Umberto Peretti

ALK/EML4 Fusion Gene May Be Found in Pure Squamous Carcinoma of the Lung

Introduction: The report of cases of lung squamous cell cancers harboring anaplastic lymphoma kinase (ALK) gene rearrangements raises the question whether this histologic subtype should be also evaluated for such molecular predictive test. Methods: A consecutive series of 40 lung pure squamous cell carcinomas were analyzed for ALK gene status by fluorescence in situ hybridization. Squamous differentiation was validated using an immunohistochemical panel including n-p63 (p40), cytokeratin (CK) 5/6, sex-determining region Y (SRY)-Box2 (SOX2), thyroid transcription factor 1, CK7, and Napsin-A. Results: Squamous differentiation was confirmed in all tumors as they stained positive for n-p63 and CK5/6 and negative for thyroid transcription factor 1 and Napsin-A. One of 40 cases (2.5%) showed an ALK rearrangement on fluorescence in situ hybridization analysis. Conclusions: ALK translocation may be found in lung pure squamous cell carcinomas. Our data suggest the opportunity to test ALK rearrangements on biopsy samples harboring squamous cell cancer differentiation.

Lung Adenocarcinoma Patient Refractory to Gefitinib and Responsive to Crizotinib, with Concurrent Rare Mutation of the Epidermal Growth Factor Receptor (L861Q) and Increased ALK/MET/ROS1 Gene Copy Number

Journal of Thoracic Oncology® • Volume 8, Number 12, December 2013 CASE REPORT A 77-year-old never-smoker woman, with a history of ischemic-hypertensive cardiopathy and diabetes, experiencing cough and dyspnea (performance status 2), underwent a totalbody computed tomography (CT) scan, which showed a large left pulmonary mass with ipsilateral parenchymal nodules and pleural effusion (Fig. 1A). Pathological examination of a tumor cell block obtained from fine-needle aspiration of a 3-cm–sized nodule in the left lower lobe showed malignant epithelial cells with adenocarcinoma structure (Fig. 2). Sequencing analysis of epidermal growth factor (EGFR) exons 18 to 21 upon genomic DNA extracted from the same paraffin-embedded material (3500-Dx Genetic Analyzer; Applied Biosystem Life Technologies, Carlsbad, CA) showed CTG-CAG point mutation (pL861Q) in exon 21. Dual-color, break-apart fluorescent in situ hybridization (FISH) for ALK at 2p23 (ALK FISH DNA Probe; Split Signal, Dako, Glostrup, Denmark) and ROS1 at 6q22 (ZytoLight SPEC ROS1 Dual Color Break Apart Probe; ZytoVision, Bremerhaven, Germany) and dual-color FISH for MET/CEP7 at 7q31 (ZytoLight SPEC MET/CEN 7 Dual Color Probe Zytovision) did not show any rearrangement, but an increased GCG was observed in 61%, 67%, and 72% cancer cells, with 2.6, 2.6, and 2.9 mean signals per cell, respectively (Fig. 2). The patient was started on gefitinib, 250 mg/day (September 18, 2012). Although an initial clinical benefit was observed (performance status 1), symptoms did rapidly worsen in the fifth to seventh weeks, and a CT scan (November 7, 2012) showed progressive pleural disease and two brain metastasis (7 and 3 mm) (Fig. 1B: lung, Fig. 1C: brain). Thus Gefitinib was stopped and given the patient’s performance and comorbidities that did not allow to start chemotherapy, she was addressed to receive crizotinib 250 mg/twice a day on the basis of ALK, MET, and ROS1 increased GCN. After 4 weeks on crizotinib, a significant improvement of symptoms (cough and dyspnea) and performance status (0–1) was obtained. Treatment was well tolerated, except for a grade 1 skin rash and increase of transaminases. The last CT scan (February 25, 2013; Fig. 1D) and clinical evaluation (March 5, 2013) still confirm a stable disease after 4 months of crizotinib.

Predictors of outcome for patients with lung adenocarcinoma carrying the epidermal growth factor receptor mutation receiving 1st-line tyrosine kinase inhibitors: Sensitivity and meta-regression analysis of randomized trials

PURPOSE We performed a sensitivity and meta-regression analysis, cumulating all randomized trials exploring the benefit of afatinib, erlotinib and gefitinib versus chemotherapy in advanced EGFR mutant NSCLC, to investigate the potential role of additional clinico-pathological predictors of TKIs efficacy. RESULTS With regard to progression-free survival (PFS), a significant interaction according to ethnicity (Asian versus Caucasian versus mixed) and to trial design (retrospective versus prospective EGFR analysis), was found; a trend toward significance with regard to type of drug (gefitinib versus erlotinib versus afatinib) was determined. No statistically significant differences in survival were observed. With regard to response, a significant interaction according to ethnicity, trial design and type of drug, was found. CONCLUSION These data, together with a deeper characterization of the molecular background sustaining the oncogenic process, may contribute to create a clinico-pathologic predictive model, aimed to improve the magnitude of benefit expected from the use of targeted agents.

