PD-L1 expression in squamous-cell carcinoma and adenocarcinoma of the lung

With introduction of immunotherapy (IT) into the treatment of advanced non-small-cell lung cancer (NSCLC), a need for predictive biomarker became apparent. Programmed death ligand 1 (PD-L1) protein expression is most widely explored predictive marker for response to IT. We assessed PD-L1 expression in tumor cells (TC) and immune cells (IC) of squamous-cell carcinoma (SCC) and adenocarcinoma (AC) patients. We obtained 54 surgically resected tumor specimens and assessed PD-L1 expression by immunohistochemistry after staining them with antibody SP142 (Ventana, USA). Clinicopathological characteristics were acquired from the hospital registry database. Results were analyzed according to cut-off values of % 5% and % 10% of PD-L1 expression on either TC or IC. 29 (54%) samples were AC and 25 (46%) were SCC. PD-L1 expression was significantly higher in TC of SCC compared to AC at both cut-off values (52% vs. 17%, p = 0.016 and 52% vs. 14%, p = 0.007, respectively) no difference in PD-L1 expression in IC of SCC and AC was found. In AC alone, PD-L1 expression was significantly higher in IC compared to TC at both cut-off values (72% vs. 17%, p < 0.001 and 41% vs. 14%, p = 0.008, respectively), while no significant difference between IC and TC PD-L1 expression was revealed in SCC. Our results suggest a significantly higher PD-L1 expression in TC of SCC compared to AC, regardless of the cut-off value. PD-L1 expression in IC is high in both histological subtypes of NSCLC, and adds significantly to the overall positivity of AC but not SCC

Various clinical presentations of uveitis associated with durvalumab treatment

BACKGROUND: Immune checkpoint inhibitors (ICI) are becoming increasingly common in treating several cancer types. Durvalumab is a human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80 and has recently been approved for the treatment of extensive-stage small-cell lung cancer (ES-SCLC) and locally advanced unresectable (NSCLC). The present review aimed to analyse immune-mediated uveitis, secondary to durvalumab treatment, through a review of the literature and a presentation of two clinical cases. PATIENTS AND METHODS: A literature review using PubMed search was conducted to identify cases of uveitis secondary to durvalumab and cases of uveitis with optic disc oedema secondary to ICI use that were reported prior to November 14, 2021. Additionally, we report two cases of uveitis consequent on durvalumab treatment. RESULTS: Five cases of uveitis secondary to durvalumab use were identified in the literature. Anterior, posterior uveitis and vasculitis were reported. Additionally, we present a case of bilateral intermediate uveitis with bilateral optic disc oedema and a case of bilateral posterior uveitis. Our further search revealed 12 cases of uveitis with optic disc oedema secondary to ICI use, with the majority of cases reported secondary to PD-1 inhibitors. CONCLUSIONS: Rarely reported, uveitis secondary to durvalumab can present various clinical pictures and requires a thorough diagnostic workup. Once the diagnosis is established, treatment, commonly with a local or systemic corticosteroid, should be adapted to the severity of the inflammation

Real-world outcomes, treatment patterns and T790M testing rates in non-small cell lung cancer patients treated with first-line first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors from the Slovenian cohort of the REFLECT study

Background. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective treatments for EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). However, routine clinical practice is different between countries/institutions. Patients and methods. The REFLECT study (NCT04031898) is a retrospective medical chart review that explored real-life treatment and outcomes of EGFRm NSCLC patients receiving first-line (1L) first-/second-generation (1G/2G) EGFR TKIs in 8 countries. This study included adult patients with documented advanced/metastatic EGFRm NSCLC with 1L 1G/2G EGFR TKIs initiated between Jan 2015 – Jun 2018. We reviewed data on clinical characteristics, treatments, EGFR/T790M testing patterns, and survival outcomes. Here, we report data from 120 medical charts in 3 study sites from Slovenia. Results. The Slovenian cohort (median age 70 years, 74% females) received 37% erlotinib, 32% afatinib, 31% gefitinib. At the time of data collection, 94 (78%) discontinuations of 1L TKI, and 89 (74%) progression events on 1L treatment were reported. Among patients progressing on 1L, 73 (82%) were tested for T790M mutation yielding 50 (68%) positive results, and 62 (85%) received 2L treatment. 82% of patients received osimertinib. Attrition rate between 1L and 2L was 10%. The median (95% CI) real-world progression free survival on 1L EGFR TKIs was 15.6 (12.6, 19.2) monthsmedian overall survival (95% CI) was 28.9 (25.0, 34.3) months. Conclusions. This real-world study provides valuable information about 1G/2G EGFR TKIs treatment outcomes and attrition rates in Slovenian EGFRm NSCLC patients. The reduced attrition rate and improved survival outcomes empha-size the importance of 1L treatment decision

