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Health Data Insight CIC, Capital Park, Fulbourn, Cambridge CB21 5BQ, UKNational Disease Registration Service, NHS Digital (NHSD), The Leeds Government Hub, 7&8 Wellington Place, Leeds LS1 4AP, UK
Analysis of recurrent/advanced endometrial cancer treatment patterns and outcomes in England
•
Results demonstrate the highly variable treatment patterns in the relapsed setting.
•
Clinical outcomes (median OS and time-to-next treatment) were poor at second-line.
•
Results highlight the need for standard of care guidance and innovative therapies.
Abstract
Objectives
In patients with recurrent/advanced endometrial cancer who have progressed after first-line treatment, there are a lack of real-world data on treatment patterns, characteristics, and survival outcomes. A novel study was conducted to determine real-world treatment patterns and outcomes in England.
Methods
This non-interventional study used routine, administrative health data from the National Cancer Registration and Analysis Service in England to identify patients diagnosed with recurrent/advanced endometrial cancer between 1 January 2013 and 31 December 2018, inclusive. A cohort of patients who progressed to second-line treatment were identified as the ‘immune checkpoint inhibitor-eligible second-line’ cohort. The co-primary objectives were to summarise baseline demographics, disease characteristics, treatments received, and depict overall survival and time-to-next-treatment (a proxy for progression-free survival) from the start of second-line therapy using Kaplan–Meier methodology.
Results
Overall, 12,058 patients were diagnosed with recurrent/advanced endometrial cancer;
999 patients were included in the immune checkpoint inhibitor-eligible second-line cohort and 77.9% (778 of 999) had advanced disease (Stage III/IV). The most common treatments received at second-line were carboplatin plus paclitaxel (27.9%), carboplatin plus liposomal doxorubicin (14.1%), liposomal doxorubicin monotherapy (13.0%), and paclitaxel monotherapy (11.6%). From initiation of second-line therapy, median (95% confidence interval) overall survival was 10.3 months (9.2–11.1), and median time-to-next-treatment was 7.7 months (7.1–8.2).
Conclusions
Treatments received in the relapsed setting were variable and survival outcomes poor at second-line, highlighting the need for standard of care guidance and innovative therapies to improve patient outcomes in England and in countries with similar treatment patterns.
The incidence of endometrial cancer has been increasing in the United Kingdom in recent years, and endometrial cancer is now the fourth most commonly diagnosed cancer, with approximately 9400 diagnoses and 2400 deaths caused by the disease annually [
]. Most patients with endometrial cancer are diagnosed at an early stage (Stage I or II) and have a more favourable prognosis compared with patients diagnosed with advanced (Stage III or IV) disease (5-year survival rates of >74% vs ≤15%, respectively) [
]. The British Gynaecological Cancer Society (BGCS) recommend chemotherapy with carboplatin plus paclitaxel for patients with advanced endometrial cancer or patients with recurrent disease who did not receive chemotherapy in the first-line setting [
Carboplatin and paclitaxel for advanced endometrial cancer: final overall survival and adverse event analysis of a phase III trial (NRG oncology/GOG0209).
]. However, the clinical efficacy and benefits of chemotherapy in the recurrent setting are not fully understood and no clear standard-of-care (SoC) exists [
], highlighting a unmet need for novel treatment regimens.
Immunotherapy with immune checkpoint inhibitors, such as anti-programmed cell death protein receptor-1 (anti-PD-1) agents, have emerged as a novel and efficacious treatment modality for patients with recurrent or advanced endometrial cancer in recent years [
Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
Journal for immunotherapy of cancer.2022; 10e003777
], dostarlimab monotherapy was conditionally approved as the first anti-PD-1 therapy in Europe for patients with recurrent or advanced endometrial cancer that has progressed on or after platinum-based chemotherapy, and is indicated for patients with mismatch repair deficient (dMMR)/microsatellite- instability-high (MSI-H) tumours [
]. Additionally, the combination regimen of the PD-1 inhibitor pembrolizumab plus lenvatinib (a tyrosine kinase inhibitor) has since been approved in Europe in the same treatment setting for patients of any biomarker status [
]. However, despite these recent approvals, most patients in Europe currently receive chemotherapy in the second-line or later setting with an aforementioned lack of SoC [
Real-world evidence is becoming increasingly valuable in enabling patient access to efficacious emerging treatment regimens, including for use in regulatory decisions and development of treatment guidelines [
]. Real-world data on characteristics and treatment patterns may help also determine optimal treatment strategies in patients with advanced endometrial cancer, provide data on SoC for use in health technology assessments, and further highlight the unmet medical need for patients with recurrent disease [
The objective of this real-world, observational study was to describe the demographics, clinical characteristics, and treatments received by patients in England with recurrent or advanced endometrial cancer and to describe the clinical outcomes observed following first-line platinum-based chemotherapy. The aim of the study was to provide insight on real-world treatment patterns and outcomes, which could be used in health technology assessments, and to help highlight unmet needs in the recurrent or advanced endometrial cancer landscape.
