Nizar M. Tannir, MD, discussed the case of a 59-year-old Black woman with clear cell renal cell carcinoma during a live event.
Targeted OncologyTM: Can you discuss the design of the phase 3 CLEAR study (NCT02811861) in advanced renal cell carcinoma (RCC)?
TANNIR: The design was frontline lenvatinib plus pembrolizumab vs lenvatinib plus everolimus [Afinitor] vs sunitinib [Sutent].1 This was a 3-arm study. For this phase 3 trial of first-line therapy in advanced clear cell RCC, the eligibility criteria were for treatment-naive patients with advanced clear cell RCC, Karnofsky performance status of 70% or better, measurable disease, and adequate organ function.
For the CLEAR study, the 2 strata were geographic region: Western Europe and North America vs the rest of the world, and MSKCC [Memorial Sloan Kettering Cancer Center] risk category: favorable, intermediate, or poor risk. In this trial, for risk stratification, they use the MSKCC; but for other trials [in this setting], the IMDC [International Metastatic RCC Database Consortium] risk model was used.
Patients were [randomly assigned] fairly, 1:1:1, to receive either lenvatinib plus pembrolizumab or lenvatinib plus everolimus or sunitinib. The primary end point was progression-free survival [PFS] by independent radiology committee or panel, using RECIST version 1.1. Secondary end points were overall survival [OS], objective response rate [ORR] by independent radiology committee using RECIST version 1.1, safety, and health-related quality-of-life outcomes. There were also key exploratory end points: duration of response and biomarkers.
What was the efficacy seen in patients in this trial?
In the Kaplan-Meier curves for PFS in the CLEAR study…I think it’s important to note that the 2 experimental arms, lenvatinib plus pembrolizumab and lenvatinib plus everolimus, in terms of PFS, showed a significant difference compared with sunitinib. The median PFS with lenvatinib/pembrolizumab was 23.9 months vs 9.2 months with sunitinib, and the median PFS for lenvatinib/everolimus was 14.7 months.
The hazard ratio for the difference for PFS between lenvatinib/pembrolizumab and sunitinib was 0.39 [95% CI, 0.32-0.49; P < .001].1 That corresponds to a 61% reduction in the risk of progression or death in favor of lenvatinib/ pembrolizumab. The hazard ratio for lenvatinib/everolimus vs sunitinib was 0.65, which corresponds to a 35% reduction in the risk of death or progression [95% CI, 0.53- 0.80; P < .001].
The prespecified analysis of adverse prognostic features included bone metastases, liver metastases, PD-L1 expression, prior nephrectomy, and sarcomatoid component.2 For all those covariables, the lenvatinib/pembrolizumab regimen performed better than sunitinib.
The difference in OS between lenvatinib/pembrolizumab vs sunitinib was significant, with a hazard ratio of 0.66 that corresponds to a reduction of mortality or death by 34% [95% CI, 0.49-0.88; P = .005].1 For the other arm of the study, lenvatinib/everolimus, the difference in OS was not statistically significant compared with sunitinib, and the hazard ratio for that comparison was 1.15 [95% CI, 0.88- 1.50; P = .3]. It’s important to note that at the time of this analysis, the median OS was not reached [for any of the treatment arms].
With a median follow-up of 33.7 months, which was presented at the Kidney Cancer Research Summit in 2021, the median OS was again not estimable for both treatment arms of lenvatinib/pembrolizumab vs sunitinib.3 The hazard ratio, 0.66 at the first analysis, is now at 0.72, and the 95% confidence intervals are less than 1.00 [0.55-0.93].
The confirmed ORR with lenvatinib/pembrolizumab in this CLEAR study was 71% compared with 36.1% with sunitinib and 53.5% with lenvatinib/everolimus.1 When you look at complete response [CR] rate, it was an impressive 16.1% with lenvatinib/pembrolizumab vs 9.8% with lenvatinib/everolimus vs 4.2% with sunitinib.
When you look at data from any phase 3 trial, you look at what the progressive disease [PD] rate is for a treatment regimen. PD with lenvatinib/pembrolizumab was very low. I think we all would like to see that PD rate as low as possible, and with lenvatinib/pembrolizumab the PD rate was 5.4% and with sunitinib it was 14.0%. Even with lenvatinib/ everolimus, the PD rate was 7.3%.
The median duration of response was an exploratory end point in the CLEAR study. The median duration of response was 25.8 months with lenvatinib/pembrolizumab vs 16.6 months with lenvatinib/everolimus vs 14.6 months with sunitinib. I think it’s important to also highlight that among patients who experienced a CR with lenvatinib/pembrolizumab in the intent-to-treat population, almost 80% of patients maintained a CR at 24 months and almost three-fourths maintained a CR at 3 years.4
How did patients respond to treatment in terms of toxicity?
Looking at treatment exposure, safety, and discontinuation in the phase 3 CLEAR study, median duration of treatment was 17 months with lenvatinib/pembrolizumab vs 11 months with lenvatinib/everolimus vs 7.8 months with sunitinib. Universally, just about every patient on this trial had any-grade treatment-emergent adverse events [TEAEs]; almost all patients developed 1 TEAE or more.
