1 July 2024
Lynparza
and Imfinzi combination recommended for
approval in the EU by CHMP for patients with
mismatch repair proficient advanced or recurrent endometrial
cancer
Imfinzi also recommended for patients
with mismatch repair deficient disease
Recommendation based on DUO-E Phase III
results, which showed both regimens demonstrated statistically
significant and clinically meaningful improvement in
progression-free survival vs. chemotherapy alone
AstraZeneca's Imfinzi (durvalumab) and Lynparza (olaparib) have been
recommended for approval in the European Union (EU) as treatment
for certain patients with primary advanced or recurrent endometrial
cancer. Imfinzi plus
chemotherapy as 1st-line treatment followed by Lynparza and Imfinzi has been recommended for
patients with mismatch repair proficient (pMMR) disease.
Imfinzi plus chemotherapy
followed by Imfinzi alone
has been recommended for patients with mismatch repair deficient
(dMMR) disease.
The Committee for Medicinal Products for Human
Use (CHMP) of the European Medicines Agency (EMA) based its
positive opinion on a prespecified exploratory
subgroup analysis by mismatch repair
(MMR) status from the
DUO-E Phase III trial, which was published in the Journal
of Clinical Oncology in October 2023.
This analysis showed a reduction in the risk of
disease progression or death for pMMR patients in the Lynparza and Imfinzi arm by 43% (median 15.0 months
versus 9.7 months, hazard ratio [HR] 0.57; 95% confidence interval
[CI] 0.44-0.73) versus the control arm.1 Results for
dMMR patients showed a reduction in the risk of disease progression
or death in the Imfinzi
arm by 58% (median not reached versus 7.0 months, HR 0.42; 95% CI
0.22-0.80) versus the control arm.1
In Europe, endometrial cancer is the fourth
most common cancer in women, with nearly 125,000 diagnoses and more
than 30,000 deaths in 2022.2,3 Patients diagnosed at an
early stage of disease have a five-year survival rate of
approximately 80-90%, but that falls to less than 20% for people
with advanced disease.4,5 There is a significant need
for new treatment options, especially for the 70-80% of patients
with pMMR disease.5,6 This
recommendation underscores the importance of MMR testing at point
of diagnosis, which is well established and widely
available.7,8
Els Van Nieuwenhuysen, Gynaecological
Oncologist at the UZ Leuven, Belgium and trial investigator, said:
"Patients with advanced or
recurrent endometrial cancer currently have a very poor prognosis,
especially those with mismatch repair proficient disease. This
recommendation underscores the significant benefit shown with
durvalumab as well as with the olaparib and durvalumab combination
for patients with both mismatch repair deficient and mismatch
repair proficient status. This marks an important step toward
improving outcomes for these patients in Europe."
Susan Galbraith, Executive Vice President,
Oncology R&D, AstraZeneca, said: "Today's recommendation for
approval in the EU recognises the potential of the Lynparza and Imfinzi combination to provide
clinical benefit for patients with endometrial cancer, especially
for those with mismatch repair proficient disease who have few
available treatments today. If approved, patients in Europe will
have a new option for combination treatment that brings the
additional benefit of PARP inhibition to immunotherapy."
The safety profiles of both experimental
regimens were manageable, well-tolerated and broadly consistent
with the known profiles of the individual
agents.1,9,10
Regulatory submissions for Imfinzi and Lynparza are currently under review in
Japan and several other countries based on the DUO-E trial.
Imfinzi plus chemotherapy
was recently approved for dMMR patients with primary advanced or
recurrent endometrial cancer in the US.11
Notes
Endometrial
cancer
Endometrial cancer is a highly heterogeneous
disease that originates in the tissue lining of the uterus and is
most common in women who have already been through menopause, with
the average age at diagnosis being over 60 years
old.12-15
The majority of patients with endometrial
cancer are diagnosed at an early stage of disease, where the cancer
is confined to the uterus.16 They are typically treated
with surgery and/or radiation, and the five-year survival rate is
high (approximately 80-90%).17 Patients with advanced
disease (Stage III-IV) usually have a much poorer prognosis, with
the five-year survival rate falling to less than 20%.4
Immunotherapy combined with chemotherapy is
emerging as a new standard of care for advanced endometrial cancer,
particularly for patients with dMMR disease, who make up
approximately 20-30% of all patients.11,17-20 There
remains a high unmet need for treatments for the remaining 70-80%
of endometrial cancer patients with pMMR
disease.5,6
DUO-E
The DUO-E trial (GOG 3041/ENGOT-EN10) is a
three-arm, randomised, double-blind, placebo-controlled,
multicentre Phase III trial of 1st-line Imfinzi (durvalumab) plus
platinum-based chemotherapy (carboplatin and paclitaxel) followed
by either Imfinzi
monotherapy or Imfinzi
plus Lynparza (olaparib)
as maintenance therapy versus platinum-based chemotherapy alone as
a treatment for patients with newly diagnosed advanced or recurrent
endometrial cancer.
