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Release date:2022/3/14 10:45:01

Despite the rapid progress of targeted therapy in the field of NSCLC (non-small cell lung cancer), there are still unmet needs. This article summarizes the latest progress in the targeted therapy of Her2, Her3 and Trop-2 in NSCLC.

1. The NSCLC and ADC  

Few lung cancer patients benefit from targeted therapy or immunotherapy, and most lung cancer patients still develop acquired drug resistance. Therefore, research on alternative treatment means is extremely important. In recent years, with the rapid development of ADC (Antibody-drug Conjugates), it has also shown good efficacy in the field of lung cancer, mainly involving targets including Her2, Her3, TROP-2, etc.  

 Schematic diagram of the structure of ADC

Figure 1 Schematic diagram of the structure of ADC

2. HER2 ADC

In the field of lung cancer, the ADC drugs under research, HER2 (human epidermal growth factor receptor 2, also known as ERBB2) target is the most.

HER2 ADC also dominates the entire development of ADC drugs, but Her2 mutations are mainly concentrated in the field of breast cancer and gastric cancer. The mutation rate of lung cancer is low, and research progress is naturally slow. However, HER2 mutations are closely related to increased disease recurrence and poor prognosis. The clinical treatment of these patients is also difficult and worth studying.

According to statistics, about 3% of NSCLC patients have HER2 mutations, of which 90% are exon 20 mutations, as shown in the figure below.

 Schematic diagram of HER2

Figure 2 Schematic diagram of HER2

Among the ADC drugs targeted Her 2, the fastest progress is T-DM1 and DS-8201 (T-DXd).

>> T-DM1

T-DM1 is an ADC drug from Roche with a drug antibody ratio (DAR) of 3.5. Trastuzumab, a monoclonal antibody that targets HER2, was selected for the antibody. The linked chemotherapy drug is Maitansine which inhibits microtubule aggregation. The side effects of Maitansine are so severe that it is almost no longer used in clinic. However, through the design of ADC drug molecules, an antibody-coupling structure is formed, which can be locally released on tumor cells, which can exert a good anti-cancer effect and effectively reduce toxicity. At present, it has become the standard regimen for second-line treatment of HER2-positive breast cancer.

In lung cancer, a Phase II basket trial of T-DM1 in patients with HER2 mutant lung cancer has been conducted in 18 patients with metastatic HER2 mutant lung adenocarcinoma, half of whom had previously received HER2-targeted therapy. The end result was encouraging:   

· The response rate of patients to T-DM1 was ~44%, which was all partial response;  
· The response time point of T-DM1 was 1-4 months, and the longest progression-free survival after response was >11 months.  

 Phase II results of T-DM1 lung cancer

Figure 3 Phase II results of T-DM1 lung cancer

This is the first clinical trial with positive results in a molecular subset of HER2-positive lung cancer.

>> DS-8201 (T-DXd)

With the further optimization of ADC technology, the research momentum of DS-8201 (T-DXd) developed by AstraZeneca/Daiichi Sankyo has overshadowed T-DM1 in recent years. In the latest version of NCCN breast cancer guidelines, the recommendation level of DS-8201 in the field of HER2-positive breast cancer is already higher than that of T-DM1. How is the progress in the field of HER2-positive lung cancer?

 Schematic diagram of the structure of T-DXd

Figure 4 Schematic diagram of the structure of T-DXd

DESTINY Lung01 is a phase II study of T-DXd in patients with Her2 mutant lung cancer. Among 42 patients enrolled, ORR was 62% (26/42) and median PFS was 14 months. On May 18, 2020, the FDA awarded T-DXd a breakthrough therapy for patients with metastatic Her2 mutated NSCLC based on its proven efficacy.

Whether it is T-DM1 or DS-8201, it has been confirmed that the effect of Her2-targeted ADC on HER2-positive lung cancer patients exists. Does the HER3 target also benefit?

3. HER3 ADC

It is worth mentioning that HER2 is a mature target for tumor therapy. So far, no ligand has been found in human body that can directly bind HER2. HER2 must form homologous or heterologous dimer with other members of the family (such as HER3). HER2 changes its conformation after dimerization, activates intracellular tyrosine kinase activity, and then reactivates downstream pathway nodes (MAPK signaling pathway and PI3K/AKT signaling pathway) to play a corresponding physiological role. In addition, HER3 is expressed in the gastrointestinal tract, reproductive system, skin, nervous system, urinary tract and endocrine system of normal adults, and overexpression of HER3 protein is associated with many cancers, including prostate cancer, bladder cancer, and breast cancer.

 HER2 HER3 heterodimer

Figure 5 HER2/HER3 heterodimer activates related downstream signaling pathways

Based on this, many R&D institutions have also shifted their attention from the highly competitive HER2 to HER3, hoping that this target of the same family as HER2 can also be used as a new target for tumor therapy. HER3 is expressed in 83% of NSCLC tumors, and HER3 overexpression is associated with metastatic progression and reduced recurrence-free survival in NSCLC patients, and is associated with multiple EGFR-TKI resistance mechanisms. Therefore, if the HER3 target can make a breakthrough in the field of lung cancer, the prospects will be unlimited.