2. Methods
2.1 Study design
This study was a non-interventional, retrospective, descriptive study that utilised routine, linked patient-level heath data made available through the National Cancer Registration and Analysis Service (NCRAS) in England to identify patients with a primary diagnosis of endometrial cancer between 1 Jan 1, 2013 and 31 Dec 31, 2018, known as the index period, and who received a platinum-based regimen after the index date. (Fig. 1). The index date was the date of a patient's earliest diagnosis of recurrent or advanced disease. Patients were followed upon study entry until death, the end of the study period (30 Sep, 2020) or if the patient moved outside England, as data collection outside England was not routine. The study protocol is available in the Supplementary Materials (p2).
Figure shows the design used for this descriptive, noninterventional study, with study periods shown above timelines and example patient flow throughout the study shown below the timeline and per the figure key.
a Progression was not reported, but movement to a subsequent therapy was reported.
b Patient was deemed recurrent if diagnosed at Stage I/II (blue X) and subsequently resumed treatment following a 90-day gap between two treatments of any kind, i.e., surgery or other (orange X).
To describe the demographics, clinical characteristics, and treatments received by patients in England with recurrent or advanced endometrial cancer, the primary objectives of these analyses were: 1) to define a cohort of patients with recurrent or advanced endometrial cancer based on eligibility criteria from recent positive immune checkpoint inhibitor clinical trials in this patient population [
Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
Journal for immunotherapy of cancer.2022; 10e003777
A multicenter, open label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: study 309/KEYNOTE 775. The Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.
Clinical activity and safety of the anti-programmed death 1 monoclonal antibody Dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial Cancer: a nonrandomized phase 1 clinical trial.
], hereafter known as the ‘immune checkpoint inhibitor-eligible’ population; 2) to describe the baseline demographics and disease characteristics for the ‘immune checkpoint inhibitor-eligible second-line’ population, comprising patients who progressed to second-line treatment; 3) to describe systemic regimens received by the immune checkpoint inhibitor-eligible second-line cohort by line of therapy; and 4) to report clinical outcomes for the immune checkpoint inhibitor-eligible second-line population, including median overall survival (OS), and time-to-next treatment (TTNT) from second-line. Due to a lack of data on disease progression in the National Cancer Registration Dataset (NCRD) [
], one of the constituent datasets managed by the NCRAS, TTNT was used as a proxy for progression-free survival (PFS). The secondary objectives of these analyses were to report time-to-treatment discontinuation (TTD) at second-line for the immune checkpoint inhibitor-eligible-second-line cohort and to describe patient baseline demographics and clinical outcomes stratified by the five most common second-line treatment regimens received at second-line.
2.2.1 Data collection
Patient cohorts were created using routine administrative data available within the Cancer Analysis System (CAS), which is managed by the NCRAS with constituent datasets including 1) the National Cancer Registration Dataset (NCRD), which contains diagnostic and pathological data submitted by National Health Service (NHS) providers for every primary cancer diagnosed in England; 2) the Hospital Episode Statistics datasets, which describe all inpatient admissions, outpatient appointments and Accident & Emergency attendances; 3) the Systemic Anti-Cancer Therapy dataset (SACT), which contains detailed systemic treatment data for patients treated or funded by the NHS with secondary care prescriptions; 4) the National Radiotherapy Dataset (RTDS), which contains radiation therapy treatment information for every appointment in England; and 5) routine death registration data provided by the Office of National Statistics (ONS) [
] (Fig. S1). The CAS allows for tracking patients along their treatment pathway. Lines of therapy are not captured in the SACT dataset and an algorithm was therefore used to approximate lines of therapy (Supplementary Materials, p1).
