Different clones, protocol conditions, instruments, and scoring/readout methods may pose challenges in introducing different PD-L1 assays for immunotherapy. The diagnostic accuracy of using different ...PD-L1 assays interchangeably for various purposes is unknown. The primary objective of this meta-analysis was to address PD-L1 assay interchangeability based on assay diagnostic accuracy for established clinical uses/purposes. A systematic search of the MEDLINE database using PubMed platform was conducted using "PD-L1" as a search term for 01/01/2015 to 31/08/2018, with limitations "English" and "human". 2,515 abstracts were reviewed to select for original contributions only. 57 studies on comparison of two or more PD-L1 assays were fully reviewed. 22 publications were selected for meta-analysis. Additional data were requested from authors of 20/22 studies in order to enable the meta-analysis. Modified GRADE and QUADAS-2 criteria were used for grading published evidence and designing data abstraction templates for extraction by reviewers. PRISMA was used to guide reporting of systematic review and meta-analysis and STARD 2015 for reporting diagnostic accuracy study. CLSI EP12-A2 was used to guide test comparisons. Data were pooled using random-effects model. The main outcome measure was diagnostic accuracy of various PD-L1 assays. The 22 included studies provided 376 2×2 contingency tables for analyses. Results of our study suggest that, when the testing laboratory is not able to use an Food and Drug Administration-approved companion diagnostic(s) for PD-L1 assessment for its specific clinical purpose(s), it is better to develop a properly validated laboratory developed test for the same purpose(s) as the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic, than to replace the original PD-L1 Food and Drug Administration-approved immunohistochemistry companion diagnostic with a another PD-L1 Food and Drug Administration-approved companion diagnostic that was developed for a different purpose.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Earlier studies suggested that the response to platinum treatment in lung cancer might be predicted according to the presence or absence of the DNA repair enzyme ERCC1. This study shows that the ...available antibodies do not predict response because they may detect nonfunctional enzymes.
In patients with resected stage IB, IIA or IIB, or IIIA non–small-cell lung cancer (NSCLC), platinum-based postoperative chemotherapy is now standard treatment, with an estimated increase in the survival rate of 4 to 5% at 5 years.
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,
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The identification of predictive biomarkers of the efficacy of adjuvant chemotherapy could lead to an improved therapeutic index.
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DNA repair capacity is a major determinant of cisplatin resistance; in particular, the excision repair cross-complementation group 1 (ERCC1) protein plays an essential role in nucleotide excision repair. Together with its partner, xeroderma pigmentosum complementation group F (XPF), ERCC1 cleaves DNA structures near the . . .
Purpose
While immunotherapy has become an increasingly attractive strategy in patients with urothelial bladder cancer, the need for a biomarker to identify patients whose cancer is the most likely to ...respond has never been more crucial. This review systematically evaluates evidence regarding PD-L1 as a predictive biomarker of response to anti-PD(L)1 monoclonal antibodies in patients with urothelial bladder carcinoma, and discusses its current limits in routine clinical practice.
Methods
We performed a critical review of PubMed/Medline according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. Prospective clinical trials evaluating anti-PD(L)1 monoclonal antibodies in urothelial bladder carcinoma together with retrospective studies evaluating PD-L1 expression in patients with bladder cancer were included.
Results
Evidence data related to PD-L1 as a predictive biomarker of response to immune checkpoint blockade monotherapy across clinical trials are detailed in this review. The different companion diagnostic assays, and the methods for PD-L1 scoring in urothelial bladder carcinoma are reported. Additionally, the issues related to the implementation of PD-L1 testing in clinical practice are discussed.
Conclusions
PD-(L)1 monoclonal antibodies atezolizumab and pembrolizumab are restricted to patients with PD-L1 positive status in the first-line setting in patients with advanced or metastatic urothelial bladder carcinoma who are ineligible to cisplatin-based chemotherapy. Importantly, the use of anti-PD(L)1 mAb in the other clinical settings is not based on PD-L1 status, but rather on patients’ clinical characteristics. Further identification of biomarkers with high negative predictive value will also be of utmost importance to identify patients who may not respond to such immunotherapies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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Basic Knowledge in Soft Tissue Sarcoma Bourcier, Kévin; Le Cesne, Axel; Tselikas, Lambros ...
