Immune Checkpoint Inhibitors in Malignant Pleural Mesothelioma: A Systematic Review and Meta-Analysis

Many clinical trials have investigated the role of ICIs in PM, with contrasting results. We performed a systematic review and meta-analysis of clinical trials testing single-agent anti-Programmed Death -1 (PD-1)/Programmed Death-Ligand 1 (PD-L1), anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) or combined treatment in PM patients, analyzing response and survival rate as well as safety data. We selected 17 studies including 2328 patients. Both OS and PFS rates were significantly higher with combined ICI treatments than with single agent anti-PD-1/PD-L1 (p < 0.001 and p = 0.006, respectively) or anti CTLA-4 (p < 0.001) treatments. ORR and DCR for all ICI treatments were 20% (95% CI 13–27%) and 56% (95% CI 45–67%), respectively, and they did not significantly differ between combined and single agent treatments (p = 0.088 and p = 0.058, respectively). The 12-month OS and 6-month PFS rates did not differ significantly (p = 0.0545 and p = 0.1464, respectively) among pre-treated or untreated patients. Combined ICI treatments had a significantly higher rate of Adverse Events (AEs) (p = 0.01). PD-L1-positive patients had a higher probability of response and survival. In conclusion, combined ICI treatments have higher efficacy than single agents but are limited by higher toxicity. Efficacy was independent of treatment line, so a customized sequential strategy should still be speculated. PD-L1 expression could influence response to ICIs; however, reliable biomarkers are warranted

SARS-CoV-2 omicron (B.1.1.529)-related COVID-19 sequelae in vaccinated and unvaccinated patients with cancer: results from the OnCovid registry

Background COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2. Methods OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974. Findings At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [ 50 center dot 7%] of 1902 patients with sex data were female and 938 [49 center dot 3%] were male). Overall, 317 (16 center dot 6%; 95% CI 14 center dot 8-18 center dot 5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the prevaccination phase (191 [19 center dot 1%; 95% CI 16 center dot 4-22 center dot 0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16 center dot 8%; 13 center dot 8- 20 center dot 3] of 653 patients, p=0 center dot 24), but significantly lower in the omicron phase (16 [6 center dot 2%; 3 center dot 5-10 center dot 2] of 256 patients, p<0 center dot 0001). In the alpha- delta phase, 84 (18 center dot 3%; 95% CI 14 center dot 6-22 center dot 7) of 458 unvaccinated patients and three (9 center dot 4%; 1 center dot 9- 27 center dot 3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7 center dot 4%; 95% CI 3 center dot 5-13 center dot 5] of 136 boosted patients, 18 [9 center dot 8%; 5 center dot 8-15 center dot 5] of 183 patients who had two vaccine doses vs 277 [ 18 center dot 5%; 16 center dot 5-20 center dot 9] of 1489 unvaccinated patients, p=0 center dot 0001), respiratory sequelae (six [4 center dot 4%; 1 center dot 6-9 center dot 6], 11 [6 center dot 0%; 3 center dot 0-10 center dot 7] vs 148 [9 center dot 9%; 8 center dot 4- 11 center dot 6], p= 0 center dot 030), and prolonged fatigue (three [2 center dot 2%; 0 center dot 1-6 center dot 4], ten [5 center dot 4%; 2 center dot 6-10 center dot 0] vs 115 [7 center dot 7%; 6 center dot 3-9 center dot 3], p=0 center dot 037)

Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters

IntroductionImmunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines.MethodsHere we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation.ResultsWe show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus.DiscussionThese data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20

Outcome of EGFR-mutated adenocarcinoma NSCLC patients with changed phenotype to squamous cell carcinoma after tyrosine kinase inhibitors: A pooled analysis with an additional case

The onset of a new histology is a resistant mechanism to tyrosine kinase inhibitors (TKI) in lung adenocarcinoma (ADK), but this phenomenon has not yet been fully clarified. We present a pooled analysis of the outcomes of EGFR-mutated ADK patients with changed phenotype to squamous cell carcinoma (SqCC) following TKI, along with the description of an additional case. A 67-year-old woman with EGFR-mutated NSCLC received gefitinib and subsequently osimertinib, due to the presence of T790 M at progression. The re-biopsy after third-generation TKI revealed SqCC histology along with the basal EGFR mutation, while T790 M disappeared. The patient rapidly progressed and died despite two chemotherapy cycles. Since this first description of SqCC transformation appearing after treatment with the third-generation TKI osimertinib, other 16 patients, with EGFR-mutated ADK developing a transformation to SqCC histology after treatment with TKIs, were up to now published. From our pooled analysis emerged that most patients were female (82%), 41% were former smokers and no current smokers were identified. Median time to SqCC onset was 11.5 months. In all cases, basal EGFR mutation was maintained, and 11 patients (65%) developed an acquired mutation on exon 20. Interestingly also 790 M mutation appeared in 8 patients (47%). The median survival after SqCC diagnosis was 3.5 months regardless the treatments received. Therefore, EGFR-mutated lung ADK destined to develop a squamous phenotype were often smokers and maintained the baseline genomic alterations. The prognosis after SqCC diagnosis was extremely poor and current treatments largely inefficacious

