The History of the Lung Cancer.
Lung cancer is a disease that causes uncontrollable growth of abnormal cells. It begins in the respiratory area of the body that take over healthy human cells, tissues and organs which ultimately result in death (Centers for Disease Control and Prevention (CDC), 2020). Medical advancements of different drug treatments and procedures have been discovered and developed to treat lung cancer that include; surgery, chemotherapy and radiotherapy.
However, in recent years, there has been increasing progress in personalised medical treatments by the completion of the Human Genome Project and identification of cancer-causing biomarkers to determine the appropriate course of treatment (Wheeler and Wang, 2013). Specialised oral lung cancer drugs have emerged and show success in slowing down cancer progression and improving cancer patients’ status by limiting side effects (National Cancer Institute (NCI), 2020a).
Nevertheless, partial data disclosed in studies funded by pharmaceutical companies leads to bias (Lexchin, 2012). While it is important that cancer specialists and researchers thoroughly examine the aetiology of lung cancer and the benefits of novel therapies that should not be overlooked in the examination of lung cancer drug research. The essay outlines the history and origins of the key processes in drug discovery to delivery of a new oral lung cancer therapy, Capmatinib (Balfour, 2020).
Capmatinib’s New Drug Application, (NDA) was granted Priority Review by the U.S. Food and Drug Administration (FDA) due to its success in combination therapy clinical trials and in crossing the blood-brain-barrier (BBB) (Balfour, 2020). Further, how current strategies of drug discovery to delivery bridge the gap between research and patients care, ultimately overcoming a disease and improving quality of life. Lastly, concludes by addressing potential challenges that Capmatinib may face post-market release.
From pre-discovery to development
Throughout the history of medicine, it has become evident that is essential to understand the scientific basis of disease before the discovery for potential treatments that is both essential and inevitable (Curt, 1996). Discovery and bringing one new drug into the market typically takes an average of 14 years of research and clinical development efforts (Hughes et al., 2010). Moreover, for every 10’000 or more drug candidate hits in early drug discovery, only one may eventually lead to a drug that reaches the market (Hughes et al., 2010).
A successful drug discovery resulted in 1962 when NCI-funded scientists screened the Taxus brevifolia (Pacific yew) and unlocked the tree’s potential for cancer treatment and developed the lifesaving compound paclitaxel (Taxol) (NCI, 2020b). This demonstrates how the success of Taxol over the years has led to a greater understanding of natural compounds and for a scientist to discover potential new drugs as medication.
A new drug as a potential therapy or medication that currently has not been used in clinical practice to prevent, treat or cure a disease or condition (FDA, 2020). In the US, the submission of a NDA is to the FDA is required, whereas, in the UK the Medicines and Healthcare Products Regulatory Agency (MHRA) and European Medicines Agency (EMA) which approves and oversees new medicines (Cancer Research UK, 2020).
Meanwhile, National Institute of Health and Care Excellence (NICE) offers a fee-based consultancy service to developers of medicines to help them ensure that they generate the evidence they will need to support a NICE evaluation (Cancer Research UK, 2020). NICE recommends that any advice is sought after the first human trials to aid planning of the more extensive trial programme.
Currently, more and more drugs are chemically synthesised in laboratories. This is initiated by a university research laboratory with research grants or the pharmaceutical industry with a drug discovery and development programme where the pre-discovery journey begins to undertake basic research to understand the processes behind a disease, often at a molecular or cellular level (Hughes et al., 2010).
Drug research and development is designed with patients as the main focus to ensure innovate new medicine are safe, effective and available in the shortest possible time. The first step in target discovery, scientists will consider investigating natural compounds from fungi, plants and marine animals to provide the earliest origin hypothesis (Dias, 2012). Moreover, scientists learn of a biological target that is involved in the biological process and deemed malfunctional in patients with a disease such as lung cancer.
The beast target for treating or preventing a disease are usually proteins in the patient’s body, and the challenge is to identify which proteins are relevant and more importantly confirm their role in the disease (Dias, 2012). Increasingly, pharmaceutical companies focus their research on understanding cellular network of proteins and pathways, as a single protein may transmit messages to several other proteins (sometimes multiple pathways) affecting protein function. Therefore, knowing how these pathways work and interact helps to identify the most appropriate target for a drug (Dias, 2012).
This knowledge and desire to address unmet medical needs helps to determine to priority in drug target discovery. In drug discovery several methods such as high-throughput screening and computer-based design are used to find chemical compounds or biologics that bind to the identified target. Additionally, if compound modulates the target in a way that is expected to alter the disease, this hit will be refined to improve its safety and effectiveness eventually becoming a drug candidate (Dias, 2012).
