In recent years, with the rapid development of molecular targeting, immunotherapy, and antibody-drug conjugates (ADCs), clinical efficacy has been continuously updated, benefiting more and more cancer patients. Lung cancer treatment methods are evolving rapidly and are at the forefront of precise treatment for solid tumors. Therefore, the research progress of ADCs in the lung cancer field continues to attract industry attention. Currently, in the lung cancer field, ADC drug exploration targeting biomarkers such as TROP2, HER2, HER3, B7-H3, EGFR, and c-MET has already taken the lead. It is also worth noting that in addition to the progress of ADC monotherapy, studies on TROP2-targeted ADC drugs combined with immunotherapy are particularly abundant. Related results may further enrich the first-line treatment options for advanced non-small cell lung cancer.

What is Lung Cancer?

Lung cancer is a malignant tumor originating from lung tissue, primarily occurring in the bronchial epithelium or alveolar epithelium. It is one of the most common malignancies, accounting for about 25% of all cancer-related deaths. According to pathological subtypes, lung cancer is mainly divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), which account for 85% and 15% of lung cancer cases, respectively. The occurrence of lung cancer is typically associated with various factors, including smoking, air pollution, genetic factors, and occupational exposures (such as asbestos and radioactive substances). In its early stages, lung cancer may not show obvious symptoms. As the tumor grows, patients may experience persistent cough, chest pain, shortness of breath, and blood-tinged sputum. The treatment methods for lung cancer mainly include surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy. Different types and stages of lung cancer have different treatment plans.

Types of Lung Cancer

Clinically, lung cancer is classified into four types based on pathological characteristics: lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and small cell lung cancer. Among them, lung adenocarcinoma, squamous cell carcinoma, and large cell carcinoma are collectively referred to as non-small cell lung cancer.

• Non-Small Cell Lung Cancer

NSCLC, which accounts for about 85% of lung cancer cases, is classified into three subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, each with distinct characteristics. Lung adenocarcinoma is the most common, making up about 50% of cases, and is often treated with targeted therapies for mutations like EGFR, ALK, and KRAS. Squamous cell carcinoma, common in smokers (30% of cases), primarily affects the central lungs, grows slowly, and is less responsive to chemotherapy but can be treated with immune therapies like PD-1 inhibitors. Large cell carcinoma, accounting for around 5% of cases, is aggressive and metastatic, with limited targeted treatment options, although some studies suggest gefitinib may be effective for EGFR mutations.

• Small Cell Lung Cancer

Small cell lung cancer (SCLC) accounts for about 15% of lung cancer cases and is closely associated with smoking. Compared to the other three types of lung cancer, SCLC develops rapidly and metastasizes early. It is sensitive to radiotherapy and chemotherapy but is prone to recurrence and drug resistance. There are currently no approved targeted drugs for small cell lung cancer. SCLC has the poorest prognosis among all types of lung cancer.

Immunotherapy for Lung Cancer

In recent years, immunotherapy has become an important treatment approach for lung cancer, particularly showing significant effectiveness in advanced and metastatic lung cancer patients. The basic principle of immunotherapy is to activate the patient's immune system, enabling immune cells to recognize and attack tumor cells. Immune checkpoint inhibitors (such as PD-1 and PD-L1 inhibitors) are the core of current lung cancer immunotherapy, working by releasing the immune system's inhibition, thus activating T-cells to identify and destroy cancer cells. Common immune checkpoint inhibitors like pembrolizumab (Keytruda) and nivolumab (Opdivo) have been widely used in the treatment of NSCLC. In addition to PD-1/PD-L1 inhibitors, CTLA-4 (cytotoxic T-lymphocyte antigen 4) inhibitors, such as ipilimumab (Yervoy), have also been utilized in lung cancer immunotherapy, often in combination with PD-1 inhibitors to enhance immune response. Meanwhile, ADC, as an emerging therapeutic option, are gradually gaining attention in lung cancer treatment. ADCs combine the targeting capability of antibodies with the potent cytotoxicity of chemotherapy drugs, providing new treatment options for lung cancer patients.

