). During this period, all consecutive outpatients 70 years or older referred for a CGA before initiation of lung cancer treatment were enrolled. The objective of this study was to compare lung and thoracic cancer management of octogenarians (≥80 years) and their geriatric profile versus patients aged 70 to 79 years (<80 years).

Findings: In our study, 228 patients were recruited. The median age was 78.7 ± 5 years. There were 94 octogenarians (41.2%), 36.2% of them were diagnosed with stage IV neoplasm and the most common treatment was chemotherapy (43.6%). The logistic regression analysis highlights that handgrip strength was the most commonly impaired domain (OR 2.3; 95% CI [1.3-4.3]) in octogenarians and that they are more likely than their younger counterparts to be treated by targeted therapy (OR 9.8; 95% CI [1.0-92.9]). Overall survival (OS) was similar in both age groups (log rank = 0,95).

Interpretation: In our study, octogenarians and patients <80 years had equivalent survival, across the different thoracic cancer treatments and tumor stages. Measure of muscle strength in CGA could be very useful in a clinical setting to help improve the management of older old patients treated for lung or thoracic cancer.
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http://dx.doi.org/10.1016/j.jgo.2020.10.005DOI Listing
April 2021

Medication Reconciliation Associated with Comprehensive Geriatric Assessment in Older Patients with Cancer: ChimioAge Study.

Clin Interv Aging 2020 8;15:1587-1598. Epub 2020 Sep 8.

Pharmacology Department, AP-HM, Marseille, France.

Background: Polymorbidity induces polypharmacy in older patients may lead to potential drug-drug interactions (DDI) which can modify the tolerance and safety of oncological treatments and alter the intended therapeutic effect. The objective of our study was to describe the decision-making process for oncological treatment and related outcomes, in a population of older adults undergoing a comprehensive geriatric assessment (CGA) associated to a comprehensive medication reconciliation (CMR) prior to initiating oncological treatment.

Methods: ChimioAge is a prospective observational study conducted between 01/2017 and 07/2018 at Marseille University Hospital and approved by the French National Ethics Committee. It comprised all consecutive patients aged 70 years and over who were referred for a CGA as part of CMR, before initiating systemic treatment.

Results: One hundred and seventy-one cancer patients were included. Mean age was 79.2 years, over half had metastatic cancers, 75% had an ECOG performance status zero or one, and two-thirds were independent in daily activities. Two-thirds of the patients had polypharmacy and the CMR identified potential DDI with systemic treatment in 43.3% of patients. Following the CGA, the CMR and the hospital oncologists decision, 30% of the patients received adapted systemic treatment with reduced doses at initiation. They presented fewer toxicities - irrespective of grade and type - than patients who received standard treatment (p<0.001) and had comparable overall survival (Log rank p=0.21).

Conclusion: This is one of the first studies to highlight the value in conducting CMR and a CGA simultaneously before initiating systemic treatment in older patients with cancer. These two evaluations could give oncologists decisive information to personalize cancer treatment of older patients and optimize treatment dose to offer the best efficacy and minimize toxicity.
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http://dx.doi.org/10.2147/CIA.S262209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489933PMC
January 2021

[Predictable toxicities with futures immunotherapies or combinations].

Bull Cancer 2020 Oct 22;107(10):1069-1078. Epub 2020 Sep 22.

AP-HM, CNRS, Inserm, CRCM, Aix-Marseille université, hôpital Nord, service d'oncologie multidisciplinaire et innovations thérapeutiques, chemin des Bourrely, 13915 Marseille cedex, France. Electronic address:

Immunotherapy by immune check-points inhibitors (ICIs) recently improved many solid tumors survival data. ICIs target and inhibit down-regulation signals between T cells and tumor cells involved in carcinogenesis, in order to enhance anti-tumor immunity. With few years' hindsight of ICIs utilization in daily practice, we learned about their safety profile. By releasing the brakes of the host immune-system, ICIs exposure leads to on-target off-tumor immune related adverse events (IRAEs). Compared to standard chemotherapiy regimens, IRAEs remain rare, but sometimes serious and compromising treatment continuation, mostly despite objective tumor response. Several immunotherapy molecules are currently developed, with various mechanisms of action but always targeting the immune anti-tumor response. New drugs imply new safety profiles, especially since a lot of ongoing clinical trials are assessing combination of multiples drugs. Consequently, a good knowledge and management of these new toxicities will be essential to choose the new therapeutic schedules in many tumor types. Indeed, despite the actual poor prognosis of concerned tumor types, the progressive outcomes improvement implies long-term exposure to treatments. Safety and quality of life under treatment will become key endpoints for therapeutic decision.
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http://dx.doi.org/10.1016/j.bulcan.2020.07.004DOI Listing
October 2020

Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial.

