First-Line Treatment Using Combination Therapy in Advanced RCC

Vaishampayan Discusses PFS Benefit With Lenvatinib/Pembrolizumab in RCC

During a live virtual event, Ulka Vaishampayan, MBBS, discussed the results of the CLEAR trial of lenvatinib and pembrolizumab compared with sunitinib in first-line treatment of advanced RCC.

During a live virtual event, Ulka Vaishampayan, MBBS, discussed the results of the CLEAR trial of lenvatinib and pembrolizumab compared with sunitinib in first-line treatment of advanced RCC.

Targeted OncologyTM: What qualities of lenvatinib (Lenvima) led to its use in the CLEAR trial (NCT02811861) as a first-line therapy for renal clear cell carcinoma (RCC)?

VAISHAMPAYAN: The combination of lenvatinib and pembrolizumab [Keytruda] is the latest combination that we have to use in this setting. Lenvatinib, I must say, is a pretty remarkable multitargeted tyrosine kinase inhibitor. It targets not just VEGF, but also it has FGFR inhibitor activity, which is somewhat unique as compared with the other VEGF inhibitors. Axitinib [Inlyta] is a pure VEGF inhibitor, and then cabozantinib [Cabometyx] has MET and AXL inhibitory activity. There is sensitization and synergistic effects with each of these in the preclinical setting when given along with immunotherapy of a PD-1 and PD-L1 inhibitor.

Could you describe the design of the CLEAR trial?

The study compared front line lenvatinib/pembrolizumab or lenvatinib/everolimus [Afinitor] with sunitinib [Sutent]. Sunitinib was the control arm, and each of these regimens were compared with the control arm of sunitinib. The primary end point in this study is progression-free survival [PFS], and secondary end points included overall survival [OS], response rates, safety, and quality of life. The duration of response and biomarkers were exploratory end points.

The study enrolled treatment-naïve patients who had advanced RCC, a decent performance status of 70% or higher, and measurable disease. They used the Memorial Sloan Kettering Cancer Center [MSKCC] risk categories. Now, we have also discussed the International Metastatic RCC Database Consortium [IMDC] risk categories. The MSKCC does not have blood counts, but it has lactose dehydrogenase [LDH], and it still has calcium and hemoglobin as some of the risk criteria, as compared with the IMDC, which still has calcium but doesn’t have LDH, and has white blood cells and platelets as the risk characteristics.

What were the PFS outcomes for patients in the CLEAR trial?

VAISHAMPAYAN: There are very intriguing PFS data with lenvatinib/pembrolizumab. The median PFS was [23.9] months [compared with 9.2 months for sunitinib], which none of the other regimens had.1 About 15 to 16 months was typical for both cabozantinib plus nivolumab [Opdivo], and for axitinib/pembrolizumab.2,3 Frankly, ipilimumab [Yervoy]/nivolumab didn’t even show a PFS benefit over sunitinib.4 There was a hazard ratio of 0.39 for lenvatinib/pembrolizumab.1 The lenvatinib/everolimus combination also showed an improvement in PFS, but that was at a median of 14.7 months. This Is only at a 2-year median follow-up, but it is very intriguing to see a long median PFS with lenvatinib/pembrolizumab.

The PFS is evaluated by independent review committee, not investigator-directed.

The study looked at PFS by subsets: age, gender, and geographic region, as well as by favorable, intermediate, and poor risk. Now, one thing I will point out is that each of the MSKCC subgroups are showing tremendous benefit with lenvatinib/pembrolizumab. Take the subgroup analysis with a grain of salt, but whether you looked at MSKCC or the IMDC risk groups, which is what we are routinely using nowadays, regardless of which risk group you categorize these patients into, lenvatinib/pembrolizumab was favored. Whether the difference in PD-L1 status was less than 1% or more than 1%, it did not seem to matter. Both groups benefited pretty equally from the lenvatinib/pembrolizumab combination.

Please describe the efficacy of the secondary end points in this trial.

The Kaplan-Meier curves for OS are very immature as of 2 years. They seem to be coming together, but clearly, the curve separates early on for lenvatinib/pembrolizumab, and there is a sustained response that is seen there which tends to have an impact on OS.1 The hazard ratio for OS was 0.66, and the P value is statistically significant [P = .005]. That favors lenvatinib/pembrolizumab over sunitinib, but the lenvatinib/everolimus combination did not show a significant OS benefit over sunitinib therapy.

The objective response rate [ORR] for lenvatinib/pembrolizumab is 71% [and the complete response rate is 16.1%]. This is the highest we’ve seen in all of these regimens; granted, though, that [axitinib/pembrolizumab and cabozantinib/nivolumab] are separate trials [that cannot be compared directly]. But still, this is significantly better compared with sunitinib. Similarly, for the lenvatinib/everolimus combination, there was a 53.5% ORR, also better than sunitinib.1

What do we know about the safety profile of these treatments from the CLEAR trial?

Grade 3 or higher treatment toxicities were common in all arms of the study, leading to dose reductions in many patients. Sixty-seven percent of those receiving lenvatinib/pembrolizumab and 69% of those receiving lenvatinib/everolimus needed some kind of dose reduction due to toxicity. In the sunitinib arm, it was close to 50% of the patients needed dose reduction.

There were severe adverse events [AEs], as well as the overall AEs for different treatment-related AEs. Diarrhea seems to be one of the potentially high incidence AEs with lenvatinib/pembrolizumab. Hypertension, stomatitis, and hypothyroidism were observed. Fatigue and hand-foot syndrome are possible and are typically attributed to lenvatinib. The diarrhea could be from either drug, because immune colitis also can cause diarrhea related to pembrolizumab.

What are the practical considerations for administering lenvatinib plus pembrolizumab?

The recommended dosage of lenvatinib is 20 mg daily with pembrolizumab.5 Pembrolizumab is the flat dose, 200 mg every 3 weeks.6 On the study, the maximum duration of therapy was 2 years, and then after the combination, you could keep going on lenvatinib as a single agent until disease progression or unacceptable toxicity. Lenvatinib does have multiple dosage forms: 4 mg and 10 mg. Typically, you start with 20 mg, and then the first reduction is down to 14 mg, then 10 mg, and then 8 mg. But I have been impressed with the efficacy of this agent. Before this, I used it frequently in the lenvatinib/everolimus setting, second or third-line, and the efficacy of this agent is pretty remarkable. That may make the toxicity worthwhile, but again, you have to be comfortable managing it, and dose reduction is critical if you have significant toxicity.


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, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

4. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

5. Lenvatinib. Prescribing information. Eisai Inc; 2021. Accessed January 4, 2022.

6. Pembrolizumab. Prescribing information. Merck & Co., Inc; 2021. Accessed January 4, 2022.