Tubulin inhibitors in non-small cell lung cancer: looking back and forward.

ABSTRACT Introduction: Although the advent of target therapy for lung cancer has brought about outstanding results, this benefit is confined to a subgroup of molecularly selected patients, whereas for most non-small cell lung cancer (NSCLC) patients, chemotherapy still represents the milestone of treatment. Since their introduction into clinics, microtubule targeting agents (MTA), including vinca alkaloids and taxanes, have been extensively used for NSCLC in different settings and combinations. Areas Covered: In this review, MTA are classified according to their mechanism of action, with a focus on the most common mechanisms of resistance. Moreover, an overview of the most remarkable clinical data regarding MTA in adjuvant, neoadjuvant and advanced setting is provided. Finally, the novel mitotic kinases inhibitors are described according to their different mechanism of action and clinical activity compared to MTA. Expert Opinion: Unfortunately, the awaited benefit deriving from the actually available chemotherapeutic regimens for advanced NSCLC has reached a plateau. In this scenario, the identification of reliable predictive biomarkers represents a major challenge. Moreover, different schedules for MTA administration are currently under investigation, such as the combination of MTA with other drugs able to bypass the resistance derived from the ‘mitotic slippage’ and the use of metronomic administration of spindle poisons with anti-angiogenic or immunomodulatory agents.

Risk Stratification Model for Resected Squamous-Cell Lung Cancer Patients According to Clinical and Pathological Factors

Introduction: The aim of this analysis (AIRC-MFAG project no. 14282) was to define a risk classification for resected squamous-cell lung cancer based on the combination of clinicopathological predictors to provide a practical tool to evaluate patients’ prognosis. Methods: Clinicopathological data were retrospectively correlated to disease-free/cancer-specific/overall survival (DFS/CSS/OS) using a Cox model. Individual patient probability was estimated by logistic equation. A continuous score to identify risk classes was derived according to model ratios and dichotomized according to prognosis with receiver operating characteristic analysis. Results: Data from 573 patients from five institutions were gathered. Four hundred ninety-four patients were evaluable for clinical analysis (median age: 68 years; male/female: 403/91; T-descriptor according to TNM 7th edition 1–2/3–4: 330/164; nodes 0/>0: 339/155; stages I and II/III and IV: 357/137). At multivariate analysis, age, T-descriptor according to TNM 7th edition, nodes, and grading were independent predictors for DFS and OS; the same factors, except age and grading, predicted CSS. Multivariate model predict individual patient probability with high prognostic accuracy (0.67 for DFS). On the basis of receiver operating characteristic-derived cutoff, a two-class model significantly differentiated low-risk and high-risk patients for 3-year DFS (64.6% and 32.4%, p < 0.0001), CSS (84.4% and 44.5%, p < 0.0001), and OS (77.3% and 38.8%, p < 0.0001). A three-class model separated low-risk, intermediate-risk, and high-risk patients for 3-year DFS (64.6%, 39.8%, and 21.8%, p < 0.0001), CSS (84.4%, 55.4%, and 30.9%, p< 0.0001), and OS (77.3%, 47.9%, and 27.2%, p < 0.0001). Conclusions: A risk stratification model including often adopted clinicopathological parameters accurately separates resected squamous-cell lung cancer patients into different risk classes. The project is currently ongoing to integrate the clinicopathological model with investigational molecular predictors.

An overview of angiogenesis inhibitors in Phase II studies for non-small-cell lung cancer

Introduction: Angiogenesis plays a major role in the development and progression of solid tumors, including lung cancer. Although some anti-angiogenic agents have demonstrated a statistically significant advantage in terms of primary outcome in clinical trials, the reliable clinical benefit obtained with these drugs is still questionable and often quantitatively limited. To better clarify this complex scenario and definitively establish the concrete benefits of anti-angiogenic strategies in lung cancer, several clinical trials have been conducted with others currently ongoing. Areas covered: In this review, the authors highlight the data ascertained from Phase II trials conducted in NSCLC patients who are treated with recently discovered innovative anti-angiogenic molecules. The authors also discuss older widely investigated anti-angiogenic drugs that have been repurposed or used in different contexts and combinations. Expert opinion: Globally considered, the results of the countless clinical trials evaluating anti-angiogenic agents suggest that angiogenesis (with its molecules and pathways) represents a non-ideal druggable process for several biologically relevant reasons. Consequently, it is important that the conceptual development and clinical validation of anti-angiogenic agents is different from those employed for traditional target agents (i.e., erlotinib, gefitinib and crizotinib). Indeed, the development and validation of these agents still represents a major challenge for modern scientific research.

