Clinical trialPhase 3Endometrial (womb) cancer

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer

N Engl J Med · 2023816 patients (225 in the dMMR cohort and 591 in the pMMR cohort)

Eskander RN, Sill MW, Beffa L, et al. N Engl J Med. 2023. 388:2159-2170

Study type: Clinical trial
Study name: NRG-GY018 (KEYNOTE-868)
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled phase 3 trial; 1:1 randomisation in two separate dMMR and pMMR cohorts, stratified by ECOG performance status and previous adjuvant chemotherapy
Sample size: 816 patients (225 in the dMMR cohort and 591 in the pMMR cohort)
Source: N Engl J Med · 2023
Trial registration: NCT03914612

In plain words

Women with advanced or recurrent womb cancer received standard chemotherapy with either the immunotherapy pembrolizumab or a placebo, followed by continued pembrolizumab or placebo. Immunotherapy delayed the growth of the cancer, especially in tumours with a DNA repair defect (dMMR): one year later, about twice as many patients in this group were free of cancer growth. Severe side effects were slightly more frequent.

Key results

74% vs 38%

dMMR: 12-month progression-free survival

HR 0.30 (95% CI 0.19–0.48); P<0.001; median follow-up 12 months

13.1 vs 8.7 months

pMMR: median progression-free survival

HR 0.54 (0.41–0.71); P<0.001; median follow-up 7.9 months

pMMR: HR 0.79; dMMR: HR 0.55

Overall survival (Nat Med 2025; immature)

pMMR 0.53–1.17; dMMR 0.25–1.19; not statistically significant

pMMR: HR 0.64; dMMR: HR 0.45

Progression-free survival by blinded independent central review (exploratory)

pMMR 0.49–0.85; dMMR 0.27–0.73

dMMR: 63.3% vs 47.2%; pMMR: 55.1% vs 45.3%

Grade 3 or higher adverse events

Regardless of attribution

Drugs in this study:Carboplatin (Paraplatin)Paclitaxel (Taxol)Pembrolizumab (Keytruda)

Dose and schedule cards

Carboplatin + paclitaxel every 3 weeks

First line for unresectable stage III or IV disease or recurrence; non-MMRd with rapidly growing or symptomatic disease, or any patient not receiving immunotherapyCycle length: Every 21 daysOn the page “Endometrial (womb) cancer” · Advanced or recurrent disease: first line

First line for unresectable stage III or IV disease or recurrence; non-MMRd with rapidly growing or symptomatic disease, or any patient not receiving immunotherapy

Drug	Dose	Route	Schedule
Paclitaxel	175 mg/m² (3-hour infusion)	IV	Day 1
Carboplatin	AUC 5 to 6	IV	Day 1

Cycle length: Every 21 days
Duration: 6 cycles [I, A]

Pan-Asian ESMO: carboplatin AUC 5 to 6 + paclitaxel 175 mg/m² every 21 days for 6 cycles is the first-line standard [I, A]; ESGO also considers 6 cycles the standard [I, A]. In GOG-0209 (carboplatin AUC 6 + paclitaxel 175 for 7 cycles), neutropenia was 80% and sensory neuropathy above grade 2 occurred in 20%. 3-hour paclitaxel infusion as in NRG-GY018.

On the page “Endometrial (womb) cancer” · Advanced or recurrent disease: first line

Pembrolizumab + carboplatin–paclitaxel (NRG-GY018)

First line: measurable stage III or IVA, IVB or recurrence; dMMR and pMMR; prior adjuvant chemotherapy allowed if at least 12 months earlier; ECOG 0 to 2; carcinosarcoma excludedOn the page “Endometrial (womb) cancer” · Advanced or recurrent disease: first line

First line: measurable stage III or IVA, IVB or recurrence; dMMR and pMMR; prior adjuvant chemotherapy allowed if at least 12 months earlier; ECOG 0 to 2; carcinosarcoma excluded

