Sjögren's Syndrome Caused by PD-1 Inhibition in a Lung Cancer Patient.

In this report, we present a patient with metastatic non-small cell lung cancer who developed Sjögren's syndrome secondary to immune checkpoint inhibition. This patient had a typical clinical presentation as well as biochemical signature, developing only 18 months after the start of treatment with PD-1 inhibition (pembrolizumab).

Liquid Biopsy in Early-Stage Lung Cancer: Current and Future Clinical Applications.

Lung cancer remains the leading cause of cancer death worldwide, with the majority of cases diagnosed in an advanced stage. Early-stage disease non-small cell lung cancer (NSCLC) has a better outcome, nevertheless the 5-year survival rates drop from 60% for stage IIA to 36% for stage IIIA disease. Early detection and optimized perioperative systemic treatment are frontrunner strategies to reduce this burden. The rapid advancements in molecular diagnostics as well as the growing availability of targeted therapies call for the most efficient detection of actionable biomarkers. Liquid biopsies have already proven their added value in the management of advanced NSCLC but can also optimize patient care in early-stage NSCLC. In addition to having known diagnostic benefits of speed, accessibility, and enhanced biomarker detection compared to tissue biopsy, liquid biopsy could be implemented for screening, diagnostic, and prognostic purposes. Furthermore, liquid biopsy can optimize therapeutic management by overcoming the issue of tumor heterogeneity, monitoring tumor burden, and detecting minimal residual disease (MRD), i.e., the presence of tumor-specific ctDNA, post-operatively. The latter is strongly prognostic and is likely to become a guidance in the postsurgical management. In this review, we present the current evidence on the clinical utility of liquid biopsy in early-stage lung cancer, discuss a selection of key trials, and suggest future applications.

Real life safety and effectiveness of nivolumab in older patients with non-small cell lung cancer: Results from the Belgian compassionate use program.

OBJECTIVES: To compare real life effectiveness and safety of nivolumab in patients with non-small cell lung cancer (NSCLC), according to age and Eastern Cooperative Group performance status (ECOG-PS). METHODS: We performed a retrospective analysis of patients treated with nivolumab for NSCLC within a Belgian compassionate use program from July 2015 until December 2016. Safety and effectiveness were compared between patients aged ≥70 years and < 70 years and between ECOG-PS 0/1 and ≥ 2. RESULTS: A total of 324 patients with NSCLC were included. There was no significant difference between older (≥70) and younger (<70 years) patients with regards to progression free survival (PFS) (4 months (95%CI 2.6;4.8) versus 3.7 months (95%CI 1;7), p = 0.483) and overall survival (OS) (9.3 months (95% CI 5.5;13.1 months) versus 8.4 months (95%CI 6.3; 10.5), p = 0,638). Patients with an ECOG-PS ≥2 had a significant lower median PFS and OS compared to patients with an ECOG-PS 0-1 (2.2 (95%CI 1.4; 2.9) versus 5.6 months (95%CI 4.1; 7.1), p = 0.001 and 3.4 (95%CI 2.3; 4.5) versus 11.1 months (95%CI 8.9; 13.2), p < 0.001 respectively). No significant difference in all grades or grade 3/4 adverse events (AEs) were observed between the different age groups (p = 0.526 and p = 0.603 respectively). Patients with an ECOG-PS 0/1 had significantly more all grades AEs (p = 0.009) but no difference in grade 3/4 AEs was observed (p = 0.406) compared to ECOG-PS ≥2. CONCLUSION: This real life retrospective study confirms that safety and effectiveness of nivolumab is similar between different age groups, but that effectiveness is driven by performance status.

Triple Trouble: A Case of Multiple Resistance Mechanisms after First Generation EGFR-TKI in NSCLC.

Epidermal growth factor receptor (EGFR)-targeted therapy has become standard of care in advanced stages EGFR-mutant non-small cell lung cancer. Acquired resistance to first-line EGFR-tyrosine kinase inhibitor (TKI) and subsequent disease progression is a common problem and mostly due to a secondary mutation (T790M) in EGFR. We report a case of a patient with EGFR-mutated lung adenocarcinoma who developed a complex resistance profile: T790M mutation, HER2 mutation and HER2 amplification after first-line EGFR-TKI. This patient was safely treated with a combination of osimertinib and trastuzumab and achieved a clinically meaningful and clear molecular response. This is the first reported case of acquired resistance to first-line EGFR-TKI based on three resistance mechanisms, treated with molecular targeted combination therapy.