But if you look at grade 3 or 4 TEAEs, 82% of patients treated with lenvatinib/pembrolizumab had grade 3 or 4. It was almost identical with lenvatinib/everolimus, and it was a little lower with sunitinib, at 71.8%. Patients with any AE leading to dose reduction of either lenvatinib or sunitinib was 68.8% in the lenvatinib/pembrolizumab arm vs 73.2% with lenvatinib/everolimus vs 50.3% with sunitinib.
It is important, in addition to AEs leading to reduction or interruption, to look at discontinuation of therapy. When you look at the lenvatinib/pembrolizumab regimen, almost a quarter of the patients had to discontinue lenvatinib in the lenvatinib/pembrolizumab arm, 22% in the lenvatinib/ everolimus arm, and 14.4% with sunitinib.
When you look at discontinuation of either pembrolizumab or everolimus in the combination arm, with the lenvatinib/pembrolizumab regimen, 28.7% discontinued pembrolizumab and 24.8% discontinued [everolimus] in the lenvatinib/everolimus arm, so a little over a quarter of the patients discontinued pembrolizumab.1 But [13.4% discontinued] both lenvatinib/pembrolizumab, and 18.9% discontinued both lenvatinib/everolimus. Looking at TEAEs with frequency of 20% or more for lenvatinib/pembrolizumab vs sunitinib…diarrhea was on top in terms of garnering the highest number of any-grade AEs, closely followed by hypertension, then stomatitis, hypothyroidism, fatigue, hand-foot skin reaction, decreased appetite, nausea, dysgeusia, asthenia, rash, and dysphonia.
I think it’s important to note that hypertension, grade 3 and 4, with lenvatinib/pembrolizumab was 25.3%; so about a quarter of the patients treated with lenvatinib/ pembrolizumab had grade 3 or 4 hypertension. With sunitinib, 17.9% had grade 3 or 4 hypertension.
In the CLEAR study, the recommended starting dose of lenvatinib was 20 mg daily, and pembrolizumab was 200 mg every 3 weeks, up to 2 years.5,6 Many of us now have also given pembrolizumab 400 mg every 6 weeks, which would be more convenient, but in the CLEAR study the dosing schedule was 200 mg every 3 weeks.
Pembrolizumab was discontinued after 2 years, and lenvatinib was continued until progressive disease or toxicity.5,6 For those of you who have used the lenvatinib/ pembrolizumab regimen, the lenvatinib capsules come in 4 mg and 10 mg. The starting dose [is] 20 mg and the first reduction is to 14 mg, in case of toxicity; for the second reduction, you go down to 10 mg, and then you go down to the third reduction, which is 8 mg. This is based on the package insert for prescribing information, as well as the dose modifications from the trial.
In practice, if I have a patient on lenvatinib/pembrolizumab and they have responded, but they had AEs and they did not tolerate the 8 mg, I go down to 4 mg. Many of my colleagues [do this] also.
Can you discuss the CheckMate 9ER trial (NCT03141177) for advanced RCC?
The phase 3 trial CheckMate 9ER investigated the regimen of nivolumab/cabozantinib [Opdivo/Cabometyx] that was approved in January 2021.7,8
The study had similar inclusion criteria to what we heard before, but unlike the CLEAR study, the IMDC grouping was selected for inclusion, for eligibility criteria. This was a 2-arm study with cabozantinib 40 mg daily and nivolumab 240 mg every 2 weeks [vs sunitinib].
Many of us rarely give nivolumab every 2 weeks at 240 mg —we give 480 mg every 4 weeks—but in the CheckMate 9ER trial, this was the dosing schedule.7 The primary end point was PFS by blinded independent radiology review. Secondary end points included OS, ORR, and safety. The stratification factors were IMDC risk scoring—many of the BMS [Bristol Myers Squibb] trials used PD-L1 expression as one of the stratification factors—and geographic region.
The median PFS with a combination of nivolumab/cabozantinib was 16.6 months, which was double the median PFS with sunitinib of 8.3 months. This had a hazard ratio of 0.51, which means a 49% reduction of death or progress of disease, and this had a significant P value [95% CI, 0.41-0.64; P < .0001].
As we saw with the CLEAR study, in the CheckMate 9ER study, [regarding] PFS by subgroup with blinded independent central radiology review compared with sunitinib, the combination of nivolumab/cabozantinib fared better vis-à-vis the covariables that they looked at.1,7
Looking at ORR and best overall response in the primary analysis, with 18-month median follow-up, there was an 8% CR rate with nivolumab/cabozantinib vs 4.6% CR rate with sunitinib.7 And that important PD rate, 5.6 months—low PD rate—with nivolumab/cabozantinib vs about 14%. That was the same PD rate in the CLEAR study with sunitinib. Median time to response: 2.8 months with the nivolumab/cabozantinib combination vs 4.2 months with sunitinib. These are similar data to what we observed in CheckMate 214 [NCT02231749] with nivolumab/ipilimumab [Yervoy] vs sunitinib.9 Median duration of response was 20.2 months with the nivolumab/cabozantinib combination vs 11.5 months with sunitinib.
