The U.S. Food and Drug Administration ( FDA ) has approved the combination of Keytruda ( Pembrolizumab ), an anti-PD-1 therapy, plus Lenvima ( Lenvatinib ), the orally available multiple receptor tyrosine kinase inhibitor, 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 following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
The approval for this population is based on results from the pivotal phase 3 KEYNOTE-775 / Study 309 trial, in which Pembrolizumab plus Lenvatinib has demonstrated statistically significant improvements in overall survival ( OS ), reducing the risk of death by 32% ( hazard ratio, HR=0.68 [ 95% CI, 0.56-0.84 ]; p=0.0001 ), and progression-free survival ( PFS ), reducing the risk of disease progression or death by 40% ( HR=0.60 [ 95% CI, 0.50-0.72 ]; p less than 0.0001 ), versus chemotherapy ( investigator’s choice of Doxorubicin or Paclitaxel ).
Pembrolizumab plus Lenvatinib have also demonstrated a statistically significant improvement in objective response rate ( ORR ), with an ORR of 30% ( 95% CI, 26-36 ) versus 15% ( 95% CI, 12-19 ) for patients who received investigator’s choice of Doxorubicin or Paclitaxel, in addition to a complete response rate of 5% for Pembrolizumab plus Lenvatinib versus 3% for Doxorubicin or Paclitaxel and a partial response rate of 25% versus 13%, respectively.
The approval was based on data from KEYNOTE-775/Study 309 that enrolled 827 patients with advanced endometrial carcinoma who had been previously treated with at least one prior Platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings.
Patients with endometrial sarcoma, including carcinosarcoma, or patients who had active autoimmune disease or a medical condition that required immunosuppression were ineligible.
Patients with endometrial carcinoma that were not MSI-H or dMMR were stratified by ECOG performance status, geographic region, and history of pelvic radiation.
Patients were randomized ( 1:1 ) to one of the following treatment arms:
Pembrolizumab ( 200 mg intravenously [ IV ] every three weeks ) in combination with Lenvatinib ( 20 mg orally once daily ); or Investigator’s choice, consisting of either Doxorubicin ( 60 mg/m2 every three weeks ) or Paclitaxel ( 80 mg/m2 given weekly, three weeks on/one week off ).
Treatment with Pembrolizumab plus Lenvatinib continued until RECIST v1.1-defined progression of disease as verified by blinded independent central review ( BICR ), unacceptable toxicity, or for Pembrolizumab, a maximum of 24 months.
Treatment was permitted beyond RECIST v1.1-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit and the treatment was tolerated.
Assessment of tumor status was performed every eight weeks. The major efficacy outcome measures were overall survival and progression-free survival as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. Additional efficacy outcome measures included ORR and DOR, as assessed by BICR.
Among the 697 not dMMR patients, 346 patients were randomized to Pembrolizumab plus Lenvatinib, and 351 patients were randomized to investigator's choice of Doxorubicin ( n=254 ) or Paclitaxel ( n=97 ).
The not dMMR population characteristics were: median age of 65 years ( range: 30 to 86 ), 52% age 65 or older; 62% white, 22% asian, and 3% black; 60% ECOG PS of 0, and 40% ECOG PS of 1.
The histologic subtypes were endometrioid carcinoma ( 55% ), serous ( 30% ), clear cell carcinoma ( 7% ), mixed ( 4% ), and other ( 3% ).
All 697 of these patients received prior systemic therapy for endometrial carcinoma: 67% had one, 30% had two, and 3% had three or more prior systemic therapies.
37% of patients received only prior neoadjuvant or adjuvant therapy.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously.
Immune-mediated adverse reactions can occur at any time during or after treatment with Pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation.
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Pembrolizumab.
Based on the severity of the adverse reaction, Pembrolizumab should be withheld or permanently discontinued and corticosteroids administered if appropriate.
Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, Pembrolizumab can cause fetal harm when administered to a pregnant woman.
Adverse reactions, some of which can be serious or fatal, may occur with Lenvatinib, including hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, renal failure or impairment, proteinuria, diarrhea, fistula formation and gastrointestinal perforation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid stimulating hormone suppression/thyroid dysfunction, impaired wound healing and osteonecrosis of the jaw.
Based on the type and/or severity of the adverse reaction, Lenvatinib may be interrupted, reduced and/or discontinued.
Based on its mechanism of action and data from animal reproduction studies, Lenvatinib can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. ( Xagena )
Source: Merck, 2021