Lancet Oncol 2020 09;21(9):1224-1233

Service de Pneumologie, CHI Créteil, Créteil, France; Institut Mondor de Recherche Biomédicale, U955 Inserm-Université Paris Est Créteil, Créteil, France. Electronic address:

Background: Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer.

Methods: In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m from day 1 to day 3]) or oral topotecan (2·3 mg/m from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346.

Findings: Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0-37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9-5·5 vs 2·7 months, 2·3-3·2; stratified hazard ratio 0·57, 90% CI 0·41-0·73; p=0·0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group.

Interpretation: Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer.

Funding: Amgen and the French Lung Cancer Group (Groupe Français de Pneumo-Cancérologie).
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http://dx.doi.org/10.1016/S1470-2045(20)30461-7DOI Listing
September 2020

Immune Oncology Biomarkers in Lung Cancer: an Overview.

Curr Oncol Rep 2020 Aug 15;22(11):107. Epub 2020 Aug 15.

CNRS, INSERM, CRCM, APHM, Multidisciplinary Oncology & Therapeutic Innovations Department, Aix Marseille University, Marseille, France.

Purpose Of Review: Lung cancer is still the first cause of cancer-related deaths worldwide. The development of immune checkpoint inhibitors (ICI) has drastically changed the prognosis of some patients, but the rate of long responders does not exceed 20%. Moreover, ICIs are not adverse events-free and remain expensive. Therefore, predictive biomarkers of long-term benefit to ICI are required.

Recent Findings: The two main fields being evaluated currently are PD-L1 expression and tumor mutational burden (TMB). The first one is the only one used in routine practice, and the second is being evaluated in phase 3 clinical trials. In addition, other biomarkers are being assessed as complex signatures, tumor-infiltrated lymphocytes, T cell receptor repertoire, or molecular profiling. The aim of this review is to summarize the current validated or promising biomarkers in lung cancer which could help to better select patients who will respond to ICI.
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http://dx.doi.org/10.1007/s11912-020-00970-3DOI Listing
August 2020

High Serum Vitamin B12 Levels Associated with C-Reactive Protein in Older Patients with Cancer.

Oncologist 2020 12 19;25(12):e1980-e1989. Epub 2020 Aug 19.

Hematology and Cellular Therapy Department, Assistance Publique-Hôpitaux de Marseille (AP-HM), Marseille, France.

Background: A Comprehensive Geriatric Assessment (CGA) has been proposed to assess prognosis and to adapt oncological care in older patients with cancer. However, few biological markers are incorporated in the CGA.

Methods: This comparative study on older patients with cancer was realized before final therapeutic decision and during a CGA that included biological markers. Our objective study was to know if the serum vitamin B12-C-reactive protein index (BCI) can help to estimate early death and unplanned hospitalization. Associations between BCI and unplanned hospitalization or mortality were analyzed using ordered multivariate logistic regression.

Findings: We included 621 older cancer adults in outpatient care with a median age of 81 years (range, 70-98 years) from September 2015 to May 2018. In this study, 5.6% of patients died within 3 months, 8.8% had unplanned hospitalization within 1 month, and 11.4% had unplanned hospitalization within 3 months. Hypercobalaminemia was present in 83 patients (13.4%), and 34 patients (5.5%) had BCI >40,000. According to the multivariate analysis, BCI was a prognostic factor of mortality within 3 months and unplanned hospitalizations at 1 and 3 months. Impaired activities of daily living (ADL) and palliative care were also risk factors for mortality within 3 months. Impaired instrumental ADL, low albumin level, and palliative care were risk factors for unplanned hospitalization at 1 month.

Interpretation: BCI could be routinely added to the CGA process, as part of a pretreatment workup, in order to assess more precisely the frailties and to adapt oncological care in older patients treated for cancer.

Implications For Practice: Aging comes with an increase of frailties and comorbidities. To identify frailties in older patients with cancer, this study used a Comprehensive Geriatric Assessment, which allowed for the adaptation of each treatment plan in accordance with the individual needs of the patients. However, biological characteristics were not included in this assessment. This study showed that hypercobalaminemia and vitamin B12 -C-reactive protein index may be potential markers for cancer with poor prognosis, particularly in the older population. These biological markers can be used in geriatric oncology and general medicine.
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http://dx.doi.org/10.1634/theoncologist.2019-0894DOI Listing
December 2020

Antibody-Drug Conjugates in Thoracic Malignancies: Clinical Trials Reveal Both Promise and Challenges.

