Cost-Consequence Analysis of Three Different Diagnostic Strategies in the First- and Second-Line Treatment of Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

BACKGROUND: Unlike the tissue one, liquid biopsy is a less invasive diagnostic method for the assessment of possible mutations of the tumor, based on the analysis of circulating free DNA (cfDNA) present in the plasma component of the blood. Because blood samples are easily obtainable, plasma biopsy is a non-invasive method, supplementing the more traditional biopsy techniques.AIM: A cost-consequence analysis was conducted to compare the adoption of three different diagnostic strategies in the first- and second-line treatment of locally advanced or metastatic NSCLC: i) tissue strategy (only tissue biopsy for first and second line), ii) combined strategy (first line: tissue biopsy. If unknown, liquid biopsy; second line: liquid biopsy. If negative, tissue biopsy) and iii) potential strategy (first line: tissue biopsy. If unknown or tissue ineligible, liquid biopsy; secondline: liquid biopsy. If negative, tissue biopsy).METHODS: A decision-analytic model was developed considering the Italian NHS’s perspective. We only evaluated direct medical costs (tissue biopsy, management of complications associated with tissue and liquid biopsies) borne by the NHS. The CCA was conducted over a time horizon of 1 year, assuming that for each patient with mNSCLC the diagnosticpathway (first- and second-line treatment) ended within such period. Key variables were tested in the sensitivity analysis.RESULTS: Considering both the first and the second line of treatment, the potential strategy constitutes the cost-effective alternative, characterized by an average cost per correctly identified case (€ 685) lower than that estimated for the combined strategy (€ 732) or for the tissue strategy (€ 1,004). The potential strategy remains cost-effective, also considering the results referred to the first- or second-line treatment only.CONCLUSION: The choice of a correct diagnostic strategy is crucial in order to optimize cancer therapies in the first- and second-line treatment of locally advanced or metastasized NSCLC. The addition to the diagnostic pathway of the liquid biopsy would correctly identify a greater number of cases, supporting the prescription of the best oncological therapy

Clinical Impact of two Different Diagnostic Strategies in the First- and Second-Line Treatment of Locally Advanced or Metastatic EGFR-Mutated Non-Small Cell Lung Cancer

BACKGROUND: A histopathological and mutational diagnosis has become a priority in the correct choice of the most appropriate cancer therapy for NSCLC. In the absence of a molecular analysis, the therapeutic choice will be directed towards platinum-based chemotherapy, thus preventing, in the presence of a specific mutation, the benefits deriving from the administration of a target therapies (TT).AIM: the present analysis was carried out with the aim of estimating the clinical impact, expressed in terms of progression free survival (PFS), associated with the use of the combined strategy (tissue biopsy and liquid biopsy) or the tissue strategy in the EGFR+ mNSCLC population.METHODS: A pre-existing cost-consequence model was adapted to estimate the annual number of mNSCLC patients with or without the EGFR mutation in order to decide the oncological treatment to be administered in first (1L) or second line (2L). In 1L, against the presence of the EGFR mutation, the administration of a Tyrosine Kinase Inhibitor (TKI), such as osimertinib, gefitinib, erlotinib or afatinib, was considered; in the absence of the EGFR mutation, the administration ofstandard platinum-based chemotherapy was instead considered. With reference to 2L, in the presence of the EGFR T790M mutation, only osimertinib was considered. In the absence of the EGFR T790M mutation, the administration of the standard platinum-based chemotherapy was also considered. The PFS data associated with each of the drugs considered were extrapolated from the respective clinical studies. Key variables were tested in the sensitivity analysis.RESULTS: The adoption of the combined strategy (tissue biopsy and liquid biopsy), by virtue of a greater number of patients treated with TKIs, would make it possible to increase the average PFS in the range of 1.1-3,7 months in the 1L and by 1.4 months in the 2L.CONCLUSION: These results show how the adoption of a correct diagnostic strategy is critical in order to optimize the choice of the therapeutic path in the 1L and 2L of mNSCLC. The addition of the liquid biopsy to the classic diagnostic path (tissue biopsy) would in fact allow to obtain an increase in therapeutic efficacy (average PFS)

Impact and management of chemotherapy/radiotherapy-induced nausea and vomiting and the perceptual gap between oncologists/oncology nurses and patients: a cross-sectional multinational survey

