REG - AstraZeneca PLC - Lynparza & Imfinzi positive CHMP in endometrial

AstraZenecaAnnouncement

01/07/2024 07:00

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RNS Number : 4391U  AstraZeneca PLC  01 July 2024

 

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
(https://www.astrazeneca.com/media-centre/press-releases/2023/imfinzi-plus-lynparza-reduced-risk-disease-progression-death-45-percent-vs-chemotherapy-advanced-recurrent-endometrial-cancer.html#!)
trial, which was published in the Journal of Clinical Oncology
(https://ascopubs.org/doi/full/10.1200/JCO.23.02132) 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
(https://clinicaltrials.gov/ct2/show/NCT04269200) .

 

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 medicines are
sold in more than 125 countries and used by millions of patients worldwide.
Please visit astrazeneca.com (https://www.astrazeneca.com) and follow the
Company on social media @AstraZeneca
(https://www.linkedin.com/company/astrazeneca/) .

Contacts

For details on how to contact the Investor Relations Team, please click here
(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html)
.

 

References

1.   Westin SN, 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. Journal of Clinical
Oncology. 2023;42(3):283-299.

2.   World Health Organization. IARC. Absolute numbers, Incidence, Females,
in 2022. Europe. Available at:
https://gco.iarc.fr/today/en/dataviz/pie?mode=cancer&cancers=24&sexes=2&group_populations=1&populations=908
(https://gco.iarc.fr/today/en/dataviz/pie?mode=cancer&cancers=24&sexes=2&group_populations=1&populations=908)
. Accessed June 2024.

3.   World Health Organization. IARC. 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
(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.

4.   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;23:31.

5.   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.

6.   Yang Y, et al. Molecular subtypes of endometrial cancer: Implications
for adjuvent treatment strategies. International Journal of Gynecology &
Obstetrics. 2024;164:436-459.

7.   Abu-Rustum N, et al. Uterine neoplasms, Version 1.2023, NCCN Clinical
Practice Guidelines in oncology. Journal of the National Comprehensive Cancer
Network. 2023;21(2):181-209.

8.   Stelloo E, et al. Practical guidance for mismatch repair-deficiency
testing in endometrial cancer. Annals of Oncology. 2017;28(1):96-102.

9.   Lynparza SmPC. Available at:
https://www.ema.europa.eu/en/documents/product-information/lynparza-epar-product-information_en.pdf
(https://www.ema.europa.eu/en/documents/product-information/lynparza-epar-product-information_en.pdf)
. Accessed June 2024.

10.  Imfinzi SmPC. Available at:
https://www.ema.europa.eu/en/documents/product-information/imfinzi-epar-product-information_en.pdf
(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
(https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-chemotherapy-mismatch-repair-deficient-primary-advanced-or-recurrent)
. Accessed June 2024.

12.  Dork T, et al. Genetic susceptibility to endometrial cancer: Risk
factors and clinical management. Cancers. 2020;12(9):2407.

13.  Oakin A, et al. Endometrial cancer: ESMO clinical practice guidelines
for diagnosis, treatment and follow-up. Annals of Oncology.
2022;33(9):860-877.

14.  American Cancer Society. What is endometrial cancer? Available at
https://www.cancer.org/cancer/endometrial-cancer/about/what-is-endometrial-cancer.html
(https://www.cancer.org/cancer/endometrial-cancer/about/what-is-endometrial-cancer.html)
. Accessed June 2024.

15.  American Cancer Society. Key statistics for endometrial cancer.
Available at:
https://www.cancer.org/cancer/types/endometrial-cancer/about/key-statistics.html
(https://www.cancer.org/cancer/types/endometrial-cancer/about/key-statistics.html)
. Accessed June 2024.

16.  National Cancer Institute. SEER. Cancer stat facts: Uterine cancer.
Available at: https://seer.cancer.gov/statfacts/html/corp.html
(https://seer.cancer.gov/statfacts/html/corp.html) . Accessed June 2024.

17.  Hamoud BH, et al. The evolving landscape of immunotherapy in uterine
cancer: A comprehensive review. Life. 2023;13:1502.

18.  Corr B, et al. Endometrial cancer: Molecular 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:
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma
(https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma)
. Accessed June 2024.

20.  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
(https://www.gov.uk/government/news/mhra-authorises-monoclonal-antibody-treatment-jemperli-to-be-used-with-chemotherapy-for-endometrial-cancer)
. Accessed June 2024.

 

 

Adrian Kemp

Company Secretary

AstraZeneca PLC

 

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