Target Oncol 2020 08;15(4):429-448

Aix-Marseille Université, Laboratoire de Pharmaco-Chimie Radicalaire, CNRS, Institut de Chimie Radicalaire ICR, UMR 7273, 13005, Marseille, France.

Thoracic malignancies are the main cause of cancer-related deaths worldwide. The need to develop new therapies is therefore urgent. The recognition of new potential therapeutic targets in thoracic malignancies has prompted the development of a number of antibody-drug conjugates. This new class of potent anticancer agents is supposed to more specifically and directly target the tumor while limiting toxicity for healthy tissues by delivering a toxic payload to tumor cells that are recognized by the presence of specific cell surface antigens. Progress in the development of antibody-drug conjugates over the last decade has been significant, with several promising advances. Unfortunately, many failures have also been encountered, often because of unexpectedly severe toxicities that contradicted the assumed mechanism of action, and major challenges remain. Various techniques to reduce the toxicities associated with antibody-drug conjugates are being studied, and the panorama of antibody-drug conjugates in clinical stages continues to increase and evolve. Current efforts in the conjugation and linker chemistries could result in the successful construction of clinically effective compounds. The future clinical development of antibody-drug conjugates could benefit from the identification of such payloads that can provide more safe and effective derivatives. Highly potent compounds with reasonable aqueous solubility, non-immunogenic profile, and stability in storage and the bloodstream should be important aspects of research into cytotoxic payloads.
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http://dx.doi.org/10.1007/s11523-020-00740-yDOI Listing
August 2020

Older Patients Treated for Lung and Thoracic Cancers: Unplanned Hospitalizations and Overall Survival.

Clin Lung Cancer 2020 Jun 12. Epub 2020 Jun 12.

Multidisciplinary Oncology and Therapeutic Innovations Department, AP-HM, Marseille, France; Aix-Marseille University, CNRS, INSERM, CRCM, Marseille, France.

Background: Lung cancer affects older adults and is the leading solid tumor in terms of death. A Comprehensive Geriatric Assessment (CGA) is recommended before cancer treatment to guide therapy management.

Patients And Methods: This study was conducted between September 2015 and January 2019. During this period of time, all consecutive older outpatients referred for a CGA before initiation of lung or thoracic tumor treatment were included. The objectives were to describe the impact of geriatric factors on unplanned hospitalizations and overall survival (OS). The study was approved by a local ethics committee.

Results: Overall, 228 patients were recruited. The median age was 78.7 ± 5 years. The majority (82%) of patients were diagnosed with non-small-cell lung cancer, and the most common (40.4%) treatment was systemic therapy. In multivariate analysis, factors associated with unplanned hospitalizations within the first 3 months were male gender (adjusted odds ratio [aOR], 3.3; 95% confidence interval [CI], 1.5-7.2), systemic therapy (aOR, 2.6; 95% CI, 1.1-6.2), and fall history (aOR, 3.6; 95% CI, 1.6-8.2). Factors associated with a decrease in OS in the multivariate Cox model analysis were male gender (hazard ratio [HR], 3.9; 95% CI, 2.1-7.3), stage IV (HR, 1.6; 95% CI, 1.0-2.6), G8 ≤ 14 (HR, 3.5; 95% CI, 1.1-11.4), systemic therapy (HR, 2.6; 95% CI, 1.2-5.5), Eastern Cooperative Oncology Group performance status ≥ 2 (HR, 2.0; 95% CI, 1.2-3.4), and impaired handgrip strength (HR, 1.6; 95% CI, 1.0-2.5).

Conclusion: G8 score and handgrip strength are important to predict OS in older adults treated for thoracic tumors. In the CGA, fall history was associated with unplanned hospitalization.
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http://dx.doi.org/10.1016/j.cllc.2020.06.004DOI Listing
June 2020

ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma.

Eur Respir J 2020 06 11;55(6). Epub 2020 Jun 11.

Dept of Radiation Oncology, Kantonsspital St Gallen, St Gallen, Switzerland.