Antibody-Drug Conjugate Lung Cancer

Antibody-drug conjugates (ADCs) are a class of novel anti-tumor drugs with unique mechanisms of action, consisting of highly specific and high-affinity antibodies, potent cytotoxic drugs, and stable linkers. ADCs combine the strong killing effect of traditional chemotherapy drugs with the precise targeting of antibody-based therapeutics. Mechanistically, once in the bloodstream, the antibody portion of the ADC binds to specific antigens on the surface of tumor cells, forming an ADC-antigen complex. This complex is internalized by the tumor cell, where it is broken down by lysosomes, releasing the cytotoxic drug, which damages DNA or prevents cell division, thereby killing the tumor cell. In recent years, ADCs targeting various markers have shown promising results in lung cancer clinical studies. Furthermore, the combination of immunotherapy and ADCs is becoming a new trend in lung cancer treatment, with several clinical studies showing their potential in improving patient survival and quality of life. Currently, the ADC drugs approved for clinical use in lung cancer include:

Fig. 1. Structure of ADCs (NPJ Precis Oncol. 2023, 7(1): 5).

• Trastuzumab deruxtecan (Enhertu) is a HER2-targeting ADC approved by the FDA for the treatment of HER2-positive NSCLC patients. Enhertu combines a monoclonal antibody targeting HER2 with a cytotoxic drug, effectively delivering the drug to HER2-overexpressing lung cancer cells for precise destruction. This treatment has shown excellent efficacy in patients who are not responsive to traditional chemotherapy or targeted therapies, with milder side effects compared to conventional chemotherapy.
• Sacituzumab govitecan (Trodelvy) is an ADC targeting Trop-2, approved for clinical use in the treatment of metastatic NSCLC. It combines an anti-Trop-2 monoclonal antibody with a cytotoxic drug, delivering chemotherapy specifically to Trop-2 high-expression lung cancer cells, enabling localized treatment. Research has shown that sacituzumab govitecan exhibits good efficacy in the treatment of metastatic NSCLC, particularly in patients resistant to traditional therapies, with significant improvements in response rate and survival.

ADCs for Lung Cancer

ADC Targets in Lung Cancer

In the treatment of lung cancer, ADCs are primarily applied in NSCLC patients. NSCLC is the most common type of lung cancer, accounting for approximately 85% of all lung cancer cases. Despite some progress in targeted therapies and immunotherapy for NSCLC, many patients still face issues such as poor treatment response and high relapse rates. The emergence of ADCs has provided a new breakthrough for these challenges. Currently, six major ADC drug targets are being explored in lung cancer: HER2, TROP2, HER3, c-MET, B7-H3, and CEACAM5.

• TROP2-Targeting ADCs

TROP2 is a cell surface glycoprotein that is highly expressed in various human epithelial cancers. In NSCLC, TROP2 is highly expressed in 64% of adenocarcinomas and is associated with poor prognosis, making it a potential therapeutic target for NSCLC. Recently, TROP2-targeting ADCs, such as Dato-DXd, SKB264, and enfortumab vedotin, have achieved significant breakthroughs in the treatment of lung cancer.

• Dato-DXd: This ADC combines a humanized TROP2 IgG1 monoclonal antibody with a topoisomerase I inhibitor payload, linked by a cleavable tetrapeptide linker, achieving a drug-to-antibody ratio (DAR) of 4:1. As the first Phase III study of TROP2 ADCs in lung cancer, the TROPION-Lung01 study, presented at the 2023 European Society for Medical Oncology (ESMO) conference, confirmed Dato-DXd's efficacy and safety in advanced/metastatic NSCLC patients with or without targetable genomic alterations after prior treatments.
• SKB264: In a Phase II study for locally advanced or metastatic NSCLC patients, SKB264 demonstrated preliminary anti-tumor activity and safety. In 43 patients with evaluable efficacy, the objective response rate (ORR) was 43.6%, with a median duration of response (DoR) of 9.3 months. SKB264 showed better efficacy in EGFR-mutant patients, with an ORR of 60%. However, its serious hematologic toxicities, particularly anemia and neutropenia, raised concerns.
• Enfortumab vedotin: Approved for the treatment of triple-negative breast cancer, enfortumab vedotin has also shown efficacy in lung cancer. In the I/II IMMU-132-01 basket trial, the confirmed ORR for the NSCLC subgroup was 16.7%. Common adverse events included gastrointestinal reactions, neutropenia, and diarrhea, which were frequently seen in over 50% of patients. The Phase II EVOKE-02 study, presented at the 2023 World Conference on Lung Cancer (WCLC), evaluated enfortumab vedotin plus pembrolizumab as first-line treatment for metastatic NSCLC, with an ORR of 56% and disease control rate (DCR) of 82%, though safety concerns persisted.

