In previously untreated patients,
AstraZeneca and Daiichi Sankyo’s datopotamab deruxtecan plus
pembrolizumab with or without platinum chemotherapy demonstrated
objective response rates of 57% and 50%, respectively, with a
disease control rate of 91% across cohorts
Three ongoing pivotal trials are evaluating
datopotamab deruxtecan and immune checkpoint inhibitor combinations
in 1st-line non-small cell lung cancer
Updated results from the TROPION-Lung02 Phase Ib trial showed,
with additional enrolment and follow-up from the initial
presentation, that datopotamab deruxtecan (Dato-DXd) in combination
with pembrolizumab with or without platinum-based chemotherapy
demonstrated promising clinical activity and no new safety signals
in both previously untreated or pretreated patients with advanced
or metastatic non-small cell lung cancer (NSCLC) without actionable
genomic alterations (AGAs).
Results will be presented on June 6 in an oral presentation at
the 2023 American Society of Clinical Oncology (ASCO) Annual
Meeting (#9004).
Datopotamab deruxtecan is a specifically engineered
TROP2-directed DXd antibody drug conjugate (ADC) being jointly
developed by AstraZeneca and Daiichi Sankyo.
More than one million people are diagnosed with advanced stage
NSCLC each year.1,2 While 1st-line treatment with immune checkpoint
inhibitors with or without chemotherapy has improved outcomes for
patients with NSCLC without AGAs, like EGFR or ALK, most patients
eventually experience disease progression.3-5 TROP2 is a protein
expressed in more than 90% of NSCLC tumors; there are currently no
TROP2-directed ADCs approved for the treatment of lung
cancer.6-8
Across previously untreated and pretreated patients, an
objective response rate (ORR) of 38% was observed (95% confidence
interval [CI], 26-51) in patients receiving doublet datopotamab
deruxtecan plus pembrolizumab (Merck & Co., Inc., Rahway, NJ,
USA), an anti-PD-1 therapy. In patients receiving triplet
datopotamab deruxtecan plus pembrolizumab and platinum
chemotherapy, an ORR of 49% was observed (95% CI, 37-61). Disease
control rates (DCR) of 84% and 87% were observed in the doublet and
triplet cohorts, respectively. Median duration of response (DoR)
was not reached across cohorts. Although immature, median
progression-free survival (PFS) was 8.3 months (95% CI, 6.8-11.8)
in the doublet cohort and 7.8 months (95% CI, 5.6-11.1) in the
triplet cohort. Response rates were highest in previously untreated
patients with ORRs of 50% (95% CI, 32-68) and 57% (95% CI, 42-70)
observed in the doublet and triplet cohorts, respectively, with a
consistent DCR of 91% observed across cohorts.
Yasushi Goto, MD, Division of Internal Medicine and Thoracic
Oncology, National Cancer Center Hospital, Tokyo, Japan, and
investigator in the trial, said: “Nearly all patients with advanced
non-small cell lung cancer experience disease progression following
initial therapy, underscoring the need for novel therapeutic
approaches across treatment lines. The updated results from
TROPION-Lung02 signal the potential for datopotamab deruxtecan
combinations to improve outcomes for patients with non-small cell
lung cancer and are a promising development in the pursuit of a new
standard treatment option beyond immunotherapy.”
Cristian Massacesi, Chief Medical Officer and Oncology Chief
Development Officer, AstraZeneca, said: “With more patients and
nearly a year of additional follow-up, the updated TROPION-Lung02
results show that datopotamab deruxtecan continues to elicit
promising and durable responses in a diverse subset of patients
with non-small cell lung cancer. These early data give us
confidence in the ongoing Phase III development programme
evaluating datopotamab deruxtecan combinations as potential
first-line treatment options for patients with advanced lung cancer
across tumor histologies and PD-L1 expression levels.”
Mark Rutstein, MD, Global Head, Oncology Clinical Development,
Daiichi Sankyo said: “We continue to be encouraged by the findings
from TROPION-Lung02, the first trial to evaluate the combination of
a TROP2-directed antibody-drug conjugate and an immune checkpoint
inhibitor with or without platinum chemotherapy in patients with
advanced non-small cell lung cancer. These data, alongside previous
results for datopotamab deruxtecan combined with an immune
checkpoint inhibitor, reinforce the potential of these combinations
to improve outcomes for patients with different advanced
cancers.”
