Despite advancements in conventional treatment modalities for non-small cell lung cancer, therapeutic options are limited and often come with severe side effects and limited efficacy. Find out how antibody-drug conjugates might be able to help address these unmet needs in non-small cell lung cancer care.
Lung cancer is the third most common cancer in the US and remains the leading cause of cancer deaths worldwide. And non-small cell lung cancer (NSCLC) accounts for approximately 85 percent of lung cancer cases.
Unfortunately, most patients are diagnosed at an advanced stage. And despite advancements in conventional treatment modalities, including surgery, chemotherapy, and radiation therapy, the prognosis for NSCLC patients remains challenging, and the treatment options are limited. These conventional treatments also often come with severe side effects and limited efficacy.
Fortunately, antibody-drug conjugates (ADCs) have emerged as a promising therapeutic approach for NSCLC, which is why we’re taking an in-depth look at them.
What Are ADCs?
ADCs consist of three components: a monoclonal antibody, a linker, and a cytotoxic payload.
- Monoclonal antibody (mAb) is a Y-shaped antibody that’s designed to bind to specific antigens on the surface of cancer cells; in the case of NSCLC, those antigens include HER2, Trop-2, MET, and others. This is followed by subsequent internalization of the ADC into the cell, while sparing normal cells.
- Linker is a chemical compound that connects the mAb to the cytotoxic payload. It’s crucial to controlling the release of the cytotoxic payload by ensuring that it’s only released inside the cancer cell, causing the payload to remain inactive while attached.
- Cytotoxic payload is the toxic drug or molecule carried by the ADC. Once the ADC binds to the cancer cell and is internalized, the linker releases the cytotoxic payload, which induces apoptosis, or programmed cell death in the cancer cell.
What Are the Advantages and Disadvantages of Using ADCs as a Treatment?
ADCs offer several advantages over traditional chemotherapy, including targeted therapy and reduced side effects, such as hair loss or even infections. In fact, efficacy is also improved while reducing systemic toxicity and enhancing the targeted cytotoxicity.
However, ADCs also have some limitations. The complex nature of developing an ADC requires optimization of the drug-to-antibody ratio, and the conjugation of the competence of ADCs is costly and comes with stability challenges compared to traditional chemotherapy. And as with other treatments—while less common—ADCs are associated with adverse effects like skin rash, nerve damage, potential for off-target effects, and the development of resistance.
What ADC Treatment Options Are There Currently and on the Horizon?
There are currently 13 FDA-approved ADCs, one of which is approved to treat NSCLC. Fam-trastuzumab deruxtecan-nxki (T-DXd), also known as Enhertu, was the first HER2-directed therapy for patients with previously treated HER2-mutant metastatic NSCLC.
With hundreds of clinical trials evaluating various ADC therapies, here’s a few that are in phase III, some showing early promise in the treatment of NSCLC and others approved for other indications.
Agent | Target | Linker | Payload |
Datopotamab deruxtecan (Dato-DXd) | TROP2 | Cleavable tetrapeptide-based linker | Topoisomerase 1 inhibitor |
Sacituzumab govitecan-hziy (Trodelvy) | TROP2 | Hydrolyzable linker that attaches to SN-38 | Topoisomerase 1 inhibitor |
Telisotuzumab vedotin (Teliso-V) | c-MET (ABT-700) | Cleavable mc-val-cit-PABC type | Monomethyl Auristatin E (MMAE) |
Tusamitamab ravtansine, SAR408701 | carcinoembryonic antigen-related cell adhesion molecule-5 (CEACAM5) and a cytotoxic maytansinoid | Cleavable disulfide linker | DM4, maytansinoid derivative |
ADCs represent a promising approach to the treatment of NSCLC. By combining the specificity of monoclonal antibodies with the cell-killing ability of cytotoxic drugs, ADCs offer the potential for targeted therapy with reduced side effects and improved efficacy. However, the development of ADCs has faced several challenges, including identification of the key components of ADCs. But ongoing research is focused on addressing these challenges and improving the efficacy of ADCs in the treatment of NSCLC.
References:
Rosner S, Valdivia A, Hoe HJ, et al. Antibody-Drug Conjugates for Lung Cancer: Payloads and Progress. American Society of Clinical Oncology Educational Book. 2023;(43). doi:10.1200/EDBK_389968
Kondrashov A, Sapkota S, Sharma A, Riano I, Kurzrock R, Adashek JJ. Antibody-Drug Conjugates in Solid Tumor Oncology: An Effectiveness Payday with a Targeted Payload. Pharmaceutics. 2023;15(8):2160. doi:10.3390/pharmaceutics15082160
Gogia P, Ashraf H, Bhasin S, Xu Y. Antibody–Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence. Cancers. 2023;15(15):3886. doi:10.3390/cancers15153886
Centers for Disease Control and Prevention. Lung Cancer Statistics. Published June 8, 2023. Accessed November 29, 2023. https://www.cdc.gov/cancer/lung/statistics/index.htm