2.2.2 Patients
Identification of the immune checkpoint inhibitor-eligible cohort of patients occurred in three phases. A general cohort was identified from the NCRD dataset including patients who were aged 18 years or above, had at least one incident primary diagnosis of endometrial cancer between 1 Jan, 2013 and 31 Dec, 2018, and were an England-resident at the time of diagnosis. Patients were excluded if there was no recorded age, date, or disease stage at diagnosis, or if diagnosis was made via death certificate only. Disease stage at time of registry diagnosis was derived by cancer registration staff and based primarily on Federation of Gynaecology and Obstetrics staging information provided by the diagnosing trust via the multidisciplinary team.
A recurrent or advanced (Stage III or IV) cohort of patients was then identified with at least one diagnosis of malignant neoplasm of corpus uteri (excluding malignant neoplasms of the myometrium). As disease progression is not documented within the NCRD, a definition of Stage I/II disease and a gap >90 days between consecutive treatments was used to identify patients with non-advanced recurrent disease, with the day of treatment resumption after the >90-day gap being used as index date for patients with recurrent disease. Treatments included surgery, systemic therapy and radiation therapy, with distinct treatment event dates extracted from the NCRD, Hospital Episode Statistics admitted patient care, SACT, and RTDS datasets.
To identify the immune checkpoint inhibitor-eligible cohort, key eligibility criteria used in recent ongoing clinical trials in this treatment setting were applied [
Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
Journal for immunotherapy of cancer.2022; 10e003777
A multicenter, open label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: study 309/KEYNOTE 775. The Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.
Clinical activity and safety of the anti-programmed death 1 monoclonal antibody Dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial Cancer: a nonrandomized phase 1 clinical trial.
], following adaptation for real-world data. These criteria included confirmed receipt of platinum-doublet therapy, and no evidence of having received any anti-PD-1, anti-PD-L1, anti-PD-L2 therapy, or bevacizumab, as identified in the SACT dataset. Prior treatment with hormone therapies was acceptable and not counted towards lines of therapy. Patients with a record of another primary malignancy, except for non-melanoma skin cancer and carcinoma in situ cervix, identified from the NCRD dataset, were excluded. Details on histologies eligible for inclusion, identified from the NCRD dataset, are shown in the supplementary materials (Table S1 in Supplementary Materials, p3).
2.2.3 Statistical analyses
Baseline demographics, disease characteristics, and treatment regimens and drug classes received at first-, second-, third- and fourth-line or later were descriptively summarised for the immune checkpoint inhibitor-eligible second-line cohort. OS, TTNT, and TTD were evaluated at second-line via Kaplan-Meier methodology, per the definitions described in the Supplementary Materials (p2). Baseline demographics, disease characteristics, and survival outcomes were then also stratified by the five most common treatments received at second-line. No formal statistical comparisons were performed. A sensitivity analysis was conducted comparing a gap of >90 days with a gap of >180 days to assess that the gap of >90 days used for the definition for recurrence was appropriate.
2.2.4 Missing data
The percentage of patients with missing data are displayed, without imputations, through a flow diagram showing the loss of patients from the study due to missing data on key inclusion criteria and any missing patient demographics and disease characteristics data are reported.
2.2.5 Role of funding source
This study (216960) was funded by GSK. GSK was involved in study design, data analysis, data interpretation, and the writing of the report. All authors had full access to the data upon request. All authors had final responsibility for the decision to submit for publication.
3. Results
3.1 Patient population
Between 1 Jan, 2013 and 31 Dec, 2018, 45,494 patients registered in the CAS were identified with a diagnosis of endometrial cancer and 12,058 (27%) of 45,494 patients had a diagnosis of recurrent or advanced endometrial cancer (Fig. 2). A sensitivity analysis provided confidence that the definition of recurrence used based on a gap of >90 days between consecutive treatment was not introducing bias (Table S2 in Supplementary Materials, p6). Overall, 28% (3415 of 12,058) of those patients met the eligibility criteria for the immune checkpoint inhibitor-eligible cohort. Most patients (7697 of 8643; 89%) were excluded from the immune checkpoint inhibitor-eligible cohort due to evidence of prior anti-PD-1 or -PD-L1/2 therapy or no evidence of platinum-doublet therapy. Few patients (645 of 8643; 7%) were excluded based on their histology. Of the immune checkpoint inhibitor-eligible cohort, only 29% (999 of 3415) of patients progressed to receive a second-line therapy, 9% (295 of 3415) received a third-line therapy, and 3% (89 of 3415) received four or more lines of therapy.
