17 June 2024
Imfinzi
plus chemotherapy
approved in the US for
mismatch repair deficient
advanced or recurrent endometrial cancer
Approval based on DUO-E trial results, which
showed Imfinzi reduced the
risk of disease progression or death by 58% vs.
chemotherapy
AstraZeneca's Imfinzi (durvalumab) in combination
with carboplatin and paclitaxel followed by Imfinzi monotherapy has been approved
in the US as treatment for adult patients with primary advanced or
recurrent endometrial cancer that is mismatch repair deficient
(dMMR).1
The approval by the Food and Drug
Administration (FDA) was based on the results of a prespecified
exploratory subgroup analysis by MMR status in the
DUO-E Phase III trial. Results from DUO-E were published in the
Journal of
Clinical Oncology.
In the trial, Imfinzi plus carboplatin and
paclitaxel followed by Imfinzi monotherapy (Imfinzi arm) reduced the risk of
disease progression or death by 58% in patients with dMMR
endometrial cancer versus chemotherapy alone (hazard ratio 0.42;
95% confidence interval 0.22-0.80).2
In the US, endometrial cancer is the fourth
most common cancer in women, with more than 66,000 patients
diagnosed and almost 12,000 deaths in 2022.3,4 Patients
diagnosed at an early stage of disease have a five-year survival
rate of approximately 80-90%, but there is a significant need for
new treatment options for people with advanced disease, where the
survival rate falls to less than 20%.5,6
Shannon N. Westin, Professor of Gynecologic
Oncology and Reproductive Medicine at The University of Texas MD
Anderson Cancer Center, and principal investigator of the trial,
said, "With the incidence and mortality of endometrial cancer
expected to continue to increase significantly in the coming
decades, it is more important than ever that we bring new treatment
options to patients at the earliest possible moment in their care.
This approval underlines clear evidence that durvalumab plus
chemotherapy followed by durvalumab monotherapy delivers important
clinical benefits for patients with mismatch repair deficient
endometrial cancer."
Dave Fredrickson, Executive Vice
President, Oncology Business Unit, AstraZeneca, said:
"There have been limited advances in the treatment of
endometrial cancer in the last few decades, and continued
innovation is critical as the burden of this cancer is expected to
grow in the future. Immunotherapy in combination with chemotherapy
is emerging as a new standard of care in this setting, and the
approval of Imfinzi offers
an important new option for patients with mismatch repair deficient
disease."
The safety and tolerability profile of the
Imfinzi and chemotherapy
regimen was generally manageable, well tolerated and broadly
consistent with prior clinical trials with no new safety
signals.1,2
The Lynparza (olaparib) and Imfinzi arm, which investigated
Imfinzi plus chemotherapy
followed by Imfinzi plus
Lynparza as maintenance
therapy, also met the primary endpoint of progression-free survival
(PFS). The trial continues to assess OS as a key
secondary endpoint for both arms. Regulatory applications for
both Imfinzi as well as
Imfinzi and Lynparza regimens are
currently under review in the EU, Japan and several other countries
based on the DUO-E results.
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.7-10 It is the sixth most common cancer in women
worldwide.11,12 Incidence and mortality of endometrial
cancer are expected to increase by approximately 61% and 87%
respectively (from 420,400 cases and 97,700 deaths in 2022 to
676,300 cases and 183,100 deaths) in 2050.13
The majority of patients with endometrial
cancer are diagnosed at an early stage of disease, where the cancer
is confined to the uterus.9,10 They are typically
treated with surgery and/or radiation, and the five-year survival
rate is high (approximately 80-90%).5,6 Patients with
advanced disease (Stage III-IV) usually have a much poorer
prognosis, with the five-year survival rate falling to less than
20%.5,6 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 with this type of
cancer.6,14,15,16 There remains a high unmet need for
treatments for the remaining 70-80% of endometrial cancer patients
with pMMR disease.15,16
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 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.
In addition to its indications in unresectable,
Stage III NSCLC and ES-SCLC, Imfinzi is currently approved in a
number of countries in combination with a short course of
tremelimumab (Imjudo) and chemotherapy for the
treatment of metastatic NSCLC.
