Cardiotoxicity secondary to immune checkpoint inhibitors in the elderly: Safety in real-world data

Producción CientíficaSimple Summary: Immunotherapy is the mainstay treatment for most solid tumours. However, its cardiotoxicity is not yet known and studied, and its uncertainty is even greater in elderly patients. For this reason, this ambispective study was conducted in 195 patients over 70 years of age who were treated with immunotherapy. The percentage of patients with cardiotoxicity was 1.54%; 1.35% of patients with previous heart disease were diagnosed with cardiotoxicity, and 1.65% of those without previous heart disease were diagnosed with cardiotoxicity. The median time from the initiation of treatment until the cardiac event was 45 days. The most frequent toxicity was myocarditis, which was identified in 66.7% of patients, followed by arrhythmias in 33.3% of patients. In conclusion, immunotherapy is shown to be a safe treatment in elderly cancer patients in terms of cardiotoxicity.Introduction: Immunotherapy represents a key pillar of cancer treatments, with high response rates and long survival. Its use is increasing, mainly at the expense of the geriatric population due to the ageing of this population. However, despite its benefit, its safety in certain areas such as cardiotoxicity is largely unknown. The aim of this study is to assess the safety of immunotherapy in elderly patients using real-world data. Methods: This is an ambispective study of patients ≥ 70 years old with solid tumours who were treated with immunotherapy at the University Hospital of Salamanca. Cardiotoxicity was assessed using the CTCAEv5.0 criteria. Results: In total, 195 patients were included (76.9% male and 23.1% female), with a mean age of 75 years [70–93]. The percentage of patients with cardiotoxicity was 1.54%; 1.35% of patients with previous heart disease were diagnosed with cardiotoxicity, and 1.65% of those without previous heart disease were diagnosed with cardiotoxicity. The median time from the initiation of treatment until the cardiac event was 45 days [14–96]. The most frequent toxicity was myocarditis in 66.7% of patients, followed by arrhythmias in 33.3% of patients. Conclusions: Immunotherapy is shown to be a safe treatment in elderly cancer patients in terms of cardiotoxicity. The event rate shows no difference between patients with or without cardiac comorbidity

Oncogenic driver mutations predict outcome in a cohort of head and neck squamous cell carcinoma (HNSCC) patients within a clinical trial

234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p<0.01). Mutational and HPV status influences patient survival, being mutated or HPV-negative tumours associated with poor overall survival (p<0.05). No association was found between mutations and clinicopathological features. This study confirmed and expanded previously published genomic characterization data in HNSCC. Survival analysis showed that non-mutated HNSCC tumours associated with better prognosis and lack of mutations can be identified as an important biomarker in HNSCC. Frequent alterations in PI3K pathway in HPV-positive HNSCC could define a promising pathway for pharmacological intervention in this group of tumours

Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy

Background Neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery. Methods Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes. Results CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of IFNG, GZMB, NKG7, and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) >0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFN gamma signaling after treatment. Additionally, the higher expression of several genes, including AKT1, BST2, OAS3, or CD8B; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples. Conclusions Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC

Determination of essential biomarkers in lung cancer : a real-world data study in Spain with demographic, clinical, epidemiological and pathological characteristics

Background The survival of patients with lung cancer has substantially increased in the last decade by about 15%. This increase is, basically, due to targeted therapies available for advanced stages and the emergence of immunotherapy itself. This work aims to study the situation of biomarker testing in Spain. Patients and methods The Thoracic Tumours Registry (TTR) is an observational, prospective, registry-based study that included patients diagnosed with lung cancer and other thoracic tumours, from September 2016 to 2020. This TTR study was sponsored by the Spanish Lung Cancer Group (GECP) Foundation, an independent, scientific, multidisciplinary oncology society that coordinates more than 550 experts and 182 hospitals across the Spanish territory. Results Nine thousand two hundred thirty-nine patients diagnosed with stage IV non-small cell lung cancer (NSCLC) between 2106 and 2020 were analysed. 7,467 (80.8%) were non-squamous and 1,772 (19.2%) were squamous. Tumour marker testing was performed in 85.0% of patients with non-squamous tumours vs 56.3% in those with squamous tumours (p-value < 0.001). The global testing of EGFR, ALK, and ROS1 was 78.9, 64.7, 35.6% respectively, in non-squamous histology. PDL1 was determined globally in the same period (46.9%), although if we focus on the last 3 years it exceeds 85%. There has been a significant increase in the last few years of all determinations and there are even close to 10% of molecular determinations that do not yet have targeted drug approval but will have it in the near future. 4,115 cases had a positive result (44.5%) for either EGFR, ALK, KRAS, BRAF, ROS1, or high PDL1. Conclusions Despite the lack of a national project and standard protocol in Spain that regulates the determination of biomarkers, the situation is similar to other European countries. Given the growing number of different determinations and their high positivity, national strategies are urgently needed to implement next-generation sequencing (NGS) in an integrated and cost-effective way in lung cancer