Establishment of a virtual transborder tumor board for cancer patients in Central and Southeastern Europe : an initiative of the Central European Cooperative Oncology Group (CECOG)

o establish a transborder virtual tumor board (VTB) fostering state-of-the-art management of cancer patients by exchanging knowledge and expertise among oncologists in Central and Southeastern Europe (CEE). Methods: We established and implemented a VTB based on the WebEx platform. This allowed for password-protected and secure upload of patient cases to be presented and discussed among colleagues from various oncology centers scattered throughout CEE in order to arrive at a recommendation for further diagnoses and/or treatment. Results: A total of 73 cases from 16 oncology centers located in 11 CEE countries were uploaded by 22 physicians71 were discussed over the course of 17 virtual meetings between June 2018 and May 2019 and 12 different kinds of malignant diseases were discussed with lung cancer (46.6%), melanoma (19.2%) and bladder cancer (13.6%) being the most commonly presented tumor entities. Of the discussed patients, 93.3% had stage IV disease at the time of presentation, 62.6% received chemotherapy or targeted treatment and 67.1% were treated with immune checkpoint inhibitors (ICPIs). The most common causes for presentation and discussion of patient cases were related to the use of ICPIs (80%). Conclusion: When the need for expertise exceeds locally available resources, web-based VTBs provide a feasible way to discuss patient cases and arrive at conclusions regarding diagnoses and/or treatment across large geographic distances. Moreover, VTBs provide an innovative way for proper, state-of-the-art management of patients with malignant diseases in times of social distancing and the resulting need for restricted interaction during the current SARS-CoV‑2 (severe acute respiratory syndrome coronavirus type 2) pandemic

Mobocertinib in patients with EGFR exon 20 insertion-positive non-small cell lung cancer (MOON)

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24–45). The response rate in treatment-naïve patients was 27% (95% CI, 8–58). The median progression-free and overall survival was 5 months (95% CI, 3.5–6.5) and 12 months (95% CI, 6.8–17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity

Transcriptome analysis of acute T-cell lymphoblastic leukemia pediatric patients

T-celična akutna limfoblastna levkemija predstavlja 10–15 % vseh akutnih limfoblastnih levkemij pri otrocih. Kljub napredku v načinu zdravljenja bolezni v zadnjih letih T-celični imunofenotip, ki je genetsko zelo heterogen, predstavlja višje tveganje za neuspešno zdravljenje bolezni kot B-celični imunofenotip. Bolniki, pri katerih se bolezen ponovi, imajo slabo prognozo, saj so relapsi pogosto odporni na zdravljenje. Delitev bolezni glede na genotip, ki bi imel pomembno napovedno vrednost za bolnike, kot je to mogoče pri B-celični akutni limfoblastni levkemiji, ne obstaja. Namen raziskave je opredeliti transkriptom T-celične akutne levkemije pri otrocih z analizo diferencialnega izražanja genov. Izolirali smo RNA iz kostnega mozga in periferne krvi otrok, ki so jim med leti 2009 in 2023 na Pediatrični kliniki v Ljubljani diagnosticirali T-celično akutno limfoblastno levkemijo. Pripravili smo knjižnice in jih sekvencirali z aparatom NovaSeq 6000, Illumina. S podatkovnim cevovodom Snakepipes in orodjema DESeq2 ter edgeR smo opredelili različno izražene gene pri bolnikih, ki so doživeli relaps v primerjavi z bolniki v remisiji. Opredelili smo tudi razlike v izražanju genov med bolniki z nezrelim in zrelim imunofenotipom ter primerjali diferencialno izražene gene pri bolnikih s T- in B-celično akutno limfoblastno levkemijo. Za ta del analize smo uporabili že pridobljene podatke sekvenciranja bolnikov z B-celično akutno limfoblastno levkemijo. Pri bolnikih s T-ALL in relapsom smo opredelili 11 genov, pri bolnikih v remisiji pa 41 genov, ki so se povečano izražali. V določenih primerih je povečano izražanje onkogenov ali zmanjšano izražanje tumorsupresorskih genov kazalo na povezavo med slabšo prognozo bolnikov z relapsom. V nekaterih primerih pa povezave niso bile jasne, saj izražanje genov v literaturi še ni bilo opisano. Rezultati analize izražanja genov pri različnih imunofenotipih so pokazali, da je povezava med imunofenotipom in genetskim profilom slaba, kar je opisano tudi v literaturi. Pri diferencialni analizi izražanja genov med bolniki s T- in B-celično akutno limfoblastno levkemijo smo opredelili največ, kar 8848 različno izraženih genov. V spletnem orodju Enrichr smo z obogatitveno analizo opredelili pot imunoregulatornih interakcij med limfoidno in nelimfoidno celico kot tisto, ki bi lahko imela vlogo pri slabšem poteku bolezni v primerjavi z B-celično akutno limfoblastno levkemijo. Da bi lahko določili izražanje genov, ki bi imelo pomembno napovedno vrednost za pediatrične bolnike s T-ALL, so potrebne nadaljnje raziskave.T-cell acute lymphoblastic leukaemia accounts for 10–15% of all acute lymphoblastic leukaemias in children. Despite advances in the treatment of the disease in recent years, the T-cell immunophenotype, which is genetically very heterogeneous, poses a higher risk of treatment failure than B-cell immunophenotype. Patients with relapse have a very poor prognosis, as relapses are often resistant to treatment. Unlike B-cell acute lymphoblastic leukaemia, in which the immunophenotype-genotype association profile is well established as outcome predictors, T-cell acute lymphoblastic leukemia still needs further investigations.The aim of the study is a transcriptome analysis in T-cell acute lymphoblastic leukemia pediatric patients with differential gene expression analysis. We isolated RNA from bone marrow and peripheral blood of children diagnosed with T-cell acute lymphoblastic leukemia at the Pediatric clinic in Ljubljana between 2009 and 2023. Then RNA libraries were prepared and sequenced using the NovaSeq 6000, Illumina. Using the Snakepipes data pipeline, DESeq2 and edgeR, we identified differential gene expression in relapsed patients compared to patients in remission. We also identified differences in gene expression between immature and mature immunophenotype and compared differentially expressed genes in T- and B-cell acute lymphoblastic leukaemia patients. Sequencing data from patients with B-cell acute lymphoblastic leukaemia patients were used for this part of the analysis. Eleven highly expressed genes were identified in relapsed and 41 genes in remission patients. In some cases, increased expression of oncogenes or decreased expression of tumour suppressor genes could indicate a poorer prognosis of relapsed patients, in other cases the association was unclear as gene expression has not yet been described in the literature. Analysis of gene expression in different immunophenotypes showed poor association between immunophenotype and genetic profile, which is also described in the literature. In differential analysis of gene expression between T- and B-cell acute lymphoblastic leukemia patients, we identified 8,848 differently expressed genes. We identified a pathway of immunoregulatory interactions between lymphoid and non-lymphoid cells using Enrichr enrichment analysis as one that could play a role in the poorer outcome of the disease compared to B-cell acute lymphoblastic leukemia. Further research is needed to determine gene expression that would have a significant prognostic value for patients

Solid cancer patients achieve adequate immunogenicity and low rate of severe adverse events after SARS-CoV-2 vaccination

