Review Article: The Evolution of Tyrosine Kinase Inhibitor in the Treatment of Non-Small Cell Lung Cancer

Abstract

Globally, the cancer that results in the greatest number of deaths in both sexes among all types of carcinomas is lung cancer. Once diagnosed, it has the highest rate of mortality. However, in the last ten years, the development of targeted therapies has fundamentally changed the treatment protocol of lung cancer. The precision of non-small cell lung cancer (NSCLC) classification has developed further, with the availability of genomic profiling. Genetic traits have significantly impacted treatment decisions for advanced-stage NSCLC. Over the past two years, more than 10 therapeutic modalities have been approved for use as first-line therapy for specific NSCLC subtypes. Nevertheless, the overall low survival rates and drug resistance remain ongoing major challenges. This paper reviewed the therapeutic methods for NSCLC and focused the discussion on the emergence of targeted therapy. An updated overview of the usual therapy for NSCLC is presented here with an emphasis on the latest guidelines.

Keywords: Non-Small Cell Lung Cancer (NSCLC); Epidermal Growth Factor Receptor (EGFR); Tyrosine Kinase Inhibitor (TKI), Disease Free Survival (DFS); Overall Survival (OS); Progression-free survival (PFS); Oncogene, Biomarker, Signaling pathway.

Introduction

Even though lung cancer incidence and mortality have steadily declined over the past 20 years, this cancer is still the leading cause of death among all kinds of carcinoma worldwide for both men and women. The main risk factor is smoking cigarettes, but anyone can develop lung cancer. Regardless of its dimension, location, or degree of the spread to other parts of the body, lung cancer is a highly treatable condition. The majority of smokers do not develop lung cancer, but almost every person with lung cancer has used tobacco at some point in their life. Recent observation shows that lung cancer can strike anyone at any time and most people who develop lung cancer these days either were not smokers or quit smoking a long time ago.¹

Non-Small Cell Lung Cancer (NSCLC)

NSCLC and small-cell lung cancer are the two main classifications of lung cancer. Different attention is given to these two types. NSCLC first manifests as an aberrant development of healthy lung cells that transforms into a mass, thus a tumor. When a lung tumor becomes malignant, it may start spreading by discharging cancer cells. The cells can pass to other locations in the body through the lymphatic system covering the lung tissues or can travel through blood.²

Types of NSCLC:

The World Health Organization (WHO) and the International Association for Study of Lung Cancer (IASLC) have categorized malignant non-small cell lung epithelial tumors into the following three primary subtypes of NSCLC:

• Squamous cell carcinoma (25% of lung cancers).
• Adenocarcinoma (40% of lung cancers).
• Large cell carcinoma (10% of lung cancers).

Adenosquamous carcino -mas, sarcomatoid carci -nomas, tumors of the salivary gland, carcinoid tumors, and various unclassified carcinomas are among the other forms.³

Molecular Features

Patients with NSCLC now have longer survival rates owing to personalized medication that targets the right molecular targets in malignancies. Anaplastic lymphoma kinase (ALK) rearrangements & mutations in the epidermal growth factor receptor (EGFR) have both been successfully treated with targeted therapies.²¹ Additional molecular alterations discovered by genomic testing include active mutations in the BRAF, HER2, and KRAS genes, amplification of the MET gene and rearrangements of the ROS1 and RET genes, all of which may serve as targets for future treatments.^4-5 The following are examples of genomic changes that can be treated with authorized medications or for which therapies are being developed:

Traditional Therapy

Although over 70 percent of NSCLC cases are categorized as meta-stage (stage III–IV), resection is advised for patients in early-stage (stage I–II) NSCLC.²³

For individuals with advanced-stage NSCLCcytotoxic treatment, targeted therapy, and immunotherapy are vital options. Significant advancements in the treatment of advanced NSCLC have been developed in recent decades, particularly in the areas of immunotherapy and targeted therapy.⁶ The recent history of the advances in the management of NSCLC are shown in Figure 2.

Targeted Therapy for NSCLC

The development of targeted medicines is especially beneficial for patients with advanced NSCLC. Estimates indicate that more than 65% of patients with advanced NSCLC have a genetic mutation that may be targeted. Targeted therapies, that includes the EGFR, ALK, ROS1, BRAF, NTRK1/2/3, MET, and RET inhibitors listed in Figure 3, are now the first-line treatment for a subset of NSCLC patients based on the identification of genetic alterations^.8

Role of Osimertinib in NSCLC

EGFR-Tyrosine Kinase Inhibitor (TKI) third generation oral form Osimertinib is used to permanently attach T790M and EGFR-activating mutations while maintaining wild-type EGFR. When combined with first- or second-generation EGFR-TKI therapy for EGFR T790M-positive NSCLCs, it already showed to be more effective than platinum-based chemotherapy. As Osimertinib performed better in the FLAURA study than Gefitinib and Erlotinib, it became the new standard of treatment for advanced NSCLCs with EGFR mutations.¹⁰

Tyrosine kinase inhibitors (TKIs) belong to the category of targeted therapy. Their mechanism of action involves inhibiting tyrosine kinase enzymes. Tyrosine kinase enzymes regulate cellular processes such as cell signaling, proliferation, and cell division frequency. Mostly indicated in the treatment of cancer, TKIs function by inhibiting tyrosine enzymes, hence impeding the proliferation of cancer cells.