Osimertinib in advanced EGFR-T790M mutation-positive non-small cell lung cancer patients treated within the Special Use Medication Program in Spain : OSIREX-Spanish Lung Cancer Group

AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain. Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. One hundred-fifty five patients were enrolled (August 2016-December 2018) from 30 sites. Primary objective: progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources. 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most patients had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. One hundred-fifty five patients were evaluable for response, 1.3% complete response, 40.6% partial response, 31% stable disease and 11.6% disease progression. Objective response rate was 42%. Median progression-free survival was 9.4 months. Of the 155 patients who received treatment, 76 (49%) did not reported any adverse event, 51% presented some adverse event, most of which were grade 1 or 2. The resource cost study indicates early use is warranted. This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events. Clinical trial registration number : NCT03790397

TTCC-2019-02: real-world evidence of first-line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck

ObjectivesThe aim of this study was to confirm the efficacy of the ERBITAX scheme (paclitaxel 80 mg/m2 weekly and cetuximab 400 mg/m2 loading dose, and then 250 mg/m2 weekly) as first-line treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) who are medically unfit for cisplatin-based (PT) chemotherapy.Materials and methodsThis retrospective, non-interventional study involved 16 centers in Spain. Inclusion criteria were to have started receiving ERBITAX regimen from January 2012 to December 2018; histologically confirmed SCCHN including oral cavity, oropharynx, hypopharynx, and larynx; age ≥18 years; and platinum (PT) chemotherapy ineligibility due to performance status, comorbidities, high accumulated dose of PT, or PT refractoriness.ResultsA total of 531 patients from 16 hospitals in Spain were enrolled. The median age was 66 years, 82.7% were male, and 83.5% were current/former smokers. Patients were ineligible to receive PT due to ECOG 2 (50.3%), comorbidities (32%), PT cumulative dose ≥ 225 mg/m2 (10.5%), or PT refractoriness (7.2%). Response rate was 37.7%. Median duration of response was 5.6 months (95% CI: 4.4–6.6). With a median follow-up of 8.7 months (95% CI: 7.7–10.2), median PFS and OS were 4.5 months (95% CI: 3.9–5.0) and 8.9 months (95% CI: 7.8–10.3), respectively. Patients treated with immunotherapy after ERBITAX had better OS with a median of 29.8 months compared to 13.8 months for those who received other treatments. The most common grade ≥ 3 toxicities were acne-like rash in 36 patients (6.8%) and oral mucositis in 8 patients (1.5%). Five (0.9%) patients experienced grade ≥ 3 febrile neutropenia.ConclusionThis study confirms the real-world efficacy and tolerability of ERBITAX as first-line treatment in recurrent/metastatic SCCHN when PT is not feasible. Immunotherapy after treatment with ERBITAX showed remarkable promising survival, despite potential selection bias

Differentially Expressed Genes Involved in Primary Resistance to Immunotherapy in Patients with Advanced-Stage Pulmonary Cancer

In the last few years, nivolumab has become the standard of care for advanced-stage lung cancer patients. Unfortunately, up to 60% of patients do not respond to this treatment. In our study, we identified variations in gene expression related to primary resistance to immunotherapy. Bronchoscopy biopsies were obtained from advanced non-small cell lung cancer (NSCLC) patients previously characterized as responders or non-responders after nivolumab treatment. Ten tumor biopsies (from three responders and seven non-responders) were analyzed by the differential expression of 760 genes using the NanoString nCounter platform. These genes are known to be involved in the response to anti-PD1/PD-L1 therapy. All the patients were treated with nivolumab. Examining the dysregulated expression of 24 genes made it possible to predict the response to nivolumab treatment. Supervised analysis of the gene expression profile (GEP) revealed that responder patients had significantly higher levels of expression of CXCL11, NT5E, KLRK1, CD3G, GZMA, IDO1, LCK, CXCL9, GNLY, ITGAL, HLA-DRB1, CXCR6, IFNG, CD8A, ITK, B2M, HLA-B, and HLA-A than did non-responder patients. In contrast, PNOC, CD19, TP73, ARG1, FCRL2, and PTGER1 genes had significantly lower expression levels than non-responder patients. These findings were validated as predictive biomarkers in an independent series of 201 patients treated with nivolumab (22 hepatocellular carcinomas, 14 non-squamous cell lung carcinomas, 5 head and neck squamous cell carcinomas, 1 ureter/renal pelvis carcinoma, 120 melanomas, 4 bladder carcinomas, 31 renal cell carcinomas, and 4 squamous cell lung carcinomas). ROC curve analysis showed that the expression levels of ITK, NT5E, ITGAL, and CD8A were the best predictors of response to nivolumab. Further, 13/24 genes showed an adverse impact on overall survival (OS) in an independent, large series of patients with NSCLC (2166 cases). In summary, we found a strong association between the global GEP of advanced NSCLC and the response to nivolumab. The classification of NSCLC patients based on GEP enabled us to identify those patients who genuinely benefited from treatment with immune checkpoint inhibitors (ICIs). We also demonstrated that abnormal expression of most of the markers comprising the genomic signature has an adverse influence on OS, making them significant markers for therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of these biomarkers