The major issue of oncological treatment administration at the end of life: a retrospective study - supplementary material

Supplementary table S1: Clinicopathological features of study case seriesSupplementary Table S3: Univariate analysis of variable potential predicting end-of-life therapy</p

High Prevalence and Early Occurrence of Skeletal Complications in EGFR Mutated NSCLC Patients With Bone Metastases

none24ObjectivesThe prevalence of Skeletal Related Adverse Events (SREs) in EGFR mutated non-small cell lung cancer (NSCLC) patients with bone metastases, treated with modern tyrosine kinase inhibitors (TKIs), has been scarcely investigated.Materials and MethodsWe retrospectively evaluated the data of EGFR mutated NSCLC patients with bone metastases treated with TKIs in 12 Italian centers from 2014 to 2019, with the primary aim to explore type and frequency of SREs.ResultsSeventy-seven out of 274 patients enrolled (28%) developed at least one major SRE: 55/274 (20%) bone fractures, 30/274 (11%) spinal cord compression, 5/274 (2%) hypercalcemia. Median time to the onset of SRE was 3.63 months. Nine patients (3%) underwent bone surgery and 150 (55%) radiation therapy on bone. SREs were more frequently observed within the 12 months from TKI start than afterwards (71 vs 29%, p 0.000). Patient Performance Status and liver metastases where independently associated with the risk of developing SREs. Median TKI exposure and overall survival were 11 and 28 months, respectively. Bone resorption inhibitors were associated with a lower risk of death (HR 0.722, 95% CI: 0.504-1.033, p = 0.075) although not statistically significant at multivariate analysis.ConclusionBone metastatic NSCLC patients with EGFR mutated disease, treated with EGFR TKIs, have a relatively long survival expectancy and are at high risk to develop SREs. The early SRE occurrence after the TKI start provides the rationale to administer bone resorption inhibitors.restrictedLaganà, Marta; Gurizzan, Cristina; Roca, Elisa; Cortinovis, Diego; Signorelli, Diego; Pagani, Filippo; Bettini, Anna; Bonomi, Lucia; Rinaldi, Silvia; Berardi, Rossana; Filetti, Marco; Giusti, Raffaele; Pilotto, Sara; Milella, Michele; Intagliata, Salvatore; Baggi, Alice; Cortellini, Alessio; Soto Parra, Hector; Brighenti, Matteo; Petrelli, Fausto; Bennati, Chiara; Bidoli, Paolo; Garassino, Marina Chiara; Berruti, AlfredoLaganà, Marta; Gurizzan, Cristina; Roca, Elisa; Cortinovis, Diego; Signorelli, Diego; Pagani, Filippo; Bettini, Anna; Bonomi, Lucia; Rinaldi, Silvia; Berardi, Rossana; Filetti, Marco; Giusti, Raffaele; Pilotto, Sara; Milella, Michele; Intagliata, Salvatore; Baggi, Alice; Cortellini, Alessio; Soto Parra, Hector; Brighenti, Matteo; Petrelli, Fausto; Bennati, Chiara; Bidoli, Paolo; Garassino, Marina Chiara; Berruti, Alfred

Real world data of cemiplimab in locally advanced and metastatic cutaneous squamous cell carcinoma

Background: Cutaneous squamous cell carcinoma (cSCC) has an overall favourable outcome, except for patients with an advanced stage disease. The programmed death protein-1 (PD-1) inhibitor cemiplimab has been approved for use in advanced cSCC. We report clinical outcomes from the named patient programme-compassionate use of cemiplimab for patients with advanced cSCC in Italy. Methods: This is a retrospective, observational, multicentre study. We analysed medical records of patients with advanced cSCC treated with cemiplimab between May 2019 and February 2020 in 17 referral Italian centres. We assessed the safety profile according to the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v 5.0), the clinical activity in terms of response rate, clinical benefit and duration of response and baseline clinical-pathologic characteristics associated with response. Results: 131 patients were included, with a median age of 79 years. Of them, 9.2% had a concurrent chronic lymphoproliferative disease and 8.5% a concomitant autoimmune disease. Some 42.7% of the total patients had at least one treatment-related adverse events (AEs); out of above, 9.2% had grade 3-4 adverse events, and there were two fatal adverse events. The overall response rate (ORR) was 58%, and the disease control rate (DCR) was 71.7%. Cutaneous squamous cell carcinomas (cSCCs) arising on the head and neck area (p = 0.007) and haemoglobin values in normal range (p = 0.034) were significantly associated with a better response, while cSCCs on the genitalia (p = 0.041), treatment with any systemic antibiotic within 1 month of cemiplimab initiation (p = 0.012), performance status &gt;1 (p = 0.012), chronic corticosteroids therapy (p = 0.038), previous radiation therapy to lymph nodes (p = 0.052) and previous chemotherapy (p = 0.0020) were significantly associated with a worse response. Conclusions: Our real-world study showed safety and effectiveness results comparable to those obtained in clinical trials. We identified some clinical and biochemical factors potentially associated with response to cemiplimab. (c) 2021 Elsevier Ltd. All rights reserved

