Real-World Treatment Patterns, Epidermal Growth Factor Receptor (EGFR) Testing and Outcomes in EGFR-Mutated Advanced Non-small Cell Lung Cancer Patients in Belgium: Results from the REVEAL Study.

BACKGROUND: Treatment of patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) continues to evolve expeditiously. OBJECTIVES: This retrospective study investigated real-world treatment patterns and EGFR mutation testing in patients with EGFRm advanced NSCLC in Belgium. METHODS: Data were extracted from medical records of adults diagnosed with EGFRm locally advanced/metastatic NSCLC between 1 September 2015 and 31 December 2017. Patients were followed retrospectively from diagnosis until 1 September 2018, end of clinical activity or death. Data on demographics, patient outcomes and disease characteristics, treatment patterns and EGFR mutation testing at diagnosis and progression were analyzed descriptively. RESULTS: A total of 141 patients were enrolled. At diagnosis, median age was 69 years, 63.1% were female, 88.7% had metastatic disease, 94.3% had adenocarcinoma histology, 76.6% had ECOG 0/1, 70.9% had common EGFR mutations and 29.1% had only rare mutations. In first line, 73.8% of patients received first/second-generation EGFR-tyrosine kinase inhibitors (1G/2G EGFR-TKIs), while 21.9% received other systemic treatments. Among 61 patients progressing on and discontinuing a first 1G/2G EGFR-TKI, 45 (73.8%) received subsequent systemic treatment while 16 (26.2%) did not; 20 (32.8%) received osimertinib. Among 65 patients progressing on a first 1G/2G EGFR-TKI, 47 (72.3%) were tested for T790M, of whom 25 (53.2%) were positive. CONCLUSION: These real-world data from Belgium show that a substantial fraction of patients with EGFRm NSCLC do not receive 1G/2G EGFR-TKIs in first line and do not receive subsequent systemic treatment after progression on 1G/2G EGFR-TKIs. Only a third receive osimertinib upon progression on 1G/2G EGFR-TKIs. These observations should be considered in first-line treatment decisions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03761901-December 3, 2018.

Coping Strategy Influences Quality of Life in Patients With Advanced Lung Cancer by Mediating Mood.

INTRODUCTION: Patients with advanced lung cancer experience high physical symptom burden with substantial psychological distress. Depressive and anxiety symptoms are common and associated with worse quality of life (QoL). Early palliative care (EPC) addresses the complex supportive care needs improving QoL and mood. The mechanisms of EPC are uncertain. We examined whether and how coping strategy, a primary component of EPC, influenced QoL in these patients. MATERIALS AND METHODS: We conducted a multicenter cross-sectional study of patients with advanced lung cancer. A total of 125 patients completed assessments of QoL (QLQ-C15-PAL), depressive and anxiety symptoms (HADS), and coping (brief COPE questionnaire). The data were analyzed by descriptive statistics. To determine whether and how coping strategy influences QoL, correlations and logistic regressions were performed. RESULTS: Positive reframing correlates significantly with global QoL (r = 0.25, P < .01), emotional well-being (r = 0.33, P < .01), pain (r = -0.30, P < .01), fatigue (r = -0.22, P < .01), loss of appetite (r = -0.22, P < .01) and nausea (r = -0.24, P < .01). Self-blame correlates significantly with worse emotional well-being (r = -0.19, P < .05) and insomnia (r = 0.19, P < .05). Using a 4-step logistic regression model, it was found that anxiety and depressive symptoms fully mediated the relationship between positive reframing and QoL. CONCLUSIONS: Patients with advanced lung cancer using positive reframing as coping strategy, experience higher QoL. The mechanism behind it seems that positive reframing goes along with less anxiety and depressive symptoms leading to a better QoL. Self-blame leads to more insomnia and worse emotional well-being. Providing skills to cope effectively could impact QoL in these patients.

The genomic landscape of nonsmall cell lung carcinoma in never smokers.

