AstraZeneca and Daiichi Sankyo’s datopotamab
deruxtecan reduced the risk of disease progression or death by 25%
in overall population and by 37% in patients with non-squamous
tumors
Datopotamab deruxtecan is the first antibody
drug conjugate to demonstrate statistically significant improvement
in PFS over docetaxel in this setting of high unmet need
Positive results from the pivotal TROPION-Lung01 Phase III trial
showed that datopotamab deruxtecan (Dato-DXd) demonstrated a
statistically significant improvement for the primary endpoint of
progression-free survival (PFS) compared to docetaxel, the current
standard of care, in patients with locally advanced or metastatic
non-small cell lung cancer (NSCLC) treated with at least one prior
line of therapy.
These data will be shared today in the second of two
late-breaking presentations for datopotamab deruxtecan in a
Presidential Symposium at the European Society for Medical Oncology
(ESMO) 2023 Congress in Madrid, Spain (LBA12).
Datopotamab deruxtecan is a specifically engineered
TROP2-directed DXd antibody drug conjugate (ADC) being jointly
developed by AstraZeneca and Daiichi Sankyo.
Datopotamab deruxtecan reduced the risk of disease progression
or death by 25% compared to docetaxel (hazard ratio [HR]=0.75; 95%
confidence interval [CI] 0.62-0.91; p=0.004) as assessed by blinded
independent central review (BICR). Median PFS was 4.4 months in
patients treated with datopotamab deruxtecan versus 3.7 with
docetaxel. Results also showed a confirmed objective response rate
(ORR) of 26.4% in patients treated with datopotamab deruxtecan
compared to an ORR of 12.8% with docetaxel.
In patients with non-squamous NSCLC, datopotamab deruxtecan
demonstrated a clinically meaningful benefit, reducing the risk of
disease progression or death by 37% compared to docetaxel (HR 0.63;
95% CI 0.51-0.78) as assessed by BICR. Median PFS was 5.6 months in
patients treated with datopotamab deruxtecan versus 3.7 with
docetaxel. A confirmed ORR of 31.2% was observed with datopotamab
deruxtecan, including four complete responses (CRs), versus 12.8%
with docetaxel which elicited no CRs. Datopotamab deruxtecan did
not demonstrate a PFS benefit in patients with squamous NSCLC.
For the dual primary endpoint of overall survival (OS), interim
results numerically favored datopotamab deruxtecan over docetaxel
in the overall population (HR 0.90; 95% CI 0.72-1.13) and in
patients with non-squamous tumors (HR 0.77 95% CI: 0.59-1.01),
however, results did not reach statistical significance at the time
of this data cut-off. The trial is ongoing and OS will be assessed
at a final analysis.
Aaron Lisberg, MD, UCLA Health, Thoracic Medical Oncology and
investigator in the trial, said: “For patients with advanced
non-small cell lung cancer, current standard of care second-line
docetaxel is associated with limited benefit and substantial
toxicity. The improvement in progression-free survival observed
with datopotamab deruxtecan, particularly in patients with
non-squamous tumors, and the improved tolerability of this antibody
drug conjugate compared to docetaxel, represent a meaningful
advance for patients with lung cancer."
Susan Galbraith, Executive Vice President, Oncology R&D,
AstraZeneca, said: “Datopotamab deruxtecan is central to the future
we envision where antibody drug conjugates improve upon and
ultimately displace entrenched standards of care, like
chemotherapy, in multiple cancer types. The TROPION-Lung01 results
demonstrate for the first time that an antibody drug conjugate can
delay disease progression or death for longer than conventional
chemotherapy in patients with advanced non-small cell lung cancer.
This is particularly noteworthy considering datopotamab deruxtecan
was also associated with a lower burden of treatment-related severe
adverse events than chemotherapy.”
Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said,
“These results shown at ESMO from the second of two pivotal trials
of datopotamab deruxtecan provide further support for the
practice-changing potential of our DXd antibody drug conjugate
technology across different targets and types of cancer. The
benefit seen in patients with non-squamous tumors is particularly
impressive and, coupled with the data from TROPION-Lung05, provides
promising evidence that datopotamab deruxtecan may play an
important role in treating patients with non-small cell lung cancer
who currently have limited effective options following initial
treatment.”
In the TROPION-Lung01 trial, no new safety concerns were
identified with datopotamab deruxtecan. The median treatment
duration for datopotamab deruxtecan was 4.2 versus 2.8 months for
docetaxel. Grade 3 or higher treatment-related adverse events
(TRAEs) occurred in 25% and 41% of patients in the datopotamab
deruxtecan and docetaxel arms, respectively. The most common Grade
3 or higher TRAEs were neutropenia (1%, 23%), stomatitis (6%, 1%),
anemia (4%, 4%), asthenia (3%, 2%), nausea (2%, 1%) and fatigue
(1%, 2%).