The European Respiratory Society (ERS)/European Society of Thoracic Surgeons (ESTS)/European Association for Cardio-Thoracic Surgery (EACTS)/European Society for Radiotherapy and Oncology (ESTRO) task force brought together experts to update previous 2009 ERS/ESTS guidelines on management of malignant pleural mesothelioma (MPM), a rare cancer with globally poor outcome, after a systematic review of the 2009-2018 literature. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. The evidence syntheses were discussed and recommendations formulated by this multidisciplinary group of experts. Diagnosis: pleural biopsies remain the gold standard to confirm the diagnosis, usually obtained by thoracoscopy but occasionally image-guided percutaneous needle biopsy in cases of pleural symphysis or poor performance status. Pathology: standard staining procedures are insufficient in ∼10% of cases, justifying the use of specific markers, including and () for the separation of atypical mesothelial proliferation from MPM. Staging: in the absence of a uniform, robust and validated staging system, we advise using the most recent 2016 8th TNM (tumour, node, metastasis) classification, with an algorithm for pre-therapeutic assessment. Monitoring: patient's performance status, histological subtype and tumour volume are the main prognostic factors of clinical importance in routine MPM management. Other potential parameters should be recorded at baseline and reported in clinical trials. Treatment: (chemo)therapy has limited efficacy in MPM patients and only selected patients are candidates for radical surgery. New promising targeted therapies, immunotherapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres.
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http://dx.doi.org/10.1183/13993003.00953-2019DOI Listing
June 2020

ERS/ESTS/EACTS/ESTRO guidelines for the management of malignant pleural mesothelioma.

Eur J Cardiothorac Surg 2020 07;58(1):1-24

Unit of Thoracic Surgery, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy.

The European Respiratory Society (ERS)/European Society of Thoracic Surgeons (ESTS)/European Association for Cardio-Thoracic Surgery (EACTS)/European Society for Radiotherapy and Oncology (ESTRO) task force brought together experts to update previous 2009 ERS/ESTS guidelines on management of malignant pleural mesothelioma (MPM), a rare cancer with globally poor outcome, after a systematic review of the 2009-2018 literature. The evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. The evidence syntheses were discussed and recommendations formulated by this multidisciplinary group of experts. Diagnosis: pleural biopsies remain the gold standard to confirm the diagnosis, usually obtained by thoracoscopy but occasionally via image-guided percutaneous needle biopsy in cases of pleural symphysis or poor performance status. Pathology: standard staining procedures are insufficient in ∼10% of cases, justifying the use of specific markers, including BAP-1 and CDKN2A (p16) for the separation of atypical mesothelial proliferation from MPM. Staging: in the absence of a uniform, robust and validated staging system, we advise using the most recent 2016 8th TNM (tumour, node, metastasis) classification, with an algorithm for pretherapeutic assessment. Monitoring: patient's performance status, histological subtype and tumour volume are the main prognostic factors of clinical importance in routine MPM management. Other potential parameters should be recorded at baseline and reported in clinical trials. Treatment: (chemo)therapy has limited efficacy in MPM patients and only selected patients are candidates for radical surgery. New promising targeted therapies, immunotherapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasize that patients who are considered candidates for a multimodal approach, including radical surgery, should be treated as part of clinical trials in MPM-dedicated centres.
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http://dx.doi.org/10.1093/ejcts/ezaa158DOI Listing
July 2020

First-line carboplatin plus pemetrexed with pemetrexed maintenance in HIV-positive patients with advanced non-squamous non-small cell lung cancer: the phase II IFCT-1001 CHIVA trial.

Eur Respir J 2020 08 27;56(2). Epub 2020 Aug 27.

Service de Pneumologie, Assistance Publique - Hôpitaux de Paris (Hôpital Tenon) and Sorbonne Université, Paris, France.

