Faculty of Pharmacy, Parul University, Vadodara, Gujarat (391760), India
In the past few years, lung cancer (LC) accounted for 18% of all cancer-related deaths, making it one of the top causes of cancer-related deaths globally. Even with improvements in early detection and treatment, LC remains a major global health concern. Surgery, radiation, and chemotherapy have been the mainstays of treatment in the past, but the advent of immunotherapy and targeted medicines in recent years has brought about a paradigm shift. These methods concentrate on signaling pathways that are essential to the growth of tumors and are controlled by driver genes including EGFR, KRAS, and MET. Patients with non- small cell lung cancer (NSCLC) now have better intermediate survival rates thanks to the development of customized therapy made possible by the identification of these genes. The FDA's clearance procedure for cancer medications is also reviewed, with special attention paid to accelerated approvals, the use of surrogate endpoints, and international programs like Project Orbis that speed up access to innovative treatments. Additionally, this article explores the mechanisms of action and effectiveness of five FDA-approved medications in treating advanced LC cases: larotrectinib, entrectinib, tepotinib, osimertinib, and repotrectinib. Notwithstanding these developments, problems including tumor recurrence and resistance to first successful treatments are still common. This emphasizes how crucial it is to conduct more research in order to get over these obstacles and enhance the long-term results for patients with lung cancer
One of the main causes of cancer-related death and a global health problem is lung cancer (LC). Lung cancer continues to have high incidence and mortality rates, contributing to 18% of all cancer deaths worldwide in 2020, according to the International Agency for Research on Cancer's (IARC) global cancer statistics report. In recent years, the standard of care for treating lung cancer has been surgery, radiation, and chemotherapy. Nonetheless, immunotherapy and targeted treatments have been used more frequently in clinical settings. The focus now is on discovering the signaling pathways of cell growth or apoptosis that are governed by driver genes related to tumor development, such as EGFR, KRAS, and MET. Patients with lung cancer now have a much higher intermediate survival rate when treatment is directed against these genes. The current first-line treatment for patients with metastatic or advanced non-small cell lung cancer (NSCLC) that has mutation-negative driving genes is immunotherapy. Unfortunately, resistance to the initially beneficial medication is frequently the result of tumor recurrence.1
Types of Lungs Cancer:
Lung cancer primarily consists of two main types:
The prevalence of adenocarcinoma has been increasing in many regions, particularly among women, while squamous cell carcinoma rates have been declining.2
Stages of Lung Cancer:
Lung cancer staging is crucial for determining treatment options and prognosis. The stages are classified as follows:
The cancer is localized to the lungs and has not spread to lymph nodes.
Most patients are diagnosed at advanced stages; approximately 66% of lung cancer cases are diagnosed at stages III or IV.3
FDA Approval Process for Oncology Drugs Specific to Lung Cancer
The FDA approval process for oncology drugs, particularly those targeting lung cancer, involves several key steps, including preclinical studies, clinical trials, and regulatory review. Recent literature provides insights into how this process unfolds for specific lung cancer therapies.
List of FDA approved Drug for Treatment of Lung Cancer:
1.Larotrectinib
2.Entrectinib
3.Tepotinib
4.Osimertinib
5.Repotrectinib
Larotrectinib
One kind of targeted treatment that has been authorized for patients with advanced solid tumors in SATs that are positive for the NTRK gene fusion is larotrectinib. Larotrectinib has demonstrated encouraging long-term benefits over standard-of-care systemic therapy in a number of tumor types, including differentiated thyroid carcinoma (DTC) and non-small cell lung cancer (NSCLC), according to prior research.7
Larotrectinib
Synthesis of Larotrectinib15
Mechanism of Action: First-generation pantropomyosin-related kinase (TRK) inhibitors, larotrectinib, exhibit action against TRKA, TRKB, and TRKC. By reducing the cellular proliferation and survival of malignancies that test positive for NTRK fusions, inhibition of TRK receptor domains has anticancer benefits.8
Entrectinib
For the treatment of patients with NTRK-fp solid tumors, entrectinib was the first TRK inhibitor to receive approval in the United States and Europe. It is a strong tyrosine kinase inhibitor (TKI) with proven CNS activity that was created especially to cross the blood–brain barrier.9
Entrectinib
Synthesis of Entrectinib16
Mechanism of Action: Entrectinib specifically inhibits ROS1 and ALK, as well as the NTRK genes that encode TRKA, TRKB, and TRKC. As oncogenic drivers, these kinases encourage downstream signaling pathways to become hyperactive, which results in uncontrollable cell growth. Entrectinib causes cancer cells to undergo apoptosis by blocking these kinases, which also interferes with the signaling pathways that drive tumor growth.10
Tepotinib
Tepotinib, marketed under the brand name Tepmetko, is an orally administered small molecule that acts as a selective inhibitor of the mesenchymal-epithelial transition (MET) receptor tyrosine kinase. It is primarily used in the treatment of non-small cell lung cancer (NSCLC) that exhibits specific mutations, particularly those involving MET exon 14 skipping. This mutation occurs in approximately 3-4% of patients with refractory NSCLC, leading to uncontrolled cell proliferation and tumor progression.