• HER2-Targeting ADCs

The human epidermal growth factor receptor (HER) family, also known as the ErbB family, includes four main members: HER1 (EGFR/ErbB1), HER2, HER3 (ErbB3), and HER4 (ErbB4). Overexpression or mutations of the HER family are commonly found in various tumor cells, and the activation of associated pathways leads to excessive cell proliferation, contributing to tumor development. In addition to targeted therapies, ADCs can also exhibit good anti-tumor activity by targeting the HER family.

• T-DM1 (trastuzumab emtansine): Composed of the HER2 monoclonal antibody trastuzumab and the microtubule inhibitor emtansine, linked via a non-reducible thioether bond. On average, 3.5 effective payload molecules are conjugated to each antibody. In a phase II basket trial involving 18 patients with HER2-mutated advanced NSCLC, 8 patients achieved partial response (PR), with a median progression-free survival (PFS) of 5 months. Another phase II study showed similar results, with an objective response rate (ORR) of 51% and a median PFS of 5 months in 49 HER2-mutated or amplified advanced NSCLC patients.
• T-Dxd (trastuzumab deruxtecan): Also known as DS-8201a, is a novel HER2-targeted ADC composed of trastuzumab, a cleavable linker, and the topoisomerase I inhibitor deruxtecan. T-Dxd has good membrane permeability and can kill not only HER2-positive tumor cells but also surrounding tumor cells, demonstrating a bystander effect. The DAR of T-DM1 is 3.5, while T-Dxd has a DAR of 8, meaning each trastuzumab antibody is conjugated to an average of 8 payload molecules. In a phase I clinical trial, T-Dxd showed good anti-tumor activity in HER2 gene-mutated solid tumors (except breast and gastric cancer). Recent data showed a 72.7% ORR and a median PFS of 11.3 months in 11 NSCLC patients pre-treated for HER2 mutations.
• U3-1402 (patritumab deruxtecan): An ADC targeting HER3, composed of a humanized anti-HER3 antibody and a topoisomerase I inhibitor. In a phase I dose-escalation/expansion trial of 39 patients with locally advanced/metastatic EGFR-mutant NSCLC who had progressed after EGFR-TKI therapy, the ORR was 39%, and the disease control rate (DCR) was 72%.
• A166: An HER2-targeted ADC linked to a microtubule inhibitor via a cleavable linker to trastuzumab. A phase I/II clinical trial evaluating A166 in 35 patients with advanced, refractory HER2-positive or amplified solid tumors showed an ORR of 26%. The study is ongoing, with further results expected. Common adverse reactions included keratitis, dry eye, blurred vision, and appetite loss.
• MRG003: A novel EGFR-targeted ADC, which has shown encouraging preliminary efficacy in phase I trials for other solid tumors. A phase II clinical study in China aims to evaluate MRG003 for advanced EGFR-mutant NSCLC, and it is expected to become China's first anti-EGFR ADC.

• c-Met-Targeting ADCs

The c-Met protein, encoded by the mesenchymal-epithelial transition (Met) gene, is a tyrosine kinase receptor expressed on epithelial and endothelial cells. Upon activation, c-Met promotes cell proliferation, growth, migration, and angiogenesis. In NSCLC, abnormal activation of the c-Met pathway is primarily due to mutations in the Met14 exon, Met amplification, Met fusion, or overexpression. Targeted therapies have shown good anti-tumor activity in cases of Met14 exon skipping mutations, though no standard treatment exists for Met amplification.

