Small-cell lung cancer (SCLC) is a very aggressive disease characterized by a high response rate to first-line chemotherapy, but most patients relapse within 1 year with disappointing results to second-line treatments. Chemotherapy has reached a plateau of effectiveness and new therapeutic strategies are needed to change the natural history of SCLC. Areas covered: This review will focus on the current results and the future development of the therapeutic approaches for the treatment of SCLC. Expert commentary: Immunotherapy is becoming a new frontier for the management of SCLC with preliminary interesting results. To date, no targeted drugs have been approved for clinical practice but several novel agents are in an advanced stage of clinical development in SCLC.
Overexpression of epidermal growth factor receptors (EGFR) occurs in >90% of pancreatic ductal adenocarcinomas (PDACs) and is associated with a poorer prognosis. A systematic review of electronic databases identified studies exploring the addition of EGFR-targeted treatment to chemotherapy in patients with locally advanced (LA)/metastatic PDAC. Efficacy, safety and tolerability of EGFR-targeted therapy were explored using meta-analysis of randomised controlled trials (RCTs). Meta-regression was utilised to explore factors associated with improved prognosis (all studies) and benefit from EGFR-targeted therapy (RCTs). Twenty-eight studies (7 RCTs and 21 cohort studies) comprising 3718 patients were included. The addition of EGFR-targeted treatment to chemotherapy did not improve progression-free (pooled hazard ratio (HR): 0.90, p = 0.15) or overall survival (HR: 0.94, p = 0.18). EGFR-targeted therapy was associated with increased treatment-related deaths (pooled odds ratio (OR): 5.18, p = 0.007), and grade (G)3/4 rash (OR: 4.82, p = 0.03). There was a borderline significant increase in G3/4 diarrhoea (OR: 1.75, p = 0.06), but no effect on treatment discontinuation without progression (OR: 0.87, p = 0.25). Neither G3/4 rash nor diarrhoea were associated with increased survival benefit from EGFR-targeted therapy. The effect of EGFR-targeted therapy on overall survival (OS) appeared greater in studies with a greater proportion of LA rather than metastatic patients (R = −0.69, p < 0.001). Further studies in unselected patients with advanced PDAC are not warranted. The benefit from EGFR inhibitors may be limited to patient subgroups not yet clearly defined.
Lung cancer is predominantly a disease of the elderly. This subgroup of patients poses many challenges and an appropriate geriatric assessment is crucial for treatment personalisation in order to reduce the risk of over- or under-treatment. Whilst cytotoxic chemotherapy has been the backbone of advanced non-small cell lung cancer (NSCLC) treatment for decades, the development of targeted agents for driver mutations such as EGFR, ALK, BRAF and ROS1 has changed the treatment paradigm and natural history of this disease. More recently, the development of immune checkpoint inhibitors has revolutionised treatment for a larger group of patients with locally advanced/metastatic disease. Limited data exist on safety and efficacy of these agents in the elderly population. Many questions remain regarding the available evidence for targeted therapies and immune checkpoint blockade in NSCLC and, in particular, their role in this subgroup of patients.
Lung cancer is the most common cause of death worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer and a third of NSCLC patients present with unresectable locally advanced disease (1). Concurrent chemo-radiotherapy [CRT (platinum-based doublet chemotherapy concurrent with RT)] is the standard treatment option for unresectable stage III NSCLC (2-4). Median progression free survival (PFS) for unresectable stage III disease is approximately 8 months and the 5-year survival rate is 15%.Recent studies incorporating modern RT techniques and use of positron emission tomography-computed tomography (PET-CT) for staging have reported a median OS of 24 months for inoperable stage III NSCLC receiving concurrent CRT. Despite treatment is given with curative intent, 50% of patients will relapse with distant disease (5). Efforts to improve survival with induction or consolidation chemotherapy have failed to improve outcomes (6,7). A pooled analysis of the literature showed that consolidation chemotherapy following concurrent chemoradiotherapy doesn't improve OS in unresectable locally advanced NSCLC (8).Immune Checkpoint inhibitors targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) now represent a standard option for advanced NSCLC. To date, Nivolumab, Pembrolizumab and Atezolizumab have been approved by FDA and EMA as a treatment option for pre-treated patients with advanced NSCLC. Pembrolizumab is also licensed as first-line treatment for advanced NSCLC patients with PD-L1 expression ≥50% (9).Durvalumab (imfinzi) is a selective, human immunoglobulin G1 kappa (IgG1k) monoclonal antibody that blocks the interaction of PD-L1 with the PD-1 and CD-80 molecule. In a phase 1 trial durvalumab showed tolerability and efficacy irrespective of PD-L1 status (10). The recently reported ATLANTIC study (11,12) showed the activity of durvalumab in a heavily pre-treated (≥3 lines) NSCLC population. PACIFIC is a phase III randomized, double-blind study comparing durvalumab vs. placebo as consolidation therapy with placebo in patients with stage III, locally advanced, unresectable NSCLC (according to TNM 7th edition) that had not progressed after platinum-based concurrent CRT. Eligible patients had ECOG PS of 0-1 and received two or more cycles of platinum-based doublet chemotherapy (containing etoposide, vinblastine, vinorelbine, taxane, pemetrexed) with concurrent radiotherapy (54-66 Gy) (13). The median age was 64 years and 91% patients were current or ex-smokers. PD-L1 expression was analyzed on archival tumour samples obtained before chemo-radiotherapy. About 22% patients had PD-L1 expression of ≥25% and 41% of patients had PD-L1 expression of <25%. PD-L1 expression was unknown in 36.7% patients. A total of 709 patients were randomized to Editorial Durvalumab after chemo-radiotherapy in stage III non-small cell lung cancer
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