Advances In Precision Medicine for Lung Cancer: From Diagnosis to Targeted Drugs

Abstract

Lung cancer continues to be one of the most common causes of cancer-related death around the world and despite advances in conventional treatment, the survival outcomes remain poor. The heterogeneity of lung cancer, which is broadly classified as non-small cell lung carcinoma (NSCLC) or small-cell lung carcinoma (SCLC), demands that more precision-based approaches be developed to treat the disease. Precision medicine is a paradigm shifting approach now using molecular profiling, biomarker selection, and when appropriate, nimbleness in therapeutic development. These advances which represent novel therapeutic opportunities to target genetically mediated alterations and associated signaling pathways in lung cancer are evolving rapidly. For example, there are new classes of agents, including repotrectinib, pralsetinib, and capmatinib targeting RET and MET mutations, while mobocertinib is being developed for EGFR exon 20 insertions and lorlatinib was successful in ALK- and ROS1-positive NSCLC. Sotorasib was the first therapy approved for KRAS G12C-mutant cancers. Recently, also lurbinectedin has provided new therapeutic options for relapsed SCLC patients. Furthermore, zenocutuzumab shows promise in patients with HER2/HER3-driven tumors.

Keywords

Introduction

Fig No. 1: The major causes of lung cancer

Types Of Lung Cancer

The vast majority of lung cancers are carcinomas, which are cancers derived from epithelial cells. A histopathologist can observe two main types of lung carcinoma microscopically, based on the size and appearance of the neoplastic cells; non-small cell lung carcinoma (80.4%) and small-cell lung carcinoma (16.8%). This histopathological classification has clinical and prognostic relevance for the disease ^[3].

Type 1:

Non-small cell lung cancer (NSCLC). Non-small cell lung cancer has three main subtypes: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Squamous cell carcinoma accounts for 31.1% of lung cancers, typically arises near the central bronchi, and is more likely to display necrosis and cavitation. It tends to be a slower growing cancer, especially when well differentiated. Although the majority of adenocarcinomas are related to smoking, adenocarcinoma is the most common type of lung cancer in "never smokers" in individuals who don't or never have smoked. Female never smokers are more likely to have bronchioloalveolar carcinoma, a subtype of adenocarcinoma which may have a different response to treatment. Large cell lung cancer, which is only 10.7% of overall lung cancers, is a rapidly expanding type, close to the surface of the lung. It is often poorly differentiated and may metastasize early ^[4].

Type-2:

Small cell lung carcinoma [SCLC]. Small cell lung cancer (SCLC), otherwise referred to as "oat cell carcinoma," is a serious and uncommon lung cancer. This type of lung cancer is fast growing and typically begins in the larger airways. This type of lung cancer spreads early and quickly, and carries a poor prognosis. This type of lung cancer can be treated at first with chemotherapy and usually has a favorable response. This type of lung cancer has dense neurosecretory granules that link it with paraneoplastic syndromes. SCLC is classified as limited stage or extensive stage disease ^[5].

Type-3:

 Metastatic tumors. The lung often is a common place for metastasis tumors in other parts of the body; these cancers remain being identified by cancer being identified by their site of origin, thus breast cancer metastasis to the lung would still be known as breast cancers. These metastases often present as characteristic round appearing masses on the chest x-ray. In general, primary lung cancers themselves most commonly metastasize to the brain, adrenal glands and bone ^[6].            

Recent Drugs for Lung Cancer

1.Repotectinib

2.Lurbinectedin

3.Capmatinib

4.Pralsetinib

5.Lorlatinib

6.Mobocertinib

7.Sotorasib

8.Zenocutuzumab           

1.Repotrectinib (Approved date: November 15 2023)

Fig. No 2: Structure of Repotrectinib

A novel RET tyrosine kinase inhibitor (TKI), reptotecitib (BOS172738), has been developed to address tumors associated with RET mutations. Existing multikinase inhibitors had disadvantages such as non-specific activity via substantial off-target inhibition of VEGFR or other kinases. Its core structure comprises a small molecule designed for specific binding to the ATP-binding site of RET kinase ^[7]. The pharmacological mechanism of action leads to inhibition of RET phosphorylation, which inhibits downstream MAPK and PI3K/AKT signalling pathways and subsequently inhibits proliferation and induces apoptosis in tumor cells ^[8]. Reptotecitib, which has shown promise in early phase clinical trials, is in clinical development for the treatment of RET fusion-positive solid tumors, including RET mutant medullary thyroid carcinoma (MTC), and non-small cell lung cancer (NSCLC). Most of the adverse events reported have been characterized as mild to moderate, including rash, fatigue, dry mouth, diarrhea, nausea, constipation, and temporary transaminitis. Interstitial lung disease, hepatotoxicity, QT prolongation, and hypertension have occurred, but are less common adverse events that may potentially be serious. Overall, Reptotecitib is a next-generation, highly-selective RET inhibitor that appears to offer a better safety profile and is more efficacious than prior agents ^[9].            

