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 3 Trial
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Daiichi Sankyo andAstraZeneca ’s datopotamab deruxtecan demonstrated meaningfully greater magnitude of progression-free survival benefit in patients with this biomarker -
AstraZeneca andRoche Tissue Diagnostics are collaborating to co-develop and commercialize the TROP2-QCS biomarker companion diagnostic
Datopotamab deruxtecan is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by
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 ADCs.3,4 QCS is a fully supervised computational pathology platform 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. Patient 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% versus 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.
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 months versus 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 (median PFS of 4.4 months versus 3.7 months; HR=0.75; 95% CI: 0.62-0.91; p=0.004) as presented at the
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% versus docetaxel (median PFS of 7.2 months versus 4.1 months; HR=0.52; CI: 95% 0.35-0.78).
“TROP2 is broadly expressed on solid tumor cells including non-small cell lung cancer, but it has yet to be established as a predictive biomarker for any TROP2 directed antibody drug conjugate,” said
“The results from the QCS analysis support the potential of TROP2, as measured by quantitative continuous scoring, as a predictive biomarker for datopotamab deruxtecan and begin to answer the question of why certain patients with non-small cell lung cancer respond better to treatment,” said
“This analysis demonstrates the power of our computational pathology platform to discover new predictive biomarkers and substantially improve patient selection for datopotamab deruxtecan. It also has great potential to help more precisely select patients across our broader antibody drug conjugate portfolio,” said
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% vs. 3%) and ocular surface events (3% vs. 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) |
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TROP2-QCS biomarker positive |
TROP2-QCS biomarker negative |
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Datopotamab
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Docetaxel
|
Datopotamab
|
Docetaxel
|
Median PFS (months) |
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) |
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ORR |
32.7% |
10.3% |
16.9% |
15.1% |
Nonsquamous histology without actionable genomic alterations biomarker-evaluable subgroup, n=221 |
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|
Datopotamab
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Docetaxel
|
Datopotamab
|
Docetaxel
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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) |
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ORR |
36.8% |
15.3% |
22.5% |
12.2% |
CI, confidence interval; HR, hazard ratio; ORR, objective response rate; PFS, progression-free survival |
About TROPION-Lung01
TROPION-Lung01 is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) versus docetaxel (75 mg/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, ORR, 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
About Advanced Non-Small Cell Lung Cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.5 NSCLC is the most common type of lung cancer, accounting for about 80% of cases.6 Approximately 75% and 25% of NSCLC tumors are of nonsquamous or squamous histology, respectively.7 While immunotherapy and targeted therapies have improved outcomes in the first-line metastatic setting, most patients eventually experience disease progression and receive chemotherapy.8,9,10 For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC, despite limited effectiveness and known side effects.9,10,11
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.11,12
About 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
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 3 trials in lung cancer and five phase 3 trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings.
About the
About the ADC Portfolio of
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by
The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with
The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.
About
References
1 Mito R, et al. Pathol Int. 2020;70(5):287-294.
2 Shvartsur A, et al. Genes & Cancer. 2015 Mar;6(3-4): 84-105.
3 Shimizu T, et al.J Clin Oncol2023;41:4678-87.
4 Heist RS, et al.J Clin Oncol. 2017;35:2790-7.
5
6Cancer.net. Lung Cancer – Non-Small Cell: Statistics. Accessed
7
8 Chen R, et al. J Hematol Oncol. 2020:13(1):58.
9 Majeed U, et al. J Hematol Oncol. 2021;14(1):108.
10 Pircher A, et al.
11 Rodríguez-Abreau D, et al.
12
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