FDA Approves Pembrolizumab plus Lenvatinib Combination for First-Line Treatment of Adult Patients with Advanced Renal Cell Carcinoma (RCC)

- KEYTRUDA® Plus LENVIMA® Is Now Approved for Two Types of Cancer, Including Advanced RCC

- Based on Phase 3 CLEAR/KEYNOTE-581 Trial, KEYTRUDA Plus LENVIMA Significantly Reduced Risk of Disease Progression or Death by 61% Versus Sunitinib

San Francisco, CA (UroToday.com) -- Merck, known as MSD outside the United States and Canada, and Eisai announced that the U.S. Food and Drug Administration (FDA) has approved the combination of KEYTRUDA®, Merck’s anti-PD-1 therapy, plus LENVIMA®, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC). The approval is based on results from the pivotal Phase 3 CLEAR (Study 307)/KEYNOTE-581 trial, in which KEYTRUDA plus LENVIMA demonstrated statistically significant improvements versus sunitinib in the efficacy outcome measures of progression-free survival (PFS), overall survival (OS) and confirmed objective response rate (ORR).

For PFS, KEYTRUDA plus LENVIMA reduced the risk of disease progression or death by 61% (HR=0.39 [95% CI: 0.32-0.49]; p<0.0001) with a median PFS of 23.9 months versus 9.2 months for sunitinib. For OS, KEYTRUDA plus LENVIMA reduced the risk of death by 34% (HR=0.66 [95% CI: 0.49-0.88]; p=0.0049) versus sunitinib. Additionally, the confirmed ORR was 71% (95% CI: 66-76) (n=252) for patients who received KEYTRUDA plus LENVIMA versus 36% with sunitinib (95% CI: 31-41) (n=129). KEYTRUDA plus LENVIMA achieved a complete response (CR) rate of 16% and partial response (PR) rate of 55% versus a CR rate of 4% and a PR rate of 32% for those who received sunitinib.

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 KEYTRUDA, 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 KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see “Selected Important Safety Information” below.

Adverse reactions, some of which can be serious or fatal, may occur with LENVIMA, 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, osteonecrosis of the jaw, and embryo-fetal toxicity. Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception. Based on the severity of the adverse reaction, LENVIMA should be interrupted, reduced, and/or discontinued. For more information, see “Selected Safety Information” below.

“This approval is based in part on data demonstrating that KEYTRUDA plus LENVIMA significantly reduced the risk of disease progression or death versus sunitinib,” said Dr. Robert Motzer, Jack and Dorothy Byrne Chair in Clinical Oncology, Kidney Cancer Section Head, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center. “This is a significant milestone for newly diagnosed patients with advanced renal cell carcinoma and introduces a promising combination option in the first-line setting.”
This FDA approval reinforces the potential of KEYTRUDA plus LENVIMA, which is now approved for two different types of cancer. In the study, KEYTRUDA plus LENVIMA demonstrated a survival benefit for patients with advanced renal cell carcinoma, supporting the importance of this combination as a new first-line treatment option for these patients,” said Dr. Gregory Lubiniecki, Vice President, Oncology Clinical Research, Merck Research Laboratories. “At Merck, we are focused on delivering meaningful innovations that extend the lives of people with cancer. We are proud to see how our collaboration with Eisai can now help to improve survival outcomes for patients with advanced renal cell carcinoma and are committed to further exploring KEYTRUDA plus LENVIMA in other difficult-to-treat cancers.”

“This FDA approval is truly significant for the advanced renal cell carcinoma community. The CLEAR/KEYNOTE-581 trial shows treatment with KEYTRUDA plus LENVIMA resulted in superior outcomes across progression-free survival, overall survival and objective response rate versus sunitinib in patients with advanced renal cell carcinoma,” said Dr. Takashi Owa, Chief Medicine Creation and Chief Discovery Officer, Oncology Business Group at Eisai. “This milestone is a testament to our dedication to developing new therapeutic options for people living with advanced cancers, which is fueled by our passion for aiming to improve cancer care for patients, and amplified by the teamwork resulting from our collaboration with Merck.”

This approval was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program, which aims to improve the efficiency of the review process for applications to ensure that treatments are available to patients as early as possible.

Dr. Motzer has provided consulting and advisory services for Merck and Eisai.

Data Supporting the Approval

The approval was based on data from the CLEAR (Study 307)/KEYNOTE-581 trial (ClinicalTrials.gov, NCT02811861), a Phase 3, multicenter, open-label, randomized trial conducted in 1,069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified by geographic region (North America and Western Europe vs. “Rest of the World”) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable vs. intermediate vs. poor risk).

