FDA Approval Announcement
KENILWORTH & WOODCLIFF, N.J.--(BUSINESS WIRE) July 22, 2021 -- Merck (NYSE: MRK, known as MSD outside the U.S. and Canada) and Eisai Inc. announced the U.S. Food and Drug Administration (FDA) has approved the combination of Keytruda (pembrolizumab) (Merck’s anti-PD-1 therapy) plus Lenvima (lenvatinib) (Eisai’s oral 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).
Indicated Patient Population
The combination is approved for patients with advanced endometrial carcinoma who meet the following criteria:
Disease progression following prior systemic therapy in any setting
Not candidates for curative surgery or radiation
Basis for Approval: KEYNOTE-775/Study 309 (Phase 3 Trial)
The approval is based on data from the pivotal Phase 3 KEYNOTE-775/Study 309 trial, which compared the Keytruda plus Lenvima combination versus chemotherapy (investigator’s choice of doxorubicin or paclitaxel) in the target patient population.
Key Efficacy Results
Overall Survival (OS): Keytruda plus Lenvima demonstrated a statistically significant improvement in OS, reducing the risk of death by 32% (HR=0.68 [95% CI, 0.56-0.84]; p=0.0001) compared to chemotherapy.
Progression-Free Survival (PFS): The combination also showed a statistically significant improvement in PFS, reducing the risk of disease progression or death by 40% (HR=0.60 [95% CI, 0.50-0.72]; p<0.0001) versus chemotherapy.
Objective Response Rate (ORR): The ORR was 30% (95% CI, 26-36) in the Keytruda plus Lenvima group, compared to 15% (95% CI, 12-19) in the chemotherapy group.
Complete Response (CR) and Partial Response (PR) Rates: The CR rate was 5% for the combination versus 3% for chemotherapy, while the PR rate was 25% for the combination versus 13% for chemotherapy.
Safety Profile
The Keytruda plus Lenvima combination carries safety risks associated with each individual agent, which require careful monitoring and management.
Keytruda (pembrolizumab)-Associated Safety Risks
Immune-Mediated Adverse Reactions: These reactions may be severe or fatal, can occur in any organ system or tissue, and may affect multiple body systems simultaneously. Examples include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation.
Management of Immune-Mediated Reactions: Early identification and management are critical. Based on the severity of the adverse reaction, Keytruda should be withheld or permanently discontinued, and corticosteroids administered if appropriate.
Infusion-Related Reactions: Keytruda can cause severe or life-threatening infusion-related reactions.
Fetal Harm: Based on its mechanism of action, Keytruda can cause fetal harm when administered to pregnant women.
Lenvima (lenvatinib)-Associated Safety Risks
Adverse reactions associated with Lenvima (some of which may be severe or fatal) include:
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
Management: Based on the type and/or severity of the adverse reaction, Lenvima may be interrupted, reduced, and/or discontinued.
Fetal Harm: Based on its mechanism of action and animal reproduction studies, Lenvima can cause fetal harm. Females of reproductive potential should be advised to use effective contraception.
Expert Commentary
“With a five-year survival rate of just 17%, women with advanced endometrial cancer who are not candidates for curative therapy, particularly those with disease progression following prior systemic therapy, have limited treatment options,” said Dr. Vicky Makker, principal investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. “This approval is an important step forward in helping patients fight this difficult-to-treat malignancy, as physicians can now provide an option that may improve survival outcomes.”