Purpose: chemotherapy/radiotherapy-induced nausea and vomiting (CINV/RINV) can affect half of oncology patients, significantly impacting daily life. Nausea without vomiting has only recently been thought of as a condition in its own right. As such, the incidence of nausea is often underestimated. This survey investigated the incidence and impact of CINV/RINV in patients compared with estimations of physicians/oncology nurses to determine if there is a perceptual gap between healthcare professionals and patients. Methods: an online research survey of physicians, oncology nurses and patients was conducted across five European countries. Participants had to have experience prescribing/recommending or have received anti-emetic medication for CINV/RINV treatment. Questionnaires assessed the incidence and impact of CINV/RINV, anti-emetic usage and compliance, and attribute importance of anti-emetic medication. Results: a total of 947 (375 physicians, 186 oncology nurses and 386 patients) participated in this survey. The incidence of nausea was greater than vomiting: 60 % of patients reported nausea alone, whereas 18 % reported vomiting. Physicians and oncology nurses overestimated the incidence of CINV/RINV but underestimated its impact on patients' daily lives. Only 38 % of patients reported full compliance with physicians'/oncology nurses' guidelines when self-administering anti-emetic medication. Leading factors for poor compliance included reluctance to add to a pill burden and fear that swallowing itself would induce nausea/vomiting. Conclusions: there is a perceptual gap between healthcare professionals and patients in terms of the incidence and impact of CINV/RINV. This may lead to sub-optimal prescription of anti-emetics and therefore management of CINV/RINV. Minimising the pill burden and eliminating the requirement to swallow medication could improve poor patient compliance with anti-emetic regimens

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

Italian multicenter survey to evaluate the opinion of patients and their reference clinicians on the &quot;tolerance&quot; to targeted therapies already available for non-small cell lung cancer treatment in daily clinical practice

INTRODUCTION: The introduction of targeted therapies in non-small cell lung cancer (NSCLC) treatment has led to emerging toxicities, whose management and impact on quality-of-life (QoL) is not clearly defined. Aim of this Italian multicenter survey was to highlight any discrepancy between patients’ and clinicians’ perception of such toxicities in order to improve their management. METHODS: From October 2013 to April 2014, 133 NSCLC advanced patients, treated with targeted therapies, were consecutively enrolled to assess toxicities and QoL with dedicated questionnaires. One hundred and sixteen patients were included in the final analysis, having attended three consecutive evaluations (T0, T1, T2), starting at least 15 days after the biological treatment. The survey required monthly compilation of both physicians and patients’ questionnaires, basing adverse event evaluation on CTCAE version 4.0. RESULTS: Most of the patients received either an EGFR-TKI or an anaplastic lymphoma kinase (ALK) inhibitor as targeted therapy (84.5% and 13.8%, respectively). At every checkpoint (T0, T1, T2) a significant difference in terms of perception of targeted therapies-related toxicities of any type and grade was described (P value =0.0001 in all cases). This difference was more pronounced for skin toxicity, fatigue and diarrhea. Furthermore, also the assessment of QoL revealed contrasting data between patients and clinicians, mainly QoL reported as good by the majority of patients and daily activities considered as slightly influenced by targeted therapies. CONCLUSIONS: In our knowledge, this is the first prospective survey in patients and doctors specifically designed for targeted therapies in advanced NSCLC. The results show an underestimation of toxicities by clinicians when compared with patients, the difference being greater for adverse events more strongly associated with daily life and QoL. Further studies are needed to confirm our first results. The discrepancy in perception of targeted therapies-related toxicities should be a result from which to start thinking about a new approach in their management

Atezolizumab Versus Docetaxel in Pretreated Patients With NSCLC: Final Results From the Randomized Phase 2 POPLAR and Phase 3 OAK Clinical Trials