The DUO-E trial randomised 699
patients with newly diagnosed advanced or recurrent epithelial
endometrial carcinoma to receive either Imfinzi (1120mg) or
placebo, given every three weeks in addition to standard-of-care
platinum-based chemotherapy. After 4-6 cycles of chemotherapy,
patients (whose disease had not progressed) then received either
Imfinzi (1500mg) or
placebo every four weeks as maintenance, plus 300mg Lynparza (300mg BID [2x150mg tablets,
twice a day]) or placebo until disease progression.
The dual primary endpoint was progression-free
survival (PFS) of each treatment arm versus standard of care. Key secondary endpoints included overall survival
(OS), safety and tolerability. The trial continues to assess OS for
both Imfinzi monotherapy
and Imfinzi plus
Lynparza as maintenance
therapy in the overall trial population. Mismatch repair (MMR)
status, recurrence status and geographic location were
stratification factors. The trial was sponsored
independently by AstraZeneca and conducted in 253 study locations
across 22 countries including the US, Europe, South America and
Asia.
For more information about the trial, please
visit ClinicalTrials.gov.
Imfinzi
Imfinzi
(durvalumab) is a human monoclonal antibody that binds to the
PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and
CD80 proteins, countering the tumour's immune-evading tactics and
releasing the inhibition of immune responses.
Imfinzi is the only
approved immunotherapy and the global standard of care in the
curative-intent setting of unresectable, Stage III non-small cell
lung cancer (NSCLC) in patients whose disease has not progressed
after chemoradiation therapy. Imfinzi is also approved for the
treatment of extensive-stage small cell lung cancer (SCLC) and in
combination with a short course of Imjudo (tremelimumab) and chemotherapy
for the treatment of metastatic NSCLC.
In addition to its indications in lung cancers,
Imfinzi is approved in
combination with chemotherapy (gemcitabine plus
cisplatin) in locally advanced or metastatic biliary
tract cancer and in combination with Imjudo in unresectable hepatocellular
carcinoma (HCC). Imfinzi
is also approved as a monotherapy in unresectable HCC in Japan and
the EU.
Since the first approval in May 2017, more than
220,000 patients have been treated with Imfinzi. As part of a broad
development programme, Imfinzi is being tested as a single
treatment and in combinations with other anti-cancer treatments for
patients with SCLC, NSCLC, bladder cancer, breast cancer, several
gastrointestinal cancers and other solid tumours.
Lynparza
Lynparza is a
first-in-class PARP inhibitor and the first targeted treatment to
block DNA damage response (DDR) in cells/tumours harbouring a
deficiency in homologous recombination-related (HRR) genes, such as
those with mutations in BRCA1 and/or BRCA2, or those where
deficiency is induced by other agents (such as new hormonal agents
[NHAs]).
Inhibition of PARP with Lynparza leads to the trapping of PARP
bound to DNA single-strand breaks, stalling of replication forks,
their collapse and the generation of DNA double-strand breaks and
cancer cell death. Lynparza may also help enhance
immunogenicity and increase the impact of anti-tumour immune
responses.
Lynparza is currently approved
in a number of countries across multiple tumour types, including
maintenance treatment of platinum-sensitive relapsed ovarian cancer
and as both monotherapy and in combination with bevacizumab for the
1st-line maintenance treatment of BRCA-mutated (BRCAm) and
homologous recombination repair deficient (HRD)-positive advanced
ovarian cancer, respectively; for germline BRCA mutation (gBRCAm),
HER2-negative metastatic breast cancer (in the EU and Japan, this
includes locally advanced breast cancer); for gBRCAm, HER2-negative
high-risk early breast cancer (in Japan, this includes all BRCAm
HER2-negative high-risk early breast cancer); for gBRCAm metastatic
pancreatic cancer; in combination with abiraterone for the
treatment of metastatic castration-resistant prostate cancer
(mCRPC) when chemotherapy is not clinically indicated (EU
only) and for BRCAm mCRPC (US and Japan);
and as monotherapy for HRR gene-mutated mCRPC in
patients who have progressed on prior NHA treatment (BRCAm only in
the EU and Japan). In China, Lynparza is approved for the treatment
of BRCA-mutated mCRPC as well as 1st-line maintenance treatment
with bevacizumab for HRD-positive advanced ovarian
cancer.