Lung cancer is the most regularly diagnosed cancer in men worldwide and in 2018 approximately 2 million cases detected (Vansteenkiste et al., 2019). Within one year of diagnosis with lung cancer, half of the patients die and survival for five more years is less than 18% (Zappa and Mousa, 2016). There are two subtypes of lung cancer; non-small-cell carcinoma (NSCLC) and small-cell lung carcinoma, that accounts for 85% and 15% of all lung cancer (Zappa and Mousa, 2016). Lung cancer can happen to anyone as its aetiology broads from genetics (inherited) and environmental factors, therefore, everyone is at risk of developing cancer.
Currently, there are many treatment options for lung cancer such as surgery, adjuvant, chemotherapy and radiotherapy. However, every individual case is different, and more research has been focused on biomarker testing in personalised medicine (Zappa and Mousa, 2016). Within NSCLC, targeted agents’ success against anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) mutations rearrangements (Zappa and Mousa, 2016).
Genomic testing and various molecular changes have been located including rearrangements of RET and ROS1, activating mutation in HER2, KRAS and BRAF genes and amplification of mesenchymal-epithelial transition factor (MET) which are proposed to be potential targets for future therapies (Zappa and Mousa, 2016). This reassures the development of Capmatinib and its recent FDA priority review (if successful, Capmatinib may be FDA approved by the end of 2020).
Capmatinib was developed by Novartis Pharmaceuticals Corporation (NPC), it works by targeting the TKI that affect the MET exon 14 skipping alterations and it is classified as a Type IB inhibitor (Novartis, 2019; NIH PubChem, 2020). c-MET is a tyrosine kinase receptor mutated or overexpressed in many tumour cell types and plays a vital role in tumour cell metastasis, proliferation, invasion, survival and tumour angiogenesis (NIH PubChem, 2020).
It is an oral bioavailable proto-oncogene c-MET inhibitor with potential antineoplastic activity NIH PubChem, 2020). Capmatinib binds selectively to c-MET, thereby disturbing c-MET signal transduction and inhibiting c-MET phosphorylation pathways. This may effectively induce cell death in tumour cells overexpressing c-MET protein or expressing constitutively activated c-MET protein (NIH PubChem, 2020). This is a first and demonstrates significance in lung cancer research as currently there are no targeted therapies approved to treat MET exon14 skipping-muted NSCLC (Novartis, 2019).
In 2016, drug research studies shown that there was at least five MET-targeted TKIs, including Crizotinib, Cabozantinib, Capmatinib, Tepotinib, and Glesatinib, that are being investigated clinically for patients with MET exon 14 altered-NSCLC. Here we focus on the recent success of Capmatinib and its ability to cross the BBB (Vansteenkiste et al., 2019). This research was financed by NPC is dedicated to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. Moreover, this potentially is a conflict of interest between producing good clinical data and results that will increase the sales of their products.
A preclinical profile of Capmatinib study
A preclinical data of Capmatinib, that reinforced the biomarker strategy for patient selection (Baltschukat et al., 2019). Capmatinib was highly selectively for MET in comparison with other kinases (Baltschukat et al., 2019). Likewise, in cancer models where MET is the dominant oncogenic driver, anticancer activity could be further enhanced by combination treatments. The mixing of Capmatinib and other kinase inhibitors caused in enhanced anticancer activity against models where MET activation co-occurred with other oncogenic drivers (Baltschukat et al., 2019).
However, the low section of cancer models that respond to Capmatinib as a single agent argues that the implementation of patient selection strategies centred on these biomarkers is critical for clinical drug development. Capmatinib is also a rational combination cohort for other kinase inhibitors to combat MET-driven resistance (Baltschukat et al., 2019). It is worth to mention that this study had potential conflict of interests were disclosed with ownership (including patents) in NPC, which increase the possibility of bias results (Baltschukat et al., 2019).
Phase I study
The dose-escalation phase I study which assessed the tolerability and safety of Capmatinib in 38 patients (no patients died in either part of the phase I study) with advanced MET+ve solid tumours (Bang et al., 2019). The efficacy and safety were observed in expansion cohorts of patients with MET-dysregulated gastric cancer, hepatocellular carcinoma (HCC), and other tumours (the results of the expansion cohort of patients with advanced NSCLC were reported (Bang et al., 2019).
Capmatinib recommended phase 2 dose (RP2D) was 400-mg bid tablet/ 600-mg bid tablet (Bang et al., 2019). It is significant to note that this study was sponsored by NPC and the success of Capmatinib tablet formulation was well tolerated and the acceptable safety profile at the RP2D and showed antitumor activity (Bang et al., 2019). While the number of clinical trials performed each year increases, the strengths and weaknesses need to be discussed throughout to evaluate the usefulness and validity of the study.
Phase Ib/II study
With further studies in this subject, randomised studies are not feasible for studies of targeted therapeutics in patients whose tumours are navigated by even more molecular variants (Waqar et al., 2016). The following clinical trial was performed in accordance to the principles of Good Laboratory Practise and the Delectation of Helsinki (Wu et al., 2018).
