Novel Lenvatinib Combinations Tested in Frontline RCC

OncologyLiveVol. 19/No. 6
Volume 19
Issue 6

The current standard-of-care therapy for patients with clear cell renal cell carcinoma is sunitinib, but many patients relapse or don't have responses to the drug.

Robert J. Motzer, MD

The current standard-of-care therapy for patients with clear cell renal cell carcinoma (ccRCC) is sunitinib (Sutent), but many patients relapse or don’t have responses to the drug. In an attempt to find a targeted therapy to better serve these patients, investigators are assessing whether lenvatinib (Lenvima) combined with everolimus (Afinitor) or pembrolizumab (Keytruda) can outperform sunitinib. Either or both combinations may provide a survival benefit, which would add new options for treating the most common type of kidney cancer.

“There’s a high unmet need to develop better treatments for first-line kidney cancer,” said Robert J. Motzer, MD, attending physician and the Jack and Dorothy Byrne chair in clinical oncology at Memorial Sloan Kettering Cancer Center, New York, New York. It is estimated that 2018 will see 65,340 new cases and 14,970 deaths for cancer of the kidney and renal pelvis, accounting for more than one-third of all urinary system cancers.1 Patients who have ccRCC need better treatment options when sunitinib is not an appropriate choice. “Depending on the results, if it looks like one combination or the other is better than sunitinib, it could replace sunitinib as the standard of care,” Motzer added.

The combinations of lenvatinib plus everolimus and lenvatinib plus pembrolizumab are being studied in the phase III CLEAR trial (NCT02811861), which will compare their efficacy as first-line treatments for ccRCC in the advanced setting (FIGURE). Patients who are eligible for the study will have ccRCC, a Karnofsky performance status of 70 or greater, and at least 1 measurable target lesion according to RECIST 1.1 criteria. Participants also cannot have any central nervous system involvement or have received any prior systemic therapy for ccRCC.

Figure. Lenvatinib Combinations in Frontline Clear Cell RCC

The trial will assess progression-free survival (PFS) as the primary endpoint, with overall survival (OS) and objective response rate (ORR) as the secondary endpoints.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI). According to Motzer, 2 important kinases in RCC in general are the vascular endothelial growth factor (VEGF) receptor and the platelet-derived growth factor receptor, which are both thought to be important in tumor angiogenesis. The third main kinase is the fibroblast growth factor receptor, which is involved in angiogenesis as well as resistance to VEGF-targeted therapies.

Everolimus is an inhibitor of the mammalian target of the rapamycin (mTOR) serine/threonine kinase signal transduction pathway. The mTOR pathway regulates cell growth, proliferation, and survival and is frequently deregulated in cancer.2 “This pathway is sometimes mutated or aberrant in kidney cancer, so [everolimus] is independently effective in kidney cancer,” Motzer noted. The drug is approved as singleagent therapy for advanced RCC following failure of sunitinib or sorafenib (Nexavar).

Pembrolizumab is a PD-1 inhibitor, which binds to the PD-1 receptor, blocking both immune-suppressing ligands—PD-L1 and PD-L2— from interacting with PD-1 to help restore T-cell response and immune response.3

Prior Evidence of Efficacy

Additionally, Motzer said, ccRCC is characterized by a VHL gene mutation, which is targeted by VEGF inhibitors such as sunitinib and lenvatinib, so these drugs already have high efficacy in kidney cancers.Prior studies have shown that both combinations have activity in RCC. In May 2016, the FDA approved the combination of lenvatinib and everolimus as a treatment for patients with advanced RCC following prior antiangiogenic therapy, based on survival and response data from a phase II study.4

In the trial, known as Study 205 (NCT01136733), the combination of lenvatinib and everolimus reduced the risk of progression or death by 63% compared with everolimus alone. Median PFS with the combination was 14.6 months versus 5 months with everolimus (HR, 0.37; 95% CI, 0.22-0.62). There was a 33% reduction in the risk of death with the combination versus singleagent everolimus.4