INTRODUCTION: The phase 2 POPLAR and phase 3 OAK studies of the anti-programmed death-ligand 1 (PD-L1) immunotherapy atezolizumab in patients with previously treated advanced NSCLC revealed significant improvements in survival versus docetaxel (p = 0.04 and 0.0003, respectively). Longer follow-up permits evaluation of continued benefit of atezolizumab. This study reports the final overall survival (OS) and safety findings from both trials. METHODS: POPLAR randomized 287 (atezolizumab,144; docetaxel,143) and OAK randomized 1225 (atezolizumab, 613; docetaxel, 612) patients. Patients received atezolizumab (1200-mg fixed dose) or docetaxel (75 mg/m(2)) every 3 weeks. Efficacy and safety outcomes were evaluated. RESULTS: A longer OS was observed in patients receiving atezolizumab versus docetaxel in POPLAR (median OS = 12.6 mo versus 9.7 mo; hazard ratio = 0.76, 95% confidence interval [CI]: 0.58-1.00) and OAK (median OS = 13.3 versus 9.8 mo; hazard ratio = 0.78, 95% CI: 0.68-0.89). The 4-year OS rates in POPLAR were 14.8% (8.7-20.8) and 8.1% (3.2-13.0) and those in OAK were 15.5% (12.4-18.7) and 8.7% (6.2-11.3) for atezolizumab and docetaxel, respectively. Atezolizumab had improved OS benefit compared with docetaxel across all PD-L1 expression and histology groups. Most 4-year survivors in the docetaxel arms received subsequent immunotherapy (POPLAR, 50%; OAK, 65%). Of the 4-year survivors, most had Eastern Cooperative Oncology Group performance status of 0 and nonsquamous histological classification and approximately half were responders (POPLAR: atezolizumab, seven of 15; docetaxel, three of four; OAK: atezolizumab, 24 of 43; docetaxel, 11 of 26). Treatment-related grade 3/4 adverse events occurred in 27% and 16% of atezolizumab 4-year survivors in POPLAR and OAK, respectively. CONCLUSIONS: Long-term follow-up suggests a consistent survival benefit with atezolizumab versus docetaxel in patients with previously treated NSCLC regardless of PD-L1 expression, histology, or subsequent immunotherapy. Atezolizumab had no new safety signals, and the safety profile was similar to that in previous studies

Activity of the EGFR-HER2 dual inhibitor afatinib in EGFR-mutant lung cancer patients with acquired resistance to reversible EGFR tyrosine kinase inhibitors

Background: The purpose of this study was to evaluate the efficacy of afatinib in EGFR-mutant metastatic NSCLC patients with acquired resistance to erlotinib or gefitinib. Materials and methods: We retrospectively analyzed the outcome of patients with EGFR-mutant advanced NSCLC treated with afatinib after failure of chemotherapy and EGFR TKIs. Results: A total of 96 individuals were included in the study. According to EGFR status, most patients (n = 63; 65.6%) harbored a deletion in exon 19, and de novo T790M mutation was detected in 2 cases (T790M and exon 19). Twenty-four (25%) patients underwent repeated biopsy immediately before starting afatinib and secondary T790M was detected in 8 (33%) samples. Among the 86 patients evaluable for efficacy, response rate was 11.6%, with a median progression free-survival (PFS) and overall survival (OS) of 3.9 and 7.3 months, respectively. No significant difference in PFS and OS was observed according to type of last therapy received before afatinib, type of EGFR mutation or adherence to Jackman criteria, and patients benefiting from afatinib therapy had longer PFS and OS (P &lt; .001). Outcome results for repeated biopsy patients were similar to the whole population, with no evidence of response in T790M-positive patients. All patients were evaluable for toxicity, and 81% experienced an AE of any grade, with grade 3 to 4 AEs, mainly diarrhea and skin toxicity, occurring in 19 (20%) patients. Conclusion: Our results showed that afatinib has only modest efficacy in a real life population of EGFR mutant NSCLC patients with acquired resistance to erlotinib or gefitinib

RNA-Based Assay for Next-Generation Sequencing of Clinically Relevant Gene Fusions in Non-Small Cell Lung Cancer

Gene fusions represent novel predictive biomarkers for advanced non-small cell lung cancer (NSCLC). In this study, we validated a narrow NGS gene panel able to cover therapeutically-relevant gene fusions and splicing events in advanced-stage NSCLC patients. To this aim, we first assessed minimal complementary DNA (cDNA) input and the limit of detection (LoD) in different cell lines. Then, to evaluate the feasibility of applying our panel to routine clinical samples, we retrospectively selected archived lung adenocarcinoma histological and cytological (cell blocks) samples. Overall, our SiRe RNA fusion panel was able to detect all fusions and a splicing event harbored in a RNA pool diluted up to 2 ng/µL. It also successfully analyzed 46 (95.8%) out of 48 samples. Among these, 43 (93.5%) out of 46 samples reproduced the same results as those obtained with conventional techniques. Intriguingly, the three discordant results were confirmed by a CE-IVD automated real-time polymerase chain reaction (RT-PCR) analysis (Easy PGX platform, Diatech Pharmacogenetics, Jesi, Italy). Based on these findings, we conclude that our new SiRe RNA fusion panel is a valid and robust tool for the detection of clinically relevant gene fusions and splicing events in advanced NSCLC