Lung cancer is the number one cause of cancer-related death worldwide with cigarette smoking as its major risk factor. Although the incidence of lung cancer in never smokers is rising, this subgroup of patients is underrepresented in genomic studies of lung cancer. Here, we assembled a prospective cohort of 46 never-smoking, nonsmall cell lung cancer (NSCLC) patients and performed whole-exome and low-coverage whole-genome sequencing on tumors and matched germline DNA. We observed fewer somatic mutations, genomic breakpoints and a smaller fraction of the genome with chromosomal instability in lung tumors from never smokers compared to smokers. The lower number of mutations, enabled us to identify TSC22D1 as a potential driver gene in NSCLC. On the other hand, the frequency of mutations in actionable genes such as EGFR and ERBB2 and of amplifications in MET were higher, while the mutation rate of TP53, which is a negative prognostic factor, was lower in never smokers compared to smokers. Together, these observations suggest a more favorable prognosis for never smokers with NSCLC. Classification of somatic mutations into six-substitution type patterns or into 96-substitution type signatures revealed distinct clusters between smokers and never smokers. Particularly, we identified in never smokers signatures related to aging, homologous recombination damage and APOBEC/AID activity as the most important underlying processes of NSCLC. This further indicates that second-hand smoking is not driving NSCLC pathogenesis in never smokers.

A Multicenter Study to Assess EGFR Mutational Status in Plasma: Focus on an Optimized Workflow for Liquid Biopsy in a Clinical Setting.

A multicenter study was performed to determine an optimal workflow for liquid biopsy in a clinical setting. In total, 549 plasma samples from 234 non-small cell lung cancer (NSCLC) patients were collected. Epidermal Growth Factor Receptor (EGFR) circulating cell-free tumor DNA (ctDNA) mutational analysis was performed using digital droplet PCR (ddPCR). The influence of (pre-) analytical variables on ctDNA analysis was investigated. Sensitivity of ctDNA analysis was influenced by an interplay between increased plasma volume (p < 0.001) and short transit time (p = 0.018). Multistep, high-speed centrifugation both increased plasma generation (p < 0.001) and reduced genomic DNA (gDNA) contamination. Longer transit time increased the risk of hemolysis (p < 0.001) and low temperatures were shown to have a negative effect. Metastatic sites were found to be strongly associated with ctDNA detection (p < 0.001), as well as allele frequency (p = 0.034). Activating mutations were detected in a higher concentration and allele frequency compared to the T790M mutation (p = 0.003, and p = 0.002, respectively). Optimization of (pre-) analytical variables is key to successful ctDNA analysis. Sufficient plasma volumes without hemolysis or gDNA contamination can be achieved by using multistep, high-speed centrifugation, coupled with short transit time and temperature regulation. Metastatic site location influenced ctDNA detection. Finally, ctDNA levels might have further value in detecting resistance mechanisms.

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.

Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined lung adenocarcinoma.

OBJECTIVES: Afatinib, an oral irreversible ErbB family blocker, has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) mutation-positive advanced lung adenocarcinoma. Other potential biomarkers predicting response to afatinib, such as human epidermal growth factor receptor-2 (HER2) mutations and EGFR gene amplification, have not been validated yet. This phase II study investigated whether afatinib conferred clinical benefit in cohorts of adenocarcinoma patients with: (1) EGFR mutation and failing on erlotinib/gefitinib; or (2) increased copy number of EGFR by fluorescence in situ hybridization (FISH); or (3) HER2 mutation. MATERIALS AND METHODS: Patients started daily afatinib 50mg monotherapy. Upon disease progression, patients could continue, at the investigator's discretion, afatinib (40mg) with the addition of paclitaxel (80mg/m(2) weekly for 3 weeks/4-week cycle). Endpoints included confirmed objective response (OR), progression-free survival (PFS), disease control, and safety. RESULTS: Of 41 patients treated (cohort 1: n=32; cohort 2: n=2; cohort 3: n=7), 33 received afatinib monotherapy; eight subsequently received afatinib plus paclitaxel. With afatinib monotherapy, one patient achieved a confirmed OR (partial response [PR]; cohort 2). Two further patients achieved unconfirmed PRs (one each in cohort 1 and cohort 3). Disease control was achieved by 17/32 (53%), 2/2 (100%) and 5/7 (71%) patients in cohorts 1, 2 and 3, respectively. In patients receiving combination therapy (median PFS: 6.7 weeks), one (cohort 3) had confirmed PR of 41.9 weeks. The most common afatinib-related adverse events were diarrhea (95%) and rash/acne (80%). CONCLUSION: Afatinib demonstrated signs of clinical activity in heavily pretreated patients with activating HER2 or EGFR mutations or EGFR FISH-positive tumors.

