Other novel molecular targets in non-small cell lung cancer: it’s not all about EGFR

Authors:

Details:

  1. The Prince Charles Hospital, Chermside, Brisbane, Queensland. 
  2. Royal Brisbane and Womens Hospital, Herston, Brisbane, Queensland

Abstract

Identification and inhibition of molecular pathways that drive malignant cells have led to improved outcomes in the understanding and management of non-small cell lung cancer. This has been illustrated by the effective use of the EGFR-tyrosine kinase inhibitors erlotinib, gefitinib and afatinib, which have been major steps forward in targeted therapy for advanced and metastatic lung cancer in patients who harbour specific epithelial growth factor receptor mutations. This success continues to drive ongoing research in identifying other novel molecular pathways in malignant cells that may be exploited for targeted therapy. Some of the other current advances in identifying targetable genetic mutations and the development of therapies that may have a potential clinical impact on the management of both adenocarcinoma and squamous cell lung cancer are reviewed.


Adenocarcinoma

Following on from the achievements of the EGFR inhibitors,13 adenocarcinoma remains the most studied histology of non-small cell lung cancer (NSCLC) in the search for effective targeted therapies. These most recent breakthroughs have resulted in less emphasis being placed on the development of new, non-specific systemic chemotherapy agents but rather, more focus has been directed toward the identification of ‘druggable’ targets in the distinct molecular pathways that promote the oncogenic drive in malignant NSCLC cells. At this point in time, more than a dozen mutations have been identified which have shown potential for being targets of therapeutic agents (figure 1). Already, many new agents directed against specific molecular targets such as ALK (anaplastic lymphoma kinase), ROS1 and MET have been developed, which are showing encouraging results in the treatment of NSCLC and are currently the subject of ongoing clinical trials.

CF July 2013 - P170_Figure1

ALK translocation
Of all the novel molecular targets under investigation, the ALK-EML4 fusion gene has seen the most advances. This alteration, which is present in approximately 3-5% of patients with NSCLC adenocarcinomas,4 involves a translocation of the ALK gene which results in a fusion rearrangement with the EML4 (echinoderm microtubule-associated protein-like 4) gene (figure 2). The activated protein arising from this fusion promotes cancer cell growth and proliferation. The rearrangment is most often found in never or light smokers, younger age patients and adenocarcinomas with signet ring or acinar morphology. ALK gene rearrangements tend to occur independent of EGFR or KRAS mutations.5

Figure 2: FISH assays for EML4-ALK fusion gene in lung adenocarcinoma tissue.

CF July 2013 - P170_Figure2

The development of crizotinib, an oral selective inhibitor of ALK and MET tyrosine kinases, has seen a significant prolongation of progression free survival in those that harbour the gene rearrangement.6 In the initial phase I trial (PROFILE 1001),7 119 ALK positive patients received crizotinib  (250mg) twice daily, administered continuously on a 28 day cycle. Overall response rate was an impressive 61% (95% C.I. 52-70) in this heavily pre-treated population, with a median duration of response of 48 weeks.

Following on from this encouraging result, the phase II trial (PROFILE 1005) enrolled 136 patients who received crizotinib (250mg) twice daily in a continuous 21 day cycle.8 The overall response rate, which was the primary endpoint of this ongoing trial, was reported to be 51.1% (95% C.I. 42.3-59.9), with a complete response reported in one patient and partial responses reported in 67 patients. The benefit of targeting ALK rearrangement positive NSCLC patients, who have received one prior platinum containing regimen, has now been confirmed in a phase III study.9 In this study, crizotinib significantly increased progression free survival compared with single agent pemetrexed or docetaxel (median 7.7 months v 3.0 months) and also improved symptom related quality of life.

Currently a phase III trial10 (PROFILE 1014) is underway, comparing chemotherapy (pemetrexed plus a platinum compound) with crizotinib in ALK positive patients with advanced NSCLC who have not received prior systemic therapy. If this trial confirms a significant progression free survival advantage, then this will establish crizotinib as the new standard of care for first line treatment of ALK rearranged NSCLC.

Second generation ALK inhibitors are now also in development and are hoped to be more potent and selective than crizotinib. In the future, these may be utilised as second line treatment to overcome acquired resistance, or may eventually supersede crizotinib as front-line therapy. One such agent, LDK378, reported an impressive objective response in 21 of 26 patients who had displayed resistance to crizotinib.11

KRAS mutation
The RAS family of oncogenes encode for membrane-bound intracellular GTP-ases, which act as mediators in various downstream pathways including the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K). These signalling pathways control cellular proliferation and apoptosis. The KRAS protein is a member of the RAS family and is an early player in these signal transduction pathways. Activating KRAS mutations are observed in approximately 20 to 25% of lung adenocarcinoma and are generally associated with a history of smoking.12 Identification of agents that specifically inhibit KRAS have proved difficult. Currently the focus of targeted therapy for patients with KRAS mutated lung cancer has been the downstream effectors of the activated RAS pathway. One such strategy is MEK inhibition. The MAPK pathway converges at the MEK1/MEK2 kinases, whose activation facilitates further downstream signalling leading to cellular proliferation.