Patient flow diagram shows the attrition for the study including for the three patient selection phases which identified the overall EC cohort diagnosed between 1 Jan, 2013 and 31 Dec, 2018, recurrent or advanced EC cohort, the immune checkpoint inhibitor-eligible cohort and also shows the identification of the immune checkpoint inhibitor-eligible second-line cohort, which comprised patients from the immune checkpoint inhibitor-eligible cohort who progressed and received second-line treatment. N numbers may not total 100 due to rounding.
2L, second-line; EC, endometrial cancer; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; ICI, immune checkpoint inhibitor; PD-1; programmed cell death protein receptor-1; PD-L1/2, ligands of PD-1.
The mean age of the immune checkpoint inhibitor-eligible second-line population was 65.5 years (standard deviation: 8.6) and most patients with available data were white (84%; 841 of 976) (Table 1). Most patients (78%; 778 of 999) had Stage III or IV disease at diagnosis. The most common tumour grade at diagnosis was Grade 3 (50%; 380 of 759 patients with tumour grade available), however, there was a high number of patients with missing grade data (24%; 240 of 999). The most common histologies (reported for over 5% of patients) were endometrioid (42%; 424 of 999), serous (40%; 401 of 999), and non-specific carcinoma (7%; 74 of 999). Almost half of patients (50%; 498 of 999) had missing Eastern Cooperative Oncology Group Performance Status (ECOG PS) data at diagnosis. The median duration of follow-up from advanced diagnosis or recurrence was 27.4 months (range: 3.5–91.1).
Table 1Patient demographics and clinical characteristics for the immune checkpoint inhibitor-eligible second-line cohort at diagnosis.
‘Asian’ was defined as ‘Bangladeshi’, ‘Chinese’, ‘Indian’, ‘Pakistani’, or ‘any other Asian background’; ‘black’ was defined as ‘African’, ‘Caribbean’, or ‘any other black background’; ‘white’ was defined as ‘white British’, ‘white Irish’, or ‘any other white background’; and ‘other’ was defined as mixed ethnicity or any other ethnic group.
Reasons may include: no histological confirmation; biopsy too small to assign a grade; grading not formally recommended for that tumour at that site (e.g. squamous cell carcinoma of lung); and grade not being useful discriminator.
96 (13)
Histology, n (%)
Endometrioid
424 (42)
Serous
401 (40)
Non-specific carcinoma
74 (7)
Clear cell carcinoma
46 (5)
Mixed carcinoma
33 (3)
Dedifferentiated/Undifferentiated carcinoma
7 (1)
Neuroendocrine
6 (1)
Squamous
5 (1)
Mucinous
2 0)
Non-specific
1 (<1)
ECOG PS – n (%)
Recorded
501 (50)
0
320 (64)
1
181 (36)
2–4
0 (0)
Not recorded
498 (50)
Median duration of follow-up from recurrence or advanced diagnosis – months (range)
27.4 (3.5–91.1)
ECOG PS, Eastern Cooperative Oncology Group performance status; SD, standard deviation.
a Percentages may not total 100 due to rounding.
b ‘Asian’ was defined as ‘Bangladeshi’, ‘Chinese’, ‘Indian’, ‘Pakistani’, or ‘any other Asian background’; ‘black’ was defined as ‘African’, ‘Caribbean’, or ‘any other black background’; ‘white’ was defined as ‘white British’, ‘white Irish’, or ‘any other white background’; and ‘other’ was defined as mixed ethnicity or any other ethnic group.
c Reasons may include: no histological confirmation; biopsy too small to assign a grade; grading not formally recommended for that tumour at that site (e.g. squamous cell carcinoma of lung); and grade not being useful discriminator.
Platinum compounds and taxanes were the two most commonly received drug classes across all lines of therapy (Table S3 in Supplementary Materials, p7). At first-line, platinum-compounds were received by all but one patient. Use of monoclonal antibodies, cytotoxic antibiotics, enzyme inhibitors, hormone treatments, immune checkpoint inhibitors, immunomodulators, and other targeted agents was low (≤3% each) at all lines of therapy.
Nearly all patients (99%; 985 of 999) in the immune checkpoint inhibitor-eligible second-line cohort received their first platinum-doublet regimen at first-line, with 93% (931 of 999) receiving carboplatin plus paclitaxel (Table 2). The next most common treatment regimen was carboplatin plus pegylated liposomal doxorubicin (2%; 17 of 999). All other first-line treatment regimens were received by ≤1% of patients.
Table 2Systemic treatments by line of therapy for the immune checkpoint inhibitor-eligible second-line cohort.
Only chemotherapy regimens received by at least three patients are presented in the table. Percentages may not total 100 for each line of therapy due to rounding.
