During a Targeted Oncology case-based roundtable event, Chung-Han Lee, MD, PhD, discussed the approved frontline regimens for patients with advanced clear cell renal cell carcinoma.
Targeted OncologyTM: What are the recommended frontline regimens for advanced patients with RCC with clear cell histology?
LEE: The recent update to the NCCN [National Comprehensive Cancer Network] guidelines for patients with intermediate- [risk] and poor-risk disease has multiple regimens that have category 1 evidence and are preferred agents. There are 3 different TKI [tyrosine kinase inhibitor] plus immunotherapy [IO] combinations, including axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab [Opdivo], and lenvatinib [Lenvima] plus pembrolizumab. There is also a combination therapy with an anti–CTLA-4 plus anti– PD-1, which is the combination of ipilimumab [Yervoy] plus nivolumab. Cabozantinib alone is considered a preferred regimen [for poor or intermediate disease]. However, that’s without category 1 evidence, but it was based off the CABOSUN trial [NCT01835158].1
The caveat is that we can’t make head-to-head comparisons across trials. There were various first-line phase 3 studies including CheckMate 214 [NCT02231749], which led to the approval of ipilimumab plus nivolumab by demonstrating an improvement in objective response rate [ORR] and overall survival [OS] compared with sunitinib [Sutent].2,3 The KEYNOTE-426 study [NCT02853331] with axitinib plus pembrolizumab vs sunitinib also demonstrated improvements in ORR, PFS [progression-free survival], and OS.4 In the CheckMate 9ER trial [NCT03141177], cabozantinib plus nivolumab demonstrated an improvement over sunitinib based off improved ORR, PFS, and OS.5 The CLEAR study [NCT02811861], which compared lenvatinib plus pembrolizumab vs sunitinib, again demonstrated improved ORR, PFS, and OS.6
At the 12-month landmark analyses, all of them showed improved OS ranging between 83% and 90% of patients being alive at 12 months.2-6 At the 24-month landmark survival, about 70% of patients were still alive, and it ranged to as high as 79%. The regimens are very reasonable choices that we would consider for first-line therapy for patients with intermediate[-risk] and poor-risk disease.
The FDA approved the 2 newest TKI plus IO regimens, with cabozantinib plus nivolumab being approved in January 2021 and lenvatinib plus pembrolizumab being approved in August 2021.7,8
What data led to the approval of lenvatinib plus pembrolizumab in the frontline advanced RCC setting?
The phase 3 CLEAR study led to the FDA approval of lenvatinib plus pembrolizumab. It was a 3-arm study. The key eligibility criteria included [patients] with clear cell RCC who were treatment naive and had KPS greater than or equal to 70%, measurable disease, and adequate organ function. The investigators used geographic stratification and MSKCC [Memorial Sloan Kettering Cancer Center] risk stratification. Patients were randomized to lenvatinib plus pembrolizumab at the 20-mg dose, with pembrolizumab 200 mg IV [intravenous] every 3 weeks. The second arm was lenvatinib plus everolimus [Afinitor] with lenvatinib at the 18-mg daily dose and everolimus at the 5-mg daily dose. The third arm was sunitinib at 50 mg on a schedule of 4 weeks on, 2 weeks off.6
The primary end point for which the study was powered was PFS by independent radiographic review. The key secondary end points included OS, ORR, safety, and quality of life. Some exploratory end points included duration of response [DOR] and biomarker analyses.6 Both lenvatinib plus pembrolizumab and lenvatinib plus everolimus showed improvements in PFS. Lenvatinib plus pembrolizumab demonstrated a hazard ratio [HR] of 0.39 [95% CI, 0.32-0.49; P < .001], which was significant.
The median PFS for lenvatinib plus pembrolizumab was 23.9 months compared with sunitinib at about 9.2 months, which was in line with the historic experience in other studies with sunitinib in this setting. Based off this study, the PFS favored the 2 combination regimens over sunitinib in all the evaluable subgroups including both the MSKCC and IMDC [International Metastatic RCC Database Consortium] risk stratification.6
The multiple subgroup analyses including age, sex, geographic location, risk stratification, performance status, number of sites with disease, and PD-L1 staining favored lenvatinib plus pembrolizumab over sunitinib. Subsequent analyses looked at some subgroups based off sites of disease and demonstrated an improvement for patients with bone metastases or baseline liver metastases, things that have historically been associated with poorer prognosis. There was benefit [with lenvatinib plus pembrolizumab] regardless of the PD-L1 status, whether they had prior nephrectomy or sarcomatoid histology.6
The Kaplan-Meier curves for OS separated early for lenvatinib plus pembrolizumab compared with the sunitinib arm [HR, 0.66; 95% CI, 0.49-0.88; P = .005], which again was significant. At the time of analysis, the median OS for all the cohorts was not yet reached. There were further updated analyses after a 34-month follow-up. Again, the median OS was not yet reached [HR, 0.72; 95% CI, 0.55-0.93].9 It is always reassuring to see this. Lenvatinib plus pembrolizumab was associated with a 16.1% CR [complete response] rate and 55% partial response rate [Table6]. Only about 5.4% of patients presented with primary progression of disease.
The relative risk from a response standpoint was almost 2, in terms of whether they had an objective response [compared with sunitinib]. The median DOR was longer for lenvatinib plus pembrolizumab compared with sunitinib, at 25.8 months vs 14.6 months. For patients who had a CR, about 80% maintained that at 24 months, and about 75% maintained that at 36 months.6
From a toxicity and drug exposure standpoint, there were more frequent drug discontinuations in the lenvatinib plus pembrolizumab arm, as you may expect from using combination therapy. The percentage of patients with any grade of adverse events [AEs] leading to discontinuation of the TKI was about 26% for patients in the lenvatinib plus pembrolizumab [arm] vs 14% for sunitinib by itself. Discontinuation of the pembrolizumab for toxicity was about 28%, and discontinuation of both drugs was at 13%. Lenvatinib plus pembrolizumab was associated with slightly higher levels of AEs like diarrhea, hypertension, and proteinuria.6
Could you discuss the recommended dosages for lenvatinib plus pembrolizumab?
