Molecularly targeted therapies in lung cancer

Molecularly targeted drugs are directed against abnormal proteins and other molecules, specific for cancer cells, participating in metabolic pathways. Excess activation of those pathways is essential for growth and unrestrained proliferation of cancer cells. Blocking these pathways results in inhibition of cell division and in cell apoptosis. Therefore, molecularly targeted drugs show high efficacy in two groups of patients:

1. if the mutation of the gene encoding a signalling pathway protein results in excessive activity while changing its structure, what allows more effective binding of the drug (e.g. activating mutations in EGFR gene and the efficacy of tyrosine kinase inhibitors of EGFR),

2. if the mutation of the gene encoding a signalling pathway protein results in excessive activity of the pathway and its blocking, regardless of the matching of the drug to the target protein, impairs tumour cell proliferation, which can be achieved at two levels:

a. direct blocking of abnormal protein b. blocking of subsequent signalling pathway proteins stimulated by the abnormal protein [21].

Therefore, many of the therapies currently under development target several signalling proteins, especially tyrosine kinase receptors (e.g. EGFR, HER2, HER3, IGF-1R, cMET) or proteins in downstream signalling pathway (RAS/RAF/MAPK/mTOR and Pi3K/AKT) [19, 21].

Excessive stimulation of epidermal growth factor receptor increases proliferation of cancer cells in different kinds of tumours, i.a. in non-small-cell lung cancer. Cell growth signal is transmitted from EGFR (HER1), after its heterodimerisation with other member of HER family (ERBB2 - HER2, HER3 or HER4), through phosphorylation of Pi3K/AKT and

RAS/RAF/MAPK/mTOR pathway. The phosphorylation takes place due to EGFR tyrosine kinase activity, which performs hydrolysis of ATP to ADP and free phosphate. Tyrosine kinases are a part of EGFR but also other cell receptors and signalling proteins. Phosphorylation disorder initiated by EGFR tyrosine kinase is associated with the development of NSCLC that is independent from tobacco smoke carcinogens. Blocking of EGFR function may be achieved by using small molecule tyrosine kinase inhibitors (TKI) or monoclonal antibodies (such as cetuximab), which bind to extracellular domain of EGFR. Inhibition of tyrosine kinase function by TKI-EGFR is much more effective if the amino acid structure of the enzyme is disrupted by activating mutations in EGFR gene (described in the previous section). Cetuximab on the other hand demonstrates better effectiveness when high expression of EGFR is present on cancer cell surface [2, 9, 11, 12, 21, 22].

At the moment, two reversible EGFR TKIs are in use: gefitinib and erlotinib. Phase III study IP ASS, carried out among Asian patients (up to 40% of EGFR gene mutation NSCLC carriers), has proven higher efficacy of gefitinib (71,2% response rate, longer progression free survival (PFS) up to 12 months and significant improvement in quality of life, but without overall survival (OS) prolongation) in compare to chemotherapy consisting of carboplatin and paclitaxel in patients with activating EGFR gene mutations. However, among patients with wild type EGFR gene, first line chemotherapy of advanced NSCLC with gefitinib was ineffective. The study included more than 1 200 adenocarcinoma patients, with a retrospective biomarker analysis performed on specimens from 437 tumour samples with evaluable EGFR gene mutation data. Mutations in EGFR gene were identified in 261 (59,7%) of these patients. Later studies comparing efficacy of erlotinib or gefitinib and standard chemotherapy had proven that EGFR TKIs are effective in first line of treatment (NEJ 002, WJTOG 3405, OPTIMAL, EURTAC studies) but only in patients with activating mutations in EGFR gene (Table 1). Moreover, OPTIMAL study showed that patients with deletion in exon 19 had longer median PFS than those with substitution L858R in exon 21 of EGFR gene. However, IPASS and WJTOG 3405 studies have not proven these observations [2, 11, 12, 21, 22, 23].

