FDA Approves Pembrolizumab Plus Lenvatinib Combination as First-Line Treatment for Advanced Renal Cell Carcinoma


The FDA approved pembrolizumab plus lenvatinib for the first-line treatment of adult patients with advanced RCC.

The FDA has approved the combination of the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) plus the orally available multiple receptor tyrosine kinase inhibitor lenvatinib (Lenvima, Eisai) for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

The approval was based on the results of the phase 3 CLEAR/KEYNOTE-581 trial. During the trial, the efficacy outcome measures of pembrolizumab plus lenvatinib demonstrated statistically significant improvements in comparison to sunitinib for progression-free survival (PFS), overall survival (OS), and confirmed objective response rate (ORR).

“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 Robert Motzer, MD, Jack and Dorothy Byrne chair in clinical oncology, Kidney Cancer Section Head, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, in a press release. “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.”

Data regarding the PFS for pembrolizumab plus lenvatinib demonstrated that the combination therapy was able to reduce disease progression or mortality risk by 61% (HR=0.39 [95% CI: 0.32-0.49]; p<0.0001) with a median PFS of 23.9 months compared with sunitinib at 9.2 months. For OS, the combination therapy was found to reduce mortality risk by 34% (HR=0.66 [95% CI: 0.49-0.88]; p=0.0049) compared with sunitinib.

Additionally, the investigators found that patients who received pembrolizumab plus lenvatinib had a confirmed ORR of 71% (95% CI: 66-76) (n=252) compared with patients who received sunitinib at 36% (95% CI: 31-41) (n=129). The combination therapy also achieved a complete response (CR) rate of 16% and partial response (PR) rate of 55%, whereas patients administered sunitinib had a CR rate of 4% and a PR rate of 32%.

“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 Gregory Lubiniecki, MD, vice president, Oncology Clinical Research, Merck Research Laboratories, in the press release.

During or after treatment with pembrolizumab, immune-mediated adverse effects (AEs) can occur, such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Such immune-mediated AEs can be severe or fatal, result from any organ system or tissue, and affect more than a single system in the body at any given time.

To ensure the safe use of pembrolizumab, early identification and management of immune-mediated AEs are critical. Dependent on the severity of the AEs, treatment with pembrolizumab may need to be disrupted or permanently discontinued, with corticosteroids administered as necessary.

Furthermore, treatment with pembrolizumab can result in severe or life-threatening infusion-related reactions. When administered to pregnant women, pembrolizumab is also capable of causing fetal harm. Because lenvatinib can cause fetal harm as well when administered to pregnant woman, patients with reproductive potential may be advised to use effective contraception while being administered this combination therapy.

With lenvatinib, serious or fatal AEs can also occur, such as 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 the severity of the AE, lenvatinib may need to be interrupted, reduced, and/or discontinued.

“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 Takashi Owa, MD, chief medicine creation and chief discovery officer, Oncology Business Group at Eisai, in the press release.

The FDA approved the application for the pembrolizumab plus lenvatinib combination therapy as a part of its Real-Time Oncology Review pilot program. This program was established to improve the efficiency of the review process for applications to ensure that treatments are accessible as early as possible.

Prior to this approval for pembrolizumab plus lenvatinib as the first-line treatment for RCC, the FDA granted priority review to pembrolizumab (Keytruda, Merck) as an adjuvant therapy for RCC. If approved, pembrolizumab would become the first adjuvant immunotherapy option for this patient population.


FDA Approves KEYTRUDA® (pembrolizumab) Plus LENVIMA® (lenvatinib) Combination for First-Line Treatment of Adult Patients With Advanced Renal Cell Carcinoma (RCC). Kenilworth, NJ: Merck; August 11, 2021. https://www.businesswire.com/news/home/20210811005902/en. Accessed August 12, 2021.

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