Clinical trialPhase 3Endometrial (womb) cancer

Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer

N Engl J Med · 2022827 patients (697 with pMMR disease and 130 with dMMR disease)

Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, et al. N Engl J Med. 2022. 386:437-448

Study type: Clinical trial
Study name: KEYNOTE-775
Phase: Phase 3
Design: Phase 3 trial with 1:1 randomisation, controlled with chemotherapy of the treating physician's choice (Study 309)
Sample size: 827 patients (697 with pMMR disease and 130 with dMMR disease)
Source: N Engl J Med · 2022
Trial registration: NCT03517449

In plain words

In this study, women with advanced endometrial cancer (cancer of the lining of the womb) who had already had platinum-containing chemotherapy received either a combination of two drugs, lenvatinib and pembrolizumab, or another chemotherapy. Patients who had the two-drug combination went longer without the disease growing and lived longer. On the other hand, severe side effects were seen somewhat more often in this group. The right treatment should be decided by the treating doctor based on each patient's situation.

Key results

6.6 vs 3.8 months

Median progression-free survival (pMMR population)

Hazard ratio for progression or death 0.60; 95% CI 0.50–0.72; P<0.001

7.2 vs 3.8 months

Median progression-free survival (all patients)

Hazard ratio 0.56; 95% CI 0.47–0.66; P<0.001

17.4 vs 12.0 months

Median overall survival (pMMR population)

Hazard ratio for death 0.68; 95% CI 0.56–0.84; P<0.001

18.3 vs 11.4 months

Median overall survival (all patients)

Hazard ratio 0.62; 95% CI 0.51–0.75; P<0.001

88.9% vs 72.7%

Grade 3 or higher adverse events

Lenvatinib plus pembrolizumab vs chemotherapy

Drugs in this study:Doxorubicin (Adriamycin)Lenvatinib (Lenvima)Paclitaxel (Taxol)Pembrolizumab (Keytruda)

Dose and schedule cards

Lenvatinib + pembrolizumab (KEYNOTE-775)

Progression after prior systemic therapy in any setting, not a candidate for curative surgery or radiotherapy; pMMR or not MSI-H (FDA indication); ESGO: non-MMRd without prior immunotherapy [I, A]Each drug’s schedule in the tableOn the page “Endometrial (womb) cancer” · Advanced or recurrent disease: after platinum-based chemotherapy

Progression after prior systemic therapy in any setting, not a candidate for curative surgery or radiotherapy; pMMR or not MSI-H (FDA indication); ESGO: non-MMRd without prior immunotherapy [I, A]

Drug	Dose	Route	Schedule
Lenvatinib	20 mg once daily	Oral	Daily, continuously
Pembrolizumab	200 mg (or 400 mg every 6 weeks per the label)	IV	Day 1 every 3 weeks

Cycle schedule: Lenvatinib daily and continuously; pembrolizumab every 3 weeks
Duration: Until progression or unacceptable toxicity; pembrolizumab for up to 24 months

Lenvatinib dose reductions: 14 mg, then 10 mg, then 8 mg daily; with creatinine clearance below 30 or severe hepatic impairment (Child-Pugh C), 10 mg daily. In the label, hypertension 67% (grade 3–4: 39%) and hypothyroidism 67%; grade 3 or worse adverse events in the trial 88.9%. Regimen page: Lenvatinib with pembrolizumab

On the page “Endometrial (womb) cancer” · Advanced or recurrent disease: after platinum-based chemotherapy

Doxorubicin every 3 weeks (KEYNOTE-775 control arm)

After platinum-based chemotherapy, especially after first-line immunotherapy or when lenvatinib + pembrolizumab is not suitable [IV, B]Cycle length: Every 21 daysOn the page “Endometrial (womb) cancer” · Advanced or recurrent disease: after platinum-based chemotherapy

After platinum-based chemotherapy, especially after first-line immunotherapy or when lenvatinib + pembrolizumab is not suitable [IV, B]

Drug	Dose	Route	Schedule
Doxorubicin	60 mg/m²	IV	Day 1

Cycle length: Every 21 days
Duration: Until progression or unacceptable toxicity, within the cumulative dose limit

Dose source:; place in the guideline:. The risk of cardiomyopathy rises with the cumulative dose (1% to 20% at cumulative doses of 300 to 500 mg/m² given every 3 weeks); check LVEF before and regularly during treatment.

On the page “Endometrial (womb) cancer” · Advanced or recurrent disease: after platinum-based chemotherapy

Weekly paclitaxel (KEYNOTE-775 control arm)

After platinum-based chemotherapy [IV, B]Cycle length: Every 28 daysOn the page “Endometrial (womb) cancer” · Advanced or recurrent disease: after platinum-based chemotherapy

After platinum-based chemotherapy [IV, B]

Drug	Dose	Route	Schedule
Paclitaxel	80 mg/m²	IV	Weekly, 3 weeks on and 1 week off

Cycle length: Every 28 days
Duration: Until progression or unacceptable toxicity

Dose source:; place in the guideline:.

On the page “Endometrial (womb) cancer” · Advanced or recurrent disease: after platinum-based chemotherapy

Len/Pembro

Advanced endometrial cancer, after platinumEach drug’s schedule in the tableOn the page “Lenvatinib with pembrolizumab in endometrial cancer”

Advanced endometrial cancer, after platinum

Drug	Dose	Route	Schedule
Lenvatinib	20 mg	Oral	Daily
Pembrolizumab	200 mg	IV	Every 3 weeks

Cycle schedule: Lenvatinib daily and continuously; pembrolizumab every 3 weeks
Duration: Until progression; pembrolizumab up to 35 cycles

As in KEYNOTE-775.

Dose source:.

On the page “Lenvatinib with pembrolizumab in endometrial cancer”

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

1Lenvatinib plus pembrolizumab (411 patients)

Lenvatinib 20 mg orally once daily, plus pembrolizumab 200 mg IV every 3 weeks.

2Chemotherapy of the treating physician's choice (416 patients)

Doxorubicin 60 mg/m² of body surface area IV every 3 weeks, or paclitaxel 80 mg/m² IV weekly (cycles of 3 weeks of treatment and 1 week off).

Source of the regimen details: Abstract of the paper

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

Patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy regimen. Of the 827 patients, 697 had mismatch repair-proficient (pMMR) disease and 130 had mismatch repair-deficient (dMMR) disease.

Endpoints

The two primary endpoints were progression-free survival (PFS) by blinded independent central review per RECIST version 1.1 and overall survival (OS). These endpoints were assessed both in patients with pMMR disease and in all patients. Safety was also assessed.

Safety and side effects

Grade 3 or higher adverse events occurred in 88.9% of patients who received lenvatinib plus pembrolizumab and in 72.7% of patients who received chemotherapy. Details of the types of adverse events are given in the full text of the paper.

Clinical significance and place in guidelines

Based on the abstract, lenvatinib plus pembrolizumab in patients with advanced endometrial cancer after platinum-based chemotherapy significantly improved both progression-free survival and overall survival compared with chemotherapy (doxorubicin or paclitaxel); this superiority was seen both in the pMMR population and in all patients. An important point is the higher rate of grade 3 or higher adverse events with this combination. Regulatory approval status and clinical guideline recommendations should be checked in up-to-date sources; they are not mentioned in the abstract.

Limitations

The abstract does not discuss the study's limitations. Because grade 3 or higher adverse events were more frequent in the lenvatinib plus pembrolizumab group, a careful review of the types and management of adverse events in the full text is essential. The trial was funded by the drug manufacturers.

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.