FDA Approves Pembrolizumab/Lenvatinib Combo for Frontline Advanced RCC Treatment


The combination of pembrolizumab and lenvatinib has been FDA approved as a frontline therapy for the treatment of adult patients with advanced renal cell carcinoma.

The combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) has been FDA approved as a frontline therapy for the treatment of adult patients with advanced renal cell carcinoma.

The regulatory decision is supported by data from the phase 3 CLEAR/KEYNOTE-581 trial (Study 307; NCT02811861), in which the doublet demonstrated statistically significant improvements in terms of progression-free survival (PFS), overall survival (OS), and confirmed objective response rate (ORR) compared with sunitinib (Sutent).

Specifically, pembrolizumab plus lenvatinib resulted in a 61% reduction in the risk of disease progression or death vs sunitinib (HR, 0.39; 95% CI, 0.32-0.49; < .0001). The median PFS in the investigative arm was 23.9 months (95% CI, 20.8-27.7) vs 9.2 months (95% CI, 6.0-11.0) in the control arm. The doublet also resulted in a 34% reduction in the risk of death over sunitinib (HR, 0.66; 95% CI, 0.49-0.88; = .0049).

Moreover, the combination regimen also a elicited confirmed ORR of 71% (95% CI, 66%-76%) vs 36% (95% CI, 31%-41%) with single-agent sunitinib. The ORR achieved with the doublet was comprised of a 16% complete response rate and a 55% partial response rate; with sunitinib, these rates were 4% and 32%, respectively.

"This approval is based in part on data demonstrating that pembrolizumab plus lenvatinib significantly reduced the risk of disease progression or death vs sunitinib," Robert J. Motzer, MD, Jack and Dorothy Byrne Chair in Clinical Oncology, Kidney Cancer section head of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center, stated in a press release. "This is a significant milestone for newly diagnosed patients with advanced RCC and introduces a promising combination option in the first-line setting."

The multicenter, open-label, phase 3 trial enrolled a total of 1069 patients with advanced RCC. Notably, patients could enroll irrespective of PD-L1 tumor expression status, and those with autoimmune disease or a condition that required immunosuppression were excluded.

Study participants were stratified based on geographic region (North American and Western Europe vs rest of the world) and Memorial Sloan Kettering Cancer Center prognostic risk groups (favorable vs intermediate vs poor risk).

Patients were randomized 1:1:1 to receive oral lenvatinib at a once-daily dose of 20 mg plus intravenous pembrolizumab at a dose of 200 mg given every 3 weeks for up to 24 months; lenvatinib at a once-daily dose of 18 mg plus oral everolimus (Afinitor) at a once-daily dose of 5 mg; or oral sunitinib at a once-daily dose of 50 mg for 4 weeks on treatment, followed by 2 weeks off treatment.

Patients continued to receive treatment until either intolerable toxicity or progressive disease. Pembrolizumab was given for a maximum of 24 months, but lenvatinib could be continued for beyond that time point. Investigators assessed tumor status at baseline and then every 8 weeks.

The median age of study participants was 62 years (range, 29-88), with 42% of patients aged 65 years or older. Moreover, 75% of patients were male, 74% were White, and 82% of patients had a Karnofsky performance status of 90 to 100 at baseline. With regard to risk, 27% were determined to have favorable risk, 64% were intermediate, and 9% were poor. The most common site of metastasis was in the lung (68%), and this was followed by the lymph node (45%) and the bone (25%).

Major efficacy measures included PFS per independent radiologic review (IRC) and RECIST v1.1 criteria, as well as OS. Another notable outcome measure was confirmed ORR per IRC assessment.

The median duration of exposure to the doublet was 17.0 months (range, 0.1-39.0).

Regarding safety, 4.3% of patients who received the doublet experienced fatal adverse reactions; these effects included cardiorespiratory 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.

Moreover, serious adverse reactions were experienced by 51% of patients on the investigative arm. Serious adverse reactions that were reported in 2% or more of patients comprised 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%).

Thirty-seven percent of patients who received pembrolizumab plus lenvatinib permanently discontinued treatment of either agent or both because of toxicity; 29% discontinued pembrolizumab only, 26% discontinued lenvatinib only and 13% stopped both treatments. The most frequent toxicities that resulted in permanent discontinuation of the doublet or either agent included pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).

Additionally, 78% of patients receiving the doublet required dose interruptions due to toxicity. Pembrolizumab was interrupted in 55% of patients, lenvatinib was interrupted in 73% of patients, and both treatments were interrupted in 39% of patients.

The most common toxicities that led to a dose interruption of the immunotherapy included 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%). Lenvatinib was dose reduced in 69% of patients. The most common toxicities that resulted in dose reduction or interruption of lenvatinib were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia syndrome (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%).

The most common toxicites observed with the doublet included 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 frequently reported grade 3 or 4 adverse effects with the combination comprised 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).


  1. FDA approves KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) combination for first-line treatment of adult patients with advanced renal cell carcinoma (RCC). News release. Merck. August 11, 2021. Accessed August 11, 2021. https://bwnews.pr/3fXk8Rj

This article was originally published on OncLive as “FDA Approves Pembrolizumab Plus Lenvatinib for Frontline Advanced RCC”

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