Cardiovascular and interventional radiology,
09/2019, Volume:
42, Issue:
9
Journal Article
Peer reviewed
Sarcoma is rare and heterogenous with various subtypes having a different prognostic. Desmoid is a tumour with a local aggressiveness; GIST with KIT mutation responds massively to target treatment as ...IMATINIB, whereas soft tissue sarcoma and leiomyosarcoma are very aggressive with poor response to systemic therapies. Interventional radiology plays an important role in the diagnosis of sarcomas with image-guided percutaneous core needle biopsy being the most commonly used biopsy technique in the diagnosis of sarcomas. Biopsy access routes discussed with the surgeon, and skin access is tattooed. Surgery is a mainstay of sarcoma treatment; the resection can be large. Indeed, resection objective is R0 because quality of surgical margins impacts local control and survival. Radiotherapy is possible in neoadjuvant or in adjuvant treatment to improve local control rate. Recently radiotherapy enhancer injected percutaneously in soft tissue sarcoma has proven benefit in increasing the rate of R0 complete surgical resection. Several studies showed better local control rate linked with post-operative radiotherapy. In patients affected by oligometastatic disease, complete surgical resection of all metastatic sites is in fact considered the primary treatment because complete remission is critical for cure. The decision making to use local therapies is complex, depends upon diverse presentations and histologies, and should always be taken in a multidisciplinary discussion. Today, percutaneous image-guided treatments with ablation technologies (radiofrequency ablation, cryotherapy, microwaves ablation) provide high rate of durable local control for small-sized malignant deposit in many organs including lung, liver and bones. Sarcoma must be managed by multimodality treatment in expert reference centres. Such management has a considerable impact on the prognosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
TGF-β is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin α
V
subunit. The activation of latent TGF-β by ...cancer-cell-expressed α
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re-shapes the tumour microenvironment, and this could affect patient responses to PD-1-targeting therapy. Here we show, using multiplex immunofluorescence staining in cohorts of anti-PD-1 and anti-PD-L1-treated lung cancer patients, that decreased expression of cancer cell α
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is associated with improved immunotherapy-related, progression-free survival, as well as with an increased density of CD8
+
CD103
+
tumour-infiltrating lymphocytes. Mechanistically, tumour α
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regulates CD8 T cell recruitment, induces CD103 expression on activated CD8
+
T cells and promotes their differentiation to granzyme B-producing CD103
+
CD69
+
resident memory T cells via autocrine TGF-β signalling. Thus, our work provides the underlying principle of targeting cancer cell α
V
for more efficient PD-1 checkpoint blockade therapy.
Purpose Three programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors are currently approved for treatment of non-small-cell lung cancer (NSCLC). Treatment with pembrolizumab in NSCLC ...requires PD-L1 immunohistochemistry (IHC) testing. Nivolumab and atezolizumab are approved without PD-L1 testing, though US Food and Drug Administration-cleared complementary PD-L1 tests are available for both. PD-L1 IHC assays used to assess PD-L1 expression in patients treated with programmed death-1/PD-L1 inhibitors in clinical trials include PD-L1 IHC 28-8 pharmDx (28-8), PD-L1 IHC 22C3 pharmDx (22C3), Ventana PD-L1 SP142 (SP142), and Ventana PD-L1 SP263 (SP263). Differences in antibodies and IHC platforms have raised questions about comparability among these assays and their diagnostic use. This review provides practical information to help physicians and pathologists understand analytical features and comparability of various PD-L1 IHC assays and their diagnostic use. Methods We reviewed and summarized published or otherwise reported studies (January 2016 to January 2017) on clinical trial and laboratory-developed PD-L1 IHC assays (LDAs). Studies assessing the effect of diagnostic methods on PD-L1 expression levels were analyzed to address practical issues related to tissue samples used for testing. Results High concordance and interobserver reproducibility were observed with the 28-8, 22C3, and SP263 clinical trial assays for PD-L1 expression on tumor cell membranes, whereas lower PD-L1 expression was detected with SP142. Immune-cell PD-L1 expression was variable and interobserver concordance was poor. Inter- and intratumoral heterogeneity had variable effects on PD-L1 expression. Concordance among LDAs was variable. Conclusion High concordance among 28-8, 22C3, and SP263 when assessing PD-L1 expression on tumor cell membranes suggests possible interchangeability of their clinical use for NSCLC but not for assessment of PD-L1 expression on immune cells. Development of LDAs requires stringent standardization before their recommendation for routine clinical use.
