Novel computational pathology-based TROP2 biomarker for datopotamab deruxtecan was predictive of clinical outcomes in patients with non-small cell lung cancer in TROPION-Lung01 Phase III trial
These results will be featured in a Presidential Symposium (PL02.11) at the IASLC 2024
TROP2 is a protein broadly expressed in NSCLC on the surface of and inside tumor cells.1,2 When assessed using conventional immunohistochemistry (IHC)-based pathology, TROP2 expression has not been predictive of patient responses to TROP2-directed antibody drug conjugates (ADC).3,4 QCS is a fully supervised computational pathology platform, developed by
Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd ADC discovered by Daiichi Sankyo and being jointly developed by
In this analysis, QCS was used to analyze tissue samples collected from patients in TROPION-Lung01. This produced a normalized membrane ratio for each tumor cell in each sample. Patients’ tumors were considered TROP2-QCS biomarker positive if the majority (≥75%) of tumor cells exhibited a ratio below a predetermined value (≤0.56), indicating a greater proportion of TROP2 in the cytoplasm.
The analysis showed a greater proportion of patients with nonsquamous NSCLC were considered TROP2-QCS biomarker positive than those with squamous NSCLC (66% vs. 44%, respectively). The threshold for biomarker positivity was optimized for progression-free survival (PFS) in the subgroup of patients with nonsquamous NSCLC without actionable genomic alterations because it represents a population with significant unmet medical need and without actionable biomarkers.
In patients with TROP2-QCS biomarker positive tumors (60% of the biomarker evaluable population including patients with nonsquamous and squamous NSCLC), datopotamab deruxtecan reduced the risk of disease progression or death by 43% versus docetaxel (median PFS of 6.9 vs. 4.1 months; hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.41-0.79).
By comparison, in the primary analysis of the overall trial population, datopotamab deruxtecan reduced the risk of disease progression or death by 25% versus docetaxel (PFS of 4.4 vs. 3.7 months; HR 0.75; 95% CI 0.62-0.91; p=0.004) as presented at the 2023
In the subgroup of patients with nonsquamous NSCLC without actionable genomic alterations and with TROP2-QCS biomarker positive tumors, datopotamab deruxtecan reduced the risk of disease progression or death by 48% (PFS of 7.2 vs. 4.1 months; HR 0.52; 95% CI 0.35-0.78).
In the biomarker evaluable population, no new safety concerns were identified and rates of Grade 3 or higher treatment-related adverse events (TRAE) were similar regardless of TROP2 status. In patients with TROP2-QCS biomarker positive tumors, Grade 3 or higher TRAEs occurred in 30% and 46% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. The most common Grade 3 or higher TRAEs were stomatitis (7%, 3%) and ocular surface events (3%, 0%). Grade 3 or higher adjudicated drug-related interstitial lung disease events occurred in 3% and 1% of patients in the datopotamab deruxtecan and docetaxel arms, respectively.
Summary of TROPION-Lung01 QCS analysis results
Overall biomarker evaluable population (n=352) |
||||
|
TROP2-QCS biomarker positive |
TROP2-QCS biomarker negative |
||
|
Dato-DXd (n=107) |
Docetaxel (n=107) |
Dato-DXd (n=65) |
Docetaxel (n=73) |
Median PFS |
6.9 months |
4.1 months |
2.9 months |
4.0 months |
HR (95% CI) |
0.57 (0.41-0.79) |
1.16 (0.79-1.70) |
||
ORR |
32.7% |
10.3% |
16.9% |
15.1% |
Nonsquamous histology without actionable genomic alterations subgroup (n=221) |
||||
|
Dato-DXd (n=68) |
Docetaxel (n=72) |
Dato-DXd (n=40) |
Docetaxel (n=41) |
Median PFS |
7.2 months |
4.1 months |
4.0 months |
4.4 months |
HR (95% CI) |
0.52 (0.35-0.78) |
1.22 (0.74-2.00) |
||
ORR |
36.8% |
15.3% |
22.5% |
12.2% |
CI, confidence interval; HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival
Under this expanded collaboration,
As the leading provider of pathology lab solutions,
Notes
Advanced non-small cell lung cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.6 NSCLC is the most common type of lung cancer, accounting for about 80% of cases.7 Approximately 75% and 25% of NSCLC tumors are of nonsquamous or squamous histology, respectively.8 While immunotherapy and targeted therapies have improved outcomes in the 1st-line metastatic setting, most patients eventually experience disease progression and receive chemotherapy.9-11 For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC, despite limited effectiveness and known side effects.9-11
TROP2 is a protein broadly expressed in the majority of NSCLC tumors.1 There is currently no TROP2-directed ADC approved for the treatment of lung cancer.12,13
TROPION-Lung01
TROPION-Lung01 is a global, randomized, multicenter, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0mg/kg) versus docetaxel (75mg/m2) in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations
The dual primary endpoints of TROPION-Lung01 are PFS as assessed by blinded independent central review (BICR) and OS. Key secondary endpoints include investigator-assessed PFS, objective response rate, duration of response, time to response, disease control rate as assessed by both BICR and investigator, and safety.
TROPION-Lung01 enrolled approximately 600 patients in
Datopotamab deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, datopotamab deruxtecan is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with
A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple-negative breast cancer and HR-positive, HER2-negative breast cancer. The program includes seven Phase III trials in lung cancer and five Phase III trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings.
Daiichi Sankyo collaboration
The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, includingosimertinib and gefitinib; durvalumab and tremelimumab-actl; fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan in collaboration with Daiichi Sankyo; savolitinib in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action.
The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that
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References
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Ahn M-J, et al. Datopotamab deruxtecan (Dato-DXd) vs doxetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase 3 study TROPION-Lung01. Presented at:
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US-93494 Last Updated 9/24
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