On September 17, 2019, the combination of pembrolizumab plus lenvatinib was granted accelerated approval for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiotherapy.^1-3

Pembrolizumab is a programmed cell death protein 1 (PD-1) inhibitor. Lenvatinib is a multikinase inhibitor that blocks the kinase activities of the vascular endothelial growth factor receptors VEGFR1, VEGFR2, and VEGFR3.

The review for this approval was conducted under Project Orbis, an initiative of the U.S. Food and Drug Administration (FDA) Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. The FDA, Australian Therapeutic Goods Administration, and Health Canada collaborated on the review, allowing for simultaneous decisions in all three countries.

Supporting Efficacy Data

Approval was based on findings in Study 111/KEYNOTE-146 (ClinicalTrials.gov identifier NCT02501096), a single-arm, multicenter, open-label, multicohort trial enrolling 108 patients with metastatic endometrial carcinoma that had progressed following at least one prior systemic therapy in any setting.^2,3 Patients received oral lenvatinib at 20 mg once daily plus intravenous (IV) pembrolizumab at 200 mg every 3 weeks until disease progression or unacceptable toxicity.

Among the 108 patients, 94 had tumors that were not MSI-H or dMMR, 11 had tumors that were MSI-H or dMMR, and 3 had unknown MSI-H and dMMR status. Tumor MSI status was determined using a polymerase chain reaction test. Tumor MMR status was determined using an immunohistochemistry test.

Among the 94 patients with tumors that were not MSI-H or dMMR, the median age was 66 years (62% ≥ 65 years); 86% were white, 6% black, 4% Asian, and 3% other; and the Eastern Cooperative Oncology Group performance status was 0 for 52% and 1 for 48%. All patients had received prior systemic therapy for endometrial carcinoma, with 51% receiving one, 38% two, and 11% three or more prior therapies.

Among the 94 patients whose tumors were not MSI-H or dMMR, the objective response rate on independent radiologic review using Response Evaluation Criteria in Solid Tumors, version 1.1, was 38.3%, including complete response in 10 patients (10.6%) and partial response in 26 (27.7%). Median duration of response was not reached at the time of data cutoff, with 25 responders (69% of responders) having response durations ≥ 6 months.

How Combined Treatment Is Used

For endometrial carcinoma, the recommended doses for combination treatment are pembrolizumab at 200 mg via IV infusion over 30 minutes every 3 weeks in combination with oral lenvatinib at 20 mg once daily until disease progression, unacceptable toxicity, or for pembrolizumab, up to 24 months in patients without disease progression.

No pembrolizumab dose reductions are recommended. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 reactions. Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling.

Pembrolizumab labeling provides recommended dosing modifications, including withholding, resuming, and discontinuing treatment for the following adverse reactions: immune-mediated pneumonitis, colitis, hepatitis in patients with and without hepatocellular carcinoma, endocrinopathies, nephritis, and skin adverse reactions as well as other immune-mediated adverse reactions and recurrent immune-mediated adverse reactions; hematologic toxicity in patients with classical Hodgkin lymphoma or primary mediastinal large B-cell lymphoma; inability to taper corticosteroid treatment; persistent grade 2 or 3 adverse reactions (excluding endocrinopathy); and infusion-related reactions.

Recommended lenvatinib dose reductions for adverse events in patients with endometrial carcinoma are stepwise from 20 to 14, 10, and 8 mg once daily. The recommended dose is 10 mg once daily in patients with severe renal impairment or severe hepatic impairment.

Lenvatinib product labeling provides recommended dosing modifications for hypertension; cardiac dysfunction; arterial thrombotic events; hepatotoxicity; renal failure or impairment; proteinuria; gastrointestinal perforation; fistula formation; QT prolongation; reversible posterior leukoencephalopathy syndrome; and other adverse reactions including persistent or intolerable grade 2 or 3 adverse reactions, grade 4 laboratory abnormalities, and grade 4 adverse reactions.