What are the most recent findings for the patients in CheckMate 9ER?
The follow-up was presented in San Francisco at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium—a median follow-up of the study of 33 months compared with 18 months for the primary analysis.10 The median PFS was exactly the same, 16.6 months vs 8.3 months, and the hazard ratio for the difference between the 2 arms was 0.56 at the follow-up. Again, 95% confidence intervals are very tight, 0.46 to 0.68.
The latest follow-up for the study showed nivolumab/ cabozantinib [vs] sunitinib was 70% vs 60% probability of OS at 24 months; so at 2 years, [with a] 10 percentage point difference in OS, probability is in favor of the combination. The median OS for the combination of nivolumab/ cabozantinib was 37.7 months vs 34.3 months with sunitinib. This had a hazard ratio of 0.70, so that’s a 30% reduction in the risk of death in favor of nivolumab plus cabozantinib [95% CI, 0.55-0.90].
The ORR with nivolumab/cabozantinib was 55.7%, basically identical to the prior analysis, vs 28.4% with sunitinib, very similar to the 27.1% in the primary analysis. But the CR rate with nivolumab/cabozantinib increased from 8% to 12.4% with further follow-up, and the CR rate with sunitinib was 5.2%. Median duration of response was about 2 years—23.1 months with the nivolumab/cabozantinib combination vs 15.1 months with sunitinib.
How did patients with RCC respond to the AEs of nivolumab/cabozantinib?
Safety is important to look at. Median duration of therapy was 14.3 months with nivolumab/cabozantinib vs 9.2 months with sunitinib.7 [Of] patients with at least 1 dose reduction —whether it’s cabozantinib or sunitinib—56.3% had to reduce the dose.
We know that for nivolumab, we do not reduce the dose; we just skip or delay the administration of nivolumab. So the dose reduction is only for the tyrosine kinase inhibitor. There were 51.6% of patients on the sunitinib arm who had to dose reduce from 15 mg down to 7.5 mg. Discontinuation for any reason, not just toxicity, was 44.4% with nivolumab/ cabozantinib vs 71.3% with sunitinib; the reason for higher discontinuation is because of a higher PD rate with sunitinib.
But when you look at treatment discontinuation due to toxicity, or any-grade treatment-related AEs, around 15% of patients on nivolumab/cabozantinib would discontinue therapy. Because of treatment-related AEs, discontinuation of nivolumab only was 5.6%, cabozantinib only was 6.6%, and both nivolumab and cabozantinib were 3.1%.
Now with the updated data with median follow-up of 33 months, discontinuation at 23.5-month follow-up was 9.7% for nivolumab only vs 7.2% for cabozantinib only vs 6.6% for the combination.11 For any-grade [AEs], there were 97%—almost universal as we saw with the other trial—AEs in both arms.10 For grades 3, 4, and higher, 65% of patients had grade 3 or 4 with the combination of nivolumab/cabozantinib vs 54% with sunitinib.
[The most common any-grade AE was] diarrhea, similar to what we saw in the CLEAR study.1,7 Then hand-foot skin reaction comes [in at] number 2, then hypertension.
1. 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
2.Choueiri TK, Eto M, Kopyltsov E, et al. Phase III CLEAR trial in advanced renal cell carcinoma (aRCC):outcomes in subgroups and toxicity update. Ann Oncol. 2021;32(suppl5):S678-S724. doi:10.1016/annonc/annonc675
3.Choueiri TK, Powles T, Porta C, et al. A phase 3 trial of lenvatinib plus pembrolizumab vs sunitinib as a first-line treatment for patients with advanced renal cell carcinoma: overall survival follow-up analysis (the CLEAR study). Abstract presented at: Kidney Cancer Research Summit; October 7-8, 2021; Philadelphia,PA.
4.Grünwald V, Powles T, Kopyltsov E, et al. Analysis of the CLEAR study in patients (pts) with advanced renal cell carcinoma (RCC):depth of response and efficacy for selected subgroups in the lenvatinib (LEN)+pembrolizumab (PEMBRO) and sunitinib (SUN) treatment arms. J Clin Oncol. 2021;39(suppl15):4560. doi:10.1200/JCO.2021.39.15_suppl.4560
5 .Lenvima. Prescribing information. Eisai Inc; 2021. Accessed October 26, 2022. https://bit.ly/3G22B8s
6.Keytruda. Prescribing information. MerckSharp & Dohme Corp; 2021. Accessed October 26, 2022.https://bit.ly/3WPC97J
7. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinibversussunitinib for advanced renal-cellcarcinoma.N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982
8. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed October 26, 2022.https://bit.ly/3rIKriw
9. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators.Nivolumab plus ipilimumabversussunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126
10. Powles T, Choueiri TK, BurottoM, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER:nivolumab plus cabozantinibversussunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl6):350. doi:10.1200/JCO.2022.40.6_suppl.350
11. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinibversussunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label,randomised, phase 3 trial. Lancet Oncol. 2022;23(7):888-898.Published corrections appear in Lancet Oncol. 2022;23(7):e319
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