Grade 3 or higher adjudicated drug-related interstitial lung
disease (ILD) events occurred in 3% and 1% of patients in the
datopotamab deruxtecan and docetaxel arms, respectively. In the
datopotamab deruxtecan arm, there were seven Grade 5 ILD events
(2%) adjudicated as drug-related by an independent committee. The
primary cause of death in four of these cases was attributed to
disease progression by the treating investigator. Of the seven
adjudicated Grade 5 ILD events, four (1.7%) were in patients with
non-squamous NSCLC and three (4.6%) were in patients with squamous
NSCLC. In the docetaxel arm, one adjudicated drug-related Grade 5
ILD event (0.3%) occurred.
Patient enrollment by tumor histology was consistent across
treatment arms and with real world incidence with 78% and 77% of
patients in the datopotamab deruxtecan and docetaxel arms,
respectively, having non-squamous tumors.1 In both arms, 17% of
patients had tumors expressing actionable genomic alterations, such
as epidermal growth factor receptor (EGFR) mutations. At the March
29, 2023 data cut-off, 52 patients remained on treatment with
datopotamab deruxtecan and 17 remained on docetaxel.
Summary of TROPION-Lung01 Efficacy Results
Overall trial population
Datopotamab deruxtecan (n=299)
Docetaxel (n=305)
Median PFS (95% CI) i
4.4 months (4.2-5.6)
3.7 months (2.9-4.2)
HR (95% CI)
0.75 (0.62-0.91)
p-value ii
p=0.004
Median OS (95% CI) iii
12.4 months (10.8-14.8)
11.0 months (9.8-12.5)
HR (95% CI)
0.90 (0.72-1.13)
ORR, confirmed (95% CI) i,iv
26.4% (21.5-31.8)
12.8% (9.3-17.1)
CR rate
1.3%
0%
PR rate
25.1%
12.8%
Median DoR (95% CI) i
7.1 months (5.6-10.9)
5.6 months (5.4-8.1)
Non-squamous histology
Datopotamab deruxtecan (n=229)
Docetaxel (n=232)
Median PFS (95% CI) i
5.6 months (4.4-7.0)
3.7 months (2.9-4.2)
HR (95% CI)
0.63 (0.51-0.78)
OS HR (95% CI) iii
0.77 (0.59-1.01)
ORR, confirmed i,iv
31.2%
12.8%
Median DoR i
7.7 months
5.6 months
Squamous histology
Datopotamab deruxtecan (n=70)
Docetaxel (n=73)
Median PFS (95% CI) i
2.8 months (1.9-4.0)
3.9 months (2.8-4.5)
HR (95% CI)
1.38 (0.94-2.02)
OS HR (95% CI) iii
1.32 (0.87-2.00)
ORR, confirmed i,iv
9.2%
12.7%
Median DoR i
5.9 months
8.1 months
CI, confidence interval; CR, complete response; DoR, duration of
response; HR, hazard ratio; ORR, objective response rate; OS,
overall survival; PFS, progression-free survival; PR, partial
response i As assessed by BICR ii p-value prespecified boundary of
0.008 iii With median follow-up of 11.8 and 11.7 months for the
datopotamab deruxtecan and docetaxel arms, respectively, OS data
were not mature iv ORR is (complete response + partial
response)
TROPION-Lung05 Results
Initial results from the TROPION-Lung05 Phase II trial showed
datopotamab deruxtecan demonstrated encouraging antitumor activity
in patients with heavily pretreated locally advanced or metastatic
NSCLC with actionable genomic alterations including those with EGFR
mutations and anaplastic lymphoma kinase (ALK) rearrangements.
These data were presented at the ESMO 2023 Congress on Saturday,
October 21 (1314MO).
In the overall population (n=137), datopotamab deruxtecan
demonstrated a confirmed ORR of 35.8%, including four CRs and 45
partial responses, and a disease control rate (DCR) of 78.8%.
Median PFS was 5.4 months. In patients with EGFR mutations (n=78),
the largest subgroup, datopotamab deruxtecan demonstrated an ORR of
43.6% and DCR of 82.1%.
The most common Grade 3 or higher TRAEs were stomatitis (10%),
anemia (6%), decreased appetite (4%) and fatigue (4%). There were
five ILD events (4%) adjudicated as drug-related by an independent
committee, including four Grade 1 or 2 events and one Grade 5
event.