• ABBV-399 (telisotuzumab vedotin): An ADC composed of a microtubule inhibitor (monomethyl auristatin E, MMAE) conjugated to a humanized anti-c-Met monoclonal antibody via a cleavable linker. A phase I study in 58 advanced c-Met-positive NSCLC patients showed an ORR of 18.8%, a median duration of response (DoR) of 4.8 months, and a median PFS of 5.7 months.
• ABBV-400 (Telisotuzumab adizutecan): A phase I study presented at the 2024 ESMO conference showed preliminary results with an ORR of 48% in EGFR wild-type NSCLC, with better efficacy in c-Met high-expressing populations.

• DLL3-Targeting ADCs

Delta-like protein 3 (DLL3) is a Notch signaling pathway inhibitor, involved in various growth and developmental processes. DLL3 is highly expressed in SCLC and neuroendocrine cells, making it a promising target for treatment.

• Rova-T (rovalpituzumab tesirine): An ADC targeting DLL3, composed of an anti-DLL3 monoclonal antibody, a DNA-damaging pyrrolo[2,1-c][1,4]benzodiazepine dimer toxin, and a cleavable linker. A phase I clinical study involving 74 patients with recurrent SCLC treated with Rova-T showed an ORR of 18%, a median PFS of 3.1 months, and a median overall survival (OS) of 4.6 months.

• AXL-Targeting ADCs

AXL is a receptor tyrosine kinase involved in tumor progression and chemoresistance. Its activation is associated with resistance to EGFR-targeted therapies and poor survival in advanced NSCLC, making it an attractive target for anti-tumor therapies.

• Enav (enapotamab vedotin): An ADC targeting AXL, composed of an anti-AXL monoclonal antibody conjugated to a microtubule inhibitor (MMAE) via a cleavable linker. A phase I/II study in 26 EGFR/ALK-negative, chemotherapy- or immunotherapy-resistant NSCLC patients showed an ORR of 19% and a median DoR of 18.1 months, indicating potential efficacy in immunotherapy-resistant patients. Common grade 3 or higher adverse reactions included gastrointestinal issues such as constipation, colitis, diarrhea, nausea, and vomiting. However, further development was halted due to its modest efficacy.
• BA3011: Another ADC targeting AXL, composed of an anti-AXL monoclonal antibody, a cleavable linker, and a microtubule inhibitor (MMAE). Phase I clinical trials in advanced solid tumors and a phase II study combining BA3011 with PD-1 inhibitors are ongoing, with results pending.

• Other Targeted ADCs

• B7-H3 (CD276): A member of the B7 superfamily and a recently discovered immune checkpoint, B7-H3 is overexpressed in 65% of SCLC cases, making it a potential therapeutic target. The I-DXd study in extensive-stage SCLC (ES-SCLC) patients showed a 54.8% ORR with a 12 mg/kg dose.
• CEACAM5: Overexpressed in most malignant tumors and associated with tumor progression and metastasis. SAR-408701 is an ADC targeting CEACAM5, and the phase III CARMEN-LC03 study showed no significant improvement in PFS and OS compared to docetaxel in platinum-resistant advanced non-squamous NSCLC patients.
• IB6: An adhesion molecule associated with poor prognosis. Sigvotatug vedotin (SV, SGN-B6A) targets IB6. A phase I study presented at ASCO 2024 showed promising anti-tumor activity and manageable safety in NSCLC patients.

In Conclusion

The advent of ADCs marks a shift towards more precise cancer therapies. HER2-targeted ADC T-DXd has made significant breakthroughs in treating HER2-mutant advanced NSCLC, opening the era of ADC treatment for this subtype. TROP2-targeted ADCs have also achieved notable progress, providing additional evidence for their use in advanced NSCLC. ADCs targeting HER3, MET, B7-H3, and other biomarkers also show promising early anti-tumor activity and safety. Furthermore, combining ADCs with immunotherapy, chemotherapy, and anti-angiogenesis agents holds great potential, as demonstrated in early studies.

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