Real-World efficacy and safety of combination nivolumab plus ipilimumab for Untreated, Unresectable, pleural Mesothelioma: The Meso-Immune (GFPC 04-2021) trial.

BACKGROUND: First-line standard-of-care for unresectable, pleural mesothelioma (PM) changed with the phase 3 CheckMate 743 study results, showing that nivolumab plus ipilimumab (Nivo + Ipi) significantly extended overall survival (OS) versus platinum + pemetrexed chemotherapy for PM (median OS 18.1 versus 14.1 months; hazard ratio: 0.74; p = 0.002). Efficacy and safety data in real-world (rw) settings are needed to confirm these results. METHODS: This French multicenter, retrospective cohort study was undertaken to assess the outcomes of treatment-naïve PM patients given Nivo + Ipi via an early-access program (EAP). The primary objective was investigator-assessed real world -progression-free survival (PFS). The secondary objectives were the combination's -overall survival (OS) and safety. RESULTS: From 1 April 2021 to 15 Feb 2022, the analysis included 201 of the 305 EAP-enrolled patients treated in 63 centers (79.6 % men; median age: 75 years; 91.8 % Eastern Cooperative Oncology Group performance status (ECOG-PS) 0/1; 74.5 % epithelioid histology). With median (95 % CI) follow-up for all patients of 18.4 (17.7-19.2) months, -PFS and OS were 6.3 (5.3-7.5) and 18.9 (17.6-not reached (NR)) months, with 1-year OS at 66.4 % (60.1-73.3 %). Median OS and 1-year survival rates were 21.0 (18.7-NR) and 70.8 % (63.9 %-780.6 %), and 14.1 (10.9-21.0) months and 54.9 % (42.8 %-70.4 %) for epithelioid and non-epithelioid PM subgroups, respectively. PFS was equal between the two subgroups. Grade 3-4 adverse events occurred in 23.3 % of patients and three deaths were treatment-related. CONCLUSIONS: For this unselected PM population, efficacy and safety outcomes compared favorably with CheckMate 743 trial results.

Immunoscore immune checkpoint using spatial quantitative analysis of CD8 and PD-L1 markers is predictive of the efficacy of anti- PD1/PD-L1 immunotherapy in non-small cell lung cancer.

BACKGROUND: Anti-PD-1 and PD-L1 antibodies (mAbs) are approved immunotherapy agents to treat metastatic non-small cell lung cancer (NSCLC) patients. Only a minority of patients responds to these treatments and biomarkers predicting response are currently lacking. METHODS: Immunoscore-Immune-Checkpoint (Immunoscore-IC), an in vitro diagnostic test, was used on 471 routine single FFPE-slides, and the duplex-immunohistochemistry CD8 and PD-L1 staining was quantified using digital-pathology. Analytical validation was performed on two independent cohorts of 206 NSCLC patients. Quantitative parameters related to cell location, number, proximity and clustering were analysed. The Immunoscore-IC was applied on a first cohort of metastatic NSCLC patients (n = 133), treated with anti-PD1 or anti-PD-L1 mAbs. Another independent cohort (n = 132) served as validation. FINDINGS: Anti-PDL1 clone (HDX3) has similar characteristics as anti-PD-L1 clones (22C3, SP263). Densities of PD-L1+ cells, CD8+ cells and distances between CD8+ and PD-L1+ cells were quantified and the Immunoscore-IC classification was computed. Using univariate Cox model, 5 histological dichotomised variables (CD8 free of PD-L1+ cells, CD8 clusters, CD8 cells in proximity of PD-L1 cells, CD8 density and PD-L1 cells in proximity of CD8 cells) were significantly associated with Progression-Free Survival (PFS) (all P < 0.0001). Immunoscore-IC classification improved the discriminating power of prognostic model, which included clinical variables and pathologist PD-L1 assessment. In two categories, the Immunoscore-IC risk-score was significantly associated with patients' PFS (HR = 0.39, 95% CI (0.26-0.59), P < 0.0001) and Overall Survival (OS) (HR = 0.42, 95% CI (0.27-0.65), P < 0.0001) in the training-set. Further increased hazard ratios (HR) were found when stratifying patients into three-category Immunoscore-IC (IS-IC). All patients with Low-IS-IC progressed in less than 18 months, whereas PFS at 36 months were 34% and 33% of High-IS-IC patients in the training and validation sets, respectively. INTERPRETATION: Immunoscore-IC is a powerful tool to predict the efficacy of immune-checkpoint inhibitors (ICIs) in patients with NSCLC. FUNDING: Veracyte, INSERM, Labex Immuno-Oncology, Transcan ERAnet European project, ARC, SIRIC, CARPEM, Ligue Contre le Cancer, ANR, QNRF, INCa France, Louis Jeantet Prize Foundation.

