General Information

Keytruda (pembrolizumab) is an anti-PD-1 therapy. Lenvima (lenvatinib) is an orally available kinase inhibitor.

The Keytruda plus Lenvima combination is specifically indicated 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 and are not candidates for curative surgery or radiation.

Keytruda is supplied as a solution for intravenous infusion. Lenvima is supplied as a capsule for oral administration.

The recommended dosage of Keytruda plus Lenvima for endometrial carcinoma is as follows: Keytruda 200 mg administered as an intravenous infusion over 30 minutes every three weeks in combination with Lenvima 20 mg orally once daily until disease progression, unacceptable toxicity, or for Keytruda, up to 24 months in patients without disease progression. Refer to the Lenvima prescribing information for recommended dosing information, as appropriate.

Clinical Results

FDA Approval

The FDA approval of Keytruda was based on data from KEYNOTE-146/Study 111, a Phase 2, multi-cohort, multicenter, open-label, single-arm trial that enrolled 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients were treated with Keytruda 200 mg intravenously every three weeks in combination with Lenvima 20 mg orally once daily until unacceptable toxicity or disease progression as determined by the investigator.

Administration of Keytruda plus Lenvima was permitted beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Keytruda dosing was continued for a maximum of 24 months; however, treatment with Lenvima could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every six weeks until week 24, followed by every nine weeks thereafter. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) by independent radiologic review committee (IRC) using RECIST 1.1.

Among the 108 patients, 87% (n=94) had tumors that were not MSI-H or dMMR, 10% (n=11) had tumors that were MSI-H or dMMR, and 3% (n=3) had tumors that had unknown status. In the 94 patients with tumors that were not MSI-H or dMMR, the Keytruda plus Lenvima combination demonstrated an ORR of 38.3%, with a complete response rate of 10.6% (n=10) and a partial response rate of 27.7% (n=26). The median follow-up time was 18.7 months. In the patients who had a response as determined by independent review (n=36), at the time of data cutoff, the median DOR was not reached (range: 1.2+ to 33.1+ months), and 69% of these patients experienced responses lasting six months or greater.

Side Effects

Adverse reactions associated with the use of Keytruda plus Lenvima may include, but are not limited to, the following:

fatigue

musculoskeletal pain

hypertension

diarrhea

decreased appetite

hypothyroidism

nausea

stomatitis

vomiting

decreased weight

abdominal pain

headache

constipation

urinary tract infection

dysphonia

hemorrhagic events

hypomagnesemia

palmar-plantar erythrodysesthesia syndrome

dyspnea

cough

rash

Mechanism of Action

Keytruda (pembrolizumab) is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Lenvima (lenvatinib) is a kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvima inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4, the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. In syngeneic mouse tumor models, lenvatinib decreased tumor-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumor activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.