Survival (DFS) in comparison to those receiving a placebo.²⁵ ADAURA demonstrated the median DFS analysis at Stage II-IIIA was 38.8 months. The result of median DFS for Stage IB-IIIA population had not matured during the experiment time. There was a total of 682 patients who were incorporated into Osimertinib (n=339) or placebo (n=343) group. A summary of ADAURA’s performance findings is given in Figure 4 below.¹¹

Untreated EGFR mutation-positive metastatic NSCLC:

In the FLAURA Clinical Trial, Osimertinib proved better than traditional EGFR-TKIs as the standard of therapy for more advanced NSCLC that has an EGFR mutation. It also showed a comparable rating for safety and a lower incidence of major adverse events. When patients assigned to Osimertinib were evaluated against Erlotinib or Gefitinib, FLAURA demonstrated a statistically significant improvement in Progression Free Survival (PFS). A total of 556 patients were randomized to Osimertinib (n=279) or to control (Gefitinib n=183; Erlotinib n=94) group. The median Overall Survival (OS) was 38.6 months and Median PFS was 18.9 months for Osimertinib, both readings were better compared to Erlotinib and Gefitinib. In the final research, as enumerated in Figure-5, the overall survival improved statistically and significantly in Osimertinib when compared to Erlotinib or Gefitinib.¹²

Progress in Targeted Therapy Resistance of NSCLC

Although Osimertinib is effective as the primary treatment along with a treatment option in T790M secondary mutation, individuals treated with first- or the second-generation EGFR-TKIs eventually develop acquired resistance to the drug. EGFR-dependent and EGFR-independent acquired mechanisms of resistance to EGFR-TKIs can be divided into two major groups. The following summarizes current knowledge regarding the Osimertinib resistance mechanisms that are developing in patients with EGFR-mutant NSCLC. A schematic summary of the main Osimertinib resistance pathways is provided in Figure 6.13

Future of Treatment Option

One of the most severe problems with cancer treatment today is drug resistance in cancer cells, as is illustrated in Table 1. Target modification is the primary cause of on-target resistance.

Advances in genetic testing have made it possible to recognize novel oncogenic factors of NSCLC. Among these, Lazertinib treatment is recommended for EGFR-T790M mutation-positive advanced locally or metastatic NSCLC that had been treated with EGFR-TKI. In the ongoing MARIPOSA trial, Lazertinib is being investigated as the first line setting alongside Amivantamab, despite not having obtained universal approval yet.¹⁵

The well-tolerated and promising nature of Anlotinib-based combinations with EGFR-TKI, chemotherapy, and immune checkpoint inhibitors (ICIs) as first-line therapies for advanced NSCLC may be confirmed by additional research.^15-16 For patients with advanced non-small cell lung cancer, Anlotinib in combination with several first-line therapeutic alternatives may be the satisfactory treatment option.²⁸

Conclusion

Lung cancer has received a great deal of interest from experts because it still has the highest death rate in the world. Even though surgery provides the best chance of recovery, the majority of NSCLC patients already have advanced stages of the disease when they first come. Cytotoxic chemotherapy was the norm for treating advanced NSCLC prior to TKIs being introduced as the first-line treatment in a number of NSCLC patient subgroups.¹⁸

In this study, a summary was presented of NSCLC treatment alternatives, with a focus on targeted therapy and the identification of resistance mechanisms. These components may become important in the development of customized treatments in the future. Changes in oncogenic factors like EGFR, ALK, BRAF, or MET can change the immune tumor microenvironment and promote tolerance to Programmed Cell Death Protein 1 (PD1/PD-L1). Moreover, there are numerous ways in which treatment resistance might develop in cancer patients. To customize targeted therapy, it is imperative to evaluate the distinct resistance mechanisms of every patient at the molecular level.¹⁹

In conclusion, targeted therapy is beginning to yield apparent benefits for patients with oncogene-driven NSCLC. Treatment options for non-small cell lung cancer are currently many. Choosing a combination of therapies that is suitable and unique for every patient can be challenging for medical professionals. Notably, new drug introductions and their innovative uses, or the addition of previously approved ones, play a role in patient survival.²⁰