CLEAR
Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma
Phase 3N = 1,069NCT02811861
- Population
- Adults with advanced renal cell carcinoma and no previous systemic therapy
- Design
- Randomised (1:1:1) phase 3 trial in people with advanced renal cell carcinoma and no previous systemic therapy. The primary end point was progression-free survival assessed by an independent review committee (RECIST 1.1); overall survival and safety were also evaluated. The lenvatinib plus everolimus arm is a separate comparison with sunitinib.
- Primary endpoint
- PFS
- Arms
- Lenvatinib plus pembrolizumab (experimental, n = 355): Lenvatinib 20 mg orally once daily plus pembrolizumab 200 mg intravenously once every 3 weeks
- Lenvatinib plus everolimus (experimental, n = 357): Lenvatinib 18 mg orally once daily plus everolimus 5 mg orally once daily
- Sunitinib (control, n = 357): Sunitinib 50 mg orally once daily, alternating 4 weeks on and 2 weeks off
- People
- Motzer R, CLEAR Trial Investigators
PFSHR 0.39 (95% CI 0.32–0.49)Δ median PFS+14.7 monthsPFSHR 0.65 (95% CI 0.53–0.80)Δ median PFS+5.5 monthsOSHR 0.66 (95% CI 0.49–0.88)OSHR 1.15 (95% CI 0.88–1.50)
Show the numbers
| Endpoint | Analysis | Lenvatinib plus pembrolizumab / Lenvatinib plus everolimus | Sunitinib | Effect |
|---|---|---|---|---|
| PFSRandomised patients as described in the abstract (analysis population not stated there) | primaryMotzer 2021 | median 23.9 months | median 9.2 months | HR 0.39 (95% CI 0.32–0.49)P<0.001 |
| PFSRandomised patients as described in the abstract (analysis population not stated there) | primaryMotzer 2021 | median 14.7 months | median 9.2 months | HR 0.65 (95% CI 0.53–0.80)P<0.001 |
| OSRandomised patients as described in the abstract (analysis population not stated there) | primaryMotzer 2021 | — | — | HR 0.66 (95% CI 0.49–0.88)P=0.005Overall survival was reported in the primary paper as a further evaluated end point. |
| OSRandomised patients as described in the abstract (analysis population not stated there) | primaryMotzer 2021 | — | — | HR 1.15 (95% CI 0.88–1.50)P=0.30Overall survival was not longer than with sunitinib. |
| OSAll randomly assigned patients (lenvatinib plus pembrolizumab versus sunitinib comparison) | finalmedian follow-up 49.8 monthsMotzer 2024 | median 53.7 months; 66.4% at 3 y (61.1–71.2%) | median 54.3 months; 60.2% at 3 y (54.6–65.2%) | HR 0.79 (95% CI 0.63–0.99)P=0.0424 (nominal)Final prespecified overall survival analysis, data cutoff 31 July 2022; descriptive and non-inferential, with nominal P values. Median overall survival follow-up 49.8 months in the lenvatinib plus pembrolizumab group and 49.4 months in the sunitinib group (308 deaths). The 95% CIs of the medians were 48.7 to not estimable (lenvatinib plus pembrolizumab) and 40.9 to not estimable (sunitinib). |
| PFSAll randomly assigned patients (lenvatinib plus pembrolizumab versus sunitinib comparison) | finalMotzer 2024 | median 23.9 months (20.8–27.7) | median 9.2 months (6–11) | HR 0.47 (95% CI 0.38–0.57)P<0.0001 (nominal)Data cutoff 31 July 2022; descriptive analysis with nominal P values. |
| ORRAll randomly assigned patients (lenvatinib plus pembrolizumab versus sunitinib comparison) | finalMotzer 2024 | 71.3% (66.6–76.0%) | 36.7% (31.7–41.7%) | P<0.0001 (nominal)Relative risk 1.94 (95% CI 1.67 to 2.26). Complete responses 18.3% with lenvatinib plus pembrolizumab and 4.8% with sunitinib. Data cutoff 31 July 2022; descriptive analysis. |