First-line (n = 999)
Carboplatin + paclitaxel
931 (93)
Carboplatin + pegylated liposomal doxorubicin
17 (2)
Cisplatin + doxorubicin
10 (1)
Carboplatin + gemcitabine
8 (1)
Carboplatin monotherapy
6 (1)
Cisplatin + etoposide
6 (1)
Capecitabine + oxaliplatin
3 (<1)
Carboplatin + epirubicin
3 (<1)
Second-line (n=999)
Carboplatin + paclitaxel
279 (28)
Carboplatin + liposomal doxorubicin
141 (14)
Liposomal doxorubicin
130 (13)
Paclitaxel
116 (12)
Carboplatin
93 (9)
Cisplatin + doxorubicin
49 (5)
Doxorubicin
38 (4)
Cisplatin
24 (2)
Carboplatin + gemcitabine
23 (2)
Carboplatin + doxorubicin
12 (1)
Third-line (n=295)
Paclitaxel
89 (30)
Liposomal doxorubicin
48 (16)
Carboplatin + paclitaxel
40 (14)
Carboplatin liposomal + doxorubicin
28 (9)
Carboplatin + gemcitabine
17 (6)
Carboplatin
15 (5)
Niraparib
8 (3)
Doxorubicin
6 (2)
Cisplatin
4 (1)
Cisplatin + cyclophosphamide doxorubicin
4 (1)
Fourth-line or later (n=89)
Paclitaxel
17 (19)
Carboplatin + paclitaxel
11 (12)
Carboplatin + gemcitabine
8 (9)
Carboplatin + liposomal doxorubicin
7 (8)
Carboplatin + gemcitabine paclitaxel
5 (6)
Carboplatin
3 (3)
a Only chemotherapy regimens received by at least three patients are presented in the table. Percentages may not total 100 for each line of therapy due to rounding.
Carboplatin plus paclitaxel was also the most common distinct treatment regimen at second-line (28%; 279 of 999). Other treatment regimens received by over 10% of patients at second-line included carboplatin plus liposomal doxorubicin (14%; 141 of 999), liposomal doxorubicin monotherapy (13%; 130 of 999), and paclitaxel monotherapy (12%; 116 of 999). In the second-line setting, an additional 20 distinct regimens were received by at least two patients and an additional 30 distinct regimens were received by one patient only. Paclitaxel monotherapy was the most common treatment regimen received in the third-line and fourth-line or later settings but was received by only 30% (89 of 295) and 19% (17 of 89) of patients, respectively.
The only non-chemotherapy-based treatment regimen in the top ten most common distinct treatment regimens at any line was niraparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), that was received by only 3% (8 of 295) of patients at third-line.
3.3 Clinical outcomes at second-line
Overall, 74% (739 of 999) of patients in the immune checkpoint inhibitor-eligible second-line cohort died (due to any cause) during the study period. Median OS from initiation of second-line treatment was 10.3 months (95% confidence interval [CI]: 9.2, 11.1) (Fig. 3A ), with an estimated 21% (95% CI: 19, 24) 2-year survival rate and 9% (95% CI: 7, 12) 5-year survival rate. Median TTNT from second-line was 7.7 months (95% CI: 7.1, 8.2)
Fig. 3Kaplan-Meier survival estimates at second-line for the immune checkpoint inhibitor-eligible second-line cohort.
Panel A shows the Kaplan-Meier curve and median survival estimate for overall survival, panel B for TTNT, and panel C for TTD. The data line represents the survivor function and shaded regions the 95% CI.
(Fig. 3B) with an estimated 11% (95% CI: 9, 14) survival at 24 months. Median TTD of second-line treatment was 3.4 months (95% CI: 3.2, 3.4) (Fig. 3C).