Background: SARS-CoV-2 vaccination in cancer patients is crucial to prevent severe COVID-19 disease course. Methods: This study assessed immunogenicity of cancer patients on active treatment receiving mRNA-based SARS-CoV-2 vaccine by detection of anti-SARS-CoV-2 S1 IgG antibodies in serum, before, after the first and second doses and 3 months after a complete primary course of vaccination. Results were compared with healthy controls. Results: Of 112 patients, the seroconversion rate was 96%. A significant reduction in antibody levels was observed 3 months after vaccination in patients receiving immune checkpoint inhibitors versus control participants (p < 0.001). Adverse events were mostly mild. Conclusion: Immunogenicity after mRNA-based vaccine in cancer patients is adequate but influenced by the type of anticancer therapy. Antibody levels decline after 3 months, and thus a third vaccination is warranted

Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platform

Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients\u27 molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency

Real-world testing practices, treatment patterns and clinical outcomes in patients from Central Eastern Europe with EGFR-mutated advanced non-small cell lung cancer: a retrospective chart review study (REFLECT)

The targeted therapy with tyrosine kinase inhibitors (TKIs) against the epidermal growth factor receptor mutation (EGFRm) in advanced non-small cell lung cancer (NSCLC) changed the treatment paradigm. REFLECT study (NCT04031898) explored EGFR/T790M testing and treatment patterns in EGFRm NSCLC patients receiving first- or second-generation (1G/2G) EGFR TKIs as front-line (1L) in eight countries. Pooled data from Central Eastern Europe (CEE) countries from this study (Bulgaria, Poland, Romania, Slovenia) are presented here. This physician-led chart review study was conducted in patients with confirmed-EGFRm NSCLC initiating 1L 1G/2G EGFR TKIs between 2015–2018. The CEE cohort included 389 patients receiving 1L erlotinib (37%), afatinib (34%), and gefitinib (29%). Overall, 320 (82%) patients discontinued 1L, and 298 (77%) progression events were registered. Median progression free survival on 1L TKIs was 14.0 (95% CI: 12.6–15.6) months. Median overall survival from 1L start was 26.6 (95% CI: 24.1–29.0) months. Attrition rate between 1L and next line was 30%. Among patients with 1L progression, 200 (67%) were tested for T790M and 58% were positive. This first CEE analysis of treatments and outcomes in EGFRm NSCLC patients highlights the importance of using the most efficacious therapies currently available in 1L to reduce attrition and improve patient outcomes

Treatment patterns, testing practices, and outcomes in the pre-FLAURA era for patients with EGFR mutation-positive advanced NSCLC : a retrospective chart review (REFLECT)

Background. Immunotherapy with immune checkpoint inhibitors (ICIs) recently became the standard treatment for patients with advanced non-small cell lung cancer (NSCLC). Here, we present the first results of a real-world observational study on the effectiveness of ICI monotherapy in patients with advanced NSCLC treated at a single academic center in a Central and Eastern European (CEE) country. Materials and methods. Overall, 66 consecutive patients with advanced NSCLC treated with ICIs in everyday clinical practice, either with first-line pembrolizumab (26 patients) or second-line atezolizumab, nivolumab, or pembrolizumab (40 patients), from August 2015 to November 2018, were included. All data were retrieved from a hospital lung cancer registry, in which the data is collected prospectively. Results. Included patients had a median age of 64 years, most were male (55%), 6% were in performance status >/=2, and 18% had controlled central nervous system metastases at baseline. In first-line, the median progression-free survival (mPFS) was 9.3 months, while the median overall survival (mOS) was not reached. The 1-year overall survival (OS) was 62%. In second-line, the mPFS and mOS were 3.5 months and 9.9 months, respectively, with a 1-year OS of 35%. In the overall population, adverse events of any grade were recorded in 79% of patients and of severe grade (3-4) in 12% of patients. Conclusion. The first real-world outcomes of NSCLC immunotherapy from a CEE country suggest comparable effectiveness to those observed in clinical trials and other real-world series, mainly coming from North America and Western European countries. Further data to inform on the real-world effectiveness of immunotherapy worldwide are needed