| Endpoint | Analysis | Lenvatinib plus pembrolizumab / Lenvatinib plus everolimus | Sunitinib | Effect |
|---|---|---|---|---|
| PFSRandomised patients as described in the abstract (analysis population not stated there) | primaryMotzer 2021 | median 23.9 months | median 9.2 months | HR 0.39 (95% CI 0.32–0.49)P<0.001 |
| PFSRandomised patients as described in the abstract (analysis population not stated there) | primaryMotzer 2021 | median 14.7 months | median 9.2 months | HR 0.65 (95% CI 0.53–0.80)P<0.001 |
| OSRandomised patients as described in the abstract (analysis population not stated there) | primaryMotzer 2021 | — | — | HR 0.66 (95% CI 0.49–0.88)P=0.005Overall survival was reported in the primary paper as a further evaluated end point. |
| OSRandomised patients as described in the abstract (analysis population not stated there) | primaryMotzer 2021 | — | — | HR 1.15 (95% CI 0.88–1.50)P=0.30Overall survival was not longer than with sunitinib. |
| OSAll randomly assigned patients (lenvatinib plus pembrolizumab versus sunitinib comparison) | finalmedian follow-up 49.8 monthsMotzer 2024 | median 53.7 months; 66.4% at 3 y (61.1–71.2%) | median 54.3 months; 60.2% at 3 y (54.6–65.2%) | HR 0.79 (95% CI 0.63–0.99)P=0.0424 (nominal)Final prespecified overall survival analysis, data cutoff 31 July 2022; descriptive and non-inferential, with nominal P values. Median overall survival follow-up 49.8 months in the lenvatinib plus pembrolizumab group and 49.4 months in the sunitinib group (308 deaths). The 95% CIs of the medians were 48.7 to not estimable (lenvatinib plus pembrolizumab) and 40.9 to not estimable (sunitinib). |
| PFSAll randomly assigned patients (lenvatinib plus pembrolizumab versus sunitinib comparison) | finalMotzer 2024 | median 23.9 months (20.8–27.7) | median 9.2 months (6–11) | HR 0.47 (95% CI 0.38–0.57)P<0.0001 (nominal)Data cutoff 31 July 2022; descriptive analysis with nominal P values. |
| ORRAll randomly assigned patients (lenvatinib plus pembrolizumab versus sunitinib comparison) | finalMotzer 2024 | 71.3% (66.6–76.0%) | 36.7% (31.7–41.7%) | P<0.0001 (nominal)Relative risk 1.94 (95% CI 1.67 to 2.26). Complete responses 18.3% with lenvatinib plus pembrolizumab and 4.8% with sunitinib. Data cutoff 31 July 2022; descriptive analysis. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.39 | 0.32–0.49 |
| PFS | 0.65 | 0.53–0.8 |
| OS | 0.66 | 0.49–0.88 |
| OS | 1.15 | 0.88–1.5 |
| OS | 0.79 | 0.63–0.99 |
| PFS | 0.47 | 0.38–0.57 |
- Lenvatinib plus pembrolizumab (experimental)
- Sunitinib (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Lenvatinib plus pembrolizumab | Sunitinib |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 15 | 64.7% | 32.3% |
| 30 | 41.9% | 10.4% |
| 45 | 27.1% | 3.4% |
| 60 | 17.5% | 1.1% |
- Lenvatinib plus everolimus (experimental)
- Sunitinib (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Lenvatinib plus everolimus | Sunitinib |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 9 | 65.4% | 50.8% |
| 18 | 42.8% | 25.8% |
| 28 | 26.7% | 12.1% |
| 37 | 17.5% | 6.2% |
Appears in
Sources
Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384(14):1289-1300.
Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, et al. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. 2024;42(11):1222-1228.