The BR.21 study concerned the effectiveness of erlotinib monotherapy in second or third line therapy in patients with advanced NSCLC. Erlotinib has prolonged PFS and improved quality of life when compared to best supportive care in the whole patients group, but an objective response was achieved in only 10% of patients. Patients with EGFR gene amplification, detected with FISH technique, responded more frequently to therapy with erlotinib. 61 (38,4%) of 159 tumours analysed in BR.21 study were positive for an increased EGFR gene copy number. Response rates were 21% and 5% in patients who were FISH-positive and FISH-negative, respectively. This benefit seemed to extend to survival (HR=0,43; p=0,004). It is not certain, if this result was related with underestimation of EGFR gene mutations in FISH-positive patients due to the use of sequencing method for EGFR gene mutation analysis. The INTEREST study confirmed this suggestion, demonstrating the superiority of gefitinib over docetaxel in second line of treatment in patients with activating mutation of EGFR gene. Application of reversible TKI-EGFR in II and III line of treatment in patients without activating mutations in EGFR gene is controversial [2, 11, 12, 21, 22, 23].

Study

Patients with mutation

Treatment arms

Response rate

Median PFS

(favouring TKI-EGFR)

IPASS

216 Asian patients

gefitinib vs. paclitaxel/carboplatin

71% vs. 47%

9,5 vs. 6,3 months

HR=0,48 (95% CI: 0,360,64)

JP 0056 (NEJ 002)

200 NorthEast Japan patients

gefitinib vs. paclitaxel/carboplatin

74% vs. 31%

10,8 vs. 5,4 months

HR=0,31 (95% CI: 0,220,41)

WJTOG 3405

177 Asian patients

gefitinib vs. docetaxel/carboplatin

62% vs. 32%

9,2 vs. 6,3 months

HR=0,49 (95% CI: 0,340,71)

OPTIMAL

gemcitabine/carboplatin

83% vs. 36%

13,1 vs. 4,6 months

HR=0,16 (95% CI: 0,100,26)

EURTAC

170 Caucasian patients

erlotinib vs. platinum doublet

58% vs. 15%

9,7 vs. 5,2 months

HR=0,42 (95% CI: 0,270,64

Table 1. Prospective, randomised studies of efficacy of first-line TKI-EGFR and standard chemotherapy in patients with EGFR gene mutations [12].

Table 1. Prospective, randomised studies of efficacy of first-line TKI-EGFR and standard chemotherapy in patients with EGFR gene mutations [12].

The phase III SATURN study was designed to examine the effect of erlotinib in maintenance therapy dedicated to patients who had clinical benefit after 4 cycles of standard chemotherapy. PFS was significantly prolonged (HR=0,71; p<0,0001) and response rate (11,9% vs. 5,4%) was improved with erlotinib compared to best supportive care in all patients. However, significantly prolonged PFS was observed with erlotinib mainly in group of patients whose tumours had EGFR mutation (HR=0,10; p<0,0001) [2, 11, 12, 23].

Although controversial clinical trial results, National Comprehensive Cancer Network (NCCN) recognises that the presence of EGFR-activating mutations represents a "critical" biomarker for appropriate patients selection for TKI-EGFR therapy [24].

Some genetic irregularities may be responsible for occurrence of primary or secondary resistance to reversible TKI-EGFR and disease progression even after more than ten months of therapy. EGFR wild-type gene and KRAS gene mutations are associated with intrinsic TKI-EGFR resistance. Moreover mutations in KRAS and EGFR genes do not occur simultaneously in the same cancer cell. Patients with mutated KRAS gene experience better PFS with standard chemotherapy than with TKI-EGFR therapy. However, a subgroup of 90 patients from SATURN study who had KRAS mutation showed no significant difference in PFS in erlotinib-arm and placebo-arm. Although KRAS mutation has been associated with clinical outcomes with cetuximab in colorectal cancer, no association was reported from analyses of clinical studies of cetuximab in combination with chemotherapy in patients with NSCLC. Currently, KRAS mutation testing is not recommended in molecular diagnosis of NSCLC patients [11, 12].

The secondary resistance to reversible TKI-EGFR is connected with the inability to extend overall survival with erlotinib or gefitinib therapy. Underlying mechanism of resistance to reversible EGFR TKIs is an amplification of IGF1R and MET gene, but also mutations in exon 20 of EGFR and HER2 genes. The presence of such abnormalities may have a pivotal role in qualification to novel therapies, currently in their last phase of clinical trials. Inhibitors of insulin-like growth factor receptor 1 (IGF1-R), both small molecule as well as monoclonal antibodies, and inhibitors of receptor for hepatocyte growth factor (cMET) (e.g. tivantinib - ARQ-197 or MetMab) may be used in some patients treated with reversible TKI-EGFR among whom a resistance for the therapy has occurred as an alternative way of Pi3K/AKT pathway stimulation created through overexpression of IGF1R and cMET (Figure 4) [25, 26, 27].