The safety profiles of datopotamab deruxtecan-based combinations
were consistent with previous data with no new safety signals
observed. Grade 3 or greater treatment-related adverse events
(TRAEs) occurred in 31% of patients receiving doublet therapy and
58% of patients receiving triplet therapy. The most frequent
adverse events of any Grade in the doublet and triplet cohorts,
respectively, were stomatitis (56% and 35%), nausea (41% and 47%),
anemia (21% and 48%) and fatigue (31% and 37%). Across treatment
cohorts, there were 27 interstitial lung disease (ILD) or
pneumonitis events adjudicated as drug-related by an independent
committee. The percentage of ILD events was similar across cohorts.
The majority of ILD events were low grade with 23 Grade 1 or Grade
2 and four Grade 3 events. No Grade 4 or Grade 5 ILD events or
Grade 5 TRAEs were observed.
In the doublet cohort of TROPION-Lung02, 58% of patients were
previously untreated and 42% were previously treated with platinum
chemotherapy (38%) or immunotherapy (19%). In the triplet cohort,
75% of patients were previously untreated and 25% were previously
treated with platinum chemotherapy (24%) or immunotherapy (25%).
Eighty percent of patients in the doublet cohort and 73% of
patients in the triplet cohort had PD-L1 tumor proportion scores of
less than 50%, including 36% and 40% of patients who had PD-L1
tumor proportion scores of less than 1% in the doublet and triplet
cohorts, respectively. As of the April 7, 2023 data cut-off, 36%
and 46% of patients remained on the doublet and triplet therapy,
respectively.
Summary of Results
Overall Population
Doublet (n=64)
Triplet (n=72)
Study Duration (range)
14.8 months (1-30.2)
12.9 months (2.6-23.4)
Efficacy Measure
Doublet (n=61)
Triplet (n=71)
ORR, %i (confirmed and pending) (95%
CI)
38% (n=23) (26-51)
49% (n=35) (37-61)
CR, % (confirmed)
0% (n=0)
1% (n=1)
CR, % (pending confirmation)
0% (n=0)
0% (n=0)
PR, % (confirmed)
34% (n=21)
48% (n=34)
PR, % (pending confirmation)
3% (n=2)
0% (n=0)
SD, %
49% (n=30)
38% (n=27)
Median DoR (months) (95% CI)
NR (8.8-NR)
NR (5.8-NR)
Median PFS (months) (95% CI)
8.3 months (6.8-11.8)
7.8 months (5.6-11.1)
DCR, % ii
84% (n=51)
87% (n=62)
1st-Line Therapy
Efficacy Measure
Doublet (n=34)
Triplet (n=53)
ORR, %i (confirmed and pending) (95%
CI)
50% (n=17) (32-68)
57% (n=30) (42-70)
CR, % (confirmed)
0% (n=0)
2% (n=1)
CR, % (pending confirmation)
0% (n=0)
0% (n=0)
PR, % (confirmed)
44% (n=15)
55% (n=29)
PR, % (pending confirmation)
6% (n=2)
0% (n=0)
SD, %
47% (n=16)
34% (n=18)
Median DoR (months) (95% CI)
NR (5.5-NR)
NR (5.7-NR)
DCR, %ii
91% (n=31)
91% (n=48)
CI, confidence interval; CR, complete response; DCR, disease
control rate; DoR, duration of response; NR, not reached; ORR,
objective response rate; PFS, progression-free survival; PR,
partial response; SD, stable disease
iORR is CR + PR
iiDCR is best overall response of confirmed CR + confirmed PR +
SD
AstraZeneca and Daiichi Sankyo have three Phase III trials
evaluating datopotamab deruxtecan as a potential 1st-line treatment
option for patients with advanced or metastatic NSCLC without AGAs
compared to the respective standard of care for the patient
population of each study:
- TROPION-Lung07 is
evaluating datopotamab deruxtecan plus pembrolizumab with or
without chemotherapy in patients with non-squamous disease and
PD-L1 expression less than 50%.
- TROPION-Lung08 is
evaluating datopotamab deruxtecan plus pembrolizumab in patients
with PD-L1 expression of 50% or greater.
