The European Commission has granted an approval to the combination of pembrolizumab and lenvatinib for the treatment of patients with advanced or recurrent endometrial carcinoma who have disease progression on or following prior platinum-containing therapy in any setting and who are not eligible for curative surgery or radiation.
The European Commission has granted an approval to the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) for the treatment of patients with advanced or recurrent endometrial carcinoma who have disease progression on or following prior platinum-containing therapy in any setting and who are not eligible for curative surgery or radiation.1
The approval is based on data from the pivotal phase 3 KEYNOTE-775/Study 309 trial (NCT03517449), in which pembrolizumab plus lenvatinib led to a 38% reduction in the risk of death vs investigator’s choice of chemotherapy (either doxorubicin or paclitaxel), which was found to be statistically significant. The median overall survival (OS) was 18.3 months with the combination vs 11.4 months for chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; P <.0001).
The combination also showed an improvement in progression-free survival (PFS) at 7.2 months vs 3.8 months with chemotherapy (HR, 0.56; 95% CI, 0.47-0.66; P <.0001).
The decision marks the first time an immunotherapy combination with a tyrosine kinase inhibitor was approved in Europe for this patient population.
“Until recently, women in Europe with advanced or recurrent endometrial cancer have faced a difficult prognosis and had few treatment options,” Corina Dutcus, MD, vice president of clinical research, Oncology Business Group at Eisai Inc, which develops lenvatinib, said in a press release. “The approval of Keytruda plus Lenvima in this setting reflects the progress that we have made in our collaboration with Merck in developing solutions for those diagnosed with difficult-to-treat cancers. We thank the patients, families and healthcare providers who made this milestone possible.”
In July 2021, the FDA granted a regular approval to pembrolizumab and lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression after previous systemic therapy in any setting, and who are not candidates for curative surgery or radiation.2,3
Previously, the combination was granted an accelerated approval in September 2019 for use in patients with advanced endometrial carcinoma.4 At the time, the decision was based on findings of 94 patients with endometrial carcinoma who were not MSI-H or dMMR. The combination elicited an overall response rate (ORR) of 38.3% in these patients, which included a complete response (CR) rate of 10.6% (n = 10) and a partial response (PR) rate of 27.7% (n = 26). A duration of response (DOR) of 6 months or longer was reported in 69% (n = 25) of patients.
The multicenter, open-label, randomized, active-controlled KEYNOTE-775/Study 309 trial enrolled 827 patients with advanced endometrial cancer who were previously treated with at least 1 platinum-based chemotherapy regimen in any setting, including the neoadjuvant and adjuvant settings.
As part of the eligibility criteria, patients could have received up to 2 platinum-containing therapies in total, if one was given in the neoadjuvant or adjuvant setting. Patients could not have endometrial sarcoma, carcinosarcoma, preexisting grade 3 or higher fistula, uncontrolled blood pressure (>150/90 mmHg), significant cardiovascular impairment or event within the past 1 year, or those who had active autoimmune disease or a medical condition requiring immunosuppression.
Patients were randomized 1:1 to receive pembrolizumab at 200 mg intravenously every 3 weeks plus lenvatinib at 20 mg orally once daily or investigator’s choice of chemotherapy, which was either doxorubicin at 60 mg/m2 every 3 weeks or paclitaxel at 80 mg/m2 weekly on a 3-weeks-on/1-week-off schedule.
Treatment with the combination was given until RECIST v1.1-defined disease progression, which was verified by BICR, unacceptable toxicity; pembrolizumab was given for a maximum of 2 years. Of note, the combination could be given beyond RECIST-defined disease progression if the treating investigator found the patient to be deriving clinical benefit and the treatment was tolerated. Twenty-nine percent of patients on the combination (n =121/411) received continued study therapy beyond RECIST-defined disease progression. The median duration of the post-progression therapy was 2.8 months, and tumor assessment was performed every 8 weeks.
The primary end point was OS, and PFS via blinded independent central review (BICR) according to RECIST v1.1 criteria; secondary end points included objective response rate (ORR) also assessed by BICR.
Furthermore, the ORR was 32% (95% CI, 27%-37%) for patients who received pembrolizumab/lenvatinib vs 15% (95% CI, 11%-18%) for patients treated with chemotherapy (P <.0001). The CR rate was 7% and the PR rate of 25% versus a 3% CR rate and a 12% PR rate of 12% for the chemotherapy arm.
Five hundred and 30 patients with advanced endometrial carcinoma who received the combination were evaluated for safety. The most common adverse effects were hypertension (63%), diarrhea (57%), hypothyroidism (56%), nausea (51%), decreased appetite (47%), vomiting (39%), fatigue (38%), decreased weight (35%), arthralgia (33%), proteinuria (29%), constipation, headache and urinary tract infection (27% each), dysphonia (25%), abdominal pain, asthenia, palmar-plantar erythrodysesthesia syndrome and stomatitis (23% each), anemia (22%) and hypomagnesaemia (20%).
“This approval is welcome news for patients in Europe and is based on the first Phase 3 study evaluating an immunotherapy and tyrosine kinase inhibitor combination that showed superior overall survival for patients with advanced or recurrent endometrial cancer compared to chemotherapy,” Gregory Lubiniecki, MD, vice president of clinical research, Merck Research Laboratories, which develops pembrolizumab, said in the press release. “Regardless of mismatch repair status, patients whose endometrial cancer progresses or returns after prior platinum-containing systemic therapies now have a combination treatment option in Keytruda plus Lenvima that demonstrated a 38% reduction in risk of death compared to chemotherapy alone.”
With the European approval, the combination can now be marketed in all 27 member states of the European Union plus Iceland, Liechtenstein, Norway, and Northern Ireland.