Does nivolumab for progressed metastatic lung cancer fulfill its promises? An efficacy and safety analysis in 20 general hospitals.

OBJECTIVES: In patients with refractory or recurrent non-small-cell lung cancer (NSCLC) after first line chemotherapy, phase III trials showed superiority of nivolumab, an IgG4 programmed death-1 immune-checkpoint-inhibitor antibody, over docetaxel. We evaluated case mix, effectiveness and safety of nivolumab upon implementation in general practice. MATERIALS AND METHODS: In 20 general hospitals, all consecutive NSCLC patients treated with nivolumab within the medical need program (inclusion period 12 months) in Flanders - Belgium were evaluated. RESULTS: There were 267 patients, Eastern Cooperative Oncology Group (ECOG) score was 2 in 24% and 0-1 in 76%. In 48%, two or more systemic regimens were given before nivolumab. The median overall survival was 7.8 months (95% confidence interval (CI) 6.3-9.3). At one year, the overall survival rate was 36.5±0.34%. Median progression-free survival was 3.7 months (95% CI 2.9-4.5). An objective response was obtained in 23.2%. ECOG score 2 and presence of liver metastasis strongly correlated with worse survival (p<0.00001). Treatment related adverse events grade 3 or 4 were reported in 21%, colitis (4%) and pneumonitis (7%) were most frequent. CONCLUSION: Upon implementation of nivolumab therapy in general hospitals, the case mix was characterized by a more heavily pretreated population with a substantial fraction of patients with ECOG score 2. The median overall survival is slightly inferior to what was published in the randomized phase III trials. An ECOG score 2 and the presence of liver metastasis correlated strongly with a worse survival. We report a high prevalence of serious adverse events.

Validation and Application of a Custom-Designed Targeted Next-Generation Sequencing Panel for the Diagnostic Mutational Profiling of Solid Tumors.

The inevitable switch from standard molecular methods to next-generation sequencing for the molecular profiling of tumors is challenging for most diagnostic laboratories. However, fixed validation criteria for diagnostic accreditation are not in place because of the great variability in methods and aims. Here, we describe the validation of a custom panel of hotspots in 24 genes for the detection of somatic mutations in non-small cell lung carcinoma, colorectal carcinoma and malignant melanoma starting from FFPE sections, using 14, 36 and 5 cases, respectively. The targeted hotspots were selected for their present or future clinical relevance in solid tumor types. The target regions were enriched with the TruSeq approach starting from limited amounts of DNA. Cost effective sequencing of 12 pooled libraries was done using a micro flow cell on the MiSeq and subsequent data analysis with MiSeqReporter and VariantStudio. The entire workflow was diagnostically validated showing a robust performance with maximal sensitivity and specificity using as thresholds a variant allele frequency >5% and a minimal amplicon coverage of 300. We implemented this method through the analysis of 150 routine diagnostic samples and identified clinically relevant mutations in 16 genes including KRAS (32%), TP53 (32%), BRAF (12%), APC (11%), EGFR (8%) and NRAS (5%). Importantly, the highest success rate was obtained when using also the low quality DNA samples. In conclusion, we provide a workflow for the validation of targeted NGS by a custom-designed pan-solid tumor panel in a molecular diagnostic lab and demonstrate its robustness in a clinical setting.

Study protocol of KLIMOP: a cohort study on the wellbeing of older cancer patients in Belgium and the Netherlands.

BACKGROUND: Cancer is mainly a disease of older patients. In older cancer patients, additional endpoints such as quality of survival and daily functioning might be considered equally relevant as overall or disease free survival. However, these factors have been understudied using prospective designs focussing on older cancer patients. Therefore, this study will focus on the impact of cancer, ageing, and their interaction on the long-term wellbeing of older cancer patients. METHODS/DESIGN: This study is an observational cohort study. We aim to recruit 720 cancer patients above 70 years with a new diagnosis of breast, prostate, lung or gastrointestinal cancer and two control groups: one control group of 720 patients above 70 years without a previous diagnosis of cancer and one control group of 720 cancer patients between 50 - 69 years newly diagnosed with breast, prostate, lung or gastrointestinal cancer. Data collection will take place at inclusion, after six months, after one year and every subsequent year until death or end of the study. Data will be collected through personal interviews (consisting of socio-demographic information, general health information, a comprehensive geriatric assessment, quality of life, health locus of control and a loneliness scale), a handgrip test, assessment of medical records, two buccal swabs and a blood sample from cancer patients (at baseline). As an annex study, caregivers of the participants will be recruited as well. Data collection for caregivers will consist of a self-administered questionnaire examining depression, coping, and burden. DISCUSSION: This extensive data collection will increase insight on how wellbeing of older cancer patients is affected by cancer (diagnosis and treatment), ageing, and their interaction. Results may provide new insights, which might contribute to the improvement of care for older cancer patients.

