Recently, the FDA officially approved Datroway (datopotamab deruxtecan, Dato-DXd), an innovative antibody-drug conjugate developed by AstraZeneca and Daiichi Sankyo, for the treatment of unresectable or metastatic hormone receptor (HR)-positive, HER2-negative adult breast cancer patients who have received endocrine therapy and chemotherapy. The key basis for the approval of Dato-DXd

for breast cancer indications

was the positive results of its Phase III clinical study TROPION-Breast01.

In the TROPION-Breast01 study, Dato-DXd showed efficacy advantages. Compared with the standard therapy selected by the researchers, the drug successfully reduced the risk of disease progression or death in patients by 37%. This data means that in patients treated with Dato-DXd, the rate of disease deterioration has slowed significantly, giving patients more survival time and treatment opportunities. Specifically, progression-free survival (mPFS) was significantly extended from 4.9 months in the control group to 6.9 months in the trial group. In terms of safety assessment, a key concern of TROP-2 ADC drugs is the incidence of interstitial lung disease (ILD). Clinical data show that the incidence of ILD is about 4.2%, which is relatively low.

It is worth noting that in September 2024, AstraZeneca announced that the Phase III clinical TROPION-Breast01 did not reach the primary endpoint of OS.

In addition to Dato-DX of Daiichi Sankyo, there are currently two ADC drugs approved for TROP-2. One is Gilead's Trodelvy, which has shown significant potential in the treatment of breast cancer. On April 22, 2020, this innovative drug was approved by the FDA for accelerated approval for adult patients with metastatic triple-negative breast cancer (mTNBC) who have undergone at least two different treatment options but have not been able to control their disease. Subsequently, on February 3, 2023, Trodelvy once again ushered in a milestone progress. The US FDA expanded its indications and approved it for the treatment of HR-positive/HER2-negative metastatic breast cancer patients who have received multiple previous treatments and whose disease is still progressing. This decision further consolidates Trodelvy's position in the field of breast cancer treatment and provides patients with more diversified treatment options.

At the same time, Kelun Biotech's independently developed Rukang Satuzumab (SKB264) also demonstrated its impressive strength. This TROP-2 ADC drug was approved for marketing by NMPA on November 27, 2024. It is mainly aimed at adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received at least two systemic treatments (at least one of which is for the advanced or metastatic stage) but have not effectively controlled the disease.

The successive approval of these three TROP-2 ADC drugs not only enriches the treatment methods for malignant tumors such as breast cancer, but also provides patients with more personalized treatment options.

Challenge lung cancer

Although Dato-DXd has made breakthroughs in the field of breast cancer treatment, the journey of lung cancer treatment is full of challenges and setbacks. Lung cancer is a highly heterogeneous disease, and tumor cells have huge differences in gene expression, biological behavior, etc. Lung cancer cells from different patients respond very differently to drugs, which requires the developed drugs to be highly adaptable and targeted. In addition, the microenvironment of lung cancer is extremely complex, filled with various cytokines, immune cells, etc., which form a complex network of interactions with tumor cells. These factors are intertwined, making drug research and development work face huge challenges.

Previously, in the field of non-small cell lung cancer treatment, Dato-DXd's biologics license application (BLA) went through a very tortuous process. First, the BLA was withdrawn, and there were many complex factors behind it. The results of the clinical data evaluation aroused the concerns of the regulatory authorities. Some data were uncertain or incomplete, and further in-depth analysis and verification were required. At the same time, the EU's non-small cell lung cancer marketing application was also withdrawn, which undoubtedly dealt a heavy blow to the advancement of new drugs in the field of lung cancer and put it in a more difficult situation.

When ImmunoGen was developing ADC drugs targeting Trop2, it also encountered bottlenecks in the advancement of lung cancer indications due to unsatisfactory clinical trial results. The drugs it developed failed to achieve the expected efficacy endpoints in clinical trials, which not only hindered the progress of research and development, but also put the company under tremendous pressure, requiring it to re-examine its research and development strategy and adjust drug design or clinical trial plans. Gilead's Trodelvy is also a typical case. It also suffered a Waterloo in the face of lung cancer indications. Its failure further exacerbated the complexity and uncertainty of competition in this field.

Despite the difficulties, many companies are still actively deploying Trop2 ADC pipelines in the field of lung cancer. Kelun Biotech is one of them. Its developed Lukang Satuzumab has not only been approved for marketing in China, but also won the breakthrough therapy certification for EGFR mutation NSCLC in the United States. At present, Kelun Biotech is working closely with Merck to launch 10 global Phase III clinical trials, committed to verifying the effectiveness and safety of drugs in the treatment of lung cancer and further expanding the indications of drugs.

Although Trop2 ADC has suffered setbacks in the field of lung cancer treatment, its story is far from over.

Trop2 ADC is in full swing

in the highly potential and challenging field of Trop2 ADC. A series of breakthrough battles are in full swing. Major pharmaceutical companies have made efforts to form a situation of competition. In this competition, companies such as Gilead, Kelun Biotech, AstraZeneca/Daiichi Sankyo have become leaders in the industry with their strong R&D capabilities and rich pipeline layout. Gilead has taken the lead in gaining a foothold in the market with its first Trop2 ADC drug Trodelvy.

In addition, many domestic companies are also actively deploying in the Trop2 ADC field. Fudan Zhangjiang's FDA018, Shijian Bio's ESG-401, and Hengrui Medicine's SHR-A1921 have all entered the Phase 3 clinical trial stage, respectively targeting solid tumors such as triple-negative breast cancer, bladder cancer, lung cancer, colorectal cancer, and solid tumors such as breast cancer. As ADC types, these drugs have demonstrated great potential in the field of tumor treatment.

There are also several TROP2-targeted ADCs in Phase 2 clinical trials, including Legochem Biosciences' LCB-84, Baili Pharmaceuticals' BL-M02D1, Bio-Care Pharmaceuticals' BI0-106, Maiwei Bio's 9MW2921, and Bio-Atla's BAT-8008, all of which target different types of solid tumors.

Overall, the competition in the Trop2 ADC field is extremely fierce. Major companies have increased their R&D investment and accelerated the process of launching new drugs in order to gain a foothold in the market.

Conclusion

The successful approval of breast cancer treatment and the difficult exploration of other cancer treatments such as lung cancer in the Trop2 ADC field have fully demonstrated the complexity, uncertainty and huge potential of biopharmaceutical research and development. Overall, the global competition for the development of TROP2-targeted ADCs is becoming increasingly fierce, and many drugs have shown good efficacy and safety in clinical trials at different stages. In the future, with the approval of more drugs, Trop2 ADC is expected to become an important force in the field of tumor treatment.

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