Emerging therapeutic agents for lung cancer
Dholaria et al. Journal of Hematology & Oncology
Emerging therapeutic agents for lung cancer
Bhagirathbhai Dholaria 0
William Hammond 0
Amanda Shreders 0
Yanyan Lou 0
0 Department of Hematology-Oncology, Mayo Clinic , 4500 San Pablo Road, Jacksonville, FL 32224 , USA
Lung cancer continues to be the most common cause of cancer-related mortality worldwide. Recent advances in molecular diagnostics and immunotherapeutics have propelled the rapid development of novel treatment agents across all cancer subtypes, including lung cancer. Additionally, more pharmaceutical therapies for lung cancer have been approved by the US Food and Drug Administration in the last 5 years than in previous two decades. These drugs have ushered in a new era of lung cancer managements that have promising efficacy and safety and also provide treatment opportunities to patients who otherwise would have no conventional chemotherapy available. In this review, we summarize recent advances in lung cancer therapeutics with a specific focus on first in-human or early-phase I/II clinical trials. These drugs either offer better alternatives to drugs in their class or are a completely new class of drugs with novel mechanisms of action. We have divided our discussion into targeted agents, immunotherapies, and antibody drug conjugates for small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). We briefly review the emerging agents and ongoing clinical studies. We have attempted to provide the most current review on emerging therapeutic agents on horizon for lung cancer.
Lung cancer; Targeted agents; Immunotherapy; Phase I/II clinical trial
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Background
Lung cancer is the second most commonly diagnosed
cancer and is the leading cause of cancer-related death
in both men and women. Implementation of tobacco
control, low-dose spiral computed tomography screening
programs, and advances in multidisciplinary treatments
have resulted in the slow decline of both incidence and
mortality. However, 52–58% of lung cancer patients
present with advanced-stage disease, and a vast majority
of these patients do not survive despite treatment.
Similarly, the prognosis remains poor even in locally
advanced disease because of the high relapse rate and
early formation of micrometastases [1].
One of the most important therapeutic advances of
lung cancer treatment in the last decade was
identification of specific driver mutations and the development
of small molecular tyrosine kinase inhibitors (TKIs) [2].
In 2009, erlotinib was the first selective epidermal
growth factor receptor (EGFR) inhibitor approved by
the US Food and Drug Administration (FDA) [3]. This
was quickly followed by crizotinib, which was initially
developed as a MET (mesenchymal-to-epithelial
transition/hepatocyte growth factor receptor) inhibitor and
was found to be highly active against small subset of
non-small-cell lung cancer (NSCLC) cases harboring
anaplastic lymphoma kinase (ALK) rearrangement [4].
These drugs promise around a 70% response rate;
however, resistance development is almost universal, and
second/third generation TKIs are being developed to
overcome these issues. Novel targeted agents directed
against EGFR, ALK, ROS1, MET, RET, BRAF, and many
more are under investigation. Figure 1 provides
summary of targets with specific focus on the drugs that
currently in early-phase clinical trials in lung cancer. In
addition to these drugs, next-generation sequencing
and cell-free DNA (cfDNA) technologies have provided
rapid and convenient tools for gene abnormality testing
and the development of targeted therapies [5].
Additionally, personalized medicine has become part of
daily practice, and tailoring treatment for individual
patients is becoming a reality.
Immunotherapy in the form of checkpoint inhibitors
represents a landmark success in NSCLC treatment, and
© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Fig. 1 Molecular targets and inhibiting agents being studied in phase I/II trials as potential therapy for patients with lung cancer. Abbreviations:
AKT protein kinase B, ALK anaplastic lymphoma kinase, CREB3L2 cyclic AMP-responsive element-binding protein 3-like protein 2, EGFR epidermal
growth factor receptor, EML4 echinoderm microtubule-associated protein-like 4, ERK extracellular signal-regulated kinase, FGFR fibroblast growth
factor receptor, HGF hepatocyte growth factor, MCL1 myeloid leukemia cell differentiatio (...truncated)