Machine learning survival models for relapse prediction in a early stage lung cancer patient

Lung cancer is one of the leading health complica tions causing high mortality worldwide. The relapsing behavior of medically treated early-stage lung cancer makes this disease even more complicated. Thus predicting such relapse using a data-centric approach provides a complementary perspective for clinicians to understand the disease. In this preliminary work, we explored off-the-shelf survival models to predict the relapse of early-stage lung cancer patients. We analyzed the survival models on a cohort of 1348 early-stage non-small cell lung cancer (NSCLC) patients in different timestamps. Using the prediction explanation model SHAP (SHapley Additive exPlanations), we further explained the best-performing survival model’s predic tions. Our explainable predictive model is a potential tool for oncologists that address an unmet clinical need for post-treatment patient stratification based on the relapse hazard.We would like to acknowledge Science Foundation Ireland (SFI/12/RC/2289 P2) and the CLARIFY project (European Commission under the grant number 875160) for funding this research

The Impact of Liquid Biopsies Positive for <em>EGFR</em> Mutations on Overall Survival in Non-Small Cell Lung Cancer Patients

In recent years, non-small cell lung cancer treatment has been revolutionized. EGFR tyrosine kinase inhibitors and our improved understanding of its alterations have driven new diagnostic strategies. Liquid biopsies have emerged as a useful tool in these contexts, showing potential utility in early diagnosis combined with low-dose CT scans, as well as potential in monitoring treatment response and predicting the development of patients. We studied the circulating tumor DNA (ctDNA) of 38 EGFR-mutated non-small cell lung cancer patients at diagnosis in different moments of their disease by liquid biopsy techniques. Our results show that mean overall survival was significantly lower when a liquid biopsy was positive for the detection of EGFR mutations compared with wild-type patients in their liquid biopsy in both univariate (29 ± 4 vs. 104 ± 19 months; p = 0.004) and multivariate analysis (p = 0.008). Taking this into consideration, liquid biopsies could be key to improving the control of this disease

Influence of DNA Mismatch Repair (MMR) System in Survival and Response to Immune Checkpoint Inhibitors (ICIs) in Non-Small Cell Lung Cancer (NSCLC): Retrospective Analysis

Mutations in the mismatch repair (MMR) system predict the response to immune checkpoint inhibitors (ICIs) like colon or gastric cancer. However, the MMR system&rsquo;s involvement in non-small cell lung cancer (NSCLC) remains unknown. Addressing this issue will improve clinical guidelines in the case of mutations in the main genes of the MMR system (MLH1, MSH2, MSH6, and PMS2). This work retrospectively assessed the role that these gene mutations play in the response to and survival of ICIs in NSCLC. Patients with NSCLC treated with nivolumab as the second-line treatment in the University Hospital of Salamanca were enrolled in this study. Survival and response analyses were performed according to groups of MMR system gene expression (MMR expression present or deficiency) and other subgroups, such as toxicity. There was a statistically significant relationship between the best response obtained and the expression of the MMR system (p = 0.045). The presence of toxicity grade &ge; 3 was associated with the deficiency expression of MMR (dMMR/MSI-H) group (p = 0.022; odds ratio = 10.167, 95% confidence interval (CI) 1.669&ndash;61.919). A trend towards greater survival and response to ICIs was observed in NSCLC and dMMR. Assessing the genes in the MMR system involved in NSCLC is key to obtaining personalized immunotherapy treatments