2.Lurbinectedin (Approved date: June 15 2020)

FIG. No 3: Structure of Lurbinectedin

The chemically-derived tetrahydroisoquinoline alkaloid lurbinectedin has a similar structure to trabectedin and is known to form adducts that distort the DNA helix and inhibit transcription by covalently binding into the DNA minor groove (D'Incalci M, Cancer Res. 2019) ^[10]. By specifically binding to guanine residues in the DNA minor groove, lurbinectedin leads to DNA double-strand breaks, inhibition of oncogenic transcription, and apoptosis. It also has anti-tumor growth effects by decreasing inflammatory cytokines that promote tumor growth and inhibiting tumor-associated macrophages ^[11]. In 2020, the FDA approved the use of lurbinectedin for clinical use in patients with metastatic small-cell lung cancer (SCLC) which had progressed despite platinum-based chemotherapy. In addition, lurbinectedin is continuing to be evaluated for solid tumors such as mesothelioma, breast cancer, ovarian cancer, and others ^[12].The most reported side effects include fatigue, nausea and vomiting, constipation, decreased appetite, elevated liver enzymes (AST, ALT), and myelosuppression (in particular neutropenia, anemia, and thrombocytopenia). Also reported side effects include hepatotoxicity, severe neutropenia with potential infections, and infrequently rhabdomyolysis ^[13].

3.Capmatinib (Approved date: August 10 2022)

FIG. No 4: Structure of Capmatinib

The small molecule capmatinib, which is a selective tyrosine kinase inhibitor (TKI), has a basic structure that has been designed to bind specifically to the ATP-binding site of the MET receptor tyrosine kinase and prevent it from being activated ^[14]. The drug inhibits downstream signaling pathways (PI3K/AKT, RAS/MAPK, and STAT3) that contribute to tumor growth, cellular survival, and metastasis while preventing MET phosphorylation ^[15]. Capmatinib is being evaluated in other solid tumors associated with MET amplification or overexpression; however, its principal clinical indication is in adult patients with metastatic non-small cell lung cancer (NSCLC) who have MET exon 14 skipping mutations as per an FDA-approved companion diagnostic ^[16]. Adverse reactions associated with capmatinib include an elevation of hepatic enzymes (ALT and AST); peripheral edema; fatigue; and photosensitivity, while gastrointestinal adverse reactions include nausea, vomiting, decreased appetite, diarrhea, and constipation. Interstitial lung disease is a rare but serious adverse reaction ^[17].

4. Pralsetinib (Approved date: August 9 2023)

FIG. No 5: Structure of Pralsetinib

Pralsetinib is a selective RET (Rearranged during Transfection) tyrosine kinase inhibitor that targets the ATP-binding site of RET with a heteroaryl-fused basic nucleus ^[18]. It has been shown to inhibit the growth of tumors by preventing RET phosphorylation along with downstream MAPK/ERK, and PI3K/AKT signaling ^[19]. Pralsetinib is used for advanced RET-mutant medullary thyroid cancer, RET fusion-positive thyroid cancer, and RET fusion-positive non-small cell lung cancer. Serious risks that have been identified with pralsetinib therapy include interstitial lung disease, hepatotoxicity and bleeding, within less severe side effects from therapy include neutropenia, anaemia, thrombocytopenia, elevated liver enzymes, hypertension, fatigue, constipation and pneumonitis ^[20].               

5.Loraltinib (Approved date: March 3 2021)

FIG. No 6: Structure of Loraltinib

Lorlatinib is classified as a third-generation macrocyclic tyrosine kinase inhibitor that targets ALK and ROS1, which encompasses resistant mutations such as ALK G1202R ^[21]. Lorlatinib inhibits phosphorylation and downstream signalling in both MAPK/ERK and PI3K/AKT pathways, with effects on suppressing tumour growth and penetrating the blood–brain barrier to treat CNS metastases ^[22]. Lorlatinib is approved for use in ALK-positive NSCLC in patients who have received prior treatment with one or more second-generation ALK inhibitors and it also has clinical activity in ROS1-positive NSCLC ^[23]. The more frequently reported adverse reactions include hypercholesterolemia, increasing triglycerides, cognitive and mood alteration, speech problems, peripheral neuropathy, hypertension, edema and fatigue; while more serious risks include ILD, hepatotoxicity, atrioventricular block and CNS toxicity ^[24].

