Introduction

Lung cancer is categorised as a common and serious type of cancer. The tumour is normally found in the lung parenchyma or within the bronchi. According to the NHS, more than 43,000 people are diagnosed with lung cancer every year. This usually affects the older population, rarely affecting those under 40. There are primarily two types of primary lung cancer: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC can be classified into three types: squamous, adenocarcinoma, and large-cell carcinoma.¹

The cause of lung cancer is a genetic mutation of genes involved in the cell cycle, like EGFR and KRAS for NSCLC and MYC and p53 for small-cell lung cancer. In turn, the dysregulation of genes can cause excessive proliferation and the inhibition of the cell’s apoptotic pathway and lead to tumour formation. Risk factors like smoking, radiation exposure, carcinogens, or metals like chromium and nickel can increase the risk of lung cancer.²

Individuals who suffer from lung cancer don’t usually have symptoms in the early stages, but eventually symptoms like a persistent cough, blood coughed up, persistent breathlessness, and tiredness can be present in those who suffer from lung cancer. Additional miscellaneous include the thickening of the pleural membrane, a lining of the lungs, which leads to the accumulation of fluids within the pleural space. Individuals who suffer from SCLC can have dilated neck veins, oedema of the face and neck, and upper extremities, which doctors have coined “superior vena cava syndrome”. Finally, metastasis of lung cancer can occur; the most common route is from the lungs to the bones, and they are frequently symptomatic. Those with metastasised lung cancer can start to experience bone pain at the site of metastasis along with elevated serum alkaline phosphatase and hypercalaemia.²

Types of targeted therapies for lung cancer

Tyrosine kinase inhibitors (TKIs)

The EGFR signalling pathway is most commonly affected in those with NSCLC. ERBB1 gene mutation causes dysregulation and is found in individuals with NSCLC. The gene codes for EGFR proteins, which are a group of membrane receptors that form homo- or heterodimer domains. This leads to intracellular signalling, which is responsible for controlling the cell cycle. So, the mutation that causes the overexpression of ERBB1 can trigger the inhibition of the apoptotic pathway. TKIs have been developed to stop chemical messengers from being released to inhibit the signalling pathway.³ Three generations of TKIs have been developed and used; currently, two EGFR TKIs have been approved by the US FDA against gefitinib and erlotinib. Several studies, like those by Gu et al. (2017), have found a significant improvement in progression-free survival (PFS) compared to chemotherapy as a first-line treatment. Gefitinib and erlotinib have been shown by a few studies to decrease mortality (2010, 2006). However, other studies have found no significant benefits for gefitinib, but for erlotinib, studies like a phase III placebo-controlled study from Canada (2005), used as first-line or second-line agents, showed a statistically significant benefit in overall survival rate. A study called the ISEL study (2005) randomised 1692 patients with advanced NSCLC refractory or intolerant to chemotherapy to gefitinib and placebo and found no significant benefit of overall survival for gefitinib.

Additionally, a Chinese study called the OPTIMAL trial (2011) randomised 154 EGFR-mutant patients to erlotinib or carboplatin/gemcitabine. They discovered that the PFS was significantly increased by 4 months in the erlotinib but had no advantage present. Furthermore, a European study (2012) selected 174 patients and randomised them into two groups: those treated with erlotinib or platinum doublet chemotherapy. They found those taking erlotinib had a significantly prolonged median PFS by five months but no difference in overall survival.⁴

However, it was discovered that patients given the first-line generation of TKIs had developed drug resistance after 10–14 months. Because lung cancer tumours have developed the mutation T790M in the ERBB1 gene, which blocks the specific binding of the first-generation TKIs. So, second-generation and third-generation TKIs were developed to overcome that mutation resistance. They work by irreversibly binding to EGFR and preventing signal transduction of the signalling pathway. An example of a second-generation TKI is afatinib, in which a study (2017) tested its effectiveness with gefitinib and exhibited improvements in PFS, with median values of 11 months and 10.9 months, respectively. There were other instances of afatinib treatment improving overall survival while overcoming the T790M resistance. Third-generation TKIs have been further upgraded to target the T790M mutation while maintaining the activity of first-generation TKIs. An example is osimertinib, which can target both the standard and resistant mutations.