A phase Ib study of 61 patients to determine the maximum tolerated dose in relation to dose-limiting toxicities of Capmatinib with Gefitinib as potential combination therapy (Wu et al., 2018). Capmatinib with Gefitinib has been revealed to be both rational and feasible, and the data from this study indicate that the mixing of Capmatinib with an EGFR-TKI may be a promising treatment option for patients with EGFR-mutated, MET-dysregulated NSCLC and for patients with MET-amplified tumours (Wu et al., 2018).
The objective of the phase II (with 100 patients) was to determine the recommend phase II dose in phase Ib and estimate the overall response rate (ORR) (Wu et al., 2018). The RP2D for Capmatinib in combination with Gefitinib 250-mg once-per-day was declared as 400-mg twice-per-day tablets on the basis of a combination of safety, PK, and PD data. It seems suffice to shut down the MET phosphorylation by immunohistochemistry (Wu et al., 2018). After treatment with Capmatinib 400-mg twice-per-day capsules, in four out of five patients, revealed substantial MET pathway inhibition (Wu et al., 2018). The association between these markers and clinical outcome, warrants additional investigation.
Phase II study (Geometry mono-1 trial)
The reason for the FDA priority review was due to the success of a NPC-sponsored GEOMETRY mono-1 trial (Wolf, 2019; Novartis, 2019). It is an international, multi-cohort, non-randomised, open-label Phase II study to evaluate the efficacy and safety of single-agent Capmatinib in adult patients with advanced NSCLC harbouring a MET amplification and/or mutation, ALK-ve rearrangement, EGFR wildtype (Wolf, 2019).
Capmatinib is under investigation for possible first-line and previously treated patients with locally metastatic or advanced METex14 mutated NSCLC (Novartis, 2019). The phase II study showed an ORR of 67.9% in first-line and previously treated patients with adverse effects grade 1-2 (Wolf, 2019). This data reinforces Capmatinib to be a promising new treatment option with a manageable toxicity profile, regardless of the line of therapy.
Resistance to Capmatinib
Unfortunately, resistance to target agents and therapies is inevitable. Resistance is expected to arise as a result of receptor tyrosine kinase mutation or from upregulation of MET ligand expression; potential strategies to overcome resistance are proposed. A study showed in vitro studies suggested that activation of EGFR signalling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by Capmatinib-resistant NSCLC cell lines (Kim et al., 2019). In addition, combined treatments with MET, EGFR, and PI3K\” inhibitors may be effective therapeutic strategies in Capmatinib-resistant NSCLC patients as well as ongoing and future clinical trials (Kim et al., 2019).
Ongoing clinical trials
Currently there are 6 active clinical trials for Capmatinib relating to lung cancer treatment and this is important to assess the new ways to detect, treat or prevent disease. The hypothesis of linking Capmatinib and EGFR inhibitors in EGFR-mutant lung cancer with MET dysregulation is clinically validated and has been explored in further trials. Furthermore, the preclinical data suggest that Capmatinib combinations can be effective beyond EGFR-targeting agents, both in tumours where MET is the dominant oncogenic driver, and in tumours with other co-occurring drivers (Baltschukat et al., 2019).
A phase II study is in the early stages to find out which of these two treatments; combination of Capmatinib with Spartalizumab or Docetaxel alone helps to control lung cancer better (NCI, 2020c). Another, ongoing phase II clinical trial is to determine the efficacy and safety of Nivolumab in combination with Nazartinib, EGF816 and of Nivolumab in combination with Capmatinib in previously treated NSCLC patients (HCI, 2020c). Additionally, phase II study to evaluate antitumor activity of oral c-MET inhibitor Capmatinib, in adult patients with EGFR wild-type, NSCLC. The study will also evaluate pharmacokinetics and safety of Capmatinib (HCI, 2020c).
All of these studies give us a better understanding of Capmatinib in current drug development as a whole by exposing us to all chorological steps that are followed in a single topic. The research approach of scientific methods made evaluative claims based on the scientist’s observation and results of laboratory experiments. Given that all studies are NPC funded it is no surprise for that each article arrives at a positive conclusion which exhibits opportunity for bias.
At the same time, the exploitation of trustworthiness and reliability of academic publishing may remain unidentified. Thus, the clear use of scientific method and laboratory experiment can enhance textualise evidence, to focus on the identify of Capmatinib and its role in MET dysregulation and anticancer targets. Only so much can be done, however, the first step to reduce ignorance is to increase awareness of potential personalised lung cancer treatment.
The overall strengths and weaknesses of Capmatinib and its journey from a preclinical profile to potential FDA approval. The evidence provided is limited to research conducted by NPC and potential future success of Capmatinib profits. Therefore, an open-mind should be maintained when interpreting NPC validity of laboratory experiment and clinical trials.
Future of combination therapy and personalised medicine ensures safety and efficacy to ensure that the benefits outweigh the risks incurred for its use. Unfortunately, unforeseen factors such as adverse reactions that have two forms dose-dependent and dose-independent from more post-market research. Finally, the awareness of these issues allows for the early implementation of measures to increase the opportunity for success.