Lung Cancer is the leading cause of cancer death among both men and women globally. Tobacco smoking is the most prominent cause of lung cancers but not the only cause. The majority of lung cancers include small cell lung cancer (SCLC) and the three non-small cell lung cancer (NSCLC) types. NSCLC tumours are highly heterogenous and despite advances in therapy, the overall 10 year survival rate remans low at 8%.
Lung cancer is the leading cause of cancer mortality worldwide, with about 1.8 million deaths in 2020. About 85% of cases are non-small cell lung cancer (NSCLC), with lung adenocarcinoma and lung squamous cell carcinoma being the prevalent sybtypes. The majority of patietns present with stage III-IV disease, with limited treamtent options and survival rates. (Gilligan, “Residual ctDNA after treatment predcits early relapse in patients with early-stage non-small cell lung cancer” March 2022, Annals of Oncology).
Diagnosis:
Usually lung cancer is initially viewed on chest X-rays or CT scans which is then confirmed with a biopsy. Four major histology types categorized by the size and appearance of malignant cells.
Recent research has shown that cirulating tumour DNA (ctDNA) in blood can be used as a liquid biopsy, providing a minimally invasive diagnostic tool to assess tumour burden in cancer patients. Fragments of DNA are released into the circulation as cell free DNA through apoptosis, necrosis or active release. In cancer patients, DNA is also released form tumour cells and this ctDNA may represent a small fraction of the total cell free DNA. (Gilligan, “Residual ctDNA after treatment predcits early relapse in patients with early-stage non-small cell lung cancer” March 2022, Annals of Oncology).
Treatment of Non-Small Cell Lung Cancer (NSCLC):
Traditional Treatment Therapies:
NSCLC was the leading cause of cancer death in 2000, claiming more than 1 million lives. Traditional therapeutics towards SCLC lung cancer is chemotherapy and/or radiotherapy while patients with NSCLC a surgical resection of the primary tumour with or without a combination of chemotherapy and chest radiotherapy. Common chemotherapy regimens include cisplatin, platinum or carboplatin in combination with one or more of gemcitabine, paclitaxel, docetaxel, etoposide, vinorelbine, topotecan, or irinotecan. However, the average 5-year survival rate of lung cancer patients is less than 15%. The survival rate has not improved over the past decade, mainly because the tumors become resistant to traditional chemotherapy and the cancer is able to expand and metastasize. In addition, chemotherapy nonspecifically kills normal proliferating cells in addition to cancerous cells.
Unpredictability in Treatment of NSCLC:
A great majority of therapies for NSCLC failed in clinical trails. In non-small-cell lung cancer alone, between 1990 and 2005, a total of 1,631 new drugs were sutdied in phase II. Only several of these new agents gained FDA approval. OSI Pharmaceuticals, LLC v. Apotex Inc. (USPTO Patent Trial and Appeal Board IPR201601284)
Anti-EGFR compounds: Activation of the EGFR triggers a cascade of events leading to cell reproduction, and inhibiting EGFR can be beneficial in treating tumor cells.
–Small Molecule Inhibitors of EGFR:
—-Erlotinib (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy-4-quinazo-linamine) (OSI Pharmaceuticals and Genentech): is and FDA anti EGFR compound. It is protected by US Patent No: 6,900,221. Erlotinib is a type of medication called a kinase inhibitor, and it works by targeting and blocking the activity of EGFR. This prevents EGFR from sending signals that promote cancer cell growth.Erlotinib is a small molecule drug that works differently than an antibody. It is a tyrosine kinase inhibitor, meaning it blocks the activity of a particular type of enzyme called a tyrosine kinase. In the case of erlotinib, it inhibits the EGFR tyrosine kinase, which is involved in cell growth and signaling. By blocking this enzyme, erlotinib can slow down or stop the growth of cancer cells that rely on EGFR signaling. Erlotinib is a small-molecule quinazolinamine that inhibits the epidermal growth factor receptor (EGFR) tyrosine kinase domain. It’s specifically a quinazoline derivative, and its chemical name is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. Erlotinib is used in the treatment of certain cancers like non-small cell lung cancer and pancreatic cancer.
–Antibody Inhbitors of EGFR:
–Rybrevant (Johnson & Johnson): is a cancer medicine used to treat adults with advanced non-small cell lung cancer (NSCLC) whose cancer cells have certain genetic changes in the epidermal growth factor receptor (EGFR) gene. When the cancer has activating EGFR exon 20 insertion mutations, Rybrevant is used n combination with other cancer medicines, carboplatin and pemetrexed, in patients who have not been treated before or on its own in patients for whom previous treatment with platinum-based cancer medicines has not worked well enough. When the cancer has EGFR exon 19 deletions or exon 21 L858R substitution mutations, Rybrevant is used in combination with the cancer medicine lazertinib in patients who have not been treated before; in combination with carboplatin and pemetrexed in patients for whom previous treatments, including an EGFR tyrosine kinase inhibitor, have not worked well enough. Rybrevant contains the active substance amivantamab, which is a monoclonal antibody (a type of protein) designed to recognise and attach to two receptors (targets) on the surface of the NSCLC cells at the same time. One part of the antibody attaches to EGFR. The other part attaches to MET, a receptor important for cancer growth and metastasis (cancer that has spread from another part of the body). By attaching to the two receptors, amivantamab blocks them from receiving the messages the cancer cells need for growing and spreading. The attached antibody also attracts and activates immune cells to kill the targeted cancer cells.
PD-1 (programmed death receptor-1): Bristol Myers Squibb Company has obained FDA approval for Opdivo (nivolumab) injection, for intravenous use, for the treatment of maetastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.
–Keytruda (Merck) which is an anti-PD-1 blocking antibody is approved for patients with metastatic non-small cell lung cancer whose tumors express PD-1 and who have disease progression after platinum containing chemotherapy.
–Zejula (niraparib -GlaxoSmith): is a PARP inhibitor for ovarian, brain and lung cancer.
Kinase Inhibitors:
–Agtyro (repotrectinib -Brtistol Myers): is a kinase inhibitor indicated for teh treamtnet of adults with locally or advancted or metastatic ROS1- positive NSCLC and for teh treamtent of adult and pediatric patients 12 years or older with solid tumors that have NTRK gene fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satsifactory alternative therapy.
Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 and of the tropomyosin receptor tyrosine kinases TRKA, TRKB, and TRKC.
Possible Treatments in Future: Recent evidence showed that cancer in general may be sustained by a small subpopulation of cancer stem cells (CSCs).
–CD133 has been identified as a surface marker of CSCs and methods of treating subjects by administering compositions antagonistics to this polypeptide have been proposed (WO 2010/126452).
–Inhibitors of farnesyltransferase (FTIs) have been demonstrated to be effective in treating Ras-dependent tumors in animal models.
–Inhibitors of B7-H3: is over-expressed in a wide range of solid tumour types, including lung.
—-CSK227 (GlaxoSmith): was granted breakthrough therapy designation for patients with extensive-stage small-cell lung cancer with disease progression on or after platinum-based chemotherpy (relapsed or refractory). GSK227 also received Priority Medicines (PRIME) Designation from the EMA. GSK227 is a B7-H3 targeted ADC for lung cancer and other solid tumours.