Mario Caccese

Current and developing therapies for the treatment of non-small cell lung cancer with ALK abnormalities: update and perspectives for clinical practice.

ABSTRACT Introduction: The treatment of patients with ALK-rearranged non-small-cell lung cancer was completely revolutionized by the introduction of Crizotinib, a small molecule inhibiting ALK, MET and ROS1. Given that resistance occurs within approximately 12 months, in order to develop more potent inhibitors and to increase drug penetration to CNS, innovative ALK-inhibitors were developed. Second-generation ALK inhibitors Ceritinib (LDK378), Alectinib (CH5424802/RO5424802) and Brigatinib (AP26113) have shown significant clinical activity, and were rapidly approved by regulatory agencies. In addition, early clinical data demonstrated that 3rd generation ALK-inhibitors Lorlatinib (PF-06463922), Entrectinib (RxDx-101) and Ensartinib (X-398) provided promising advantages in terms of both clinical activity and safety. Areas covered: In this review, the efficacy and tolerability of Crizotinib for 1st and 2nd-line treatment, and the clinical and preclinical data that led to the development of innovative second and third generation ALK-inhibitors are described. Expert opinion: The better characterization of the mechanisms of resistance to Crizotinib led to the development of newest drugs, which are active both after Crizotinib failure and in patients naïve from ALK-inhibitors. Tumor characterization at disease progression will allow to further personalize the treatment by establishing optimal sequences, which represent tough challenges for the future research in this field of cancer treatment.

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.

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.

The coming of ramucirumab in the landscape of anti-angiogenic drugs: potential clinical and translational perspectives.

Introduction: Angiogenesis plays a pivotal role in the development and progression of tumors and it represents a crucial target for therapeutic strategies. Until now, regulatory agencies approved antiangiogenic agents targeting the VEGF and multi-target agents carrying antiangiogenic and anti-proliferative effects. They often provide only a modest survival benefit and their role in clinical practice is debated. The limited efficacy may be partially explained by the complexity of the molecular background of angiogenic processes, composed of several pathways interacting with both tumor cells and the microenvironment. Areas covered: Ramucirumab is a fully human monoclonal antibody selectively binding and inhibiting the VEGF receptor 2 (VEGFR-2), a crucial molecule involved in angiogenesis. A series of Phase I–II trials conducted in a wide spectrum of malignancies reported promising antitumor activity. In 2014, data from large Phase III clinical trials in gastrointestinal, lung and breast malignancies were released. Expert opinion: Considering the evidences of efficacy emerging from the available Phase III trials, the antiangiogenic approach emerged as a promising strategy particularly for the treatment of gastric cancer. Nevertheless, the identification and validation of potentially predictive biomarkers are necessary to improve the selection of patients and the globally awaited clinical benefit.

Putative predictors of efficacy for immune checkpoint inhibitors in non-small-cell lung cancer: facing the complexity of the immune system.

ABSTRACT Introduction: In non-small-cell lung cancer (NSCLC) the recent introduction of immunotherapy in daily clinical practice produced a wave of enthusiasm, however, this was rapidly moderated by the evidence that only some patients could experience a relevant clinical benefit. Therefore, a great effort from the scientific community has been dedicated to the identification and validation of reliable biomarkers able to drive the activity of immunotherapeutic agents. Areas covered: This analysis aims to review the main findings about predictive biomarkers for immunotherapy in lung cancer, retracing the history of PD-L1 and focusing on a series of innovative candidates, such as mutational load, immune cell populations and microbiome. Expert commentary: Considering the complexity of the immune system-cancer interactions, the idea of identifying a single biomarker able to drive the activity of different immunotherapeutic agents alone, borrowing the idea of targeted therapy, is likely to represent an unrealistic objective. Nevertheless, the identification of those factors either positively or negatively affecting the response is mandatory in order to recruit the appropriate patients, but also to deeply understand the mechanisms of immune response and improve the clinical benefit deriving from these agents in monotherapy or in a biologically-rationale combination.

Necitumumab in the treatment of non-small-cell lung cancer: clinical controversies

ABSTRACT Introduction: Over the last decade, epidermal growth factor receptor (EGFR) signaling was investigated as a potential target for tyrosine kinase inhibitors in the treatment of non-small-cell lung cancer (NSCLC). Necitumumab is a fully humanized IgG1 monoclonal antibody directed against the binding domain of EGFR, approved in combination with cisplatin–gemcitabine for the first-line treatment of squamous NSCLC. Areas covered: The purpose of this manuscript is to systematically review the state of the art of necitumumab for the treatment of metastatic NSCLC, focusing on predictive factors, cost-effectiveness, and future potential combinations with additional agents. Expert opinion: Despite recent therapeutic advances, platinum-based chemotherapy still represents the most widely used first-line treatment for advanced NSCLC, particularly for the squamous histotype. Necitumumab is nowadays the first targeted agent providing an (statistically significant) additional survival gain to squamous NSCLC patients when combined with first-line chemotherapy at the cost of an increased (although manageable) toxicity, as shown in the SQUIRE trial. Hopefully, improvement in patients’ selection by identifying reliable predictive markers and the combination with new agents may help to maximize the benefit of this targeted treatment, which is currently limited by a not optimal cost–benefit ratio.

Adjuvant therapy for resected early-stage small-cell lung cancer: is now time to rethink about that?

Small-cell lung cancer (SCLC) has historically been considered a highly chemo-radiosensitive malignancy, rarely susceptible of surgical resection due to advanced stage presentation with bulky nodal disease and frequent systemic involvement. Actually, surgical series documented SCLC in just 2–3% of patients (1) and, although several randomized trials contributed to define the management of extensive and limited stage SCLC, very few data are available for the early stage, possibly resectable, disease.

Acquired hemophagocytic syndrome in a patient with synovial sarcoma: a case report

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by severe hyperinflammation due to an overwhelming ineffective immune response to different triggers. Most important symptoms are fever, hepatosplenomegaly and cytopenias. Biochemical signs include elevated ferritin, hypertriglyceridemia and low fibrinogen. Hemophagocytosis in the bone marrow is a hallmark of this syndrome. Based on the pathogenetic mechanism, it can be classified into primary (inherited) or secondary (acquired) HLH. We report, to our knowledge, the first case of acquired hemophagocytic syndrome that arose in a 20-year-old man affected by synovial sarcoma as a complication during chemotherapy.