The occurrence of T790M mutation in exon 20 of EGFR gene and mutations in exon 20 of HER2 gene may be important for the proper qualifications for the treatment with irreversible EGFR TKIs. Drugs like afatinib (BIBW-2992), PF-00299804 or neratinib (HKI-272) may be effective in case of resistance to reversible TKI-EGFR when a secondary mutation is present (e.g. T790M). The action of afatinib remains until the EGFR protein is removed from the cancer cell surface. Furthermore, afatinib also blocks HER2 and HER4 proteins which are preferential heterodimerisation partners for EGFR during stimulation by EGF. In LUX-Lung 1 study, afatinib efficacy (prolongation of PFS) was proven as a rescue treatment after failure of erlotinib or gefitinib if duration of second-line TKI-EGFR treatment exceeded 24 weeks (HR=0,38, p<0,0001). Irreversible TKI-EGFR may also be more effective than reversible TKI-EGFR in first-line of treatment of patients with activating mutations of EGFR gene. In the LUX-Lung 2 study, 129 patients with activating EGFR mutations and no previous TKI-EGFR treatment received afatinib as a single agent. Overall response rate was 60% with a promising PFS of 14 months. LUX-Lung 3 and LUX-Lung 6 studies are designed to compare effectiveness of afatinib and chemotherapy based on pemetrexed and cisplatin or gemcitabine and cisplatin in patients with EGFR mutations. As first-line treatment of patients with known EGFR mutation, PF-00299804 showed encouraging efficacy, which exceeded the erlotinib effectiveness. In patients with T790M and T854A mutations in EGFR gene, the combination of irreversible TKI-EGFR therapy with application of monoclonal antibody against EGFR (cetuximab) may be also reasonable [11, 12, 25, 26, 27].

Big hopes for the development of lung adenocarcinoma therapy are related to phase III studies over a novel, small molecule, molecularly targeted drug - crizotinib, an inhibitor of ALK, ROS1 and cMET. Crizotinib is particularly active in patients with EML4-ALK fusion gene, inducing disease control in up to 90% of such patients and prolonging their overall survival. In patients with EML4-ALK fusion gene, 64% of patients treated with crizotinib survived more than 2 years and 77% of patients survived more than 1 year. Newly defined kinase fusions (KIF5B with RET and ROS1 with ALK and with other fusion partners) may be also promising targets for molecular therapies [11, 12, 14, 15, 26, 27].

Figure 4. EGFR pathway components and possibility of new molecularly targeted therapies application in resistance to reversible TKI-EGFR.

Drugs inhibiting neoangiogenesis within the tumour have also found an application in molecularly targeted therapy of patients with NSCLC. These drugs are bevacizumab - a monoclonal antibody directed against vascular endothelial growth factor (VEGF) and small molecule drugs, inhibiting tyrosine kinase functions of VEGFR, PDGFR, FGFR, RET and c-Kit (vargatef, sunitinib) [26, 27]

American Lung Cancer Mutation Consortium (LCMC) had screened NSCLC tumour samples not only for EGFR and ALK mutations, but also for other known mutations such as KRAS, EGFR, EML4-ALK, BRAF, HER2, PIK3CA, NRAS, MEK1, AKT1 and MET gene irregularities.

Mutations were found in 54% (280/516) of completely tested tumours, in 15 certified genetic laboratories. Mutation screening is not only for research purposes, but is also designed to determine patients who might benefit from molecularly targeted therapies. Molecular testing could definitely identify the mutations associated with response or resistance to targeted therapies [16]. Nowadays, we have an opportunity to match molecularly targeted therapies with the structure of proteins that are taking part in signalling pathways of neoplasm cells. The efficiency of tyrosine kinase inhibitors of EGFR (erlotinib, gefitinib) and ALK (crizotinib) in NSCLC patients bearing EGFR or ALK activating mutations is the example of such relationship. These observations create new possibilities for personalisation of known molecularly targeted therapies (registered and tested in clinical trails) in large population of NSCLC patients [16]. LCMC idea was used to describe potential capability of therapy of NSCLC patients, based on presence of mutations in cancer cells. Similarly, the BATTLE program at the M.D. Anderson Cancer Centre in Houston assessed biomarker-guided treatment in patients with previously treated, advanced NSCLC and biopsy-amenable disease. For this purpose, cancer gene databases should be created to determine what is known about germline and somatic gene variants as well as treatment options and their outcomes. According to recent cancer genomic knowledge, clinical trials of novel molecularly targeted drugs, could be offered to cancer patients who are unlikely to benefit from a standard therapy, with relatively poor prognosis and to patients who are more likely to benefit from a novel therapy due to the presence of tumour genetic abnormalities that predict sensitivity, lack of resistance or toxicity of a treatment (Table 2) [4, 16, 19, 26, 27].

