AtTEnd - Atezolizumab in Endometrial cancer
Research type
Research Study
Full title
Phase III Double-blind, randomised, placebo controlled trial of atezolizumab in combination with paclitaxel and carboplatin in women with advanced/ recurrent endometrial cancer
IRAS ID
251207
Contact name
Emma Hudson
Contact email
Sponsor organisation
Mario Negri Gynecology Oncology Group (MaNGO)
Eudract number
2018-001072-37
Clinicaltrials.gov Identifier
Duration of Study in the UK
4 years, 0 months, 0 days
Research summary
Research Summary
The study will assess the efficacy of atezolizumab compared to placebo, against a background of a standard chemotherapy regime (carboplatin and paclitaxel) in women with advanced or recurrent endometrial cancer.\nAtezolizumab has been recently licenced for urothelial cancer and an earlier small pilot study showed an Overall Response Rate in 15% of the patients.\nAtezolizumab is an immunotherapy which is targeted against the PD-L1 (a lymphocyte protein involved in stopping programmed cell death). This target has been identified as being important in tumours with a highly mutated cancers, such as endometrial cancer.\nAdvanced or recurrent endometrial cancer patients are associated with a very poor prognosis.
Summary of Results
"• Who carried out the research?
The research was Sponsored by Mario Negri Gynecology Oncology Group (MaNGO) - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano and funded by F. Hoffmann-La Roche Ltd. In the UK, the NHS Greater Glasgow & Clyde was the UK Lead Group, UK Chief Investigator was Dr Emma Hudson (Velindre Cancer Centre, Cardiff) and UK participation was co-ordinated by the Glasgow Oncology Clinical Trials Unit (formerly known as Cancer Research UK Glasgow Clinical Trials Unit).
• Where and when the study took place
The study started recruiting globally in October 2018 and opened to recruitment at the first site in the UK on 9th Oct 2019. Ten sites participated in the UK; The Beatson West of Scotland Cancer Centre, Derriford Hospital, Hammersmith Hospital, Nottingham City Hospital, Royal Derby Hospital, Royal Devon & Exeter Hospital, The Royal Marsden Hospital, St Bartholomew’s Hospital, The Christie Hospital and Velindre Cancer Centre. Other participating countries were Italy, Spain, Germany, Austria, Switzerland, Japan, Australia, New Zealand, South Korea and Taiwan. Recruitment ended on 7th Jan 2022, with overall study end date 20th Jan 2025.• Why was the research needed?
Endometrial cancer (a cancer of the lining of the uterus) is one of the most common cancers in women. Many women are cured when the cancer is found early, but for those with advanced or recurrent disease, the outcome is still poor. The current standard treatment is chemotherapy with carboplatin and paclitaxel. However, when the cancer comes back or spreads to other organs, expectation of life is usually limited to about 12–15 months; for these reasons, new and more effective treatments are urgently needed.
Research has shown that cancer cells have many genetic changes compared to normal cells. These changes allow the immune system to detect and eliminate cancer cells; however, to survive, cancer cells may implement several strategies to evade immune system detection. Among these, the PD- 1/PD-L1 pathway is one of the most studied; it has been shown that drugs (called immunotherapic) blocking the PD-1/PD-L1 pathway can shrink tumors or slow disease progression in women with endometrial cancer, especially those whose tumors have specific features such as microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR). Based on these results, some immunotherapy drugs (such as pembrolizumab and dostarlimab) have already been approved for specific groups of patients.
Combining immunotherapy with standard chemotherapy has also shown promising results in large clinical trials. These studies suggest that chemotherapy may help the immune system better recognise the cancer, and that the combination could be more effective than chemotherapy alone.
Atezolizumab is an immunotherapy drug that blocks PD-L1. It is already used to treat several types of cancer and has shown encouraging early results in women with advanced endometrial cancer.• What were the main questions studied?
The main question studied was whether adding atezolizumab to standard carboplatin-paclitaxel chemotherapy in patients with severe/very severe endometrial cancer increases the time during which the tumour shrinks or, at least, does not grow (progression-free survival) and the time the patients are alive (overall survival) when compared with placebo (an identical-looking drug but with no medicine in it).• Who participated in the study?
549 patients were recruited globally, with 56 patients recruited from the UK participating sites.• What treatments or interventions did the participants take/receive?
All women received standard chemotherapy with paclitaxel and carboplatin every 3 weeks for 6–8 cycles. The two groups differed only in the additional medicine they received:
• One group received chemotherapy plus a placebo.