Treatment strategies for thymic carcinoma in a real-life setting. Insights from the RYTHMIC network.

BACKGROUND: Thymic carcinomas are aggressive and difficult to treat a subset of thymic epithelial tumours that represent a heterogeneous group of rare intrathoracic malignancies. The treatment strategy of thymic carcinomas is based on whether surgical resection may be achieved, which represents the most significant favourable prognostic factor on survival. For this study, we took advantage of the unique prospective Réseau tumeurs THYMiques et Cancer (RYTHMIC) database to describe baseline characteristics, analyse treatment strategies in light of existing guidelines and provide landmark patient outcomes data with regards to response and survival of patients in a real-life clinical practice setting. METHODS: Inclusion criteria for this analysis were the following: (1) histologically-confirmed thymic carcinomas - excluding neuroendocrine tumours-after pathological review by the RYTHMIC pathology panel, (2) discussion of the case at the RYTHMIC multidisciplinary tumour board, (3) at least one active treatment modality. RESULTS: A total of 213 patients were analysed. Overall, 60 (28%) patients were considered as surgical candidates upfront, 91 (43%) patients received primary chemotherapy, and 62 (29%) patients received exclusive chemotherapy. Median overall survival (OS) was 49.2 months (IC95%: 34.8-63.6); OS was significantly longer in patients with a lower stage at diagnosis (p < 0.001), who were operated on upfront, as opposed to patients who received primary or exclusive chemotherapy (p < 0.001). Surgery, conducted upfront or after primary chemotherapy, was significantly associated with more prolonged OS (p < 0.001); complete resection and postoperative radiotherapy were also predictors of better outcome (p = 0.018 and p = 0.051, respectively). CONCLUSIONS: Our cohort is the first to analyse in-depth outcomes and treatment strategies in a prospective cohort of consecutive patients with thymic carcinoma. While we confirm the major prognostic impact of surgery, our data highlight the need for optimised multidisciplinary management and innovative therapies as the survival of patients remains limited.

Prognostic value of Thyroid Transcription Factor-1 expression in lung adenocarcinoma in patients treated with anti PD-1/PD-L1.

Anti-PD1/PD-L1-directed immune checkpoint inhibitors are game changers in advanced non-small-cell lung cancer, but biomarkers are lacking. The aim of our study was to find clinically relevant biomarkers of the efficacy of ICI in non-squamous NSCLC. We conducted a retrospective study of patients receiving ICI for advanced non squamous NSCLC in two cohorts. For a subset of patients, RNAseq data were generated on tumor biopsy taken before ICI. The primary end point was progression-free survival under ICI. Secondary end point was overall survival from ICI initiation. In the cohort, we studied 231 patients. Clinico-pathological characteristics included KRAS mutant status (n = 88), TTF1-positive expression (n = 136), LIPI (Lung Immune Prognostic Index) score of 0 (n = 116). In our cohort, lack of TTF1 expression, LIPI score >0, line of treatment >1, and liver metastases were associated with poorer PFS. TTF1 and PD-L1 status could be used to stratify survival and improve the AUC for prediction of prognosis in comparison with the PD-L1 gold standard. Using an external cohort of 154 patients, we confirmed the independent prognostic role of TTF1. TTF1 expression and PD-L1 can be used to stratify risk and predict PFS and OS in patients treated with ICI for NS-NSCLC.

Central Nervous System Metastases in Thymic Epithelial Tumors: A Brief Report of Real-World Insight From RYTHMIC.