Safety Profile

Among the 94 patients with tumors that were not MSI-H or dMMR in KEYNOTE-146, the most common adverse events of any grade (≥ 20%) were fatigue (65%), hypertension (65%), musculoskeletal pain (65%), diarrhea (64%), decreased appetite (52%), hypothyroidism (51%), nausea (48%), stomatitis (43%), vomiting (39%), decreased weight (36%), abdominal pain (33%), headache (33%), constipation (32%), urinary tract infection (31%), dysphonia (29%), hemorrhagic events (28%), hypomagnesemia (27%), palmar-plantar erythrodysesthesia (26%), dyspnea (24%), cough (21%), and rash (21%). The most common grade 3 or 4 adverse events were hypertension (38%), fatigue (17%), abdominal pain (6%), and nausea (5%). The most common grade 3 or 4 laboratory abnormalities were increased lipase (18%), hyponatremia (13%), lymphopenia (7%), and increased creatinine (7%).

Serious adverse events occurred in 52% of patients, with the most common being hypertension (9%), abdominal pain (6%), musculoskeletal pain (5%), hemorrhage (4%), fatigue (4%), nausea (4%), confusional state (4%), pleural effusion (4%), adrenal insufficiency (3%), colitis (3%), dyspnea (3%), and pyrexia (3%). Adverse events led to discontinuation of treatment in 21% of patients and to discontinuation of pembrolizumab in 19%, irrespective of action taken with lenvatinib.

The most common causes of pembrolizumab discontinuation were adrenal insufficiency (2%), colitis (2%), pancreatitis (2%), and muscular weakness (2%); the most common causes of lenvatinib discontinuation were gastrointestinal perforation or fistula (2%), muscular weakness (2%), and pancreatitis (2%). Fatal adverse events occurred in 3% of patients, including gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome with intraventricular hemorrhage, and intracranial hemorrhage.

Pembrolizumab carries warnings/precautions for immune-mediated pneumonitis, colitis, hepatitis (and hepatotoxicity in combination with axitinib), endocrinopathies (including hypophysitis, thyroid disorders, and type 1 diabetes), nephritis, skin adverse reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, and other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment; and embryofetal toxicity. Treatment of patients with multiple myeloma with a PD-1 or programmed cell death ligand 1–blocking antibody in combination with a thalidomide analog plus dexamethasone is not recommended outside of controlled clinical trials. Patients should be monitored for hepatic, renal, and thyroid function and for hyperglycemia.

Lenvatinib carries warnings/precautions for hypertension and cardiac dysfunction; arterial thromboembolic events; hepatotoxicity; proteinuria; diarrhea, renal failure and impairment; gastrointestinal perforation and fistula formation; QT-interval prolongation; hypocalcemia; reversible posterior leukoencephalopathy syndrome; hemorrhagic events; impairment of thyroid-stimulating hormone suppression/thyroid dysfunction; wound-healing complications; and embryofetal toxicity. Patients should be regularly monitored for blood pressure, clinical signs/symptoms of cardiac dysfunction, liver function, renal function, proteinuria, electrolyte imbalance, blood calcium levels, and thyroid function.

Patients should be advised not to breastfeed during treatment with the combination of pembrolizumab and lenvatinib or either agent alone. 

REFERENCES

1. U.S. Food and Drug Administration: Simultaneous review decisions for pembrolizumab plus lenvatinib in Australia, Canada, and the United States. Available at www.fda.gov/drugs/resources-information-approved-drugs/simultaneous-review-decisions-pembrolizumab-plus-lenvatinib-australia-canada-and-us. Accessed October 7, 2019.

2. U.S. Food and Drug Administration: Keytruda (pembrolizumab) injection for intravenous use prescribing information. Merck & Co, September 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s065lbl.pdf. Accessed October 7, 2019.

3. U.S. Food and Drug Administration: Lenvima (lenvatinib) capsules prescribing information. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/206947s011lbl.pdf. Accessed October 7, 2019.