Geriatric screening results and the association with severe treatment toxicity after the first cycle of (radio)chemotherapy.

BACKGROUND: Screening tools are used in geriatric oncology to determine who should receive a Comprehensive Geriatric Assessment (CGA). However, in this prospective study, we evaluated the association between geriatric screening results, measured with the G8 and Groningen Frailty Indicator (GFI), and severe treatment toxicity. METHODS: Patients over 65 years with various types and stages of cancer were screened with the G8 and the GFI prior to the start of treatment. The association between geriatric screening results and Serious Adverse Events (SAE) after the first cycle of (radio)chemotherapy were studied with bivariate analysis (normal versus abnormal screening test) and logistic regression analysis. RESULTS: From 170 screened patients, 85 patients were eligible for this study. The median age was 76 years (range: 66-88 years). The treatment intent was curative in 46% and palliative in 54%. A SAE occurred in 15 patients (18%) of which three resulted in death. There was no significant association between the G8, as a dichotomous predictor (p = 0.376) or as a continuous predictor (p = 0.298), and risk of a SAE. We also found no significant association for the GFI analysed as a dichotomous predictor (cut-off ≥4: p = 0.384; cut-off ≥3: p = 0.773), nor as a continuous predictor (p = 0.734). All associations remained insignificant when adjusted for treatment type and comorbidity. CONCLUSION: The G8 and the GFI can be used to select patients for CGA, but they do not seem to be predictive for short-term severe treatment toxicity.

Evaluation of the Groningen Frailty Indicator and the G8 questionnaire as screening tools for frailty in older patients with cancer.

OBJECTIVE: In this study, we evaluated the Groningen Frailty Indicator (GFI) and the G8 questionnaire as screening tools for a Comprehensive Geriatric Assessment (CGA) in older patients with cancer. PATIENTS AND METHODS: Eligible patients with various types and stages of cancer were evaluated for frailty before treatment. Patients were categorized as patients with a normal CGA and abnormal CGA (≥2 impaired tests). The diagnostic performance of the screening tools was evaluated against the CGA with Receiver Operating Characteristic analysis. RESULTS: In total, 170 patients (79 women) with median age 77years old (range 66-97years) were included. Sixty-four percent of patients had an abnormal CGA while according to the GFI (GFI≥4) and G8 questionnaire (G8≤14) 47% and 76% of patients had an abnormal screening test, respectively. Overall, there was no significant difference (p=0.97) in diagnostic performance between the two screening tools. The Area Under the Curve was 0.87 for both tools. For the GFI and G8 questionnaire the sensitivity was respectively 66% (95% CI: 56-75%), 92% (95% CI: 85-96%); the negative predictive value (NPV): 59% (95 CI%: 49-69%), 78% (95% CI: 63-88%); and the specificity: 87% (95% CI: 76-94%), 52% (95% CI: 39-65%). CONCLUSION: In this study, we showed that overall both the GFI and the G8 questionnaire were able to separate older patients with cancer with a normal and abnormal CGA. For the G8 questionnaire, an adequate sensitivity and NPV were demonstrated, however at the expense of the specificity. For the GFI, we suggest to lower the threshold with one point to GFI ≥3 to screen patients for a CGA.

Expressed wishes and incidence of euthanasia in advanced lung cancer patients.

This study explores expressed wishes and requests for euthanasia (i.e. administration of lethal drugs at the explicit request of the patient), and incidence of end-of-life decisions with possible life-shortening effects (ELDs) in advanced lung cancer patients in Flanders, Belgium. We performed a prospective, longitudinal, observational study of a consecutive sample of advanced lung cancer patients and selected those who died within 18 months of diagnosis. Immediately after death, the pulmonologist/oncologist and general practitioner (GP) of the patient filled in a questionnaire. Information was available for 105 out of 115 deaths. According to the specialist or GP, one in five patients had expressed a wish for euthanasia; and three in four of these had made an explicit and repeated request. One in two of these received euthanasia. Of the patients who had expressed a wish for euthanasia but had not made an explicit and repeated request, none received euthanasia. Patients with a palliative treatment goal at inclusion were more likely to receive euthanasia. Death was preceded by an ELD in 62.9% of patients. To conclude, advanced lung cancer patients who expressed a euthanasia wish were often determined. Euthanasia was performed significantly more among patients whose treatment goal after diagnosis was exclusively palliative.