Thymic epithelial tumors (TETs) are rare malignancies ranging from indolent thymoma A to aggressive thymic carcinomas (TCs). Brain metastases are extremely infrequent for TETs and have only been described in case reports or small single-center series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French nationwide network mandated to systematically review every TET case and prospectively includes all consecutive patients discussed by national or regional tumor boards. We analyzed patients with TETs and central nervous system (CNS) metastasis during their cancer history from this large French registry. In an 8-year period, 2909 patients were included in the database, including 248 TCs (8.5%). A total of 14 patients had CNS metastases, five (36%) at diagnosis and nine (64%) at relapse. Among them, 12 patients (86%) had a diagnosis of TC and two (14%) had thymoma A and B3. Surgical biopsies were performed, and the histologic subtype for non-TC tumors was centrally confirmed. Median overall survival was 22 months (95% confidence interval [CI]: 9.8-34.2), with longer, albeit not significant, overall survival when CNS metastases were present at diagnosis versus relapse (not reached versus 17 mo; p = 0.29); median progression-free survival was 13 versus 8 months (p = 0.06), respectively. A higher risk of death (hazard ratio = 5.34, 95% CI: 1.3-21.9, p = 0.02) and relapse (hazard ratio = 1.89, 95% CI: 0.9-3.7, p = 0.06) was observed for patients suffering from TC with brain metastases compared with those without CNS extension. CNS disease was extremely rare in our TET cohort (0.48%), reported at both diagnosis and progression, present primarily in TC, with prevalence rising to 4.9%.

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

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/m2 intravenously] plus cisplatin [75 mg/m2 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.

Immune Checkpoint Inhibitors Rechallenge Efficacy in Non-Small-Cell Lung Cancer Patients.

BACKGROUND: Immune checkpoint inhibitor (ICPi) rechallenge could represent an attractive option in non-small-cell lung cancer (NSCLC), yet no sufficient data supporting this strategy are available. This retrospective observational multicenter national study explored the efficacy of anti-programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) rechallenge in advanced NSCLC patients, looking for potential clinical features associated with greater outcomes. PATIENTS AND METHODS: We retrospectively collected data from 144 advanced NSCLC patients whose disease was rechallenged with ICPis after ≥ 12 weeks of discontinuation. The progression-free survival (PFS) and overall survival (OS) were calculated from first or second ICPi initiation to disease progression (PFS1 and PFSR, respectively), death, or last follow-up (OS1, OSR), respectively. RESULTS: The median (interquartile range) age was 63 (58-70) years. Most patients were male (67%) and smokers (87%). Most had adenocarcinomas (62%) and/or stage IV disease at diagnosis (66%). The best response at rechallenge was not associated with that under the first ICPi (P = 1.10-1). The median (95% confidence interval) PFS1 and PFSR were 13 (10-16.5) and 4.4 (3-6.5) months, respectively. The median (95% confidence interval) OS1 and OSR were 3.3 (2.9-3.9) and 1.5 (1.0-2.1) years, respectively. Longer PFSR and OSR were found in patients discontinuing first ICPi because of toxicity or clinical decision, those not receiving systemic treatment between the two ICPis, and those with good Eastern Cooperative Oncology Group performance status at rechallenge. Only performance status proved to affect outcomes at multivariate analysis. CONCLUSION: Patients discontinuing first ICPi because of toxicity or clinical decision, those able to maintain a treatment-free period, and those with good performance status may be potential candidates for rechallenge.

Impact of pharmacist interventions on clinical outcome and cost avoidance in a university teaching hospital.