Imfinzi is also
approved in a number of countries in combination with chemotherapy
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.
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
medicines are sold in more than 125 countries and used by millions
of patients worldwide. Please visit astrazeneca.com and
follow the Company on social media @AstraZeneca.
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References
1. Imfinzi (durvalumab) US prescribing
information; Jun 2024.
2. Shannon N. Westin
et al. Durvalumab Plus Carboplatin/Paclitaxel Followed
by Maintenance Durvalumab With or Without Olaparib as First-Line
Treatment for Advanced Endometrial Cancer: The Phase III DUO-E
Trial. JCO 42, 283-299(2024).
3. World Health Organization. IARC.
Absolute numbers, Incidence, Females, in 2022. United States of
America. Available at:
https://gco.iarc.fr/today/en/dataviz/pie?mode=cancer&cancers=24&sexes=2&group_populations=1&populations=840.
Accessed Jun 2024.
4. World Health Organization. IARC.
Corpus Uteri. Estimated numbers from 2022 to 2050, United States,
Females, age [0-85+]. Available at:
https://gco.iarc.who.int/tomorrow/en/dataviz/trends?multiple_populations=1&cancers=24&populations=840.
Accessed Jun 2024.
5. Cao SY, et al. Recurrence and
survival of patients with stage III endometrial cancer after
radical surgery followed by adjuvant chemo- or chemoradiotherapy: a
systematic review and meta-analysis. BMC Cancer. 2023 Jan
9;23(1):31.
6. Haj Hamoud B, et
al. The Evolving Landscape Of Immunotherapy In Uterine
Cancer: A Comprehensive Review. Life. 2023;13(7):1502.
7. Dork T, et al. Genetic
Susceptibility to Endometrial Cancer: Risk Factors and Clinical
Management. Cancers (Basel). 2020;12(9):2407.
8. American Cancer Society. What is
Endometrial Cancer? Available at
https://www.cancer.org/cancer/endometrial-cancer/about/what-is-endometrial-cancer.html.
Accessed Jun 2024.
9. Oakin A, et al.
ESMO Guidelines. Endometrial Cancer: ESMO Clinical
Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann
Oncol. 2022;33(9):860-877.
10. Cancer.Net. Uterine Cancer:
Statistics. Available at:
https://www.cancer.net/cancer-types/uterine-cancer/statistics.
Accessed Jun 2024.
11. World Cancer Research Fund
International. Endometrial Cancer Statistics. Available at
https://www.wcrf.org/cancer-trends/endometrial-cancer-statistics/.
Accessed Jun 2024.
12. World Health Organisation. IARC.
Corpus Uteri. Absolute numbers, Incidence, Females in 2022.
Available at:
https://gco.iarc.who.int/today/en/dataviz/pie?mode=cancer&group_populations=1&populations=900&sexes=2.
Accessed Jun 2024.
13. World Health Organization. IARC.
Corpus Uteri. Estimated Numbers From 2022 To 2050, Females, Age
[0-85+] World. Available at
https://gco.iarc.who.int/tomorrow/en/dataviz/trends?multiple_populations=1&cancers=24.
Accessed Jun 2024.
14. Gov.uk. MHRA Authorises Monoclonal
Antibody Treatment, Jemperli, To Be Used With Chemotherapy For
Endometrial Cancer. Available at
https://www.gov.uk/government/news/mhra-authorises-monoclonal-antibody-treatment-jemperli-to-be-used-with-chemotherapy-for-endometrial-cancer.
Accessed Jun 2024.
15. Yang Y, et al. Molecular Subtypes Of
Endometrial Cancer: Implications For Adjuvant Treatment Strategies.
International Journal of Gynecology & Obstetrics.
2023;00:1-24.
16. Kelkar SS, et al. Treatment Patterns
And Real-World Clinical Outcomes In Patients With Advanced
Endometrial Cancer That Are Non-Microsatellite Instability High
(Non-MSI-High) Or Mismatch Repair Proficient (Pmmr) In The United
States. Gynecologic Oncology Reports. 2022;42:101026.
Adrian Kemp
Company Secretary
AstraZeneca PLC