Preferred and actual involvement of advanced lung cancer patients and their families in end-of-life decision making: a multicenter study in 13 hospitals in Flanders, Belgium.

CONTEXT: Death is often preceded by medical decisions that potentially shorten life (end-of-life decisions [ELDs]), for example, the decision to withhold or withdraw treatment. Respect for patient autonomy requires physicians to involve their patients in this decision making. OBJECTIVES: The objective of this study was to examine the involvement of advanced lung cancer patients and their families in ELD making and compare their actual involvement with their previously stated preferences for involvement. METHODS: Patients with Stage IIIb/IV non-small cell lung cancer were recruited by physicians in 13 hospitals and regularly interviewed between diagnosis and death. When the patient died, the specialist and general practitioner were asked to fill in a questionnaire. RESULTS: Eighty-five patients who died within 18 months of diagnosis were studied. An ELD was made in 52 cases (61%). According to the treating physician, half of the competent patients were not involved in the ELD making, one-quarter shared the decision with the physician, and one-quarter made the decision themselves. In the incompetent patients, family was involved in half of cases. Half of the competent patients were involved less than they had previously preferred, and 7% were more involved. Almost all of the incompetent patients had previously stated that they wanted their family involved in case of incompetence, but half did not achieve this. CONCLUSION: In half of the cases, advanced lung cancer patients-or their families in cases of incompetence-were not involved in ELD making, despite the wishes of most of them. Physicians should openly discuss ELDs and involvement preferences with their advanced lung cancer patients.

Are patients' preferences for information and participation in medical decision-making being met? Interview study with lung cancer patients.

We examined the degree to which newly diagnosed patients with advanced lung cancer wanted to be informed and involved in medical decision-making, and whether the patients felt their preferences were met. Patients from 13 hospitals in Flanders were interviewed with a standard questionnaire. A total of 128 patients (68%) participated. Of the patients who wanted to be informed about life expectancy, half (53%) reported they were informed, and of those who wanted to be informed about palliative care and end-of-life decisions, 25% and 31% said they were informed, respectively. With regard to participation in medical decision-making (in general, about treatment, transfer or end-of-life), patients who preferred the doctor to make decisions or those who preferred to make the decision themselves often achieved this (in their perception), while patients who wanted an in-between position with some involvement, often did not. To conclude, preferences of patients with lung cancer for information concerning delicate topics and for shared decision-making with the physician were not well met.

Preferences of patients with advanced lung cancer regarding the involvement of family and others in medical decision-making.

OBJECTIVE: To explore the preferences of competent patients with advanced lung cancer regarding involvement of family and/or others in their medical decision-making, and their future preferences in case of loss of competence. METHODS: Over 1 year, physicians in 13 hospitals in Flanders, Belgium, recruited patients with initial non-small­cell lung cancer, stage IIIb or IV. The patients were interviewed with a structured questionnaire every 2 months until the fourth interview and every 4 months until the sixth interview. RESULTS: At inclusion, 128 patients were interviewed at least once; 13 were interviewed 6 consecutive times. Sixty-nine percent of patients wanted family members to be involved in medical decision-making and this percentage did not change significantly over time. One third of these patients did not achieve this preference. Ninety-four percent of patients wanted family involvement if they lost competence, 23% of these preferring primary physician control over decision-making, 41% shared physician and family control, and 36% primary family control. This degree of preferred family involvement expressed when competent did not change significantly over time at population level, but did at individual level; almost half the patients changed their minds either way at some point during the observation period. CONCLUSIONS: The majority of patients with lung cancer wanted family involvement in decision-making, and almost all did so in case of future loss of competence. However, as half of the patients changed their minds over time about the degree of family involvement they wanted if they lost competence, physicians should regularly rediscuss a patient's preferences.