Background A significant number of clinical pharmacy services have shown to improve in-hospital medication safety and patient outcome. Prescription review and pharmacist interventions are a fundamental part of hospital clinical pharmacy activities. In a context of restricted financial resources, proving the economic and clinical impact of this activity seems necessary. Objective The aim of this study was to assess the clinical impact on patient outcomes and economic benefit of prescription review by pharmacists. Setting 1624-bed tertiary French university teaching hospital. Method Prospective single center study evaluating prescriptions for which a pharmacist intervention was issued over a 6-month period. The clinical impact of every pharmacist intervention was evaluated by a multidisciplinary experts committee. Economic benefit was evaluated from the public health care system spending standpoint. Main outcome measures Number of avoided hospitalization days and associated public health care system cost-avoidance. Results Prescription review and interventions by pharmacists prevented 73 intensive care unit hospitalization days, 74 continuous monitoring unit hospitalization days and 66 days of conventional hospitalization. €252,294.00 in public health expenditure were thus prevented. For every Euro invested in the prescription review activity, €5.09 of public health spending were potentially saved. Conclusion Our study shows that prescription review and clinical pharmacists' interventions had an impact on clinical outcomes which translated into prevented hospitalization days. Prescription optimization through pharmacist interventions allows significant health care cost savings which makes this service highly efficient.

Multidisciplinary Tumor Board Decision Making for Postoperative Radiotherapy in Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort.

INTRODUCTION: Thymic epithelial tumors (TETs) are rare intrathoracic malignancies for which surgery represents the mainstay of the treatment. Current practice for postoperative radiotherapy (PORT) is highly variable, and there is a lack of prospective, high level evidence. Réseau Tumeurs Thymiques et Cancer (RYTHMIC) is the nationwide network for TETs in France. Established in 2012, it prospectively collects data on all TET patients, for whom management is discussed at a national multidisciplinary tumor board (MTB). We assessed whether PORT decisions at the MTB were in accordance with RYTHMIC guidelines and ultimately implemented in patients. METHODS: All consecutive patients for whom PORT was discussed at the MTB from 2012 to 2015 were identified from the RYTHMIC prospective database, and a complete review of their medical records was performed. RESULTS: A total of 274 patients, including 243 with thymoma (89%) and 31 with thymic carcinoma (11%), were analyzed. The decision of the MTB was in accordance with guidelines in 221 patients (92%) of the 241 with stage I or III TET. An MTB decision to deliver PORT was made for 117 patients (43%). PORT was ultimately initiated in 101 patients. The most frequent reason for not delivering PORT was excessive (>3 months) delay after surgery. Dose-volume constraints defined by the International Thymic Malignancy Interest Group were followed in all but four patients. CONCLUSION: Our data provide a unique insight into the decision-making process for PORT in TETs, highlighting the need for systematic discussion at an expert MTB, while stressing the value of current available guidelines.

Generating harmonized SUV within the EANM EARL accreditation program: software approach versus EARL-compliant reconstruction.

BACKGROUND: Evolutions in hardware and software PET technology, such as point spread function (PSF) reconstruction, have been shown to improve diagnostic performance, but can also lead to important device-dependent and reconstruction-dependent variations in standardized uptake values (SUVs). This may preclude the multicentre use of SUVs as a prognostic or diagnostic tool or as a biomarker of the early response to antineoplastic treatments. This study compared two SUV harmonization strategies using a newer reconstruction algorithm that improves lesion detection while maintaining comparability with older systems: (1) the use of a second reconstruction compliant with harmonization standards and (2) the use of a proprietary software tool (EQ.PET). METHODS: PET data from 50 consecutive non-small cell lung cancer patients were reconstructed with PSF reconstruction for optimal tumor detection and an ordered subset expectation maximization (OSEM3D) reconstruction to mimic a former generation PET. An additional PSF reconstruction was performed with a 7 mm Gaussian filter (PSF7, first method), and, post-reconstruction, the EQ filter (same Gaussian filter) was applied to the PSF data (PSFEQ, second method) for harmonization purposes. The 7 mm kernel filter was chosen to comply with the European Association of Nuclear Medicine (EANM) standards. SUVs for all reconstructions were compared with regression analyses and/or Bland-Altman plots. RESULTS: Overall, 171 lesions were analyzed: 55 lung lesions (32.2%), 87 lymph nodes (50.9%), and 29 metastases (16.9%). In these lesions, the mean PSF7/OSEM3D ratios for SUVmax and SUVpeak were 1.02 (95% CI: 0.93-1.11) and 1.04 (95% CI: 0.95-1.14), respectively. The mean PSFEQ/OSEM3D ratios for SUVmax and SUVpeak were 1.01 (95% CI: 0.91-1.11) and 1.04 (95% CI: 0.94-1.14), respectively. When comparing PSF7 and PSFEQ, Bland-Altman analysis showed that the mean PSF7/PSFEQ ratios for SUVmax and SUVpeak were 1.01 (95% CI: 0.96-1.06) and 1.01 (95% CI: 0.97-1.04), respectively. CONCLUSION: The issue of reconstruction dependency in SUV values that hampers the comparison of data between different PET systems can be overcome using two reconstructions for harmonized quantification and optimal diagnosis or using the EQ.PET technology. Both technologies produce similar results, EQ.PET sparing reconstruction and interpretation time. Other manufacturers are encouraged to either emulate this solution or to produce a vendor-neutral approach.