ALK inhibitors

ALK inhibitors are under the same category as TKIs, but these mostly target the ALK gene. An example would include crizotinib, a potent competitive inhibitor that targets the ALK gene. The gene's exact physiological mechanism hasn’t been established, but its receptor has some sort of involvement in cellular processes. Mutation of the ALK gene occurs via gene amplification, causing the fusion with other proteins and producing proteins with altered properties. So, crizotinib was documented as being effective against lung adenocarcinoma when the ALK gene mutation was also first discovered. Ceritinib, a second-generation ALK inhibitor, has also been approved to treat those with the ALK mutation. A trial (2016) testing the effectiveness of crizotinib looked at two groups both given ceritinib. Still, one group was given the ALK inhibitor, while the other group didn’t. They found that the group treated with ceritinib alone had a better response (72%) and longer PFS (18.4) than those who were given both. Other second-generation ALK inhibitors have also been developed and approved as treatments like alectinib and ensartinib, which have shown promising results.³

A phase II study in 2010 tested the effectiveness of crizotinib and found that it had a good response rate of 57%. Furthermore, a phase II study was conducted with 82 patients with ALK-rearranged advanced non-small cell lung cancer and reported that 83% of patients had some tumour shrinkage, with 54% having had regressions of their lesions by more than 30%. 

Immunotherapy and other therapies

Immunotherapy has increasingly become a viable option for treating cancers. One of the most common immunotherapy treatments is the use of monoclonal antibodies, that target specific receptors present in tumour cells. An example would be Nivolumab and pembrolizumab, two anti-PD-1 antibodies which target receptors called programmed cell death (PD-1) and its respective ligand (PD-L1). The drugs were first tested against metastatic NSCLC in 2015. This antibody treatment works by blocking the binding of PD-1 and its ligand to allow T cells to activate and start killing tumour cells. Additionally, another trial in 2016 called Checkmate032 showed impressive results in response rates for nivolumab and ipilimumab in relapsed small cell cancers.⁵

Recently, a new immunotherapy drug was developed and approved to treat advanced NSCLC called cemiplimab.⁶ A checkpoint inhibitor blocking the PD-1 signalling pathway showed tremendous results in overall survival and PFS compared to chemotherapy. Moreover, many of these immunotherapy drugs have relatively few side effects compared to their targeted therapy counterparts and can be a new approach to targeting the resistant versions of lung cancer that targeted therapy has struggled to overcome.

Finally, other therapeutic drugs include temsirolimus, which is a PI3K inhibitor that targets the PI3K pathway downstream and shows promising activity against NSCLC in phase I trials. Another is sorafenib, an oral drug that serves as a multikinase inhibitor that mainly targets the RAS and VEGF pathways, important for regulating cell proliferation. Trials have shown it is well-adapted and tolerated and had a 2-week improvement in PFS but no difference in overall survival compared to a placebo (2012). Another immunotherapeutic drug was bevacizumab, a recombinant monoclonal antibody that binds to VEGF to prevent tumour growth.⁵

Summary

In summary, lung cancer is a common form of cancer that normally occurs in the bronchi or the lung’s parenchyma. The main population affected by lung cancer are older people over the age of 75 years. Lung cancer can be diagnosed in two types: non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The main targeted therapy treatments are tyrosine kinase inhibitors (TKIs) and ALK gene inhibitors. They target the EGFR signalling pathway and prevent the inhibition of the cell death pathway, whilstALK inhibitors can stop the gene from being amplified and fuse their proteins with other proteins. 

Finally, immunotherapy drugs are a new approach to target lung cancer; anti-PD1 antibodies are used to activate T cells to initiate the killing of tumours. These treatments have shown impressive responses against lung cancer, giving patients a longer survival rate; however, a few targeted therapy treatments present a few side effects, which can be a discomfort to patients taking them.