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Lenvatinib plus pembrolizumab as frontline treatment for patients with advanced clear-cell renal cell carcinoma

Results of the phase III CLEAR study demonstrate that the combination of lenvatinib and pembrolizumab significantly improves the overall response rate (ORR), the progression-free (PFS) and overall survival (OS) compared to sunitinib in previously untreated patients with clear-cell renal cell carcinoma (RCC). Also the combination of lenvatinib and everolimus was shown to improve the response rate and delay disease progression compared to sunitinib, but this did not lead to a significantly longer OS than what was seen with sunitinib monotherapy.


Recently, the combination of lenvatinib (LEN) and pembrolizumab (PEMBRO) demonstrated promising antitumour activity in a phase Ib/II study with previously treated RCC patients. Similarly, also the combination of LEN in with everolimus (EVE) was shown to prolong the PFS in the second-line treatment for these patients. In the randomized, phase III CLEAR study these two combinations were compared to sunitinib (SUN) as a frontline treatment strategy for patients with advanced clear-cell RCC. first-line. To this end, the study randomised (1:1:1) 1,069 treatment-naïve, advanced clear-cell RCC patients to receive LEN (20 mg, 4 times daily) plus PEMBRO (200 mg every 3 weeks) or LEN (18 mg, 4 time daily) plus EVE (5mg, four times daily) or SUN (50 mg, 4 times daily, 4 weeks on, 2 weeks off). The primary endpoint of this study was PFS, with OS, ORR and safety as key secondary objectives.

Lenvatinib plus pembrolizumab induces an ORR of 71%

The median age of participants in this trail was 64, 62 and 61 in the LEN plus PEMBRO, LEN plus EVE and SUN arms, respectively. Approximately two thirds of patients had an intermediate MSKCC prognostic risk score, and about 30% of participants had PD-L1 expression ≥1%. Over 70% of patients underwent a prior nephrectomy. At a median follow-up of 27 months, LEN plus PEMBRO was found to be associated with a median OS of 23.9 months, which was significantly longer than the 9.2 months median PFS seen with SUN (HR[95%CI]: 0.39[0.32-0.49], p< 0.001). For LEN plus EVE treated patients, the median PFS mounted to 14.7 months (HR[95%CI]: 0.65[0.53-0.80], p< 0.001) which was also significantluy longer than what was seen in SUN-treated patients. The PFS benefit obtained with LEN plus PEMBRO vs. SUN was comparable across all pre-specified subgroups. OS data were still immature at time of analysis, with a median OS not being reached in all 3 cohorts. However, LEN plus PEMBRO did prove to be associated with a statistically significant OS benefit compared to SUN with a hazard ratio of 0.66 (95%CI: 0.49-0.88; p= 0.005). This was not the case for the LEN plus EVE combination (HR[95%CI]: 1.15[0.88-1.50], p= 0.03). With LEN + PEMBRO an ORR of 71% was reported (16.1% complete [CR] and 54.9% partial responses [PR]), which was significantly higher than the 36.1% ORR seen with SUN (CR: 4.2%; PR: 31.9%) (RR[95%CI]: 1.97[1.69-2.29]; p< 0.001). For LEN + EVE the ORR was 53.5% with a CR in 9.8% of patients and a PR in 43/7% (vs. SUN: RR[95%CI]: 1.48[1.26-1.74]). Finally, response to LEN + PEMBRO also proved to be most durabla with a median duration of response of 25.8 months (vs. 16.6 and 14.6 months for LEN + EVE and SUN, respectively).

Grade ≥3 treatment-related adverse events (TRAEs) occurred at a rate of 71.6%, 73% and 58.8% of patients in the LEN + PEMBRO, LEN + EVE and SUN arms, respectively. Generally, the safety profiles observed were consistent with the known profile of each individual drug.


The phase III CLEAR demonstrates the significant improvements in PFS, OS and ORR, with LEN + PEMBRO, compared to sunitinib. LEN + EVE also provided significant improvements in PFS and ORR in this trial but this did not (yet) translate into a significant OS benefit. Combined with a manageable safety profile, this study supports the future evaluation of LEN + PEMBRO as a potential first-line treatment option for patients with advanced RCC.


Motzer RJ et al., Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). Presented at ASCO GU 2021; Abstract 269.

Speaker Robert J. Motzer

Robert J. Motzer

Robert J. Motzer, MD, Memorial Sloan Kettering Cancer Center, New York, United States


See: Keyslides

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