[Resistances to targeted therapies and strategy for following therapeutic lines in metastatic NSCLC]. / Résistances aux thérapeutiques ciblées et stratégies des lignes ultérieures dans les CBNPC métastatiques.

EGFR, ALK, ROS1 Tyrosine Kinase Inhibitors (TKis) have changed natural history of 12 to 15% of patients with metastatic Non-Small Cell Lung Cancer (NSCLC) and molecular alterations (mutations or translocations) in these genes. Median Progression Free Survival (PFS) of these patients has increased from 12 months with a platinum-based chemotherapy associated with bevacizumab, to 18 months with TKIs, overall survival reaching several years in these patients. However, rare primary resistance have been described in less than 10% of patients with EGFR or ALK-mutated cancer, whereas secondary resistance occur systematically. New generations TKIs are currently in clinical development, which are active on tumor clones harboring a resistance mutation, and some of them diffuse perfectly well into brain, a classical sanctuary for metastasis. Strategies are developed to delay secondary resistance apparition, to prolong PFS, and then overall survival. These strategies use combinations, as soon as first linesetting, of TKIs with either an anti-angiogenic drug (bevacizumab), or with an immunological checkpoint inhibitors, or with Heat-Shock Protein (Hsp) inhibitors. In order to delay acquired resistance to EGFR TKIs, the French Intergroup (IFCT) has launched a combination trial of EGFR TKIs with an anti-estrogen (fulvestrant) in postmenopausal women, whereas other trials associate EGFR TKIs with EFGR monoclonal antibody cetuximab, or with a monoclonal antibody targeting c-met.

Retrospective observational study of diagnostic accuracy of the Xpert® MTB/RIF assay on fiberoptic bronchoscopy sampling for early diagnosis of smear-negative or sputum-scarce patients with suspected tuberculosis.

BACKGROUND: Fiberoptic bronchoscopy (FOB) is a useful diagnosis tool in low-burden countries for patients with suspected pulmonary tuberculosis (TB) who are smear-negative or sputum-scarce. This study sought to determine the accuracy of the Xpert® MTB/RIF (XP) assay using FOB samples. METHODS: We retrospectively reviewed clinical, radiological, and microbiological characteristics of 175 TB-suspected patients requiring diagnostic FOB (bronchial aspirate or bronchoalveolar lavage) with XP assay. Polymerase chain reaction (PCR) and smear microscopy (SM) performances were first compared to culture, then to the final diagnosis, established based on clinical or radiological evolution when cultures were negative. RESULTS: Of the total 162 included patients, 30 (18.5%) had a final diagnosis of pulmonary TB, with positive cultures reported in 23. As compared to culture, sensitivity and specificity values were 80.0% and 98.6% for the XP assay, and 25.0% and 95.8% for SM, respectively. As compared to final diagnosis, the corresponding performance values were 60.0% and 100.0% for the XP assay, and 16.7% and 95.5% for SM, respectively. The sensitivity of the XP assay was significantly higher than that of SM in both cases (p=0.003 and p=0.001). Concerning the final diagnosis, both XP assay and culture sensitivities were similar (60% vs. 66.7%). PCR assay enabled pulmonary TB to be diagnosed earlier in 13 more cases, compared to SM. CONCLUSION: Our study has confirmed the clinical benefits provided by XP assay compared to SM for the early diagnosis of suspected pulmonary TB cases requiring FOB, on per procedure samples, especially in a low TB-burden country.