• The other group received chemotherapy plus the study drug atezolizumab, given as an intravenous (IV) infusion every 3 weeks.After finishing the chemotherapy cycles, women continued to receive either placebo or atezolizumab alone every 3 weeks until their cancer got worse or they needed to stop for another medical reason.
• What medical problems (adverse reactions) did the participants have?
All side effects in this study were recorded from the time the participant signed the consent form to participate until 135 days after the end of study treatment. Conditions participants had before the study that got worse were also reported as side effects.
Some side effects resulted in death, in a continuing or significant disability, in a hospitalization or extension of an existing hospital stay, or were life-threatening or important medical events; these events were marked as serious side effects, with the exclusion of the following events:
• Death due to endometrial cancer progression
• Hospitalizations already programmed before the study or for protocol-mandated procedures.This study had an independent data and safety monitoring committee that reviewed the trial data every 6 months and closely watched for any safety concerns.
48 participants out of 385 (13.5%) had 58 atezolizumab-related serious side effects, while 6 participants (3.2%), among 185, had 6 placebo-related serious side effects.
270 participants out of 385 (76%) had atezolizumab-related non-serious side effects, while 118 participants out of 185 (64%) had placebo-related non-serious side effects.
The data collected showed that the participants enrolled in the atezolizumab+chemotherapy group had more side effects; however, this result was expected.
Two patients died due to side effects, one in each group, both for lung infection (pneumonia).
To ensure participant safety, the blinding of treatments was lifted whenever the treating clinician deemed it necessary for the appropriate management of an adverse event. This allowed the clinical team to make the most suitable medical decisions for patient care.
• What happened during the study?
Between 3rd Oct 2018 and 7th Jan 2022, 669 patients were screened for eligibility, and 549 patients from 89 centres were randomised (189 in Arm A and 360 in Arm B). Two patients were excluded from all the analyses because of the lack of consent to use their data. At study closure, 8 patients (1.5%) had not received any study treatment, 46 patients (8.4%) were on treatment with atezolizumab as maintenance at the study closure, 150 (27.3%) were in follow-up and 345 (63.8%) patients withdrew from the study, mainly due to death (304 patients, 88.1%). The median duration of follow-up was 49.1 months in the dMMR population and 48.9 months in the all-comer population.• What were the results of the study?
Overall, the study found that adding atezolizumab to standard chemotherapy helped patients with advanced or recurrent endometrial cancer live longer without their disease getting worse, especially in those whose tumors had a specific genetic feature called dMMR. The side effects seen with atezolizumab were in line with what is normally expected for this type of treatment. However, when looking at overall survival in the whole group of patients, the addition of atezolizumab did not show a clear improvement. In patients with dMMR tumors, the overall survival results supported the benefit already seen in how long the cancer stayed under control. The final results are being prepared for publication in a scientific journal.• How has this study helped patients and researchers?
Endometrial cancer is one of the most common gynecologic cancers, and patients with advanced or recurrent disease often face limited treatment options. This study tested whether adding atezolizumab, an immunotherapy, to standard chemotherapy could help control the disease for longer.
The study showed that:
• Patients whose tumors had a specific genetic feature called dMMR lived longer without their cancer getting worse when they received atezolizumab plus chemotherapy.
• In these patients, the encouraging results for overall survival supported the benefit already seen in delaying disease progression.
• The side effects seen with atezolizumab were consistent with what is normally expected for this type of treatment, helping doctors better understand its safety in this patient population.
• For the group of patients overall, the study did not show a clear improvement in how long they lived, which will help researchers understand which patients are most likely to benefit from this treatment.
This study will help researchers better understand the role of immunotherapy in endometrial cancer, especially for patients with dMMR tumors. The results may drive the development of future treatment strategies and help identify which patients might benefit most from adding immunotherapy to chemotherapy.• Details of any further research planned
Additional analyses are currently being performed on tumour tissue samples collected during the study. These analyses aim to identify certain characteristics of the tumour that may help to understand which patients are more likely to benefit from immunotherapy and which patients are unlikely to benefit from this treatment.• Where can I learn more about this study?
The manuscript reporting the updated PFS and the final OS results is under preparation to be published in a peer-reviewed journal. ClinicalTrials.gov will be updated with a summary of results.More information on this study can be found on the websites listed below:
• https://clinicaltrials.gov/study/NCT03603184?cond=Endometrial%20Cancer&intr=Atezolizumab&rank=2
• https://www.mango-group.it/studi/recruitment-closed/endometrial
• https://pubmed.ncbi.nlm.nih.gov/39102832/"REC name
Wales REC 3
REC reference
18/WA/0417
Date of REC Opinion
29 Jan 2019
REC opinion
Further Information Favourable Opinion