In a recent phase II trial, 87 previously treated patients with KRAS mutant advanced NSCLC were randomly assigned to docetaxel with or without selumetinib, an oral MEK inhibitor.13 The addition of selumetinib to docetaxel showed promising efficacy, with improved progression free survival (median 5.3 v 2.1 months, HR 0.58, 80% CI 0.42-0.79) and a trend toward increased overall survival (median 9.4 v 5.2 months, HR 0.80, 80% CI 0.56-1.14). Given that KRAS mutations in NSCLC have been associated with a poorer prognosis,14 these findings warrant ongoing trials with such targeted therapies and further clinical investigation of these downstream pathways to identify other appropriate targets.

ROS1 translocation
ROS1 is another receptor tyrosine kinase whose translocation acts as a driver oncogene in 1 to 2% of NSCLC patients. Several ROS1 translocation fusions with other genes have been discovered in tumour types including gliomas, cholangiocarcinomas and NSCLC: CD74, SLC24A2 and FIG.15 In NSCLC, these translocation are commonly associated with adenocarcinoma histology, younger patients and never smokers.16

Initial case reports found the ROS1 tyrosine kinase to be highly sensitive to crizotinib due to the high homology between the ROS1 and ALK kinase domains. Fourteen patients with the ROS1 mutation were treated in the original phase I trial with crizotinib. Eight patients (57%) showed an objective response to treatment.17 Although the translocation is rare, current evidence supports the exploration of ROS1 as a target for existing and novel ALK inhibitors. 1617 An open label trial (NCT00585195) using crizotinib in patients with ROS1 fusion NSCLC is in progress.

MET over expression
MET is a tyrosine kinase receptor for hepatocyte growth factor. MET mediates activation of several downstream signalling pathways (PIK3/AKT, Ras-Rac/Rho, MAPK) which stimulate morphogenic, proliferative and anti-apoptotic activities. These pathways also promote cell detachment, motility and invasiveness.18

Of notable clinical significance is that MET amplification has been associated with resistance to EGFR inhibitors. One postulated resistance mechanism is the parallel activation of the MET signalling pathway, providing an alternative route for activation of downstream signals when EGFR is inhibited.  MET over expression has been found in 5-22% of NSCLC patients with secondary resistance to EGFR-TKIs.19 Accordingly, targeting the MET pathway has potential clinical significance.

Tivantinib (ARQ 197) is a selective tyrosine kinase inhibitor of MET. A phase II trial investigated erlotinib plus tivantinib in 173 previously treated (but EGFR-TKI naïve) patients.20 The median progression free survival was 3.8 months for erlotinib plus tivantinib and 2.3 months for erlotinib alone. A subset analysis of patients with KRAS mutant tumours (n=10) showed a marked progression free survival benefit with the combination therapy (HR 0.18, 95% CI 0.05-0.70). Prior studies have shown that the presence of a KRAS mutation in NSCLC may confer a poorer prognosis. Based on these promising results, a phase III trial (MARQUEE) was undertaken involving patients with previously treated metastatic nonsquamous NSCLC, comparing erlotinib and tivantinib versus erlotinib and placebo.21 The final results are yet to be presented, but the trial was closed after interim analysis indicated it would fail to meet its primary endpoint of overall survival improvement.

Another investigational agent targeting MET which is showing promising results is onartuzumab, an anti-MET monoclonal antibody. A randomised phase II trial was conducted involving pre-treated patients who were treated with onartuzumab and placebo, or onartuzumab and erlotinib.22 In a subgroup analysis of patients with MET immunohistochemistry positive tumours, the progression free survival (HR 0.53; 95% CI 0.3-1.0) and overall survival (HR 0.4; CI, 0.2-0.7) outcomes were better with the combination over erlotinib alone. Based on these results, a randomised phase III trial comparing erlotinib plus onartuzumab with erlotinib plus placebo in NSCLC patients with MET over expression is underway.23

HER2 mutation
HER2 (ERBB2) is an EGFR family receptor tyrosine kinase. Mutations in exon 20 of HER2 have been detected in 1 to 4% of NSCLC tumours and, like ALK and ROS1, are seen more frequently in non-smokers.24

A phase II study involving afatinib, a potent irreversible ErbB family blocker, showed clinical activity in patients with metastatic lung adenocarcinomas bearing mutations in the kinase domain of HER2 gene.25 Objective responses were observed in three patients, even after failure of other EGFR and/or HER2-targeted treatments such as gefitinib, trastuzumab and lapatinib. Larger trials are ongoing to further define its significance in NSCLC.

