First-Line Treatment Using Combination Therapy in Advanced RCC

Lenvatinib/Pembrolizumab for mRCC Shows Efficacy and Limited Treatment Discontinuation

During a live virtual event, Thomas Hutson, DO, PharmD, discussed the outcomes of the CLEAR trial of lenvatinib plus pembrolizumab for patients with advanced renal cell carcinoma.


  • A 59-year-old Black woman received a diagnosis of clear cell renal cell carcinoma (RCC)​
  • She underwent left radical nephrectomy in December 2019​
  • Nine months later, she developed metastatic disease to both lungs, mediastinum (35 x 38 mm), and retroperitoneal lymph nodes​
  • Diagnosis: stage IV RCC, clear-cell histology, with metastases to lungs and retroperitoneum​
  • Karnofsky performance status 90%​
  • Hemoglobin, 11.1 g/dL​
  • Corrected calcium, neutrophils, platelets within normal limits
  • The patient received lenvatinib (Lenvima) plus pembrolizumab (Keytruda) as part of a clinical trial.

Targeted OncologyTM: What data support the use of frontline lenvatinib and pembrolizumab for patients with advanced clear cell RCC?

THOMAS HUTSON, DO, PHARMD: The rationale was based on the phase 3 CLEAR study [NCT02811861]. The eligibility criteria were advanced clear cell RCC, treatment naive, measurable disease. Stratification was based on the patients’ region of the world, as well as MSKCC [Memorial Sloan Kettering Cancer Center] risk groups. It was a 3-arm study, but the statistics were designed to compare each of the lenvatinib-containing arms against sunitinib [Sutent], not the lenvatinib-containing arms against each other. The lenvatinib-containing arms did beat sunitinib, so lenvatinib/everolimus was powerful. However, the focus has been on the greatest benefit, which is lenvatinib/pembrolizumab versus sunitinib.1

The lenvatinib dose was 20 mg daily, and the pembrolizumab dose was 200 mg IV [intravenously] every 3 weeks. This is a higher starting dose than what one traditionally uses with the lenvatinib/everolimus oral regimen. The sunitinib dose was the standard 50 mg, 4 weeks on, 2 weeks off. The primary end point was PFS [progression-free survival] by independent review; secondary end points were overall survival [OS], objective response rate [ORR], safety, and quality of life. They also looked at end points such as duration of response and biomarkers. I acknowledge that I am one of the authors of this trial, and I am on the steering committee for it.

Looking at the Kaplan-Meier curve [for PFS], I’ve already mentioned that [both] lenvatinib-containing arms had [PFS] benefit. The curves separate out at the first scan, which is at about 2 months. The lenvatinib/pembrolizumab arm remains separated at a high level. It’s a [difference in median PFS] of 14.7 months over sunitinib; the hazard ratio is 0.39.

What subgroups stood out in this trial?

If we look at subgroup analysis…and we look at all these prespecified demographic groups, there is no one group that does not benefit clearly with lenvatinib/pembrolizumab over sunitinib. This included favorable-risk patients, although it a small percentage—it was 20% of patients. So, the favorable-risk patients benefit from the IO/TKI with a hazard ratio of 0.36, which is pretty good.1

If you look at PD-L1 status, irrespective if the patient has a [combined positive score] greater than, less than, or equal to 1, they benefited. This speaks to the reason why we don’t test PD-L1 status in kidney cancer, because it doesn’t matter. Patients benefit regardless of whether they are PD-L1 positive or not.

If we…look at particular adverse prognostic features—bone metastases, liver metastases, PD-L1 status, whether or not patients had a nephrectomy, and whether or not there was sarcomatoid histology—there was clear benefit in favor of the lenvatinib/pembrolizumab arm over sunitinib, without a doubt.2 Lenvatinib/pembrolizumab does work in bone metastasis, with a hazard ratio of 0.33. A lot of oncologists…will use bone metastases as a differentiator. This regimen clearly works in bone metastases.

What were the secondary end points of OS and best response in this trial?