Tepotinib
Synthesis of Tepotinib17
Mechanism of Action: Tepotinib functions by inhibiting the activity of the MET receptor tyrosine kinase. It binds to the MET receptor in a U-shaped conformation, specifically interacting with residues such as Y1230, D1222, and M1160 within the hinge region. This binding blocks the phosphorylation of MET and subsequent downstream signaling pathways that promote tumor cell proliferation, survival, and migration. By inhibiting MET activity, tepotinib can effectively reduce tumor growth and metastasis in cancers dependent on MET signaling.11
Osimertinib
A new irreversible TKI called osimertinib has a stronger affinity for mutant EGFR than for wild-type EGFR. Osimertinib's discovery approach was just as innovative as the drug itself. Structure-based design for irreversible inhibitors and property-based evolution for kinase selectivity were used in a methodical approach to compound production.
Osimertinib
Synthesis of Osimertinib18
Mechanism of action: Osimertinib is a member of a class of small-molecule TKIs that attach to different intracellular receptor tyrosine kinase domains in an irreversible manner. Osimertinib is structurally distinct from other EGFR TKIs and inhibits HER2, HER3, HER4, ACK1, and BLK in addition to sensitizing EGFR mutations. Osimertinib's intracellular binding reduces EGFR downstream signaling pathways by blocking tyrosine kinase activation, which lowers angiogenesis and cancer cell growth.12
Repotrectinib
A next-generation tyrosine kinase inhibitor (TKI), repotrectinib (TPX-0005) is specifically made to target the fusions of ROS1, ALK, and TRK (tropomyosin receptor kinases) in solid tumors, especially non-small cell lung cancer (NSCLC). It was created to address the resistance mechanisms linked to previous TKIs, particularly those involving ROS1 G2032R and other solvent front mutations (SFMs). In clinical trials, repotrectinib has demonstrated promise for individuals who have not yet received treatment and those who have improved with previous medications.13
Repotrectinib
Synthesis of Repotrectinib19
Mechanism of action: Several receptor tyrosine kinases, such as ROS1, TRKA, TRKB, and TRKC, are specifically inhibited by repotrectinib. Its structure enables it to attach to these kinases' ATP-binding pocket efficiently, preventing their activity and interfering with subsequent signaling pathways that support tumor growth and survival.14
CONCLUSION:
With the development of targeted treatments and immunotherapy, which have transformed the treatment of advanced and metastatic patients, lung cancer treatment has undergone tremendous change. Despite the fact that these treatments increase patients' chances of survival and quality of life, resistance and tumor recurrence continue to be significant obstacles. Targeting certain genetic mutations has advanced significantly thanks to FDA- approved medications such as larotrectinib, entrectinib, Tepotinib, osimertinib, and repotrectinib. To evaluate long-term benefits and address resistance mechanisms, however, continuous clinical trials and strict post-marketing surveillance are necessary. To further lower the worldwide burden of lung cancer, more study into signaling networks, driver mutations, and creative therapeutic approaches is essential.
REFERENCES
Mayur Ghuge*, Vishnu Rajbhar, A Detailed Review of FDA-Approved Drugs for Lung Cancer: Progress in Precision Medicine, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 12, 3173-3180. https://doi.org/10.5281/zenodo.14562290
10.5281/zenodo.14562290