Drug	Dose	Route	Schedule
With chemotherapy: 6 cycles every 21 days
Pembrolizumab	200 mg (30-minute infusion)	IV	Day 1, before chemotherapy
Paclitaxel	175 mg/m² (3-hour infusion)	IV	Day 1
Carboplatin	AUC 5 (30- to 60-minute infusion)	IV	Day 1
Maintenance: up to 14 cycles
Pembrolizumab	400 mg (30-minute infusion)	IV	Day 1 every 6 weeks

Cycle length: 21 days with chemotherapy, then 6 weeks
Duration: Up to 20 cycles of pembrolizumab (about 24 months), or until progression or unacceptable toxicity

Patients with measurable disease and a partial response or stable disease after cycle 6 could continue chemotherapy with pembrolizumab for up to 10 cycles at the investigator's discretion. FDA label: 200 mg every 3 weeks or 400 mg every 6 weeks with carboplatin–paclitaxel, regardless of MMR status, for up to 24 months. Grade 3 or worse adverse events: dMMR 63.3% vs 47.2%; pMMR 55.1% vs 45.3%.

On the page “Endometrial (womb) cancer” · Advanced or recurrent disease: first line

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Pembrolizumab + paclitaxel and carboplatin

Pembrolizumab 200 mg IV (30-minute infusion) every 3 weeks with paclitaxel 175 mg/m² IV (3-hour infusion) and carboplatin AUC 5 IV (30 to 60 minutes) on day 1, for 6 cycles; then maintenance pembrolizumab 400 mg IV (30 minutes) every 6 weeks for up to 14 cycles (maximum 20 cycles of pembrolizumab). Patients with measurable disease and a partial response or stable disease after cycle 6 could continue chemotherapy for up to 10 cycles at the investigator's discretion.

2Placebo + paclitaxel and carboplatin

Placebo every 3 weeks with the same paclitaxel and carboplatin for 6 cycles; then maintenance placebo every 6 weeks for up to 14 cycles.

Source of the regimen details: Full text of the paper (PMC10351614, Trial Design section) and the FDA label for Keytruda

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Women aged 18 or older with newly diagnosed stage III or IVA endometrial cancer with measurable disease (RECIST version 1.1), or stage IVB or recurrent disease with or without measurable disease, of any histological type except carcinosarcoma; ECOG performance status 0, 1 or 2. Previous adjuvant chemotherapy was allowed if the treatment-free interval was at least 12 months; previous radiotherapy or hormonal therapy was allowed. MMR status was determined by immunohistochemistry.

Endpoints

Primary endpoint: progression-free survival in both cohorts (investigator-assessed per RECIST version 1.1). Secondary endpoints: overall survival and safety. Interim analyses were planned after at least 84 events in the dMMR cohort and 196 events in the pMMR cohort.

Safety and side effects

Grade 3 or higher adverse events were reported in 63.3% of the pembrolizumab group and 47.2% of the placebo group in the dMMR cohort, and in 55.1% and 45.3% in the pMMR cohort. Fatal adverse events occurred in 3 patients in the dMMR cohort (1 in the pembrolizumab group) and 8 patients in the pMMR cohort (6 in the pembrolizumab group). Adverse events matched the known profile of pembrolizumab and combination chemotherapy.

Clinical significance and place in guidelines

Together with RUBY, NRG-GY018 made the addition of a PD-1 inhibitor to carboplatin–paclitaxel the standard first-line treatment for advanced or recurrent endometrial cancer. The FDA has approved pembrolizumab with carboplatin and paclitaxel, followed by pembrolizumab alone, for primary advanced or recurrent endometrial cancer regardless of MMR status. The ESGO/ESTRO/ESP 2025 guideline recommends this approach in MMRd disease [I, A] and lists it as an option in non-MMRd disease [I, B].

Limitations

Overall survival was immature at the primary analysis and was still not statistically significant at the later analysis. Follow-up in the pMMR cohort was short (median 7.9 months). Carcinosarcoma was excluded. Results appeared heterogeneous by geographic region, and some subgroups were small.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.