When stratifying clinical outcomes by the five most common treatment regimens received at second-line (Table 3), median OS was numerically longest (14.2 months [95% CI: 12.4, 16.1]) for the subgroup of patients who received carboplatin plus paclitaxel therapy at second-line, followed by patients who received carboplatin plus liposomal doxorubicin (13.9 months [95% CI: 11.2, 15.7]), with similar trends observed for median TTNT. Median OS and TTNT were numerically shorter for all singlet regimens when compared with doublet regimens, and was shortest for liposomal doxorubicin monotherapy, with a median OS of 4.9 months (95% CI: 4.2, 6.1) and median TTNT of 4.1 months (95% CI: 3.4, 4.6). Median TTD was numerically longest for carboplatin plus liposomal doxorubicin (4.6 months [95% CI: 4.0, 4.6]) and shortest for liposomal doxorubicin monotherapy at 2.8 months (95% CI: 2.1, 2.9). Some numerical differences were observed in patient baseline characteristics between groups: fewer younger patients received carboplatin monotherapy and liposomal doxorubicin monotherapy (<65 years; 31% [29 of 93] and 33% [43 of 130], respectively) than the other regimens (39–45%); a higher percentage of patients that received carboplatin monotherapy and liposomal doxorubicin monotherapy had unknown ECOG PS status (not recorded; 53% ([49 of 93] and 54% [70 of 130], respectively) when compared with other regimens (43–49%); and carboplatin plus paclitaxel was given to a higher percentage of patients with advanced disease (Stage III/IV; 84% [235 of 279]) than the other regimens (65–80%) (Table S4 in Supplementary Materials, p8).
Table 3Survival outcomes for the immune checkpoint inhibitor-eligible second-line cohort, including by the five most common second-line treatment regimens.
The aim of this real-world, retrospective, observational study was to describe the treatment patterns and clinical outcomes at second-line for patients diagnosed with recurrent or advanced endometrial cancer in England between 2013 and 2018 and followed-up from diagnosis to 30 Sep, 2020 and to gain real-world data which could be used in health technology assessments and highlight unmet needs in this patient population. To our knowledge, this is the first report of real-world treatment patterns and clinical outcomes for this patient population in England.
There was consistency in treatment received by patients at first-line, with 93% receiving SoC carboplatin plus paclitaxel as their first-line treatment regimen [
Carboplatin and paclitaxel for advanced endometrial cancer: final overall survival and adverse event analysis of a phase III trial (NRG oncology/GOG0209).
]. In the relapsed setting, however, there was great variability in the drug classes and treatment regimens received, with >60 distinct regimens received at second-line. The most common treatment regimens received at second-, third-, and fourth-line or later, respectively, were carboplatin plus paclitaxel, received by 28% of patients, and paclitaxel monotherapy received by 30% and 19% of patients, respectively. These analyses also support that less than one-third of patients received treatment beyond first-line, and limited efficacy and a high toxicity profile of these treatments may be a contributing factor [
A multicenter, open label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: study 309/KEYNOTE 775. The Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.
Treatment of advanced or recurrent endometrial carcinoma with doxorubicin in patients progressing after paclitaxel/carboplatin: Memorial Sloan-Kettering Cancer Center experience from 1995 to 2009.
], the need for new treatment options for this patient population, and in due course, updated guidelines. To note, the PARPi niraparib was the only non-chemotherapy-based treatment received at any line, however, is approved for use in advanced ovarian cancer [
Treatment of advanced or recurrent endometrial carcinoma with doxorubicin in patients progressing after paclitaxel/carboplatin: Memorial Sloan-Kettering Cancer Center experience from 1995 to 2009.
]. Information as to whether this treatment was received as part of a clinical trial or as treatment for metastasis was not available and given the limitations in the data source we are unable to exclude an additional diagnosis of advanced ovarian cancer in these patients (see Supplementary Materials, p2).
Survival outcomes at second-line were very poor in these analyses. However, whilst no formal comparisons were performed, outcomes were generally in line with previous clinical trial data for chemotherapy in the second-line setting for advanced or recurrent patients (median OS <12.3 months and median PFS <4.7 months) [
Treatment of advanced or recurrent endometrial carcinoma with doxorubicin in patients progressing after paclitaxel/carboplatin: Memorial Sloan-Kettering Cancer Center experience from 1995 to 2009.
ZoptEC: phase III randomized controlled study comparing zoptarelin with doxorubicin as second line therapy for locally advanced, recurrent, or metastatic endometrial cancer (NCT01767155).
Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin.
]. Median OS for all patients in these analyses was 10.3 months (95% CI: 9.2, 11.1), median TTNT was 7.7 months (95% CI: 7.1, 8.2) (which was used as a proxy for PFS due to a lack of data on progression in the NCRD), and median TTD was 3.4 months (95% CI: 3.2, 3.4), highlighting the unmet need for efficacious treatment regimens in this patient population. Whilst hormone therapy is recommended by ESMO-ESGO-ESTRO guidelines for the treatment of recurrent or advanced endometrial cancer [
LBA28 a randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial.