HIV infection is an exclusion criterion in lung cancer trials. This multicentre phase II trial aimed to assess feasibility, efficacy and safety of first-line carboplatin plus pemetrexed (CaP) followed by pemetrexed (P) maintenance in people living with HIV (PLHIV) with advanced non-squamous non-small cell lung cancer (NS-NSCLC).Four cycles of CaP were followed by P-maintenance therapy in patients with Eastern Cooperative Oncology Group performance status ≤2. The primary objective was a disease control rate (DCR) ≥30% after 12 weeks.Of the 61 PLHIV enrolled, 49 (80%) had a performance status of 0-1, and 19 (31%) had brain metastases. Median CD4 lymphocyte count was 418 cells·µL (range 18-1230), median CD4 lymphocyte nadir was 169.5 cells·µL (1-822); 48 (80%) patients were virologically controlled. Four-cycle inductions were achieved by 38 (62%) patients, and 31 (51%) started P-maintenance (median of 4.1 cycles (range 1-19)). The 12-week DCR was 50.8% (95% CI 38.3-63.4) and partial response rate 21.3%. Median progression-free survival and overall survival were 3.5 (95% CI 2.7-4.4) and 7.6 months (5.7-12.8), respectively. Patients with a performance status of 0-1 had the longest median progression-free survival (4.3 months, 95% CI 3.1-5.2) and overall survival (11.9 months, 95% CI 6.4-14.3). During induction, CaP doublet was well tolerated apart from grade 3-4 haematological toxicities (neutropenia 53.8%; thrombocytopenia 35.0%; anaemia 30.0%). Two fatal treatment-related sepses were reported. No opportunistic infections were experienced.In PLHIV with advanced NS-NSCLC, first-line four-cycle CaP induction followed by P-maintenance was effective and reasonably well-tolerated. Further studies should evaluate combination strategies of CaP with immunotherapy in PLHIV.
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http://dx.doi.org/10.1183/13993003.02066-2019DOI Listing
August 2020

Lorlatinib: an additional option for ALK-positive non-small cell lung cancer?

Transl Lung Cancer Res 2019 Dec;8(Suppl 4):S383-S386

Department of Multidisciplinary Oncology & Therapeutic Innovations, Aix Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France.

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http://dx.doi.org/10.21037/tlcr.2019.05.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987344PMC
December 2019

Targeted next-generation sequencing to assess tumor mutation burden: ready for prime-time in non-small cell lung cancer?

Transl Lung Cancer Res 2019 Dec;8(Suppl 4):S323-S326

Department of Multidisciplinary Oncology and Therapeutic Innovations, Assistance Publique Hopitaux de Marseille, Aix-Marseille University, Marseille, France.

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http://dx.doi.org/10.21037/tlcr.2019.09.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987355PMC
December 2019

EORTC Lung Cancer Group survey on the definition of NSCLC synchronous oligometastatic disease.

Eur J Cancer 2019 11 28;122:109-114. Epub 2019 Oct 28.

Department of Pulmonary Diseases, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. Electronic address:

Background: Synchronous oligometastatic disease (sOM) has been described as a distinct disease entity; however, there is no consensus on OM definition (OM-d) in non-small-cell lung cancer (NSCLC). A consensus group was formed aiming to agree on a common OM-d that could be used in future clinical trials. A European survey was circulated to generate questions and input for the consensus group meeting.

Methods: A European Organisation for Research and Treatment of Cancer Lung Cancer Group (LCG)/sOM-d consensus group survey was distributed to LCG, sOM-d consensus group, and several European thoracic oncology societies' members.

Results: 444 responses were analysed (radiation oncologist: 55% [n = 242], pulmonologist: 15% [n = 66], medical oncologist: 14% [n = 64]). 361 physicians (81%) aimed to cure sOM NSCLC patients and 82% (n = 362) included the possibility of radical intent treatment in their sOM-d. The maximum number of metastases considered in sOM-d varied: 12% replied 1 metastasis, 42% ≤ 3, and 17% ≥ 5 metastases. 79% (n = 353) stated that number of organs involved was important for sOM-d, and most (80%, n = 355) considered that only ≤3 involved organs (excluding primary) should be included. 317 (72%) included mediastinal lymph node involvement in the sOM-d and 22% (n = 70/317) counted mediastinal lymph node as a metastatic site. Most physicians completed sOM staging with brain magnetic resonance imaging (91%, n = 403) and positron emission tomography/computed tomography (98%, n = 437). Pathology proof of metastatic disease was a requirement to define sOM for 315 (71%) physicians. The preferred primary outcome for sOM clinical trials was overall survival (73%, n = 325).

Conclusion: Although consensual answers were obtained, several issues remain unresolved and will require further research to agree on a sOM-d.
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http://dx.doi.org/10.1016/j.ejca.2019.09.012DOI Listing
November 2019

Efficacy and Safety of Rovalpituzumab Tesirine in Third-Line and Beyond Patients with DLL3-Expressing, Relapsed/Refractory Small-Cell Lung Cancer: Results From the Phase II TRINITY Study.

Clin Cancer Res 2019 12 10;25(23):6958-6966. Epub 2019 Sep 10.

Ohio State University, Columbus, Ohio.

