The Treatment of a New Entity in Advanced Non-Small Cell Lung Cancer: MET exon 14 Skipping Mutation.

BACKGROUND: MET (MET Proto-Oncogene, Receptor Tyrosine Kinase) exon 14 skipping mutation represents one of the most common MET alterations, accounting for approximately 1-3% of all mutations in advanced lung adenocarcinomas. While until 2020 no specific treatment was available for this subset of patients, as of today, three MET Tyrosine Kinase Inhibitors (TKIs) are currently approved in this setting, namely capmatinib, tepotinib and savolitinib. OBJECTIVE: This article aims to provide an extensive overview of the current therapeutic standard of care for exon 14 skipped advanced Non-Small Cell Lung Cancer (NSCLC) patients, alongside with mentions of the main future challenges and opportunities. CONCLUSION: FDA-approved MET-TKIs currently represent the best option for treating exon 14 skipped advanced NSCLC patients, thanks to their excellent efficacy profile, alongside their manageable safety and tolerability. However, we currently lack specific agents to treat patients progressing on capmatinib or tepotinib, due to a limited understanding of the mechanisms underlying both on- and off-target resistance. In this respect, on-target mutations presently constitute the most explored ones from a mechanistic point of view, and type II MET-TKIs are currently under investigation as the most promising agents capable of overcoming the acquired resistance.

Recently approved and emerging monoclonal antibody immune checkpoint inhibitors for the treatment of advanced non-small cell lung cancer.

INTRODUCTION: CTLA-4/PD-1/PD-L1- directed immune checkpoint inhibitors (ICIs) are one of the standard therapies for the treatment of advanced non-small cell lung cancer (NSCLC). However, some new classes of monoclonal antibodies are emerging as promising therapies for advanced NSCLC. AREAS COVERED: Therefore, this paper aims to provide a comprehensive review of the recently approved as well as emerging monoclonal antibody immune checkpoint inhibitors for the treatment of advanced NSCLC. EXPERT OPINION: Further and larger studies will be needed to explore the promising emerging data on new ICIs. Future phase III trials could allow us to properly assess the role of each immune checkpoints in the wider context of the tumor microenvironment and thus the best new ICIs to use, the best approach and the most effective subset of patients to select.

Multicenter Real-World Study on Effectiveness and Early Discontinuation Predictors in Patients With Non-small Cell Lung Cancer Receiving Nivolumab.

BACKGROUND: Real-world (RW) evidence on nivolumab in pretreated patients with non-small cell lung cancer (NSCLC) by matching data from administrative health flows (AHFs) and clinical records (CRs) may close the gap between pivotal trials and clinical practice. METHODS: This multicenter RW study aims at investigating median time to treatment discontinuation (mTTD), overall survival (mOS) of nivolumab in pretreated patients with NSCLC both from AHF and CR; clinical-pathological features predictive of early treatment discontinuation (etd), budget impact (BI), and cost-effectiveness analysis were investigated; mOS in patients receiving nivolumab and docetaxel was assessed. RESULTS: Overall, 237 patients with NSCLC treated with nivolumab were identified from AHFs; mTTD and mOS were 4.2 and 9.8 months, respectively; 141 (59%) received at least 6 treatment cycles, 96 (41%) received < 6 (etd). Median overall survival in patients with and without etd were 3.3 and 19.6 months, respectively (P < .0001). Higher number, longer duration, and higher cost of hospitalizations were observed in etd cases. Clinical records were available for 162 patients treated with nivolumab (cohort 1) and 83 with docetaxel (cohort 2). Median time to treatment discontinuation was 4.8 and 2.6 months, respectively (P < .0001); risk of death was significantly higher in cohort 2 or cohort 1 with etd compared with cohort 1 without etd (P < .0001). Predictors of etd were body mass index <25, Eastern Cooperative Oncology Group performance status >1, neutrophile-to-lymphocyte ratio >2.91, and concomitant treatment with antibiotics and glucocorticoids. The incremental cost-effectiveness ratio of nivolumab was 3323.64 euros ($3757.37) in all patients and 2805.75 euros ($3171.47) for patients without etd. Finally, the BI gap (real-theoretical) was 857 188 euros ($969 050.18). CONCLUSION: We defined predictors and prognostic-economic impact of nivolumab in etd patients.