Systematic review of symptom control and quality of life in studies on chemotherapy for advanced non-small cell lung cancer: how CONSORTed are the data?

BACKGROUND: The effect of chemotherapy on survival of patients with advanced NSCLC is modest, therefore patient reported outcomes (PRO's) are of high interest in randomized controlled trials (RCTs). CONSORT (CONsolidated Standards On Reporting Trials) is a quality checklist of 22 items for the conduct and reporting of RCTs. The aim of this report was to analyse to what extent the different RCTs with information on PRO's adhere to the CONSORT statement. METHODS: Systematic review of RCTs using PRO's either as primary or secondary endpoint. Compliance with the (revised) CONSORT statement was checked by 2 independent reviewers by making for each study the simple sum of the 22 CONSORT items, or a weighted score with a maximum rating of 31 points. RESULTS: The median weighted CONSORT score of the different RCTs was 25, with a remarkable difference from 12 till 30. There was no significant change over time, nor difference between academic and commercial studies, but a significant correlation between CONSORT agreement and journal type (P<0.0001). Adherence to CONSORT was similar for studies comparing chemotherapy with best supportive care alone, comparing different first-line chemotherapies with PRO either as primary or secondary endpoint, or studies looking at second-line chemotherapy. Benefit in PRO's was reported in all of these settings. CONCLUSION: The overall adherence of peer-reviewed RCTs to CONSORT is reasonable, with nonetheless major differences between journals, and with no clear sign of change over time. Apart from modest survival differences, benefits in PRO endpoints are present in all categories of studies we analysed.

The effect of chemotherapy on symptom control and quality of life in patients with advanced non-small cell lung cancer.

Differences in survival outcomes with various treatments for advanced non-small cell lung cancer are very modest. Despite this, end points looking at the patients' subjective benefit, such as symptom control, quality of life or clinical benefit, have only been sparsely implemented into clinical trials as primary points of interest. This review focuses on available evidence regarding these patients' subjective end points in recent clinical trials. Compared with best supportive care, chemotherapy offers symptom control, not only in patients with objective response to chemotherapy, but also in a proportion of patients with disease stabilization. However, interpretation of quality-of-life objectives is more difficult, owing to several methodological problems, but improvement in various domains of quality of life is also reported. Different treatment options, such as older platinum-based schedules, modern platinum-based doublets, single-agent treatment with a new drug or nonplatinum-based doublets, are comprehensively reviewed. Future randomized studies should take up the challenge of looking at the patients' benefit as a primary end point.

Flexible dosing with Darbepoetin alfa for the treatment of chemotherapy-induced anemia.

Anemia is frequent in cancer patients with chemotherapy, and has an important negative effect on health-related quality of life (QoL). Darbepoetin alfa belongs to a new class of erythropoietic proteins with a unique molecular structure and interesting properties compared with classic recombinant human erythropoietin. Darbepoetin alfa is effective for chemotherapy-induced anemia when administered once weekly at a dose of 2.25 mug/kg, as shown in two large phase III placebo-controlled trials in patients with solid tumors and hematological malignancies. Furthermore, it was safe and well tolerated. More recently attention has been focused on optimizing Darbepoetin alfa therapy. Front-loaded dosing was explored to accelerate the hemoglobin (Hb) response and effect on QoL, but this idea could not be confirmed in a large phase III study. Based on the prolonged half-life of Darbepoetin alfa, administration every 3 weeks was appealing. In a large phase III trial, noninferiority of administration of 500 mug every 3 weeks compared with the weekly dosing could be confirmed, both in terms of reduction of red blood cell transfusion, Hb parameters, and QoL. This schedule is very convenient for patients and caregivers as it allows synchronization of erythropoietic therapy and common chemotherapy schedules. Questions for future study are the optimal iron supplementation strategy and the effect of Darbepoetin alfa on outcome. This article reviews the clinical development of Darbepoetin alfa with emphasis on recent data.