A Definitive Prognostication System for Patients With Thoracic Malignancies Diagnosed With Coronavirus Disease 2019: an update from the TERAVOLT registry

BACKGROUND: Patients with thoracic malignancies are at increased risk for mortality from Coronavirus disease 2019 (COVID-19) and large number of intertwined prognostic variables have been identified so far. METHODS: Capitalizing data from the TERAVOLT registry, a global study created with the aim of describing the impact of COVID-19 in patients with thoracic malignancies, we used a clustering approach, a fast-backward step-down selection procedure and a tree-based model to screen and optimize a broad panel of demographics, clinical COVID-19 and cancer characteristics. RESULTS: As of April 15, 2021, 1491 consecutive evaluable patients from 18 countries were included in the analysis. With a mean observation period of 42 days, 361 events were reported with an all-cause case fatality rate of 24.2%. The clustering procedure screened approximately 73 covariates in 13 clusters. A further multivariable logistic regression for the association between clusters and death was performed, resulting in five clusters significantly associated with the outcome. The fast-backward step-down selection then identified seven major determinants of death ECOG-PS (OR 2.47 1.87-3.26), neutrophil count (OR 2.46 1.76-3.44), serum procalcitonin (OR 2.37 1.64-3.43), development of pneumonia (OR 1.95 1.48-2.58), c-reactive protein (CRP) (OR 1.90 1.43-2.51), tumor stage at COVID-19 diagnosis (OR 1.97 1.46-2.66) and age (OR 1.71 1.29-2.26). The ROC analysis for death of the selected model confirmed its diagnostic ability (AUC 0.78; 95%CI: 0.75 - 0.81). The nomogram was able to classify the COVID-19 mortality in an interval ranging from 8% to 90% and the tree-based model recognized ECOG-PS, neutrophil count and CRP as the major determinants of prognosis. CONCLUSION: From 73 variables analyzed, seven major determinants of death have been identified. Poor ECOG-PS demonstrated the strongest association with poor outcome from COVID-19. With our analysis we provide clinicians with a definitive prognostication system to help determine the risk of mortality for patients with thoracic malignancies and COVID-19

A definitive prognostication system for patients with thoracic malignancies diagnosed with COVID-19: an update from the TERAVOLT registry

Background: Patients with thoracic malignancies are at increased risk for mortality from Coronavirus disease 2019 (COVID-19) and large number of intertwined prognostic variables have been identified so far. Methods: Capitalizing data from the TERAVOLT registry, a global study created with the aim of describing the impact of COVID-19 in patients with thoracic malignancies, we used a clustering approach, a fast-backward step-down selection procedure and a tree-based model to screen and optimize a broad panel of demographics, clinical COVID-19 and cancer characteristics. Results: As of April 15, 2021, 1491 consecutive evaluable patients from 18 countries were included in the analysis. With a mean observation period of 42 days, 361 events were reported with an all-cause case fatality rate of 24.2%. The clustering procedure screened approximately 73 covariates in 13 clusters. A further multivariable logistic regression for the association between clusters and death was performed, resulting in five clusters significantly associated with the outcome. The fast-backward step-down selection then identified seven major determinants of death ECOG-PS (OR 2.47 1.87-3.26), neutrophil count (OR 2.46 1.76-3.44), serum procalcitonin (OR 2.37 1.64-3.43), development of pneumonia (OR 1.95 1.48-2.58), c-reactive protein (CRP) (OR 1.90 1.43-2.51), tumor stage at COVID-19 diagnosis (OR 1.97 1.46-2.66) and age (OR 1.71 1.29-2.26). The ROC analysis for death of the selected model confirmed its diagnostic ability (AUC 0.78; 95%CI: 0.75 - 0.81). The nomogram was able to classify the COVID-19 mortality in an interval ranging from 8% to 90% and the tree-based model recognized ECOG-PS, neutrophil count and CRP as the major determinants of prognosis. Conclusion: From 73 variables analyzed, seven major determinants of death have been identified. Poor ECOG-PS demonstrated the strongest association with poor outcome from COVID-19. With our analysis we provide clinicians with a definitive prognostication system to help determine the risk of mortality for patients with thoracic malignancies and COVID-19