Dato-DXd is an antibody-coupled drug (ADC) targeting TROP2. According to WCLC 2021 and ESMO 2021, Dato-DXd treatment of non-small cell lung cancer and NSCLC with abnormal driving genes has an objective response rate of 30 About %, hematological toxicity is less, and interstitial lung disease is an adverse reaction that needs attention.
TROP2, an emerging pan-tumor species target
TROP2 is a cell surface glycoprotein encoded and expressed by the TACSTD2 gene, also known as tumor-associated calcium signal transducer 2 (TACSTD2). Previous studies have shown that it has different levels of expression in human healthy tissues, with the highest expression levels being the epithelial tissues of breast, kidney, and pancreas. Regardless of the expression level of TROP2 in healthy tissues, its expression level in a variety of tumors will be significantly increased, including breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, prostate cancer, and cervical cancer Cancer, head and neck cancer and ovarian cancer etc. The high expression of TROP2 plays a key role in tumor growth and is also associated with more aggressive diseases and poor prognosis. In lung cancer, the expression of adenocarcinoma , squamous cell carcinoma or small cell lung cancer TROP2 is elevated.
Because TROP2 is widely expressed in a variety of solid tumors and is a protein on the cell surface that can be effectively recognized by the antibody , it has become one of the popular targets for ADC development.ADCs targeting TROP2 have the potential to treat a variety of cancer types.
Daiichi Sankyo’s unusual ADC technology
Antibody Coupling (ADC) drugs generally combine monoclonal antibodies with chemotherapeutic drugs, and chemotherapeutic drugs can be accurately delivered to specific expressions through monoclonal antibodies The protein inside the tumor cell is called "magic bullet".
Dato-DXd (DS-1062) was developed by Daiichi Sankyo, Japan. It is a combination of a monoclonal antibody targeting TROP2 and an innovative DNA topoisomerase I inhibitor-Drutecan (DXd). As a result, DXd has a unique mechanism of action. Compared with the common chemotherapy drug irinotecan, the activity is increased by 10 times. DXd has a strong ability to penetrate cell membranes, allowing them to kill tumor cells that have swallowed ADC, but also to kill nearby tumor cells, creating a "bystander effect".
Dato-DXd A single monoclonal antibody can carry four DXd, ensuring safety with a low carrying amount. In terms of linkers, the linker of Dato-DXd can be specifically cleaved by lysosomal proteases that are highly expressed in tumors, making it easier to release DXd in tumors.
Dato-DXd treatment of treated NSCLC objective response rate of 28%
WCLC 2021 reported the NSCLC cohort data in the phase I study of Dato-DXd treatment of solid tumors. The study included 180 cases of treated NSCLC who received three different doses of Dato-DXd. 74%-88% of patients have received immunotherapy, 96%-98% of patients have received platinum-containing chemotherapy, 82%-90% of patients have non-squamous cell carcinoma, 14%-19% of patients have EGFR mutations, 34 %-41% of patients have brain metastases.
Figure 1 Baseline characteristics and drug exposure of treated NSCLC patients
The objective response rate (ORR) of patients in different dose groups exceeded 20%, of which the recommended dose of 6mg/kg group The ORR reached 28%, the median duration of remission was 10.5 months, and 40% of patients had stable disease.
Figure 2 NSCLC efficacy and duration of tumor remission in different dose groups
In terms of safety, 54% of patients in the 6mg/kg group had ≥ grade 3 adverse reactions, 48 % Of patients had serious adverse reactions, 26% of patients had ≥3 grade drug-related adverse reactions, 14% of patients discontinued treatment due to adverse reactions, 30% of patients suspended treatment due to adverse reactions, and 10% Of patients have reduced dosage due to adverse reactions.
It is worth noting that 6% of the patients in the 6mg/kg group developed drug-related interstitial lung disease (ILD), 4% were grade ≤2, and 2% were grade 3-4 . In the 8mg/kg group, 4% of patients died of drug-related ILD .
Adverse reactions observed during treatment in ≥30% of patients include (all grades, ≥3 grades) : nausea (52%,1%), stomatitis (48%, 2%), hair loss (39%, 0%) and fatigue (32%, 1%) . Compared with another ADC drug targeting TROP2, decreased neutrophil count/neutropenia (6%, 1%) and diarrhea (16%, 0%) occurred during Dato-DXd treatment The rate is low .
Figure 3 Safety summary of NSCLC patients
Dato-DXd treatment driver gene abnormal NSCLC ORR 35%
ESMO treatment of solid tumors in the Dato-DXd phase 2021 report Data on treated NSCLC patients with driver gene abnormalities. 34 patients have reported driver gene abnormalities, including EGFR mutation (85%), ALK fusion (9%), ROS1 fusion and RET fusion each 3% .
41% of patients had previously received immunotherapy, 91% of patients had received platinum-containing chemotherapy, 85% of patients had received TKI targeted therapy, and 69% of had received osimertinib treatment .
Figure 4 Baseline characteristics and drug exposure of patients with driver gene abnormalities
The ORR of 34 patients was 35%, the median duration of remission was 9.5 months, and 41% of patients had stable disease. All kinds of EGFR mutations, including 20ins, T790M and patients who have received osimertinib treatment have partial remission cases. One patient with ALK fusion had partial remission.
Figure 5 The efficacy of different mutation types
The safety of patients with abnormal driving genes receiving Dato-DXd is similar to that of NSCLC patients.The most common adverse reactions of any grade are nausea (62%) and stomatitis (56%). Hematological toxicity is uncommon. Most patients who received osimertinib treatment did not seem to increase the incidence of ILD. Only one patient with developed drug-related ILD at a dose of 8mg/kg, and the patient died (Grade 5) .
Figure 6 Summary of the safety of driver gene abnormalities
In general, Dato-DXd has a definite effect in NSCLC that has received multiple lines of therapy, regardless of whether there is driver gene abnormality. The adverse reactions can be tolerated, has less hematological toxicity, which is friendly to patients who have received platinum-containing chemotherapy, but interstitial lung disease needs attention, especially the 8mg/kg dose Fatal ILD event. ILD seems to be related to the Drunotecan carried by Dato-DXd, and T-DXd, the ADC drug targeting HER2 with Drunotecan, also has more drug-related ILD events.
Dato-DXd has moderate efficacy in the treatment of treated NSCLC. Previous studies of different targeted TROP2 ADC drugs have shown that the expression of TROP2 has nothing to do with the efficacy , and it is still necessary to continue to explore biomarkers for predicting efficacy.
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