Dr. Akshaya Keerti on Datopotamab Deruxtecan’s Promise in the TROPION-Lung01 Trial

Akshaya Keerti, International Council Deputy Director at Federation of Medical Students Association, shared on LinkedIn:

“Revolutionizing Lung Cancer Treatment: Datopotamab Deruxtecan’s Promise in the TROPION-Lung01 Trial

Nearly 2.5 million lung cancer cases were diagnosed globally in 2022. Non-Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer, accounting for about 80% of cases. Approximately 75% and 25% of NSCLC tumours are of nonsquamous or squamous histology, respectively. While immunotherapy and targeted therapies have improved outcomes in the 1st-line setting, most patients eventually experience disease progression and receive chemotherapy. For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC, despite limited effectiveness and known side effects.

What is TROP2?

TROP2, short for “trophoblast cell surface antigen 2,” is a protein found on the surface of certain cells, including some epithelial cells. In cancer, TROP2 levels are often abnormally high, especially in cancers like breast, lung, and pancreatic cancers. This overexpression helps tumours grow and spread by promoting cell division and survival.

Researchers are interested in TROP2 because targeting it with specific drugs could help stop cancer cells from growing. Treatments like antibody-drug conjugates (ADCs) are being developed to bind to TROP2 and deliver cancer-killing agents directly to the tumour cells, potentially leading to more effective and less toxic cancer therapies.

TROP2 is a protein broadly expressed in the majority of NSCLC tumours. There is currently no TROP2-directed ADC approved for lung cancer treatment.

What is Datopotamab Deruxtecan?

Datopotamab Deruxtecan (Dato-DXd) is a promising new drug in the field of oncology, particularly in the treatment of solid tumours. It is an antibody-drug conjugate (ADC), a type of targeted cancer therapy that combines an antibody with a potent chemotherapy drug.

Here’s a detailed overview of Datopotamab Deruxtecan:

Mechanism of Action

1. Antibody Component: The antibody part of Datopotamab Deruxtecan specifically targets TROP2, a protein frequently overexpressed on the surface of various cancer cells. This targeting ensures the drug is delivered primarily to cancer cells, sparing most normal cells.

2. Chemotherapy Component: The payload, Deruxtecan, is a powerful cytotoxic agent. Once the ADC binds to TROP2 on the cancer cell surface, it is internalised into the cell. Inside the cell, the chemotherapy drug is released, causing DNA damage and leading to cell death.

What is the TROPION-Lung01 Phase III trial?

The TROPION-Lung 01 Phase 3 trial is a crucial clinical study evaluating the efficacy and safety of Datopotamab Deruxtecan (Dato-DXd) in patients with advanced or metastatic non-small cell lung cancer (NSCLC). This trial specifically targets patients whose tumors express TROP2 and who have previously been treated with standard therapies but experienced disease progression.

Objective:

The primary objective of the TROPION-Lung 01 trial is to assess the overall survival (OS) and progression-free survival (PFS) of patients treated with Datopotamab Deruxtecan compared to standard chemotherapy. Secondary objectives include evaluating the overall response rate (ORR), duration of response (DoR), and safety profile of the drug.

Participants:

The trial enrolls patients with advanced or metastatic NSCLC who have failed at least one prior line of systemic therapy, including platinum-based chemotherapy and/or immune checkpoint inhibitors. All participants must have tumors that test positive for TROP2 expression.

Methodology:

– Randomization: Patients are randomly assigned to receive either Datopotamab Deruxtecan or the physician’s choice of standard chemotherapy.

– Blinding: The trial is conducted in an open-label fashion, meaning both the researchers and participants know which treatment is being administered.

– Endpoints: The primary endpoints are overall survival (OS) and progression-free survival (PFS). Secondary endpoints include overall response rate (ORR), duration of response (DoR), and safety/tolerability measures.

Interim Results and Significance

While the final results of the TROPION-Lung 01 trial are pending, interim analyses have shown promising trends. Datopotamab Deruxtecan has demonstrated significant tumor shrinkage and disease control in a substantial number of patients. Key observations include:

1. Improved Survival Rates:

Early data suggest that patients receiving Dato-DXd may have longer overall survival (OS) and progression-free survival (PFS) compared to those receiving standard chemotherapy.

2. Response Rates:

The overall response rate (ORR) has been favorable, with many patients experiencing partial or complete tumor reduction.

3. Manageable Side Effects:

The safety profile of Datopotamab Deruxtecan appears consistent with other ADCs, with common side effects including nausea, fatigue, and hematologic toxicities. Importantly, interstitial lung disease (ILD), a serious potential side effect, is being closely monitored and managed.

Implications for Lung Cancer Treatment

The TROPION-Lung 01 trial holds significant implications for the treatment landscape of advanced NSCLC:

1. New Therapeutic Option:

If Datopotamab Deruxtecan continues to show positive results, it could become a new standard of care for patients with TROP2-expressing NSCLC who have exhausted other treatment options.

2. Targeted Therapy Advantage:

By specifically targeting TROP2, Dato-DXd offers a precision medicine approach, potentially leading to more effective and less toxic treatments.

3. Hope for Refractory Cases:

For patients whose cancers have not responded to existing therapies, Datopotamab Deruxtecan provides new hope for better outcomes.

In the overall trial population, survival results numerically favoured AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan but did not reach statistical significance

TROPION-Lung01 previously met the dual primary endpoint of progression-free survival in the overall trial population

Results support applications currently under review by regulatory authorities globally including in the US and EU

Conclusion

The TROPION-Lung 01 Phase 3 trial is a pivotal study in the ongoing development of Datopotamab Deruxtecan for the treatment of advanced non-small cell lung cancer. With its targeted mechanism of action and encouraging interim results, this trial represents a significant step forward in providing new therapeutic options for patients with limited alternatives. As the study progresses, it has the potential to reshape the standard of care for TROP2-expressing NSCLC and improve survival rates and quality of life for many patients.”

Source: Akshaya Keerti/LinkedIn