At the first report [at a median follow-up of 26.6 months], we saw a hazard ratio of 0.66, which was right within the range of median OS.1 At 33 months, there was this crossover effect, and that [led to investigators] wondering “Why is there a crossover effect?” But, on longer follow-up now, we see that that crossover effect reverts, and it’s still lenvatinib/pembrolizumab that is doing better than sunitinib out there, with a hazard ratio of 0.72 [at 33.7 months follow-up].3 So, that crossover effect was a blip, and with longer follow-up you see the curves remain separated.

Lenvatinib/pembrolizumab maintains separation from sunitinib. Sunitinib doesn’t catch up with further follow-up. That tells you that you need to start with your best therapy first, because you will never catch up; you can’t salvage a patient starting them with a single-agent TKI [tyrosine kinase inhibitor] and then give them an IO [immune-oncology] later, thinking that you’re going to catch up to their survival benefit that they had. It still tracks higher, and that’s the way it’s been with the other IO/TKI trials, which is one of the reasons…to recommend starting with the best therapy you have first.

The CR [complete response] rate is 16.1% with lenvatinib/pembrolizumab, with a very low progressive disease rate. So, it’s a generalizable therapy. As they follow this out to 36 months, there is maintenance of benefit. A few patients [progress] as time goes on, but 74% of patient have a maintained CR at 36 months. What we want to see is at least 30% or more patients maintained at 5 years, which is in the ipilimumab/nivolumab range.4 I think there’s a good chance we’ll get there.

Please discuss the safety profile on the CLEAR study.

If we look at treatment exposure, safety, and discontinuation rate, that is probably the better indicator. All of these regimens have adverse events [AEs]. And, although some of the AEs look a little bit more intense than others, they’re all very similar; there are just nuances. Whether your patient has an AE or not, what matters most is can you handle that AE in clinic, such that the patient is able to stay on therapy? That’s the biggest issue, and the answer with lenvatinib/pembrolizumab is yes.

Lenvatinib/pembrolizumab does have a high number of patients that require dose reductions, 68.8% of patients.1 With lenvatinib/everolimus it was 73%, and with sunitinib it was 50%. I go into this therapy telling my patients that two-thirds of the time, they’re going to need a dose reduction. But we’re going to start all patients at the full dose. When the recommendation is to start at full dose, we have studies now that show starting at lower doses is not going to give you as good of a result.5 There are 20% of patients who need to be at the full dose. If the AEs declare themselves over the first few weeks to the first few months of therapy, [then] we will lower the dose. That’s what happened two-thirds of the time. But you can do lower the dose so that 80% of patients are able to stay on therapy. It’s only about 20% of patient that ultimately end up having to discontinue therapy due to AEs; although there are AEs, 4 out of 5 patients are going to be able to handle the AEs, and be able to stay on therapy and get the benefit.

As expected with combination therapy, patients are getting more AEs, but not that much, and the differences in most of the AEs between both arms is going to be in the grade 1 or 2 level. When you look at grade 3 or 4 AEs, it’s a little bit more in the combination arm, but not that much more. [Grade 3 or 4] AEs that stand out are hypertension and proteinuria with this regimen. Hand-foot syndrome occurred at about the same rate as it did with sunitinib.


1. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

2. Choueiri TK, Eto M, Kopyltsov E, et al. 660P - Phase III CLEAR trial in advanced renal cell carcinoma (aRCC): Outcomes in subgroups and toxicity update. Ann Oncol. 2021;32(suppl_5):S678-S724. doi:10.1016/annonc/annonc675

3. Choueiri TK, Powles T, Porta C, et al. A phase 3 trial of lenvatinib plus pembrolizumab versus sunitinib as a first-line treatment for patients with advanced renal cell carcinoma: overall survival follow-up analysis (the CLEAR study). Presented at: Kidney Cancer Research Summit 2021. October 7-8, 2021. Philadelphia, PA. Accessed July 25, 2022.

4. Motzer RJ, Tannir NM, McDermott DF, et al. 661P - Conditional survival and 5-year follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Ann Oncol. 2021;32(suppl_5):S678-S724. doi:10.1016/annonc/annonc675

5. Pal SK, Puente J, Heng DYC, et al. Assessing the safety and efficacy of two starting doses of lenvatinib Plus everolimus in patients with renal cell carcinoma: a randomized phase 2 trial [published online ahead of print, 2022 Feb 21]. Eur Urol. 2022;S0302-2838(21)02272-7. doi:10.1016/j.eururo.2021.12.024