Non-small cell lung cancer
More than one million people worldwide are diagnosed with
advanced NSCLC each year.2,3 Approximately 30% and 70% of NSCLC
tumors are of squamous or non-squamous histology, respectively, the
latter including adenocarcinoma and large cell carcinoma.1 While
immunotherapy and targeted therapies have improved outcomes in the
first-line setting, most patients eventually experience disease
progression and receive chemotherapy.4-6 For decades, chemotherapy
has been the last treatment available for patients with advanced
NSCLC in the absence of other treatment options and despite limited
effectiveness and known side effects.4-6
TROP2, a transmembrane glycoprotein, is broadly expressed in a
large majority of NSCLC tumors.7 There are currently no
TROP2-directed ADCs approved for the treatment of lung
cancer.8,9
TROPION-Lung01
TROPION-Lung01 is an ongoing global, randomized, multicenter,
open-label Phase III trial evaluating the efficacy and safety of
datopotamab deruxtecan (6.0 mg/kg) versus docetaxel (75 mg/m2) in
patients with locally advanced or metastatic NSCLC with and without
actionable genomic alterations previously treated with at least one
therapy. Patients with actionable genomic alterations were 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 BICR and OS. Key secondary endpoints include
investigator-assessed PFS, ORR, DoR, time to response, DCR as
assessed by both BICR and investigator, and safety.
TROPION-Lung01 enrolled approximately 600 patients at sites in
Asia, Europe, North America and South America. For more information
visit ClinicalTrials.gov.
About TROPION-Lung05
TROPION-Lung05 is an ongoing global, multicenter, single-arm,
open-label Phase II study evaluating the efficacy and safety of
datopotamab deruxtecan (6.0 mg/kg) in patients with locally
advanced or metastatic NSCLC with actionable genomic alterations
with disease progression on or after at least one tyrosine kinase
inhibitor and at least one regimen of platinum-based chemotherapy
(with or without other systemic therapies). Patients with one or
more genomic alterations including EGFR, ALK, ROS1, NTRK, BRAF,
RET, or MET and who received up to four prior lines of treatment
were eligible for the study.
The primary trial endpoint is ORR as assessed by BICR. Secondary
efficacy endpoints include DoR, best percentage change in the sum
of diameters of measurable tumors, DCR, clinical benefit rate, PFS,
time to response and OS. Safety endpoints include treatment
emergent adverse events and other safety parameters. TROPION-Lung05
enrolled 137 patients globally. 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 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 development program called TROPION is underway
globally with more than 12 trials evaluating the efficacy and
safety of datopotamab deruxtecan across multiple tumors, including
NSCLC, triple-negative breast cancer and HR-positive, HER2-low or
negative breast cancer. Beyond the TROPION program, datopotamab
deruxtecan is also being evaluated in novel combinations in several
ongoing trials. AstraZeneca is also researching a potential
diagnostic test to help identify patients most likely to benefit
from treatment with datopotamab deruxtecan.
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;
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.
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 100 countries and its innovative
medicines are used by millions of patients worldwide. Please visit
www.astrazeneca-us.com and follow us on social media
@AstraZeneca.
References
- National Cancer Institute. SEER Cancer Statistics Factsheets:
Lung and Bronchus Cancer, 2015. Available at: SEER Cancer
Statistics Factsheets: Lung and Bronchus Cancer, 2015. Accessed
October 2023.
- Siegel R, et al. Cancer Statistics, 2021. CA Cancer J Clin.
2021;71:7-33.
- World Health Organization. International Agency for Research on
Cancer. Lung Fact Sheet. Available at:
https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf.
Accessed October 2023.
- Chen R, et al. Emerging therapeutic agents for advanced
non-small cell lung cancer. J Hematol Oncol. 2020;13(1):58.
- Majeed U, et al. Targeted therapy in advanced non-small cell
lung cancer: current advances and future trends. J Hematol Oncol.
2021;14(1):108.
- Pircher, A, et al. Docetaxel in the Treatment of Non-small Cell
Lung Cancer (NSCLC) – An Observational Study Focusing on Symptom
Improvement. Anticancer Research. 2013;33(9):3831-3836.
- Mito R, et al. Clinical impact of TROP2 in non‐small lung
cancers and its correlation with abnormal p53 nuclear accumulation.
Pathol Int. 2020;70(5):287-294.
- Rodríguez-Abreau D et al. Pemetrexed plus platinum with or
without pembrolizumab in patients with previously untreated
metastatic nonsquamous NSCLC: protocol-specified final analysis
from KEYNOTE-189. Ann Onc. 2021 Jul;32(7): 881-895.
- American Cancer Society. Targeted Drug Therapy for Non-Small
Cell Lung Cancer. Available at:
https://www.cancer.org/cancer/types/lung-cancer/treating-non-small-cell/targeted-therapies.html.
Accessed October 2023.
US-81577 Last Updated 10/23
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Brendan McEvoy, +1 302 885 2677 Chelsea Ford +1 302 885 2677 US
Media Mailbox: usmediateam@astrazeneca.com
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