The recommended FDA-approved dose is 20 mg of lenvatinib every day, pembrolizumab 200 mg IV every 3 weeks, up until progression of disease, for up to 2 years. After 2 years, the lenvatinib is continued as a single agent to either progression of disease or toxicity. Lenvatinib comes as a 4-mg or 10-mg pill. Per the clinical trial, the dose reduction scheme started at 20 mg, went down to 14 mg, went down to 10 mg, and then 8 mg.
You certainly can go down a little bit more than 10 mg if necessary. That would be perfectly OK, just like in the clinical trial.10 The typical way that we’d manage is to hold the drug, reduce, and then discontinue lenvatinib as necessary. For pembrolizumab, the plan is to either hold or discontinue. There’s not really a dose reduction that can be done for it.11
What data led to the approval of nivolumab plus cabozantinib in the frontline advanced RCC setting?
Cabozantinib plus nivolumab was studied for the first-line space in the CheckMate 9ER study. The key inclusion criteria included patients with untreated or advanced RCC with a clear-cell component and any IMDC risk. Patients were randomized to 200 mg of IV nivolumab every 2 weeks and 40 mg of oral cabozantinib daily, or 50 mg of oral sunitinib using the schedule of 4 weeks on and 2 weeks off. In combination with nivolumab, cabozantinib was given at the 40-mg dose, as opposed to the monotherapy dose of 60 mg.5
This study met its primary end point, showing an improvement in PFS. The median PFS for cabozantinib plus nivolumab was 16.6 months compared with sunitinib, which was 8.3 months [HR, 0.51; 95% CI, 0.41-0.64; P < .0001].5 There was a 33-month updated follow-up for this protocol, which, again, showed a very similar median PFS of 16.6 months vs 8.3 months [HR, 0.56; 95% CI, 0.46-0.68].12 Cabozantinib plus nivolumab demonstrated superiority to sunitinib, regardless of geographic region, IMDC prognostic risk stratification, PD-L1 status, age, sex, KPS, whether there were bone metastases, and whether a nephrectomy was done prior.5
The Kaplan-Meier curves for OS separated very early, at [approximately] 1.5 months. At 24 months, 70.3% of the patients on cabozantinib plus nivolumab were alive compared with 60% of patients in the sunitinib arm [HR, 0.70; 95% CI, 0.55-0.90].12
The percentage of patients who had significant shrinkage of their disease in objective response was 56% on cabozantinib plus nivolumab and 27% on sunitinib, with a CR rate of 8% compared with 4.6% on sunitinib. Again, very few patients had primary progression of disease, at 5.6% for cabozantinib plus nivolumab vs 13.7% on sunitinib.
The median time to response was also rapid, so at 2.8 months they saw an objective response, so that was at the first scan. The median DOR for cabozantinib plus nivolumab was 20.2 months.5 These numbers certainly held up at the longer follow-up at 33 months. There was an increase in the CR rate for the cabozantinib plus nivolumab at 12.4% compared with 8% at the earlier cutoff.12
How did cabozantinib and nivolumab perform in terms of safety and tolerability?
The median duration of therapy for cabozantinib plus nivolumab was about 14 months, and sunitinib was 9.2 months. About half of the patients ultimately discontinued the drug. However, more than half of the patients who discontinued the drugs did so because of progression of disease. Patients discontinuing due to toxicities for cabozantinib plus nivolumab made up about 15%. It was only about 5.6% [who discontinued] nivolumab alone and 6.6% for cabozantinib alone, and about 3.1% of patients had to discontinue both.5,12
From a drug tolerability standpoint, cabozantinib plus nivolumab was in general comparable to sunitinib. However, there were slightly more levels of grade 3 diarrhea. There was more evidence of AST [aspartate aminotransferase] and ALT [alanine aminotransferase] increases on cabozantinib plus nivolumab, but AEs like hypothyroidism, fatigue, nausea, mucositis, and stomatitis [as well as] decreased appetite were all comparable to what was seen with sunitinib.5
1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2023. Accessed June 21, 2022. https://bit.ly/3tQpaWN
2. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128(11):2085-2097. doi:10.1002/cncr.34180
3. Albiges L, Tannir NM, Burotto M, et al. First-line nivolumab plus ipilimumab versus sunitinib in patients without nephrectomy and with an evaluable primary renal tumor in the CheckMate 214 trial. Eur Urol. 2022;81(3):266-271. doi:10.1016/j.eururo.2021.10.001
4. Rini BI, Plimack ER, Stus V, et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/ NEJMoa1816714
5. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/ NEJMoa2026982
6. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/ NEJMoa2035716
7. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed June 21, 2022. https://bit.ly/3O9DBgt
8. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. August 11, 2021. Accessed June 21, 2022. https://bit.ly/3N7yGLN
9. 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 June 23, 2022. https://bit.ly/3HNYLOV
10. Lenvima. Prescribing information. Eisai. Updated December 2021. Accessed June 21, 2022. https://bit.ly/3tSHiiB
11. Keytruda. Prescribing information. Merck Sharp & Dohme. Updated May 2022. Accessed June 21, 2022. https://bit.ly/39KhOgn
12. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl 6):350. doi:10.1200/ JCO.2022.40.6_suppl.350