Lynparza is being
jointly developed and commercialised by AstraZeneca and MSD, both
as a monotherapy and in combination with other potential medicines.
Independently, the companies are developing and will commercialise
Lynparza in combination
with their respective PD-L1 and PD-1 medicines, Imfinzi (durvalumab) and Keytruda (pembrolizumab). Lynparza has been used to treat
approximately 140,000 patients worldwide. Lynparza has a broad clinical trial
development programme, and AstraZeneca and MSD are working together
to understand how it may affect multiple PARP-dependent tumours as
a monotherapy and in combination across multiple cancer types.
Lynparza is the foundation
of AstraZeneca's industry-leading portfolio of potential new
medicines targeting DDR mechanisms in cancer cells.
AstraZeneca in
immuno-oncology (IO)
AstraZeneca is a pioneer in introducing the
concept of immunotherapy into dedicated clinical areas of high
unmet medical need. The Company has a comprehensive and diverse IO
portfolio and pipeline anchored in immunotherapies designed to
overcome evasion of the anti-tumour immune response and stimulate
the body's immune system to attack tumours.
AstraZeneca aims to reimagine cancer care and
help transform outcomes for patients with Imfinzi as monotherapy and in
combination with Imjudo as
well as other novel immunotherapies and modalities. The Company is
also exploring next-generation immunotherapies like bispecific
antibodies and therapeutics that harness different aspects of
immunity to target cancer.
AstraZeneca is boldly pursuing an innovative
clinical strategy to bring IO-based therapies that deliver
long-term survival to new settings across a wide range of cancer
types. With an extensive clinical programme, the Company also
champions the use of IO treatment in earlier disease stages, where
there is the greatest potential for cure.
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 catalyse 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 (LSE/STO/Nasdaq: AZN) is a global, science-led
biopharmaceutical company that focuses on the discovery,
development, and commercialisation of prescription medicines in
Oncology, Rare Diseases, and BioPharmaceuticals, including
Cardiovascular, Renal & Metabolism, and Respiratory &
Immunology. Based in Cambridge, UK, AstraZeneca's innovative
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References
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carboplatin/paclitaxel followed by maintenance durvalumab with or
without olaparib as first-line treatment for advanced endometrial
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2023;42(3):283-299.
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Absolute numbers, Incidence, Females, in 2022. Europe. Available
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https://gco.iarc.fr/today/en/dataviz/pie?mode=cancer&cancers=24&sexes=2&group_populations=1&populations=908.
Accessed June 2024.
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Estimated numbers from 2022 to 2050, Females, age [0-85+]. Europe.
Available at:
https://gco.iarc.fr/tomorrow/en/dataviz/trends?types=0_1&sexes=2&mode=cancer&group_populations=0&multiple_populations=0&multiple_cancers=1&cancers=24&populations=908.
Accessed June 2024.
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cancer that are non-microsatellite instability high (Non-MSI-high)
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Accessed June 2024.
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https://www.ema.europa.eu/en/documents/product-information/imfinzi-epar-product-information_en.pdf.
Accessed June 2024.
11. FDA. FDA approves durvalumab with
chemotherapy for mismatch repair deficient primary advanced or
recurrent endometrial cancer. Available at:
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-chemotherapy-mismatch-repair-deficient-primary-advanced-or-recurrent.
Accessed June 2024.
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endometrial cancer? Available at
https://www.cancer.org/cancer/endometrial-cancer/about/what-is-endometrial-cancer.html.
Accessed June 2024.
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https://www.cancer.org/cancer/types/endometrial-cancer/about/key-statistics.html.
Accessed June 2024.
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Cancer stat facts: Uterine cancer. Available at: https://seer.cancer.gov/statfacts/html/corp.html.
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immunotherapy in uterine cancer: A comprehensive review.
Life.
2023;13:1502.
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classification and future treatments. BMJ Medicine.
2022;1(1):e000152.
19. FDA. FDA approves pembrolizumab with
chemotherapy for primary advanced or recurrent endometrial
carcinoma. Available at:
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Accessed June 2024.
20. Gov.uk. MHRA authorises monoclonal
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Accessed June 2024.
Adrian Kemp
Company Secretary
AstraZeneca PLC