Lenvatinib + pembrolizumab vs sunitinib in advanced RCC: the CLEAR trial

The CLEAR trial was a large phase III randomised study evaluating first-line treatments for patients with advanced clear cell renal cell carcinoma (RCC). A recent subanalysis presented at ESMO focused on the outcomes of patients with bone metastases, which are present in about one-third of advanced RCC cases and are often associated with pain, hypercalcemia, and fractures. These skeletal-related events significantly worsen morbidity, quality of life, and overall survival.

In the main CLEAR trial, treatment-naïve patients were randomised to receive lenvatinib plus pembrolizumab, lenvatinib plus everolimus, or sunitinib, which was the standard of care at the time. The primary endpoint was PFS per central review, with secondary endpoints including OS, response rate, safety, and quality of life. The study, published in the NEJM in 2021, showed that lenvatinib plus pembrolizumab achieved a clear and statistically significant improvement in PFS and OS compared with sunitinib, with a median PFS exceeding 23 months.

The new subgroup analysis assessed whether the presence of bone metastases affected outcomes. As expected, patients with bone metastases had poorer results than those without, showing shorter PFS and OS, lower response rates, and shorter response duration across all treatment arms. This confirmed the negative prognostic impact of bone metastases in advanced RCC.

Despite this, the combination of lenvatinib plus pembrolizumab remained superior to sunitinib, even in this high-risk subgroup. Median PFS was 17.2 months for lenvatinib plus pembrolizumab versus 5.6 months with sunitinib (HR 0.50), while median OS was 36.9 versus 31.5 months (HR 0.67). The overall response rate was also higher with the combination (60% vs. 27%), demonstrating robust efficacy regardless of metastatic site.

Analysis of prognostic trends showed that patients receiving lenvatinib plus pembrolizumab often maintained or improved their IMDC risk scores during treatment. About one-third experienced an improvement, while 42% remained stable, indicating that the combination therapy preserved prognostic stability even in patients with bone involvement.

In conclusion, this subanalysis confirmed that bone metastases are associated with worse clinical outcomes in metastatic RCC but also showed that lenvatinib plus pembrolizumab significantly improves survival and response compared with sunitinib, independent of bone status. These findings support lenvatinib plus pembrolizumab as a standard first-line treatment for advanced RCC, offering meaningful clinical benefit even in patients with bone metastases—a group traditionally considered difficult to treat.