6.Mobocertinib (Approved date: September 15 2021)

FIG. No 7: Structure of Mobocertinib

Mobocertinib is an oral tyrosine kinase inhibitor with a quinazoline-based nucleus, which selectively inhibits EGFR exon 20 insertion mutations in non-small cell lung cancer ^[25]. It irreversibly binds to the EGFR kinase domain, thereby interfering with downstream signalling pathways (MAPK/ERK, PI3K/AKT) and downstream phosphorylation, which leads to inhibition of tumour cell proliferation and causes apoptosis ^[26]. Mobocertinib is approved for adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions who have received prior platinum-based chemotherapy ^[27]. Serious adverse effects include interstitial lung disease, QT prolongation, and severe diarrhoea, while more common adverse events include diarrhoea, nausea/vomiting, rash, fatigue, and paronychia ^[28].

7.Sotorasib (Approved date: May 28 2021)

FIG. No 8: Structure of Sotorasib

Sotorasib, a small-molecule inhibitor, covalently binds to the cysteine residue at position 12 to specifically target the KRAS G12C mutant ^[29], locking KRAS in its GDP-bound inactive state. By inhibiting downstream signaling through the PI3K/AKT and MAPK/ERK pathways, this suppresses tumor cell proliferation ^[30]. It is under investigation for other solid tumors and is approved for non-small-cell lung cancer (NSCLC) with KRAS G12C mutation ^[31]. Atually rare events of hepatotoxicity and interstitial lung disease have occurred, while more commonly reported adverse effects include diarrhea, nausea, fatigue, musculoskeletal pain and elevated liver enzymes ^[32].

8. Zenocutuzumab (Approved date: December 4 2024)

FIG.No9: Structure of Zenocutuzumab

A bispecific monoclonal antibody named zenocutuzumab is designed to target HER2 and HER3 receptors. It achieves this by binding both proteins simultaneously and preventing HER2 and HER3 from heterodimerizing ^[33]. Inhibition of these receptors blocks downstream signaling pathways important for growth and survival of tumor cells, such as PI3K/AKT and MAPK signaling. Zenocutuzumab also promotes immune-mediated tumor cell death through antibody-dependent cellular cytotoxicity (ADCC) ^[34]. The primary tumor type studied includes solid tumors with fusions of the NRG1 gene, including breast, lung, and pancreatic cancers, which are often reliant on HER2/HER3 signaling for expansion. Both anti-tumor activity and response have been seen in clinical studies in this setting. Infusion-related side effects include fever and chills, fatigue, nausea, diarrhea and increased liver enzymes, necessitating premedication or dose modifications on occasion. In summary, zenocutuzumab is a targeted treatment strategy for HER2/HER3-driven cancers ^[35].

CONCLUSION

Lung cancer still represents the leading cause of cancer-related morbidity and mortality worldwide and has a poor prognosis. More recently, targeted therapies and immunotherapies have improved prognosis and quality of life for patients. Promising efficacy has been seen with novel drugs such as repotrectinib, lurbinectidin, capmatinib, and sotorasib. Ongoing challenges involve drug resistance, side effects of treatment, and availability in many areas of the world. Personalized medicine and early detection are key to reducing the burden of lung cancer around the world.