Both the anti-PD-1 inhibitor dostarlimab and the combination of pembrolizumab plus lenvatinib have recently been approved as treatment regimens in Europe for recurrent or advanced endometrial cancer in the post‑platinum setting, however their use is not yet widespread due to limited reimbursement [
]. The anti-PD-1 inhibitor dostarlimab, was conditionally approved in 2021 for dMMR/MSI-H recurrent or advanced endometrial cancer that has progressed on or after platinum-based chemotherapy, based on a reported overall response rate of 43.5% (95% CI: 34.0, 53.4) in the Phase I GARNET trial [
]. The median duration of response had not been reached at a median follow-up of 27.6 months and median disease control rate was 60.1% (95% CI: 51.6, 68.2) [
Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): The GARNET study.
Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): The GARNET study.
Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
Journal for immunotherapy of cancer.2022; 10e003777
]. In February 2022, NICE recommended dostarlimab monotherapy for its licensed indication through the Cancer Drugs Fund in England, a recommendation based on both GARNET trial outcomes and subsequently-identified real-world standard-of-care outcomes [
]. The combination of pembrolizumab plus lenvatinib was approved for the treatment of patients with recurrent or advanced endometrial cancer who progressed on or following platinum-based therapy, regardless of biomarker status, and approval was based on a median OS of 18.3 months (95% CI: 15.2, 20.5) and a median PFS of 7.2 months (95% CI:5.7, 7.6) [
Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
Journal for immunotherapy of cancer.2022; 10e003777
A multicenter, open label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: study 309/KEYNOTE 775. The Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.
Clinical activity and safety of the anti-programmed death 1 monoclonal antibody Dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial Cancer: a nonrandomized phase 1 clinical trial.
Safety and Antitumor Activity of Dostarlimab in Patients with Advanced or Recurrent DNA mismatch repair deficient ( dMMR ) Or Proficient ( MMRp ) Endometrial cancer: Results from GARNET.
European Society for Medical Oncology (ESMO),
2020
], these data suggest that immune checkpoint inhibitors could achieve improved survival outcomes for patients with recurrent or advanced endometrial cancer in the post‑platinum setting. With these recent approvals in the second-line setting, there is now considerable interest with regards to immunotherapy in the first-line setting, either as monotherapy or in combination with a variety of treatment agents, with a number of Phase III randomised trials initiated [
A Study to Evaluate Dostarlimab Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Participants With Recurrent or Primary Advanced Endometrial Cancer (RUBY).
Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma (MK-3475-C93/KEYNOTE-C93/GOG-3064/ENGOT-en15).
]. These may offer further treatment options for women with recurrent or advanced endometrial cancer in the future.
To gain further granularity on current real-world clinical outcomes, outcomes were stratified by the five most common second-line treatment regimens. Median OS and TTNT from second-line were numerically longer with carboplatin plus paclitaxel, and with 94% patients receiving carboplatin plus paclitaxel at first-line, these data support that rechallenge with the regimen may be most acceptable in terms of survival outcomes if no novel treatment options are available. However, safety analyses were not performed, and survival outcomes were still poor. Comparison of survival data between groups is also limited as no formal comparisons were performed and not all factors that impact response to treatment were collected in this study, such as the platinum-free interval [
Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin.
]. Additionally, whilst median OS and TTNT were longest for doublet regimens when compared with singlet regimens, some variations in demographics and disease characteristics were observed between the treatment groups. This may reflect that certain patient populations are more likely to receive some type of treatments than others, which may thereby impact response to treatment, however, conclusions on bias and causal effects cannot be made based on these observational data.
Retrospective database studies can provide invaluable information on real-world clinical practice to complement clinical trial data, however, limitations can include the quality of data recording, lack of standardisation, or availability of relevant data items [
Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
Journal for immunotherapy of cancer.2022; 10e003777
Clinical activity and safety of the anti-programmed death 1 monoclonal antibody Dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial Cancer: a nonrandomized phase 1 clinical trial.
]; however, MMR/MSI status data is not commonly available in the NCRAS and could not be included as an eligibility-criteria for these analyses, nor clinical outcome subanalyses performed [
Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial.
Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
Journal for immunotherapy of cancer.2022; 10e003777
A multicenter, open label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: study 309/KEYNOTE 775. The Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.
Clinical activity and safety of the anti-programmed death 1 monoclonal antibody Dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial Cancer: a nonrandomized phase 1 clinical trial.