The most rapidly progressing target is the HER3-DXd developed by Daiichi Sankyo, whose Phase I clinical study in the field of lung cancer included patients with advanced NSCLC who had previously received EGFR-TKI treatment. Fifty-seven patients received HER3-DXd at 5.6 mg/kg every 3 weeks. The ORR of these patients was 39%, the median duration of response (DOR) was 6.9 months, the median follow-up period was 10.2 months, and the median PFS was 8.2 months. Treatment responses were observed in patients with different mechanisms of resistance.  

 Schematic diagram of the structure of HER3-DXd

Figure 6 Schematic diagram of the structure of HER3-DXd

In addition to lung cancer, the exploration of HER3-DXd in breast cancer and colorectal cancer is also ongoing, which is expected.  

4. TROP-2 ADC

In recent years, the research interest of Trop2 (human trophoblast surface glycoprotein antigen 2) has also continued to increase. It is an important tumor development factor. It is highly expressed in a variety of tumors, such as breast cancer, gastric cancer, non-small cell lung cancer, small cell lung cancer, colon cancer, pancreatic cancer, etc. It can promote the process of tumor cell proliferation, invasion, metastasis and spread. Its high expression is closely related to the shortened survival time and poor prognosis of tumor patients. Therefore, it is of great significance to study anti-tumor drugs targeting Trop2.  

The most rapidly progressing Trop2--ADC drug is DS-1062, also developed by Daiichi Sankyo. DS-1062 links a humanized monoclonal antibody targeting the tumor cell surface specific antigen TROP2 to a novel topoisomerase 1 inhibitor exatecan derivative (DX-8951 derivative, DXd) via a 4-peptide linker together. DXd is an innovative DNA topoisomerase I inhibitor with ten times the activity of irinotecan (SN-38), which interferes with DNA replication, recombination and gene expression.

ADC drugs, in addition to the expansion of HER2, HER3, and TROP-2 targets, ADC drugs targeting TF (tissue factor) have also been used clinically.

 Schematic diagram of the structure of DS-1062

Figure 7 Schematic diagram of the structure of DS-1062

5. Targeted tissue factor ADC

On September 20, 2021, Seattle Genetics (Seagen) and Genmab A/S announced that their investigational Tisotumab vedotin received accelerated FDA approval for the treatment of recurrent or metastatic cervical cancer, becoming the first TF (tissue factor) targeted cervical cancer drug. It is the 12th ADC drug to be approved worldwide.

 Mechanism of action of Tisotumab vedotin

Figure 8 Mechanism of action of Tisotumab vedotin

Tisotumab vedotin is a novel ADC drug that contains monoclonal antibody portions targeting tissue factor (TF) and monomethyl auristatin E (MMAE). TF is abnormally expressed in a variety of solid tumors. Tisotumab vedotin can promote tumor growth, angiogenesis and accelerate tumor metastasis. After binding and internalization with TF on the surface of tumor cells, tisotumab vedotin can release MMAE to induce cytotoxicity, thus effectively killing tumor cells, showing a very good therapeutic effect in the field of cervical cancer.  Currently, the research layout is being carried out in many solid tumor fields including NSCLC, expecting to bring benefits to more patients.  

Conclusion  

Although targeted therapy and immunotherapy-based strategies have become the first-line standard of care for patients with advanced lung cancer, acquired drug resistance and disease progression remain inevitable in most cases. In such cases, chemotherapy is a common salvage option, with unsatisfactory toxicity and therapeutic efficacy. The advent of the ADC offers an attractive alternative. ADC combines the specificity of monoclonal antibodies with the cytotoxic effects of chemotherapy to facilitate directly targeted delivery of cytotoxic payloads to cancer cells. But we should not relax the consideration of its toxicity while focusing on its efficacy.  

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References:
[1] Reuss JE et al.
Clinical Lung Cancer, Vol. 22, No. 6, 483–499.
[2] Mishra, Rosalin,et al. "
HER3 signaling and targeted therapy in cancer." Oncologyreviews 12.1 (2018).
[3] Mujoo, Kalpana,et al. "
Regulation of ERBB3/HER3 signaling in cancer." Oncotarget5.21 (2014): 10222.

Related articles:
[1]
The Rise of the TROP2-Directed ADCs for Solid Tumors
[2] FDA Approves Tivdak - First Tissue Factor (TF)-Targeted Antibody Conjugate Drug (ADC)
[3] Global Antibody-drug Conjugates (ADCs): Approvals & Clinical Trails Review
[4] Progresses Of ADC Technology For Cancer Therapy
[5] ADCs for Clinical Research in the Global Market
[6] FDA Approved Antibody-Drug Conjugates (ADCs) Up To 2022

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