REFERENCE

1. Kelloff, G.J., Crowell, J.A., Steele, V.E., Lubet, R.A., Malone, W.A., Boone, C.W., Kopelovich, L., Hawk, E.T., Lieberman, R., Lawrence, J.A., Ali, I., Viner, J.L., Sigman, C.C. Progress in cancer chemoprevention: development of diet-derived chemopreventive agents. Journal of Nutrition 2000; 130 (2): 467S–471S.
2. Corner, J. What is cancer? In: Cancer Nursing Care in Context (eds J. Corner and C. Bailey), Blackwell Publishing; Oxford.; 2001.
3. Travis,  W  .D,  Travis, L.B.,  Devesa,  S.S., "Lungcancer". Cancer 75 (Suppl. 1): Jan 1995; 191–202.
4. Raz,  D.  J.,  He,  B.,  Rosell,  R.,  Jablons,  D.  M."Bronchioloalveolar  carcinoma:  a  review.  Cln.Lung Cancer 2006; 7(5): 313–322.
5. Barbone,  F;  Bovenzi  M,  Cavallieri  F,  Stanta  G.Cigarette  smoking  and  histologi
6. c  type  of  lungcancer in men" (PDF). Chest 1997; 112(6): 1474–1479.24. Seo,  J.  B;  Im  J.G,  Goo  J.M.,  et  al.  "Atypicalpulmonary  metastases:  spectrum  of  radiologicfindings". Radiographics 2001; 21(2): 403–41
7. Subbiah V et al., Nat Rev Clin Oncol. 2021
8. Drilon A., Clin Cancer Res. 2021
9. Gainor JF et al., Ann Oncol. 2021; ClinicalTrials.gov Identifier: NCT03780517
10. D’Incalci M, Galmarini CM. A Review of Trabectedin (ET-743) and Lurbinectedin (PM1183): The Tale of Two Related Drugs. Cancer Res. 2019;79(21):5125–5132
11. Santamaria Nuñez G, et al. Lurbinectedin Specifically Triggers the Degradation of Transcribing RNA Polymerase II and Inhibits the Transcription of Genes Overexpressed in Tumors. Mol Cancer Ther. 2016;15(10):2399–2412.
12. Trigo J, et al. Lurbinectedin as Second-Line Treatment for Patients With Small-Cell Lung Cancer: A Single-Arm, Open-Label, Phase 2 Basket Trial. Lancet Oncol. 2020;21(5):645–654.
13. U.S. Food and Drug Administration. Zepzelca (lurbinectedin) Prescribing Information. FDA, 2020.
14. Markham A. Capmatinib: First Approval. Drugs. 2020;80(11):1125–1131
15. Paik PK, Felip E, Veillon R, et al. Clinical activity of capmatinib in MET exon 14–mutated advanced non–small-cell lung cancer. Cancer Discov. 2020;10(6):842–853.
16. Subbiah V, Hu MI, Wirth LJ, et al. Pralsetinib: A Next-Generation RET Inhibitor for RET-Driven Cancers. Cancer Discovery. 2021;11(3):369–384. doi:10.1158/2159-8290.CD-20-0799
17. U.S. Food and Drug Administration (FDA). Gavreto (pralsetinib) prescribing information. Blueprint Medicines Corp; 2020.
18. Subbiah V, Hu MI, Wirth LJ, et al. Pralsetinib: A Next-Generation RET Inhibitor for RET-Driven Cancers. Cancer Discovery. 2021;11(3):369–384. doi:10.1158/2159-8290.CD-20-0799
19. U.S. Food and Drug Administration (FDA). Gavreto (pralsetinib) prescribing information. Blueprint Medicines Corp; 2020.
20. Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET Fusion–Positive Non–Small-Cell Lung Cancer (ARROW Trial). Lancet Oncology. 2021;22(7):959–969. doi:10.1016/S1470-2045(21)00144-3 .
21. Shaw AT, et al. Lorlatinib in advanced ROS1-positive non-small-cell lung cancer: a multicentre, open-label, single-arm, phase 1–2 trial. Lancet Oncol. 2017;18(12):1590–1599.
22. Solomon BJ, et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 2018;19(12):1654–1667.
23. U.S. Food and Drug Administration (FDA). Lorbrena (lorlatinib) Prescribing Information. Pfizer; 2018.
24. Johnson TW, et al. Discovery of Lorlatinib: a highly potent, selective, and brain-penetrant ALK/ROS1 inhibitor. J Med Chem. 2014;57(11):4720–4744.
25. U.S. Food and Drug Administration (FDA). Mobocertinib (EXKIVITY) Prescribing Information. 2021.
26. Zhou C, et al. Mobocertinib in NSCLC with EGFR Exon 20 Insertions: Results from EXCLAIM Study. Lancet Oncol. 2021;22(12):1681–1692.
27. Piotrowska Z, et al. Mobocertinib for patients with EGFR exon 20 insertion–positive metastatic NSCLC. Cancer Discov. 2021;11(9):2158–2173.
28.  FDA Oncology Center of Excellence. Clinical development of mobocertinib for EGFR exon 20 insertions in NSCLC. Clin Cancer Res. 2022;28(11):2190–2194.
29. Canon J, et al., 2019 – Describes the discovery and mechanism of Sotorasib targeting KRAS G12C.
30. Hong DS, et al., 2020 – Clinical trial results in KRAS G12C–mutated NSCLC.
31. FDA Prescribing Information, 2021 – Official approved uses, dosing, and adverse reactions.
32. 4.Awad MM, et al., 2021 – Reports additional clinical activity and safety data in KRAS G12C lung cancer
33. Le X, et al. Clin Cancer Res. 2022;28(17):3790–3802.
34.  Hyman DM, et al. Cancer Discov. 2021;11(8):1952–1967.
35. Trarbach T, et al. J Clin Oncol. 2020;38(15_suppl): TPS3654.