], a large number of patients (50%) had unrecorded ECOG PS. Patients with unknown ECOG PS were included in these analyses to avoid bias and small sample sizes. Most of these patients are assumed to have an ECOG PS of 0–1 as physicians may consider those with ECOG PS of ≥2 ineligible for chemotherapy, as an ECOG PS ≥2 is associated with worse prognosis in patients treated for advanced solid tumours [
Treatment of advanced or recurrent endometrial carcinoma with doxorubicin in patients progressing after paclitaxel/carboplatin: Memorial Sloan-Kettering Cancer Center experience from 1995 to 2009.
], a proxy of TTNT was used for PFS and a definition based on a gap of >90 days between consecutive treatment was used to identify patients with recurrence; however, this definition was validated by sensitivity analyses. Finally, the number of patients receiving some oral or hormone therapies may have been underreported as only secondary-care treatments were captured in the SACT constituent database [
Overall, these observational, descriptive analyses have provided a valuable insight into real-world treatment patterns and outcomes for patients with recurrent or advanced endometrial cancer in England, which have been used in health technology assessments and also highlight the utility of datasets available through the NCRAS for providing such real-world data. Further, the data provide evidence for a lack of available treatment options, the need for novel options to improve the poor clinical outcomes observed at second-line and, in due course, the need for updated guidelines on SoC for patients with recurrent or advanced endometrial cancer. Considering the increasing utilisation of real-world data in regulatory and healthcare technology assessments, data reported in these analyses may be useful to help ensure patient access to novel therapeutics in future, including immune checkpoint inhibitors which are emerging as the backbone combination agent for recurrent or advanced endometrial cancer.
Data sharing statement
GSK makes available anonymised individual participant data and associated documents from interventional clinical studies that evaluate medicines, upon approval of proposals submitted to www.clinicalstudydatarequest.com. To access data for other types of GSK sponsored research, for study documents without patient-level data, and for clinical studies not listed, please submit an enquiry via this website.
Author contributions
KH, FSN, US, and HSC contributed to conception or design of the study and data analysis or interpretation. CK contributed to conception or design of the study, acquisition of data, and data analysis or interpretation. KH and CK have verified the data.
All authors had full access to all the data in the study and were involved at each stage of manuscript preparation, approved the final version, and accept responsibility to submit for publication.
Declaration of Competing Interest
KH, FSN, US, and HSC are employees of GSK. CK has no conflicts of interest to declare.
Prior presentation: These data were presented in part at the European Society for Medical Oncology (ESMO) (virtual) congress 16–21 September 2021.
Acknowledgements
This work uses data that has been provided by patients and collected by the National Health Service (NHS) as part of their care and support. The data are collated, maintained and quality assured by the National Disease Registration Service, which is part of NHS Digital.
This study was funded by GSK (GSK; 216960). GSK contributed to the study design, implementation, data collection, interpretation and analysis. Medical writing support was provided by Jo Mehat, PhD, and Victoria Hunter, MSc, of Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.
Carboplatin and paclitaxel for advanced endometrial cancer: final overall survival and adverse event analysis of a phase III trial (NRG oncology/GOG0209).
Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET-a phase I, single-arm study.
Journal for immunotherapy of cancer.2022; 10e003777
A multicenter, open label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: study 309/KEYNOTE 775. The Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer.
Clinical activity and safety of the anti-programmed death 1 monoclonal antibody Dostarlimab for patients with recurrent or advanced mismatch repair-deficient endometrial Cancer: a nonrandomized phase 1 clinical trial.
Treatment of advanced or recurrent endometrial carcinoma with doxorubicin in patients progressing after paclitaxel/carboplatin: Memorial Sloan-Kettering Cancer Center experience from 1995 to 2009.
ZoptEC: phase III randomized controlled study comparing zoptarelin with doxorubicin as second line therapy for locally advanced, recurrent, or metastatic endometrial cancer (NCT01767155).
Second-line chemotherapy for advanced or recurrent endometrial carcinoma previously treated with paclitaxel and carboplatin, with or without epirubicin.
LBA28 a randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial.
Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): The GARNET study.
Safety and Antitumor Activity of Dostarlimab in Patients with Advanced or Recurrent DNA mismatch repair deficient ( dMMR ) Or Proficient ( MMRp ) Endometrial cancer: Results from GARNET.
European Society for Medical Oncology (ESMO),
2020(Virtual 2020)
A Study to Evaluate Dostarlimab Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Participants With Recurrent or Primary Advanced Endometrial Cancer (RUBY).
Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Mismatch Repair Deficient (dMMR) Advanced or Recurrent Endometrial Carcinoma (MK-3475-C93/KEYNOTE-C93/GOG-3064/ENGOT-en15).
Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial.
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