The role of antiangiogenic monoclonal antibodies combined to EGFR-TKIs in the treatment of advanced non-small cell lung cancer with activating EGFR mutations: acquired resistance mechanisms and strategies to overcome them.

As of today, only two antiangiogenic monoclonal antibodies plus epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) combinations are FDA and EMA-approved and are recommended by American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network for the first-line treatment of EGFR+ advanced non-small cell lung cancer patients: erlotinib plus bevacizumab and erlotinib plus ramucirumab. However, all treated patients eventually become unresponsive to such drugs, due to several different acquired resistance mechanisms, mainly represented by T790M substitutions and MET amplifications. While osimertinib treatment in T790M+ patients still represents the only approved treatment, MET-TKIs will likely change this status quo in the near future. In fact, existing clinical data strongly support a role for MET-TKI-based combinations in EGFR+ MET-amplified patients, possibly revolutionizing our current treatment algorithm. Chemotherapy plus immunotherapy plus antiangiogenic therapy combinations could also represent another useful addition.

New immunotherapeutic drugs in advanced non-small cell lung cancer (NSCLC): from preclinical to phase I clinical trials.

INTRODUCTION: The development of immune checkpoint inhibitors (ICI) has represented a revolution in the treatment of non-small cell lung cancer (NSCLC) and has established a new standard of care for different settings. However, through adaptive changes, cancer cells can develop resistance mechanisms to these drugs, hence the necessity for novel immunotherapeutic agents. AREAS COVERED: This paper explores the immunotherapeutics currently under investigation in phase I clinical trials for the treatment of NSCLC as monotherapies and combination therapies. It provides two comprehensive tables of phase I agents which are listed according to target, drug, drug class, mechanism of action, setting, trial identifier, and trial status. A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed and ClinicalTrials.gov. EXPERT OPINION: A key hurdle to success in this field is our limited understanding of the synergic interactions of the immune targets in the context of the TME. While we can recognize the links between inhibitors and some particularly promising new targets such as TIM-3 and LAG3, we continue to develop approaches to exploit their interactions to enhance the immune response of the patient to tumor cells.

From Diagnostic-Therapeutic Pathways to Real-World Data: A Multicenter Prospective Study on Upfront Treatment for EGFR-Positive Non-Small Cell Lung Cancer (MOST Study).

INTRODUCTION: Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice. METHODS: MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous EGFR-mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials. RESULTS: An EGFR mutation test was performed in 447 enrolled patients, of whom 124 had EGFR mutation and who received gefitinib (n = 69, 55%), erlotinib (n = 33, 27%), or afatinib (n = 22, 18%) as first-line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression-free survival from pivotal phase III trials was €1,813,557.88. CONCLUSION: Good regional adherence and compliance to the diagnostic-therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real-world data in the process of drug price negotiation. IMPLICATIONS FOR PRACTICE: The MOST study is a real-world data collection reporting a multicenter adherence and compliance to diagnostic-therapeutic pathways defined for patients with epidermal growth factor receptor-mutant non-small cell lung cancer. This represents an essential element of evidence-based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn-around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging-to-treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.

Treatment of advanced non-small cell lung cancer in the elderly.

INTRODUCTION: Lung cancer is predominantly a disease that affects the elderly; about 30-40% of lung cancers are diagnosed in patients aged 70 or more. The increasing number of elderly patients over the next decades is generating a new social and health problem; despite that, these patients are underrepresented in clinical trials and undertreated in clinical practice. Areas covered: The main difficulty in treating elderly patients is to maximize the therapy benefits while minimizing the treatment risk. Elderly patients show a vulnerable clinical profile due to the higher prevalence of comorbid disease, higher polypharmacy interactions and aged organ dysfunction that increase the risk of mortality and toxicity with cancer treatments compared to younger patients. Expert commentary: The choice to treat or not to treat elderly patients cannot be taken only on the basis of the chronological age. Thus, the clinical approach should be to select patients who are effectively suitable for treatment having a better individual functional reserve and a better life expectancy. Elderly patients are a heterogeneous population and those who are fit to receive cancer treatment can be treated similarly to younger patients.

