AstraZeneca and Daiichi Sankyo’s datopotamab
deruxtecan demonstrated meaningfully greater magnitude of
progression-free survival benefit in patients with this
biomarker
AstraZeneca and Roche Tissue Diagnostics are
collaborating to co-develop and commercialize the TROP2-QCS
biomarker companion diagnostic
Results from an exploratory analysis of the TROPION-Lung01 Phase
III trial showed TROP2 as measured by AstraZeneca’s proprietary
computational pathology platform, quantitative continuous scoring
(QCS), was predictive of clinical outcomes in patients with
advanced or metastatic non-small cell lung cancer (NSCLC) who were
treated with datopotamab deruxtecan (Dato-DXd). In patients with
TROP2-QCS biomarker positive tumors, datopotamab deruxtecan
demonstrated a meaningfully greater magnitude of efficacy versus
docetaxel than in the overall trial population.
These results will be featured in a Presidential Symposium
(PL02.11) at the IASLC 2024 World Conference on Lung Cancer (WCLC)
hosted by the International Association for the Study of Lung
Cancer.
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 AstraZeneca, that analyzes
digitized images of patient tissue samples and precisely quantifies
targets, like TROP2, on and inside a tumor cell.
Datopotamab deruxtecan is a specifically engineered
TROP2-directed DXd ADC discovered by Daiichi Sankyo and being
jointly developed by AstraZeneca and Daiichi Sankyo.
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 European Society for Medical Oncology Congress.5
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).
Marina Garassino, MD, The University of Chicago, Professor of
Medicine and investigator in the trial, said: “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. We have shown with
this analysis that the more precise quantitative measurement of
TROP2 on and inside tumor cells, enabled by AstraZeneca’s
computational pathology platform, can identify which patients with
non-small cell lung cancer are most likely to benefit from
treatment with datopotamab deruxtecan.”
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, 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. We are excited to extend our collaboration
with Roche Tissue Diagnostics with the aim of validating this
exploratory approach for TROP2, developing the companion diagnostic
and bringing it to the clinic as quickly as possible.”
Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, 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. These insights are critical to
advancing our understanding of how we can more precisely identify
patients with non-small cell lung cancer who may benefit from
treatment with our TROP2-directed antibody drug conjugate.”
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
AstraZeneca and Roche Tissue Diagnostics collaborate to
co-develop and commercialize the TROP2-QCS biomarker companion
diagnostic
AstraZeneca and Roche Tissue Diagnostics are extending their
existing collaboration to co-develop a novel companion diagnostic
incorporating AstraZeneca’s proprietary computational pathology
platform, QCS, which will be deployed within Roche's navify®
Digital Pathology image management system.
Jill German, Head, Roche Tissue Diagnostics, said: “Our
collaboration with AstraZeneca continues to push the boundaries of
traditional cancer diagnostics. By developing an innovative Al tool
that goes beyond human capabilities, the solution will be able to
help determine which cancer patients are most likely to benefit
from targeted therapies, potentially improving patient care.”
Under this expanded collaboration, Roche Tissue Diagnostics and
AstraZeneca will co-develop and commercialize a novel companion
diagnostic in Roche’s navify® Digital Pathology platform, based on
the QCS computational pathology platform, to aid pathologists in
interpreting an investigational VENTANA TROP2 assay.
As the leading provider of pathology lab solutions, Roche Tissue
Diagnostics is delivering an end-to-end digital pathology workflow
from tissue staining to producing high-quality digital images that
can be reliably assessed using automated clinical image analysis
algorithms.
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 who require systemic therapy
following prior treatment. Patients with actionable genomic
alterations were previously treated with platinum-based
chemotherapy and an approved targeted therapy. Patients without
known actionable genomic alterations were previously treated,
concurrently or sequentially, with platinum-based chemotherapy and
a PD-1 or PD-L1 inhibitor.
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 Asia,
Europe, North America, Oceania and South America. For more
information visit ClinicalTrials.gov.
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 Sapporo
Medical University, attached to a number of topoisomerase I
inhibitor payloads (an exatecan derivative, DXd) via
tetrapeptide-based cleavable linkers.
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
AstraZeneca and Daiichi Sankyo entered into a global
collaboration to jointly develop and commercialize fam-trastuzumab
deruxtecan-nxki in March 2019 and datopotamab deruxtecan in July
2020, except in Japan where Daiichi Sankyo maintains exclusive
rights for each ADC. Daiichi Sankyo is responsible for the
manufacturing and supply of fam-trastuzumab deruxtecan-nxki and
datopotamab deruxtecan.
AstraZeneca in lung cancer
AstraZeneca is working to bring patients with lung cancer closer
to cure through the detection and treatment of early-stage disease,
while also pushing the boundaries of science to improve outcomes in
the resistant and advanced settings. By defining new therapeutic
targets and investigating innovative approaches, the Company aims
to match medicines to the patients who can benefit most.
The Company’s comprehensive portfolio includes leading lung
cancer medicines and the next wave of innovations, including
osimertinib 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.
AstraZeneca is a founding member of the Lung Ambition Alliance,
a global coalition working to accelerate innovation and deliver
meaningful improvements for people with lung cancer, including and
beyond treatment.
AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the
ambition to provide cures for cancer in every form, following the
science to understand cancer and all its complexities to discover,
develop and deliver life-changing medicines to patients.
The Company’s focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day,
eliminate cancer as a cause of death.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization of
prescription medicines in Oncology, Rare Diseases and
BioPharmaceuticals, including Cardiovascular, Renal &
Metabolism, and Respiratory & Immunology. Based in Cambridge,
UK, AstraZeneca operates in over 125 countries, and its innovative
medicines are used by millions of patients worldwide. For more
information, please visit www.astrazeneca-us.com and follow us on
social media @AstraZeneca.
References
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in previously treated advanced/metastatic (adv/met) non-small cell
lung cancer (NSCLC): results of the randomized phase 3 study
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- Rodríguez-Abreau D, et al. Pemetrexed plus platinum with or
without pembrolizumab in patients with previously untreated
metastatic nonsquamous NSCLC: protocol-specified final analysis
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https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html.
Accessed September 2024.
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