Patients were randomized (1:1:1) to one of the following treatment arms:

  • LENVIMA (20 mg orally once daily) in combination with KEYTRUDA (200 mg intravenously [IV] every three weeks for up to 24 months); or
  • LENVIMA (18 mg orally once daily) in combination with everolimus (5 mg orally once daily); or
  • Sunitinib (50 mg orally once daily for four weeks on treatment, followed by two weeks off treatment).

Treatment continued until unacceptable toxicity or disease progression. 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 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 eight weeks.

The study population characteristics were: median age of 62 years (range: 29 to 88 years), 42% age 65 or older; 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had a baseline Karnofsky Performance Status (KPS) of 70 to 80 and 90 to 100, respectively; patient distribution by MSKCC risk categories was 27% favorable, 64% intermediate, and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%).

The major efficacy outcome measures were PFS, as assessed by independent radiologic review (IRC) according to RECIST v1.1, and OS. Additional efficacy outcome measures included confirmed ORR as assessed by IRC. KEYTRUDA in combination with LENVIMA demonstrated statistically significant improvements in PFS, OS, and ORR compared with sunitinib. Efficacy results showed:


The median duration of exposure to the combination therapy of KEYTRUDA and LENVIMA was 17 months (range: 0.1 to 39 months).

Fatal adverse reactions occurred in 4.3% of patients who received KEYTRUDA in combination with LENVIMA, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, and subarachnoid hemorrhage.

Serious adverse reactions occurred in 51% of patients receiving KEYTRUDA plus LENVIMA. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).

Permanent discontinuation of either KEYTRUDA, LENVIMA, or both due to an adverse reaction occurred in 37% of patients receiving KEYTRUDA in combination with LENVIMA; 29% KEYTRUDA only, 26% LENVIMA only, and 13% both treatments. The most common adverse reactions (≥2%) resulting in permanent discontinuation of KEYTRUDA, LENVIMA, or the combination were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).

Dose interruptions of KEYTRUDA, LENVIMA, or both due to an adverse reaction occurred in 78% of patients receiving KEYTRUDA in combination with LENVIMA. KEYTRUDA was interrupted in 55% of patients, LENVIMA was interrupted in 73% of patients, and both treatments were interrupted in 39% of patients. The most common adverse reactions (≥3%) resulting in interruption of KEYTRUDA were diarrhea (10%), hepatotoxicity (8%), fatigue (7%), lipase increased (5%), amylase increased (4%), musculoskeletal pain (3%), hypertension (3%), rash (3%), acute kidney injury (3%), and decreased appetite (3%). LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia syndrome (PPE) (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased alanine aminotransferase (ALT) (5%), and increased amylase (5%). Fifteen percent (15%) of patients treated with KEYTRUDA in combination with LENVIMA received an oral prednisone equivalent to ≥40 mg daily for an immune-mediated adverse reaction. Grade 3 and 4 increased ALT or increased aspartate aminotransferase (AST) was seen in 9% of patients. Grade ≥2 increased ALT or AST was reported in 64 (18%) patients, of whom 20 (31%) received ≥40 mg daily oral prednisone equivalent. Recurrence of Grade ≥2 increased ALT or AST was observed in three patients on rechallenge in patients receiving LENVIMA and 10 patients receiving both KEYTRUDA and LENVIMA.

The most common adverse reactions (All Grades ≥20%) for KEYTRUDA plus LENVIMA were fatigue (63%), diarrhea (62%), musculoskeletal disorders (58%), hypothyroidism (57%), hypertension (56%), stomatitis (43%), decreased appetite (41%), rash (37%), nausea (36%), weight loss, dysphonia and proteinuria (30% each), PPE syndrome (29%), hemorrhagic events and abdominal pain (27% each), vomiting (26%), constipation and hepatotoxicity (25% each), headache (23%), and acute kidney injury (21%). The most common adverse reactions (Grades 3-4) for KEYTRUDA plus LENVIMA were hypertension (29%), diarrhea (10%), fatigue and hepatotoxicity (9% each),  weight loss and proteinuria (8% each), acute kidney injury, hemorrhagic events and rash (5% each), musculoskeletal disorders, decreased appetite and PPE (4% each), nausea and vomiting (3% each), stomatitis and abdominal pain (2% each), and constipation, hypothyroidism and headache (1% each).

Clinically relevant adverse reaction (<20%) that occurred in patients receiving KEYTRUDA plus LENVIMA were myocardial infarction (3%) and angina pectoris (1%).

Source: "FDA Approves KEYTRUDA® (Pembrolizumab) Plus LENVIMA® (Lenvatinib) Combination For First-Line Treatment Of Adult Patients With Advanced Renal Cell Carcinoma (RCC)". 2021. Eisai Newsroom. 

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