The median OS with the combination was 25.5 months compared with 15.4 months with everolimus alone (HR, 0.67; 95% CI, 0.42-1.08). At 2 years, 51% of patients remained alive in the combination arm versus 26% with single-agent everolimus. The 1-year PFS rate was 31% with the combination versus 14% with everolimus. The ORR with the lenvatinib combination was 37% versus 6% with everolimus alone. One patient in the combination arm experienced a complete response versus none with everolimus alone.4

All patients experienced at least 1 treatment-emergent adverse event (AE) across all treatment arms. The most common serious AEs with the combination were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%). AEs led to a dose reduction or interruption for 89% of patients in the combination arm versus 54% with single-agent everolimus.4

The most frequently reported grade 3/4 AEs with the combination versus single-agent were diarrhea (19% vs 2%), fatigue (18% vs 2%), hypertension (13% vs 2%), hyponatremia (11% vs 6%), lymphocyte count decrease (10% vs 20%), renal failure (10% vs 2%), proteinuria (8% vs 2%), and hemoglobin decrease (8% vs 16%).4

The FDA also granted a breakthrough designation to the combination of pembrolizumab and lenvatinib in January 2018 for treating patients with advanced or metastatic RCC.5 The designation is based on the RCC cohort of the multicenter, open-label phase Ib/II Study 111 (NCT02501096), in which patients treated with the combination had an ORR of 63.3% (95% CI, 43%-80%).6 At the time of the data cutoff, the median PFS was not yet reached.

The median duration of therapy was 9.5 months. The ORR at 24 weeks was 83% (95% CI, 52-98) in the treatment-naïve cohort, and 50% in patients who received previous treatment. All responses were partial responses. Two patients in the treatment-naïve group and 8 in the previously-treated population had stable disease. One patient in each cohort had primary progressive disease.6

AEs led to lenvatinib dose reductions in 18 patients. Five patients (17%) discontinued at least 1 study drug. The most common AEs of any grade were diarrhea (83%), fatigue (70%), hypothyroidism (67%), stomatitis (60%), hypertension (57%), and nausea (57%). The 2 grade 5 AEs were related to disease progression and not considered related to the study drugs.6

Motzer predicts that further analysis after the completion of the CLEAR trial will reveal which therapy option is ideal for different subsets of patients. “I think the next steps for these various drugs is to look at the tumors of patients who are studied, and see if you can find the signature of the various drugs to see which patients will do better with either the pembrolizumab or everolimus, and maybe some patients would still do better with sunitinib. It’s to try and find the underlying biology and to tailor the treatment to find the therapy that the patient is most likely to benefit from based on their tumor profile,” he said.

Lenvatinib is being developed by Eisai Inc. Pembrolizumab is made by Merck & Co, Inc, and everolimus is made by Novartis.


  1. Cancer facts and figures: 2018. American Cancer Society. Published 2018. Accessed February 26, 2018.
  2. Hasskarl J. Everolimus. Recent Results Cancer Res. 2014;201:373-392. doi: 10.1007/978-3-642-54490-3_23.
  3. Keytruda: anti—PD-1 receptor blockade. Keytruda website. Updated 2018. Accessed February 27, 2018.
  4. Lenvatinib in combination with everolimus. US FDA website. Updated May 16, 2016. Accessed February 27, 2018.
  5. Eisai and Merck receive breakthrough therapy designation from FDA for Lenvima (lenvatinib mesylate) and Keytruda (pembrolizumab) as combination therapy for advanced and/or metastatic renal cell carcinoma [news release]. Kenilworth, NJ: PR Newswire; January 9, 2018. Accessed February 27, 2018.
  6. Eisai and Merck receive breakthrough therapy designation from FDA for Lenvima (lenvatinib mesylate) and Keytruda (pembrolizumab) as combination therapy for advanced and/or metastatic renal cell carcinoma [news release]. Kenilworth, NJ: PR Newswire; January 9, 2018. Accessed February 27, 2018.
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