Purpose: Although extensive-stage small-cell lung cancer (SCLC) is highly responsive to first-line therapy, virtually all patients develop resistance with short survival. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting delta-like 3 protein (DLL3). This open-label, single-arm, phase II study (TRINITY) assessed safety and efficacy of Rova-T in patients with DLL3-expressing SCLC in the third-line and beyond (3L+) setting.

Patients And Methods: Patients with DLL3-expressing SCLC (determined by mouse antibody immunohistochemistry [IHC] assay), and ≥2 prior regimens, received 0.3 mg/kg Rova-T once every 6 weeks for two cycles. During study, a rabbit antibody IHC assay was developed and used for the final analysis, with DLL3-positive and DLL3-high defined as ≥25% and ≥75% of tumor cells positive for DLL3, respectively. The primary endpoints were objective response rate (ORR) and overall survival (OS).

Results: Among 339 patients enrolled, 261 (77%) had two prior lines of therapy and 78 (23%) had ≥3. DLL3-high and DLL3-positive tumors by rabbit IHC were seen in 238 (70%) and 287 (85%) patients, respectively. The remaining 52 (15%) were DLL3-negative only by rabbit IHC or had missing results. ORR was 12.4%, 14.3%, and 13.2% in all, DLL3-high, and DLL3-positive patients, respectively. Median OS was 5.6 months in all patients and 5.7 months in DLL3-high patients. The most common adverse events (AE) were fatigue, photosensitivity reaction, and pleural effusion. Grade 3-5 AEs were seen in 213 (63%) patients.

Conclusions: Rova-T is the first targeted agent in SCLC to use DLL3, a novel biomarker. However, results demonstrate modest clinical activity in 3L+ SCLC, with associated toxicities.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105795PMC
December 2019

Definition of Synchronous Oligometastatic Non-Small Cell Lung Cancer-A Consensus Report.

J Thorac Oncol 2019 12 6;14(12):2109-2119. Epub 2019 Aug 6.

Oncology Department, University of Turin, AOU San Luigi, Orbassano (TO), Italy.

Introduction: Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process.

Methods: A pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting.

Results: It was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography-computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography-computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits.

Conclusion: A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials.
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http://dx.doi.org/10.1016/j.jtho.2019.07.025DOI Listing
December 2019

Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort.

Clin Lung Cancer 2019 09 13;20(5):e564-e575. Epub 2019 May 13.

Normandie Université, UNICAEN, CEA, CNRS, ISTCT/CERVOxy Group, GIP CYCERON, Caen, France; Department of Pathology, CHU de Caen, Caen, France.

Background: Anticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456).

Patients And Methods: Tumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables.

Results: PD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1-expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1-stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1-positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047).

Conclusion: Although high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.
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http://dx.doi.org/10.1016/j.cllc.2019.04.010DOI Listing
September 2019

Health-Related Quality of Life Impact from Adding Bevacizumab to Cisplatin-Pemetrexed in Malignant Pleural Mesothelioma in the MAPS IFCT-GFPC-0701 Phase III Trial.

Clin Cancer Res 2019 10 7;25(19):5759-5765. Epub 2019 Jun 7.

Department of Thoracic Oncology, Centre d'investigation clinique Institut national de la santé et de la recherche médicale 1425, Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris-Diderot University (Paris 7), Paris, France.

Purpose: The IFCT-GFPC-0701 MAPS phase III trial highlighted significant improvement in overall survival from adding bevacizumab to the standard first-line chemotherapy regimen [cisplatin plus pemetrexed (PC)] in advanced malignant pleural mesothelioma (MPM). We present the results of health-related quality of life (HRQoL), a secondary endpoint of MAPS.

Patients And Methods: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 and the lung cancer-specific module QLQ-LC13 at randomization and then every 9 weeks until disease progression.HRQoL deterioration-free survival (QFS), used to analyze longitudinal HRQoL data, was defined as the interval between randomization and the occurrence of the first clinically relevant definitive deterioration compared with the HRQoL score at baseline, or death.

Results: A total of 448 patients were included in the MAPS trial between 2008 and 2014. At baseline, 425 patients (94.8%) completed the HRQoL questionnaire. We report that adding bevacizumab to cisplatin and pemetrexed (PCB) significantly improved QFS for the peripheral neuropathy dimension, with a median QFS of 12.09 months [95% confidence interval (CI), 9.59-13.67] in the PCB arm versus 7.59 months (95% CI, 6.57-8.61) in the PC arm [HR (PCB vs. PC) = 0.74; 95% CI, 0.61-0.91; = 0.004]. QFS was also longer in the PCB arm for the pain dimension (HR = 0.84; 95% CI, 0.69-1.02; = 0.08).