Genetic abnormality

Treatment

Mechanism of action

activating mutation of EGFR

erlotinib or gefitinib

small molecule, reversible TKI-EGFR

activating mutation of EGFR

erlotinib + OSI-906 or MM-121 or MK-0646

small molecule, reversible TKI-EGFR + small molecule TKI IGF-1R or fully human monoclonal antibody against ErbB3

KRAS mutation; MET amplification

erlotinib + tivantinib (ARQ-197) or onartuzumab (MetMAb); JTP-74057 (GSK1120212);

small molecule TKI-EGFR + small molecule TKI cMET or monovalent (one-armed) monoclonal antibody against cMET; small molecule inhibitor of MEK 1/2 serine/threonine kinase;

fusion gene EML4-ALK and fusion genes with ROS1 gene component; ROS1 mutation

crizotinib, AP-26113, LDK-378, AF-802

small molecule TKI of ALK, ROS1 and cMET; small molecule TKI of ALK and EGFR; small molecule TKI of ALK

NRAS, MEK1 or BRAF mutation

GSK-1120212

small molecule inhibitor of MEK 1/2 serine/threonine kinase

BRAF, NRAS mutation

GSK-2118436; vemurafenib (PLX-4032)

small molecule inhibitor of BRAF serine/threonine kinase

mutation in exon 20 of EGFR (e.g. T790M); HER2 mutation

Afatinib (BIBW2992), neratinib, PF299804, CI-1033, EKB-569, AV-412/MP-412, lapatinib

small molecule, irreversible TKI of pan-HER; small molecule, irreversible TKI of EGFR and HER2

PIK3CA mutation

BEZ-235, GDC-0491, SAR-245409, BKM-120, BYL-716, 0SI-027, PX-866, MK-8669

small molecule inhibitor of mTOR and PI3K kinases; small molecule inhibitor of pan-PI3K; small molecule selective inhibitor of PI3Ka

MEK1 mutation

JTP-74057 (GSK-1120212); selumetinib (AZD-6244), GDC-0973, MEK-162, MSC-1936369B

small molecule inhibitor of MEK 1/2 serine/threonine kinase (MAPK/ERK kinase1/2 kinases);

DDR2 mutation (S768R)

erlotinib + dazatinib or nilotynib

small molecule inhibitor of BCR-ABL, SRC, c-Kit, EPH and PDGFR|

FGFR amplification

PD-173074, ponatinib (AP24534), BGJ-398, FP-1039

small molecule TKI of FGFR and VEGFR; small molecule kinase inhibitor of native and mutated BCR-ABL, VEGFR2, FGFR1, PDGFRa, mutated FLT3 and LYN; small molecule TKI of FGFRs; monoclonal antibody against FGFR1

PDGFR amplification, PDGFR mutation, c-Kit mutation

MEDI-575, IMC-3G3, sunitinib, sorafenib, OSI-930, pazopanib (votrient)

Monoclonal antibody against PDGFR a; small molecule inhibitors of kinases of VEGFR1-3, RET, c-Kit, PDGFR a and |

FGFR and/or PDGFR amplification

intedanib (BIBF-1120), dovitinib (TKI258)

small molecule inhibitor of angiokinase (FGFR, PDGFR, VEGFR)

BRCA1 deficiency

olaparib + cisplatin

small molecule inhibitor of poly(ADP-ribose) polymerase (PARP)

AKT1 mutation

MK-2206, GSK-2110183

AKT inhibitors

Table 2. An example of qualification possibilities for molecularly targeted therapies based on NSCLC cell molecular signature (in most countries gefitinib, erlotinib and crizotinib are the only registered drugs in NSCLC therapy; other indications for therapy are hypothetical and are based only on the results of early clinical trials).

Table 2. An example of qualification possibilities for molecularly targeted therapies based on NSCLC cell molecular signature (in most countries gefitinib, erlotinib and crizotinib are the only registered drugs in NSCLC therapy; other indications for therapy are hypothetical and are based only on the results of early clinical trials).

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