In the phase 3 multicenter, open-label, randomized CLEAR trial, lenvatinib in combination with pembrolizumab or everolimus demonstrated significant benefits over sunitinib in patients with advanced renal cell carcinoma (RCC). Physician’s Weekly interviews Alain Ravaud (MD, PhD), Head of Department of Medical Oncology and Professor of Medical Oncology at the Centre Hospitalier Universitaire de Bordeaux, France, to ask for his perspectives on the CLEAR trial and its implications for the treatment of advanced renal cell carcinoma.

Several phase 3 trials have demonstrated that immune checkpoint inhibitors, either in dual therapy or in combination with kinase inhibitors, lead to better therapy outcomes in comparison with the standard first-line treatment of sunitinib in patients with metastatic renal cell carcinoma.

The CLEAR trial (NCT02811861) follows this trend by investigating lenvatinib plus pembrolizumab or everolimus as possible combination therapies for the frontline treatment of renal cell carcinoma. The CLEAR trial topline results were presented by Dr. Robert Motzer (Memorial Sloan Kettering Cancer Center, New York, USA) at the 2021 ASCO Genitourinary Cancers Symposium [1], and were simultaneously published in the New England Journal of Medicine with an accompanying editorial [2,3].

Lenvatinib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, and pembrolizumab, an anti-programmed cell death 1 (PD-1) immune checkpoint inhibitor, have demonstrated antitumor activity in renal cell carcinoma as monotherapies in previous clinical trials. Moreover, combination therapies of lenvatinib plus everolimus (an mTOR kinase inhibitor), and lenvatinib plus pembrolizumab have shown promising results. The CLEAR trial compares the efficacy of these combination regimens with sunitinib (which is also a VEGFR tyrosine kinase inhibitor), the standard first-line treatment.

The 1,069 patients with advanced renal cell carcinoma who had not received previous systemic therapy were randomly assigned to receive lenvatinib (20mg PO, once daily) plus pembrolizumab (200 mg IV, once every three weeks), lenvatinib (18mg PO, once daily) plus everolimus (5mg PO, once daily), or sunitinib (50mg PO, once daily, alternating 4 weeks of treatment with 2 weeks of no treatment).

The primary endpoint of this trial was progression-free survival. Key secondary endpoints were overall survival and objective response. The lenvatinib plus pembrolizumab and the lenvatinib plus everolimus group demonstrated a significantly longer progression-free survival than the sunitinib group (lenvatinib plus pembrolizumab: 23.9 months, 95% CI 20.8 – 27.7; lenvatinib plus everolimus: 14.7 months; 95% CI CI 11.1 – 16.7; sunitinib: 9.2 months; 95% CI 6.0 – 11.0). The overall survival analysis at 24 months follow-up favored the lenvatinib plus pembrolizumab group (79.2% survival) over the sunitinib group (70.4% survival, HR 0.66, 95% CI 0.49-0.88, P=0.005).  This advantage in overall survival over the sunitinib group was not found for the lenvatinib plus everolimus group (66.1% survival, HR 1.15, 95% CI 0.88-1.50, P=0.30). Importantly, median overall survival was not reached with any treatment.

Almost all patients experienced adverse events during treatment. Grade 3 or higher adverse events occurred respectively in 82.4% (lenvatinib plus pembrolizumab), 83.1% (lenvatinib plus everolimus) and 71.8% (sunitinib) of the patients. The most common any-grade adverse events during treatment were hypertension and diarrhea. Diarrhea, hypertension, an elevated lipase level, and hypertriglyceridemia occurred in at least 10% of the patients in any treatment group as grade 3 or higher adverse events.

Confirmed objective response to treatment percentages and median duration of response were 71.0% and 25 months for the lenvatinib plus pembrolizumab group, 53.5% and 16.6 months for the lenvatinib plus everolimus group, and 36.1% and 14.6 months for the sunitinib group.

The authors concluded that the combination therapy of lenvatinib plus pembrolizumab provides significant benefits in progression-free survival and overall survival in comparison with sunitinib.

Our journalist asked Prof. Ravaud for his perspectives:

What does the CLEAR trial specifically add to our understanding of renal cell carcinoma treatment in your opinion?

“This trial confirms what we have seen in previous trials in recent years, combining immunotherapy with another immunotherapy or an antiangiogenic medicine in the treatment of advanced renal cell carcinoma. These combination regimens show clear benefits over the standard first-line treatment of sunitinib. The improvement in progression-free survival with these therapies is evident and increases in overall survival and complete response are likely to be confirmed in follow-up analyses. In this way the lenvatinib plus pembrolizumab and lenvatinib plus everolimus therapies of the CLEAR trial show us that combination therapies, PD-1 immune checkpoint inhibitor plus (VEGFR) tyrosine kinase inhibitor therapies in particular, hold a place in the future in the treatment of advanced renal cell carcinoma.”

“Since these treatment regimens are so new, it is still an open question what the magnitude of these combination therapies will be in clinical practice. For example, is it possible that we can cure patients with this approach or turn metastatic renal cell carcinoma into a chronic disease with a high quality of life for patients? We don’t know that at this point in time.”

“Another important and complicated issue is selecting patients for the right combination therapy. If you look at the side effects I think dual immunotherapy is probably the better option. In clinical practice we are able to manage most side effects in patients when administering this type of medicine. Antiangiogenic drugs on the other hand give continuous mild side effects, since they are taken on a daily basis. Nevertheless I would probably choose the therapy with the strongest anti-cancer activity and follow the patient carefully in managing the side effects. But this is a difficult decision to make.”

“In my opinion we need the subgroup analyses from the follow-up results of these trials and apply these combination regimens in clinical practice to gain a better perspective on therapy efficacy and patient selection. Despite the unanswered questions we are facing, I believe we are turning the page on renal cell carcinoma treatment. In the foreseeable future, combination regimens will be replacing sunitinib as the standard-of-care option in first-line therapy in patients with advanced renal cell carcinoma.”

What are the next challenges to overcome in RCC and kidney cancer in general?

“First, we need patients to have no metastases. I think adjuvant trials in the coming months and years will give us a better understanding of how much work remains to be done to achieve this result. The second point for me is the rapid progression we see in 10-20% of the patients despite the administering of combination therapies. Mostly these patients have a different histological profile. We see good results in clear cell RCC patients, but papillary tumors and sarcomatoid patients do not respond all that well. We need to learn why this is the case and what we can do about it. Finally, like the large breast cancer and colon cancer trials we need a vast amount of participants to accelerate our understanding of renal cell carcinoma and other kidney cancers.  In this way it could be possible to improve therapy outcomes by making a concise patient selection based on patient profiles, disease presentation and metastatic development. I hope to see this kind of progress in three to five years.”


Written by Rachel Giles, PhD, Contributing Writer, Medicom Medical Publishers

  1. Motzer R, ASCO Genitourinary Cancers Symposium of (ASCO-GU), 11-13 Feb 2021. Abtract 269.
  2. Motzer R, et al (2021). Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. The New England Journal of Medicine, 10.1056/NEJMoa2035716. Advance online publication.
  3. Ravaud A. (2021). A Step Ahead in Metastatic Renal Cell Carcinoma. The New England Journal of Medicine, 10.1056/NEJMe2101777. Advance online publication.