The safety of second-line treatment options for non-small cell lung cancer.

INTRODUCTION: Non-small-cell lung cancer (NSCLC) patients after first-line therapy ultimately suffer progression. At this time, many patients still have a good performance status and can be considered for further active treatment. Two chemotherapeutic agents, docetaxel and pemetrexed (only in non-squamous histology), and the biological drug anti-epidermal growth factor receptor (EGFR) erlotinib, were approved for clinical use in the second-line treatment of NSCLC patients. In the last few years further new second-line therapies have become available in the clinical practice. Areas covered: This review will discuss the adverse events of the pivotal trials ledding to the approval of second-line therapies for the treatment of not oncogene-addicted NSCLC patients. Expert opinion: In recent years, new second-line options for NSCLC are: the anti-EGFR, afatinib (only in squamous NSCLC); the anti-angiogenics, nintedanib (only in lung adenocarcinoma) and ramucirumab, in combination with docetaxel; the immunotherapeutics, nivolumab, pembrolizumab, and atezolizumab. In the second-line approach, the main endpoint of treatment should always be survival, but with great respect for symptoms palliation and preserving patients' quality of life. Therefore, differing toxicity profiles of the available therapeutic options are often a deciding factor in second-line setting for NSCLC.

Developments in pharmacotherapy for treating metastatic non-small cell lung cancer.

INTRODUCTION: Most patients with non-small cell lung (NSCLC), including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, have advanced disease at diagnosis and systemic therapy is the standard-of-care. About 20% of Caucasian patients are affected by an oncogene-addicted advanced NSCLC for which correspondent inhibitors are available. Areas covered: The main state-of-the-art synthetic anticancer drugs in the groups of chemotherapeutics, epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for NSCLC treatment, are reviewed and discussed from phase III randomized practice-changing trials onwards. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken. Expert opinion: The survival of NSCLC patients is increasing, regardless of the presence or not of a specific target, due to the availability of new generation drugs. The continuous deep knowledge of the mechanisms of NSCLC development and the constant research into new drugs should lead to the discovery of new potential targets and the synthesis of corresponding inhibitors to improve the outcomes of each subgroup of patients in order to control the disease in a constantly growing percentage of patients.

The role of pembrolizumab in the treatment of advanced non-small cell lung cancer.

Lung cancer is the leading cause of death cancer related worldwide. The standard therapies have unmet medical needs both due to the limited activity and relevant toxicity of platinum-based chemotherapy and to the low frequency of specific alterations required to use targeted therapies. Immune checkpoint inhibition due to restoring the immune system's capacity to eradicate tumors is undergoing in extensive investigation in non-small cell lung cancer (NSCLC) as a new treatment approach. Programmed cell death protein-1 (PD-1) and its ligand, programmed cell death-ligand 1 (PD-L1) have recently led to significantly and durable improvements in the clinical outcome of several kind of tumors including lung cancer. Pembrolizumab, approved by the U.S. FDA for the treatment of advanced NSCLC progressed after other therapies and with expression of PD-L1, has demonstrated durable response and prolonged overall survival (OS) especially in patients with high PD-L1 expression. Further investigation are needed to improve treatment outcomes through combination of immunotherapy or combined with other targeted therapies.

Resistance to Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) with ALK Rearrangement: Mechanisms, Treatment Strategies and New Targeted Therapies.

Non-small cell lung cancers (NSCLCs) harboring anaplastic lymphoma kinase (ALK) rearrangement are generally responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first-in-class TKI approved as front-line or salvage therapy in advanced ALK-rearranged NSCLC. Unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms preserving or not the dominance of ALK signaling in the crizotinib-resistant state. The distinction between patients who preserve ALK dominance (secondary mutations alone or in combination with the number of copy ALK gain) compared to those that have decreased ALK dominance (separate or second oncogenic drivers, with or without concurrent persistence of the original ALK signal) is important in order to overcome resistance. Novel second-generation ALK inhibitors are currently in clinical development with promising results in ALK-rearranged NSCLC, as well as in crizotinib-resistant patients. Among these, ceritinib in the United States was granted by Food and Drug Administration accelerated approval for treatment of patients with ALK-rearranged, metastatic NSCLC with progression disease on or intolerance to crizotinib. Fully understanding of the different mechanisms of resistance to crizotinib will help us to continue to exploit personalized medicine approaches overcoming crizotinib resistance in these patients in the future. This review aims to discuss on strategy overcoming crizotinib-resistance starting from molecular mechanisms of resistance until novel ALK kinase inhibitors in ALK-rearranged NSCLC patients.