- AVANZAR is evaluating
datopotamab deruxtecan plus durvalumab and platinum chemotherapy in
patients regardless of PD-L1 expression or tumor histology.
Notes
Non-small cell lung cancer
More than one million people are diagnosed with advanced stage
NSCLC each year. 1,2 While targeted therapies and immune checkpoint
inhibitors have improved patient outcomes, advanced NSCLC has a
poor prognosis and is associated with worsening outcomes after each
line of subsequent therapy.3-5
Most patients with NSCLC have tumors that do not express a known
AGA (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET or MET).9-11 The
current 1st-line standard of care for these patients is treatment
with immune checkpoint inhibitors with or without platinum-based
chemotherapy. Approximately 40-60% of tumors will not respond to
this initial treatment and while these therapies may improve
survival for patients whose tumors do respond, most will experience
disease progression.5,7
TROP2, a transmembrane glycoprotein, is expressed in more than
90% of NSCLC tumors.6 There are currently no TROP2-directed ADCs
approved for the treatment of lung cancer.7,8
TROPION-Lung02
TROPION-Lung02 is an ongoing global, open-label, six-cohort
Phase Ib trial evaluating the safety and efficacy of datopotamab
deruxtecan at two dose levels (4 mg/kg and 6 mg/kg) in combination
with pembrolizumab (200 mg) with or without four cycles of platinum
chemotherapy (carboplatin or cisplatin) in both previously
untreated and pretreated patients with advanced or metastatic NSCLC
without AGAs (e.g., EGFR, ALK, ROS1, NTRK, BRAF, RET, MET or other
known AGAs).
The primary endpoints of TROPION-Lung02 are dose-limiting
toxicities and treatment-emergent adverse events. Secondary
endpoints include ORR, DoR, PFS as assessed by investigator,
overall survival, pharmacokinetics and anti-drug antibodies for
datopotamab deruxtecan and pembrolizumab.
TROPION-Lung02 is one of three clinical trials, alongside
TROPION-Lung07 and TROPION-Lung08, in a collaboration and supply
agreement between Daiichi Sankyo, AstraZeneca and a subsidiary of
Merck & Co., Inc., Rahway, NJ., USA to evaluate the combination
of datopotamab deruxtecan and pembrolizumab.
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 the three lead
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, 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 hormone receptor-positive,
HER2-low or negative breast cancer. Beyond the TROPION program,
datopotamab deruxtecan is also being evaluated in novel
combinations in several ongoing trials.
Daiichi Sankyo collaboration
Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as
Daiichi Sankyo] and AstraZeneca entered into a global collaboration
to jointly develop and commercialize fam-trastuzumab
deruxtecan-nxki (a HER2-directed ADC) in March 2019, and
datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July
2020, except in Japan where Daiichi Sankyo maintains exclusive
rights. Daiichi Sankyo is responsible for the manufacturing and
supply of ENHERTU 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. For more
information, please visit www.astrazeneca-us.com and follow us on
Twitter @AstraZenecaUS.
References
- Siegel R, et al. Cancer Statistics, 2021. CA Cancer J Clin.
2021;71:7-33.
- World Health Organisation. International Agency for Research on
Cancer. Available at:
https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf.
Accessed June 2023.
- Shields MD, et al. Immunotherapy for Advanced Non–Small Cell
Lung Cancer: A Decade of Progress. Am Soc Clin Oncol Educ Book.
2021;41:1-23.
- Walsh RJ, et al. Resistance to Immune Checkpoint Inhibitors in
Non-Small Cell Lung Cancer: Biomarkers and Therapeutic Strategies.
Ther Adv Med Oncol. 2020;12:1758835920937902.
- Paz-Ares L, et al. A Randomized, Placebo-Controlled Trial of
Pembrolizumab Plus Chemotherapy in Patients With Metastatic
Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407. J
Thorac Oncol. 2020;15(10):1657-1669.
- 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 June 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.
- Adib E, et al. Variation in Targetable Genomic Alterations in
Non-Small Cell Lung Cancer by Genetic Ancestry, Sex, Smoking
History, And Histology. Genome Med. 2022; 14(1): 39.
US-76654 Last Updated 06/23
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