Lenvatinib Plus Everolimus

Lenvatinib is an oral kinase inhibitor of VEGFR-1, FGFR1-4, PDGFRα, RET, and KIT, that like cabozantinib, is approved for the treatment of metastatic, progressive thyroid cancer.7

Because a phase 1 trial demonstrated manageable toxicity and antitumor activity with lenvatinib in combination with everolimus, researchers sought to evaluate the safety and efficacy of the combination compared with that of lenvatinib alone and everolimus alone.7

The phase 2 study, which was published in the journal The Lancet Oncology, showed that the combination improved progression-free survival and objective response rate vs everolimus alone (P < .001). Researchers found that median progression-free survival was 14.6 months with the combination compared with 7.4 months with lenvatinib alone and 5.5 months with everolimus alone. Importantly, lenvatinib plus everolimus also statistically significantly improved overall survival as compared with everolimus (HR, 0.51; P = .024).7

For the study, researchers enrolled 153 patients with progressive clear cell mRCC who had received 1 VEGF-targeted therapy. Of those, 18% had received prior immunotherapy. Subjects were randomly assigned 1:1:1 to receive lenvatinib 18 mg orally daily plus everolimus 5 mg orally daily, lenvatinib 24 mg daily alone, or everolimus 10 mg daily alone.7

Eisai Co., developer of lenvatinib, has submitted a supplemental New Drug Application for the kinase inhibitor in combination with everolimus for the treatment of advanced or metastatic RCC, and a randomized phase 3 study of the combination in mRCC is planned.8

“The combination compared to everolimus showed an increase in response rate, progression-free survival, and overall survival benefit; however, this was a small study of almost 50 patients in each arm,” Dr Choueiri said. “This drug was granted Priority Review by the FDA and could be approved.”


Bevacizumab has been the only immunotherapy indicated for the treatment of advanced RCC until the approval of nivolumab in November 2013. Now, pembrolizumab in combination with bevacizumab is being evaluated for advanced RCC in a multicenter, phase 2 trial.9

A phase 1 study, which enrolled 16 patients with clear cell mRCC who had failed at least 1 systemic therapy, demonstrated that pembrolizumab at a fixed dose of 200 mg and bevacizumab 15 mg/kg given every 3 weeks was safe. Preliminary data from a phase 1 study showed that the combination achieved tumor reduction in heavily pretreated patients.9

Another immunotherapy combination being evaluated is nivolumab plus ipilimumab for previously untreated mRCC. Sites across the world are still enrolling patients for the phase 2 trial comparing the combination with sunitinib monotherapy.10

Antibody Drug Conjugates

“There are also some antibody drug conjugates being investigated in clinical trials,” Dr Choueiri said. “Usually that targets a protein on the surface of the renal cell cancer, to which the antibody would attach and release a toxin.”

RELATED: Percutaneous Ablation for Small Renal Masses Appears Safe, Effective

One such example is AGS16F, a novel antibody drug conjugate directed against ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3), which is highly expressed in clear cell RCC. AGS16F comprises an anti-ENPP3 antibody conjugated with maleimidocaproyl monomethyl auristatin F (mcMMAF). It is currently being evaluated in a phase 1 clinical trial.11


  1. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373:1814-1823.
  2. Exelixis announces positive overall survival results from
  3. METEOR, the phase 3 pivotal trial of cabozantinib in advanced renal cell
  4. carcinoma [news release]. South San Francisco, CA; February 1, 2016. http://ir.exelixis.com/phoenix. zhtml?c=120923&p=irol-newsArticle_print&ID=2133957.
  5. Accessed March 16, 2016.
  6. Exelixis announces U.S. FDA deems New Drug Application sufficiently complete and grants Priority Review for cabozantinib as a treatment for advanced renal cell carcinoma [news release]. South San Francisco, CA: Exelixis; January 28, 2016. http://www.exelixis.com/investors-media/press-releases. Accessed March 15, 2016.
  7. Voss MH, Plimack ER, Rini BI, et al. DART Study: A phase II randomized trial of dalantercept plus axitinib versus placebo plus axitinib in advanced clear cell renal cell carcinoma (RCC): Results from Part 1. J Clin Oncol. 2015; 33 (suppl 7; abstr 407).
  8. AVEO Oncology announces presentation of final results of extension study 902 and FDA regulatory feedback for advancing tivozanib in renal cell carcinoma [news release]. Cambridge, MA; May 20, 2015. http://www.aveooncology.com/wp-content/uploads/2015/05/AVEO-FDA-2015-05-20.pdf. Accessed March 15, 2016.
  9. Hutson T, Nosov D, Tomczak P, et al. Tivozanib vs sorafenib targeted therapy for advanced renal cell carcinoma: Final results of a phase III trial (901) and efficacy results of a 2nd line tivozanib extension study (902). J Clin Oncol. 2015; 33 (suppl; abstr 4557).
  10. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015; 16(15):1473-1482.
  11. U.S. FDA accepts for priority review snda for eisai’s anticancer agent lenvatinib seeking approval for renal cell carcinoma [news release]. Tokyo, Japan: Eisai Co.; January 18, 2016. http://www.eisai.com/news/news201603.html. Accessed March 15, 2016.
  12. Dudek AZ, Sica RA, Sidani A, et al. Phase Ib study of pembrolizumab in combination with bevacizumab for the treatment of metastatic renal cell carcinoma: Big Ten Cancer Research Consortium BTCRC-GU14-003. J Clin Oncol. 2016; 34 (suppl 2S; abstr 559).
  13. Hammers HJ, Plimack ER, Sternberg C, et al. CheckMate 214: A phase III, randomized, open-label study of nivolumab combined with ipilimumab versus sunitinib monotherapy in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2015; 33 (suppl; abstr TPS4578).
  14. Donate F, Raitano A, Morrison K, et al. AGS16F is a novel antibody drug conjugate directed against ENPP3 for the treatment of renal cell carcinoma [published online ahead of print November 20, 2015]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-15-1542.