Optimal drugs for second-line treatment of patients with small-cell lung cancer.

INTRODUCTION: Despite the high response rate to chemotherapy, there have been few advances in the treatment of small-cell lung cancer (SCLC) in the last decades. The state-of-the-art second-line therapy and future research developments in relapsed SCLC are reviewed. AREAS COVERED: There are no optimal drugs for second-line treatment of recurrent SCLC but only agents registered for this use. Topotecan remains the standard-of-care for the treatment of second-line platinum-sensitive SCLC patients worldwide, while amrubicin is another option, but registered only in Japan. To date, no targeted agents reporting interesting results in second-line SCLC treatment are available. The next-generation DNA sequencing should discover somatic gene alterations and their roles in SCLC to help in selecting patients who could benefit from a targeted agent. Two immunotherapeutics, ipilimumab and nivolumab, have shown promising preliminary results and are being investigated in ongoing trials. EXPERT OPINION: Second-line treatment is not an option for most SCLC patients. Given the evidence up to now, the potentials for immuno-oncology in SCLC are high. The hope is that these expectations are met, and that all drugs being developed will offer new and improved treatment options for SCLC patients.

Anti PD-1 and PDL-1 Immunotherapy in the Treatment of Advanced Non- Small Cell Lung Cancer (NSCLC): A Review on Toxicity Profile and its Management.

The better understanding of immunology and antitumor immune responses have prompted the development of novel immunotherapy agents like PD-1 checkpoint inhibitors (anti-PD-1 and anti- PDL-1 antibodies) that improve the capacity of the immune system to acknowledge and delete tumors, including lung cancer. Currently, two anti-PD-1 (nivolumab and pembrolizumab) and one anti- PD-L1 (MPDL-3280A) agents are in advanced stages of development in advanced or metastatic non-small cell lung cancer (NSCLC). Among these, nivolumab demonstrated a survival benefit versus docetaxel in refractory squamous NSCLC, reporting 41% reduction in risk of death (median overall survival: 9.2 versus 6.0 months; objective response rate: 20% versus 9%), and better safety profile than standard-of-care chemotherapy (grade 3-4 adverse events: 7% versus 55%). However, the enhancement of immune response to cancer targeting specific immune regulatory checkpoints is associated with a toxicity profile different from that related to traditional chemotherapeutic agents and molecularly targeted therapies. The success of immunotherapy is related to ongoing evaluation/identification and treatment of these immunerelated side effects. Herein, first clinical results of PD-1 agents in lung cancer are reviewed, focusing on toxicity profile and its management.

Agents in the preclinical development stage for non-small cell lung cancer.

Despite recent advancements in identifying distinct molecular subtypes with driver oncogenes and advances in developing targeted treatments such as epidermal growth factor receptor and anaplastic lymphoma kinase inhibitors, current therapeutic approaches for tumors with no driver mutation have achieved a plateau of effectiveness. Thus, the overall outlook of lung cancer survival for most patients remains dismal. Moreover, the inevitable acquisition of resistance to targeted therapies has prompted significant efforts to develop second-generation inhibitors. In recent years, several agents for targeted therapy of lung cancers are rapidly migrating from bench to bedside and multiple small molecule inhibitors with activity against distinct receptors, genes or molecular pathways have been developed.

Current challenges of lung cancer care in an aging population.

Lung cancer is the most common cancer in the elderly with a high mortality rate. Despite the high incidence, the elderly are under-represented in clinical trials and under-treated in clinical practice. These patients have a higher prevalence of comorbid disease, higher polypharmacy interactions, and an increased risk of mortality and toxicity with cancer treatments, compared to younger patients. Often data about their treatments come from retrospective analysis including patients who do not reflect the general elderly population. However, elderly patients can often receive cancer treatment similar to younger patients and an active treatment should not be denied based on older age.