BRAF mutation
BRAF is a downstream signalling mediator of KRAS which activates the MAP kinase pathway. BRAF mutations have been observed in 1 to 3% of NSCLC and are associated with a history of smoking.26 Activating BRAF mutations can occur at the V600 position of exon 15 (similar to that seen in melanoma) 2728 or outside this codon. BRAF mutations have also been described as a resistance mechanism in EGFR mutation positive NSCLC.29

The BRAF inhibitor, dabrafenib, is being evaluated in a phase II study of patients with NSCLC containing the BRAF V600E mutation.30 

Squamous cell lung cancer

The advances in molecular targets and targeted therapies, while somewhat favouring adenocarcinoma to date, are not simply limited to this histological subtype of NSCLC. Recently, several molecular targets have also been identified in squamous cell NSCLC (figure 3) and currently, various therapeutic agents are being trialled with potential clinical impact.

CF July 2013 - P172_Figure3

Fibroblast growth factor receptor -1 (FGFR1) is a cell surface tyrosine kinase receptor. Its activation by fibroblast growth factor (FGF), leads to downstream signalling via PI3K/AKT, RAS/MAPK pathways that mediate cell growth, survival, migration and angiogenesis. Approximately 20% of squamous cell cancers have oncogenic FGFR1 amplication.31 This results in aberrant receptor activation and consequently, deregulated downstream signalling. Activating mutations of FGFR have also been identified in lung cancers.32 With several mechanisms potentially involved in aberrant behaviour of malignant cells, it follows that targeted inhibition of FGFR offers a valuable modality for therapeutic intervention across multiple targets of genetic alterations.

Several FGFR inhibitors are in phase I or phase II trials; many of these are multi-targeted tyrosine kinase inhibitors. One of these is NVP-BGJ398, a potent pan-FGFR kinase inhibitor, which is currently in clinical phase I trials.33 Results of a NSCLC patient who had tumour regression in response to BGJ398 have been published.34 Other small molecule FGFR inhibitors such as AZD4547,35 and Brivanib,36 are also undergoing phase I and II trials.

DDR2 mutation
The discoidin domain receptor 2 (DDR2) gene encodes a cell surface receptor tyrosine kinase that is mutated to an active form in about 4% of squamous cell lung carcinomas.37 DDR2 binds collagen and has been shown to promote cell migration, proliferation and survival.38 Dasatinib inhibits proliferation and ectopic expression of mutated DDR2 cell lines. Clinical trials are underway to determine its effectiveness. A case has been reported of a patient treated with a combination of dasatinib and erlotinib who was shown to have a tumour response.37

PI3 kinase pathway
Phosphatidyl 3-kinase (PI3K) is an intracellular kinase that activates intracellular signalling through downstream effectors including AKT and mTOR. The PIK3-AKT pathway plays a central role in the survival and proliferation of many cancers.39 One gene identified to be primarily involved in this pathway is the PIK3CA gene, which encodes for the catalytic subunit of PI3K. Gain of function mutations and somatic mutations have been found in PIK3CA which promote activation of the PI3K signalling pathway. 40,41 PIK3CA mutations may also promote resistance to EGFR-tyrosine kinase inhibitors in EGFR-mutant NSCLC.42 PIK3CA mutations have been reported in 6.5% of squamous cell lung cancers.43 Multiple inhibitors are in development which target PIK3 (BYL719),44 PI3K/MTOR (PF-04691502),45 and the downstream AKT kinase (MK-2206).46

PTEN loss
PTEN is a tumour suppressor gene which encodes a lipid phosphatise that inhibits the PI3K/AKT pathway. Reduction or loss of PTEN expression leads to up regulation of PI3K-AKT signalling. Its alteration has been reported in up to 70% of NSCLC, both in adenocarcinoma and squamous histology.47 Cancers with PTEN loss may be more sensitive to inhibitors of the PI3K pathway and trials are underway to assess this.48

Conclusion 

Recognising the heterogeneity of mutations in individual cancers has brought about a new paradigm in our approach to cancer care in the 21st century. The growing range of molecular targets suitable as drug targets and the development of therapeutic agents directed against them, represents the keys to success in the personalised medicine approach to the treatment of cancer. In recent times, lung cancer leads the way in making this paradigm shift a reality. 

Targeted therapies are already in existence which can be utilised to effectively manage advanced disease in lieu of traditional systemic cytotoxic chemotherapy.13 Agents that are equally or more effective than traditional chemotherapy, have the advantage of less toxicity than that associated with systemic therapy, which is one of the goals that drives their development. Ongoing research to improve the understanding of the molecular pathways that drive malignancy will continue to transform the treatment of lung cancer in this way. Continuing to identify those molecular alterations with a view to targeting their specific pathways, will ultimately bring to fruition the concept of ‘personalised medicine’ in treating the various sub-types of lung cancer, with improved outcomes for patients.

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