Platelet-derived growth factor receptor inhibitors for non-small cell lung cancer: is the odyssey over?

Angiogenesis is a complex and dynamic process involving a continuous cross talk of several pathways beyond the universally known vascular endothelial growth factor (VEGF) signaling. Among these, the platelet-derived growth factor (PDGF) signaling pathway, including four polypeptide chains (PDGF-A to PDGF-D) functioning as ligands for two PDGF receptors (PDGFR-α and PDGFR-β), has been demonstrated to play a crucial role in non-small cell lung cancer (NSCLC) aberrant vascularization.[1] The activation of pathways alternative to the VEGF signaling, such as the fibroblast growth factor (FGF), the hepatocyte growth factor (HGF), and the PDGF pathways, represents a potential mechanism of resistance to anti-VEGF or anti-VEGF receptor (VEGFR) agents, which emerges as a compensatory signaling to overcome the VEGF inhibition.[2] Given the crucial role of angiogenesis in lung cancer development and proliferation, a series of agents targeting simultaneously multiple mediators of this process has been extensively evaluated both in clinical and in preclinical settings. The strategy to concurrently targeting multiple molecules in NSCLC has been developed in order to improve the results obtained with the single inhibition of the VEGF pathway, which resulted to be sometimes statistically significant but often clinically questionable, and to overcome the resistance to anti-VEGF/VEGFR agents.[3] Notwithstanding these premises, controversial and disappointing results have been obtained from clinical trials conducted with tyrosine kinase inhibitors (TKIs) targeting PDGF and other signaling pathways as single agents or in combination with chemotherapy or other TKIs, reflecting the complex biology behind the angiogenesis and the non-oncogene-addicted lung cancer disease. In this regard, to date, only nintedanib, a potent TKI targeting the PDGFR, VEGFR, and FGF receptor, has been approved on November 2014 by the European Medicines Agency. The approval of nintedanib in combination with docetaxel for second-line treatment of patients affected by locally advanced, locally recurrent, or metastatic NSCLC with adenocarcinoma histology was granted on the basis of the LUME-Lung 1 and 2 phase III trials’ results. Indeed, according to the subgroups analysis of the LUME-Lung 1 study, patients with adenocarcinoma histology experienced a significant median overall survival (OS) improvement of 2.3 months by the combination of nintedanib with docetaxel compared with docetaxel alone (HR: 0.83; 95% confidence interval [CI]: 0.70– 0.99; p = 0.04). In the overall study population, only a modest median progression-free survival (PFS, primary end point) benefit (3 weeks) of adding nintedanib to docetaxel was demonstrated (HR: 0.79; 95% CI: 0.68–0.92; p = 0.0019).[4] In the LUME-Lung 2 trial (early stopped at the preplanned interim analysis for futility), the association of nintedanib with pemetrexed in patients affected by non-squamous NSCLC resulted in a statistically significant improvement of less than a month in PFS (HR: 0.83; 95% CI: 0.70-0.99; p = 0.04).[5] As for the LUME-Lung 1 trial, no difference in OS was detected between arms. To draw definitive conclusions about the impact of nintedanib in association with docetaxel for the second-line treatment of NSCLC patients with adenocarcinoma histology, results from an ongoing phase III trial (LUME-Columbus) should be awaited. However, even if the LUME-Columbus trial will demonstrate a benefit from the addition of nintedanib to docetaxel, it is necessary to consider that the comparator arm (docetaxel plus placebo) today is no longer the best therapeutic option available for the second-line treatment of advanced NSCLC. Indeed, recent results of clinical trials exploring immunotherapy in pretreated NSCLC patients have demonstrated the superiority of immune checkpoint inhibitors in comparison to docetaxel monotherapy, revolutionizing the standard strategy for this disease setting. As for nintedanib, based on the encouraging results coming from phase II trials, many other TKIs targeting PDGF and other angiogenetic pathways have been evaluated in phase III trials conducted in advanced NSCLC, both in first-line setting and after disease progression (Table 1). However, all these agents failed to demonstrate a sufficient outcome benefit to be included in the therapeutic strategy for NSCLC. For