New Antiangiogenetic Therapy Beyond Bevacizumab in the Treatment of Advanced Non Small Cell Lung Cancer.

Lung cancer is the leading cause of death from cancer worldwide with limited available treatment options in absence of specific molecular alteration. New therapeutic approaches for addressing non small cell lung cancer (NSCLC) are urgently needed. Angiogenesis plays a central role in the tumor growth and metastatic dissemination which stimulates multiple cells to build new abnormal microvessels and leads to tumor microenvironment alterations. This process involves many factors, such as, the vascular endothelial growth factor (VEGF) that has a dominant role, the fibroblast growth factors (FGFs) and the plateled-derived growth factor (PDGF) that together contribute to resistance to VEGF/VEGFR- directed therapy. To date, bevacizumab is currently the only angiogenesis inhibitor that has been approved for the treatment of patients with advanced NSCLC in first-line setting. Moreover, in the last year, two new antiangiogenic agents have been approved for the treatment of patients with advanced NSCLC in second line setting. This review describes the new antiangiogenic agents in the treatment of advanced NSCLC.

Necitumumab for the treatment of stage IV metastatic squamous non-small-cell lung cancer.

Over the past two decades, progress in the treatment of patients with metastatic squamous non-small-cell lung cancer has been limited. The EGFR is involved in tumor progression and invasion and therefore it has become the target of several studies in lung cancer. Strategies to block this pathway are focused on the development of small molecule (tyrosine kinase inhibitor) and monoclonal antibodies (mAbs). Some mAbs have been studied in patients with advanced non-small-cell lung cancer. For the first time, a fully human immunoglobulin G (IMC-11F8), subclass 1 (IgG1) mAb targeting the EGFR, in combination with standard chemotherapy (cisplatin + gemcitabine), has been shown to increase overall survival in chemo-naïve patients with metastatic confirmed squamous cell histology.

Emerging drugs targeting PD-1 and PD-L1: reality or hope?

INTRODUCTION: Some tumors evade immune responses by exploiting immune checkpoint pathways and other regulatory mechanisms. Recent advances in the understanding of immune evasion strategies has given rise to development of novel immunotherapies that can restore the patient's own immune system to respond to and eliminate cancer cells. AREAS COVERED: Multiple agents targeting the programmed cell death protein 1 (PD-1) pathway, both anti-PD-1 and anti-programmed death ligand-1 (a key ligand for PD-1) compounds, are currently in active clinical development for lung cancer. Preliminary data of efficacy as monotherapy or in combination with chemotherapy are promising. In this review, we will summarize the immunomodulatory environment in NSCLC, we will focus on immune-checkpoint inhibitors, and the data currently available in lung cancer. EXPERT OPINION: The immune-mediated therapies represent an exciting new therapeutic approach, but evidences are still early in lung cancer, and more data from clinical studies are needed to optimize the clinical impact of these therapies.

ALK inhibitors and advanced non-small cell lung cancer (review).

Treatment of unselected patients with advanced non-small cell lung cancer (NSCLC) receiving third-generation platinum-based chemotherapy has reached a plateau of effectiveness. Histology and molecular analyses are the cornerstone in the initial diagnosis of NSCLC and are key determinants to address the appropriate strategy of treatment. In non-squamous histology the combination of cisplatin plus pemetrexed or carboplatin plus paclitaxel plus bevacizumab are considered today the best regimens yielding better activity and efficacy. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib are the standard-of-care for patients with advanced NSCLC harbouring activating EGFR mutations. The identification of anaplastic lymphoma kinase (ALK) rearrangements in 2-5% of NSCLC patients led to the rapid clinical development of its oral TKI, crizotinib, also targeting the proto-oncogene MET and ROS1. The results reported from the first phase III trial showed superiority of crizotinib compared with standard chemotherapy in second-line treatment of ALK-positive NSCLC, which was recently approved in several countries in this setting. Unfortunately, after initial activity of crizotinib, patients will ultimately develop acquired resistances within 1 or 2 years of therapy. A second generation of ALK inhibitors, such as LDK378, alectinib and AP26113 may represent a promising treatment approach: they are under investigation with very promising early results. This review discusses ALK rearrangements, the clinical development and use of crizotinib, and other ALK-TKIs in advanced NSCLC.