Summary Background MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lung cancer. TG4010 is a modified vaccinia Ankara expressing MUC1 and interleukin 2. ...In a previous study, TG4010 combined with chemotherapy showed activity in non-small-cell lung cancer and the baseline value of CD16, CD56, CD69 triple-positive activated lymphocytes (TrPAL) was shown to be potentially predictive of TG4010 efficacy. In this phase 2b part of the phase 2b/3 TIME trial, we further assess TG4010 in combination with first-line chemotherapy and use of the TrPAL biomarker in this setting. Methods In this phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, we recruited previously untreated patients aged 18 years or older with stage IV non-small-cell lung cancer without a known activating EGFR mutation and with MUC1 expression in at least 50% of tumoural cells. Patients were randomly allocated (1:1) by an external service provider to subcutaneous injections of 108 plaque-forming units of TG4010 or placebo from the beginning of chemotherapy every week for 6 weeks and then every 3 weeks up to progression, discontinuation for any reason, or toxic effects, stratified according to baseline value of TrPAL (≤ or > the upper limit of normal ULN) and, in addition, a dynamic minimisation procedure was used, taking into account chemotherapy regimen, histology, addition or not of bevacizumab, performance status, and centre. Patients, site staff, monitors, the study funder, data managers, and the statistician were masked to treatment identity. The primary endpoint was progression-free survival, assessed every 6 weeks, to validate the predictive value of the TrPAL biomarker. If patients with TrPAL values of less than or equal to the ULN had a Bayesian probability of more than 95% that the true hazard ratio (HR) for progression-free survival was less than 1, and if those with TrPAL values of greater than the ULN had a probability of more than 80% that the true HR for progression-free survival was more than 1, the TrPAL biomarker would be validated. We did primary analyses in the intention-to-treat population and safety analyses in those who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Monitors, site staff, and patients are still masked to treatment assignment. This trial is registered with ClinicalTrials.gov , number NCT01383148. Findings Between April 10, 2012, and Sept 12, 2014, we randomly allocated 222 patients (TG4010 and chemotherapy 111 50%; placebo and chemotherapy 111 50%). In the whole population, median progression-free survival was 5·9 months (95% CI 5·4–6·7) in the TG4010 group and 5·1 months (4·2–5·9) in the placebo group (HR 0·74 95% CI 0·55–0·98; one-sided p=0·019). In patients with TrPAL values of less than or equal to the ULN, the HR for progression-free survival was 0·75 (0·54–1·03); the posterior probability of the HR being less than 1 was 98·4%, and thus the primary endpoint was met. In patients with TrPAL values of greater than the ULN, the HR for progression-free survival was 0·77 (0·42–1·40); the posterior probability of the HR being greater than 1 was 31·3%, and the primary endpoint was not met. We noted grade 1–2 injection-site reactions in 36 (33%) of 110 patients in the TG4010 group versus four (4%) of 107 patients in the placebo group. We noted no grade 3 or 4 nor serious adverse events deemed to be related to TG4010 only. Four (4%) patients presented grade 3 or 4 adverse events related to TG4010 and other study treatments (chemotherapy or bevacizumab) versus 11 (10%) in the placebo group. No serious adverse event was related to the combination of TG4010 with other study treatments. The most frequent severe adverse events were neutropenia (grade 3 29 26%, grade 4 13 12% in the TG4010 group vs grade 3 22 21%, grade 4 11 10% in the placebo group), anaemia (grade 3 12 11% vs grade 3 16 15%), and fatigue (grade 3 12 11%, grade 5 one 1% vs grade 3 13 12%; no grade 4 events). Interpretation TG4010 plus chemotherapy seems to improve progression-free survival relative to placebo plus chemotherapy. These data support the clinical value of the TrPAL biomarker in this clinical setting; because the primary endpoint was met, the trial is to continue into the phase 3 part. Funding Transgene, Avancées Diagnostiques pour de Nouvelles Approches Thérapeutiques (ADNA), and OSEO.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Purpose
We aimed to evaluate if imaging biomarkers on FDG PET are associated with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint ...inhibitors (ICIs).
Methods
In this retrospective monocentric study, we included 109 patients with advanced NSCLC who underwent baseline FDG PET/CT before ICI initiation between July 2013 and September 2018. Clinical, biological (including dNLR = neutrophils/leukocytes minus neutrophils), pathological and PET parameters (tumor SUVmax, total metabolic tumor volume TMTV) were evaluated. A multivariate prediction model was developed using Cox models for progression-free survival (PFS) and overall survival (OS). The association between biomarkers on FDG PET/CT and disease clinical benefit (DCB) was tested using logistic regression.
Results
Eighty patients were eligible. Median follow-up was 11.6 months (95%CI 7.7–15.5). Sixty-four and 52 patients experienced progression and death, respectively. DCB was 40%. In multivariate analyses, TMTV > 75 cm
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and dNLR > 3 were associated with shorter OS (HR 2.5, 95%CI 1.3–4.7 and HR 3.3, 95%CI 1.6–6.4) and absence of DCB (OR 0.3, 95%CI 0.1–0.9 and OR 0.4, 95%CI 0.2–0.9). Unlike TMTV, dNLR was a significant prognostic factor for PFS (HR 1.9, 95%CI 1.1–3.3) along with anemia (HR 1.9, 95%CI 1.2–3.8). No association was observed between tumor SUVmax and PFS or OS.
Conclusion
Baseline tumor burden (TMTV) on FDG PET/CT scans and inflammatory status (dNLR) were associated with poor OS and absence of DCB for ICI treatment in advanced NSCLC patients, unlike tumor SUVmax, and may be used together to improve the selection of appropriate candidates.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target ...cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations.
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