Conclusions: This study demonstrated that adding bevacizumab to standard chemotherapy in patients with advanced MPM had no negative impact on HRQoL. A significant improvement in the peripheral neuropathy and pain HRQoL dimensions was even observed.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2860DOI Listing
October 2019

Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases.

Ther Adv Respir Dis 2019 Jan-Dec;13:1753466619831906

Service d'Oncologie Multidisciplinaire et Innovations Thérapeutiques, Hôpital Nord, Chemin des Bourrely, 13915 Marseille Cedex, FranceAix Marseille University, APHM, CNRS, INSERM, CRCM, Hôpital Nord, Oncologie Multidisciplinaire et Innovations Thérapeutiques, Marseille, France.

Molecular profiling of metastatic nonsquamous non-small cell lung cancer (NSCLC) is required to guide the treatment strategy. Anaplastic lymphoma kinase ( ALK) gene rearrangements are found in approximately 5% of lung adenocarcinomas and are associated with specific clinical features including a high risk of brain metastases. Crizotinib was the first ALK inhibitor developed and it demonstrated improved outcomes in patients with ALK-positive advanced NSCLC in comparison with chemotherapy. However, despite an initial response, all ALK-positive NSCLC patients develop acquired resistance to crizotinib. Because the most frequent mechanism of resistance is the development of a secondary ALK mutation, second (ceritinib, alectinib, brigatinib) and third-generation (lorlatinib) ALK inhibitors were developed. Alectinib is a second-generation ALK inhibitor and was shown to be effective for a broad spectrum of ALK rearrangements and ALK mutations. It was also shown to have high intracranial efficacy. In this article, we review clinical trial evidence of alectinib efficacy as well as publications reporting the experience of alectinib in daily practice, with a focus on brain metastases.
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http://dx.doi.org/10.1177/1753466619831906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385324PMC
August 2019

MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial.

Br J Cancer 2019 02 11;120(4):387-397. Epub 2019 Feb 11.

Department of Thoracic Oncology & CIC1425, Hôpital Bichat-Claude Bernard, Assistance Publique Hôpitaux de Paris, Université Paris-Diderot, Paris, France.

Background: The Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS/NCT00651456) phase 3 trial demonstrated the superiority of bevacizumab plus pemetrexed-cisplatin triplet over chemotherapy alone in 448 malignant pleural mesothelioma (MPM) patients. Here, we evaluated the prognostic role of Hippo pathway gene promoter methylation.

Methods: Promoter methylations were assayed using methylation-specific polymerase chain reaction in samples from 223 MAPS patients, evaluating their prognostic value for overall survival (OS) and disease-free survival in univariate and multivariate analyses. MST1 inactivation effects on invasion, soft agar growth, apoptosis, proliferation, and YAP/TAZ activation were investigated in human mesothelial cell lines.

Results: STK4 (MST1) gene promoter methylation was detected in 19/223 patients tested (8.5%), predicting poorer OS in univariate and multivariate analyses (adjusted HR: 1.78, 95% CI (1.09-2.93), p = 0.022). Internal validation by bootstrap resampling supported this prognostic impact. MST1 inactivation reduced cellular basal apoptotic activity while increasing proliferation, invasion, and soft agar or in suspension growth, resulting in nuclear YAP accumulation, yet TAZ cytoplasmic retention in mesothelial cell lines. YAP silencing decreased invasion of MST1-depleted mesothelial cell lines.

Conclusions: MST1/hippo kinase expression loss is predictive of poor prognosis in MPM patients, leading to nuclear YAP accumulation and electing YAP as a putative target for therapeutic intervention in human MPM.
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http://dx.doi.org/10.1038/s41416-019-0379-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461894PMC
February 2019

Efficacy of Immune Checkpoint Inhibitors in KRAS-Mutant Non-Small Cell Lung Cancer (NSCLC).

J Thorac Oncol 2019 06 6;14(6):1095-1101. Epub 2019 Feb 6.

Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, France; Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Marseille, France.

Introduction: KRAS mutation is the most frequent molecular alteration found in advanced NSCLC; it is associated with a poor prognosis without available targeted therapy. Treatment options for NSCLC have been recently enriched by the development of immune checkpoint inhibitors (ICIs), and data about its efficacy in patients with KRAS-mutant NSCLC are discordant. This study assessed the routine efficacy of ICIs in advanced KRAS-mutant NSCLC.

Methods: In this retrospective study, clinical data were extracted from the medical records of patients with advanced NSCLC treated with ICIs and with available molecular analysis between April 2013 and June 2017. Analysis of programmed death ligand 1 (PD-L1) expression was performed if exploitable tumor material was available.

Results: A total of 282 patients with ICI-treated (in the first line or more) advanced NSCLC (all histological subgroups) who were treated with ICIs (anti-programmed death 1, anti-PD-L1, or anti-cytotoxic T-lymphocyte associated protein 4 antibodies), including 162 (57.4%) with KRAS mutation, 27 (9.6%) with other mutations, and 93 (33%) with a wild-type phenotype, were identified. PD-L1 analysis was available for 128 patients (45.4%), of whom 45.3% and 19.5% had PD-L1 expression of 1% or more and 50%, respectively (49.5% and 21.2%, respectively, in the case of the 85 patients with KRAS-mutant NSCLC). No significant difference was seen in terms of objective response rates, progression-free survival, or overall survival between KRAS-mutant NSCLC and other NSCLC. No significant differences in overall survival or progression-free survival were observed between the major KRAS mutation subtypes (G12A, G12C, G12D, G12V, and G13C). In KRAS-mutant NSCLC, unlike in non-KRAS-mutant NSCLC, the efficacy of ICIs is consistently higher, even though not statistically significant, for patients with PD-L1 expression in 1% or more of tumor cells than for those with PD-L1 expression in less than 1% of tumor cells, and this finding is especially true when PD-L1 expression is high (PD-L1 expression ≥50%).

Conclusion: For patients with KRAS-mutant NSCLC (all mutational subtypes), the efficacy of ICI is similar to that for patients with other types of NSCLC. PD-L1 expression seems to be more relevant for predicting the efficacy of ICIs in KRAS-mutant NSCLC than it is in other types of NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2019.01.011DOI Listing
June 2019

A Randomized Non-Comparative Phase II Study of Anti-Programmed Cell Death-Ligand 1 Atezolizumab or Chemotherapy as Second-Line Therapy in Patients With Small Cell Lung Cancer: Results From the IFCT-1603 Trial.

J Thorac Oncol 2019 05 18;14(5):903-913. Epub 2019 Jan 18.

Service de Pneumologie Aiguë Spécialisée et Cancérologie Thoracique, Centre Hospitalier Lyon, Lyon, France.

Introduction: This randomized phase II trial aimed at evaluating the engineered programmed cell death ligand 1 (PD-L1) antibody atezolizumab in SCLC progressing after first-line platinum-etoposide chemotherapy.

Methods: Patients were randomized 2:1 to atezolizumab (1200 mg intravenously every 3 weeks) until progression or unacceptable toxicity, or conventional chemotherapy (up to 6 cycles of topotecan or re-induction of initial chemotherapy). Patients were not selected based on PD-L1 tissue expression. The primary endpoint was objective response rate at 6 weeks. A two-stage design with 2:1 randomization and O'Brien-Fleming stopping rules was used. The null hypothesis was rejected if more than 12 of 45 patients were responders.

Results: Overall, 73 patients were randomized (atezolizumab n = 49; chemotherapy n = 24). At 6 weeks, 1 of 43 eligible atezolizumab patients achieved an objective response (2.3%, 95% confidence interval [CI]: 0.0-6.8), whereas 8 others had stable disease (20.9% disease control rate; 95% CI: 8.8-33.1). Among eligible chemotherapy patients (n = 20), 10% achieved an objective response (65% disease control rate). Median progression-free survival was 1.4 months (95% CI: 1.2-1.5) with atezolizumab and 4.3 months (95% CI: 1.5-5.9) with chemotherapy. Overall survival did not significantly differ between groups. Median overall survival was 9.5 months versus 8.7 months for the atezolizumab and the chemotherapy group, respectively (adjusted hazard ratio : 0.84, 95% CI: 0.45-1.58; p = 0.60). Two atezolizumab patients (4.2%) experienced grade 3 fatigue, and two others grade 1 dysthyroidism. Among 53 evaluable specimens, only 1 (2%) had positive immunohistochemical PD-L1 staining (SP142 clone).

Conclusions: Atezolizumab monotherapy in relapsed SCLC failed to show significant efficacy. No unexpected safety concerns were observed.
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http://dx.doi.org/10.1016/j.jtho.2019.01.008DOI Listing
May 2019