Lenvatinib plus pembrolizumab improves PFS, OS, ORR across RCC subgroups

First-line treatment with lenvatinib plus pembrolizumab improves progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) vs sunitinib across subgroups of patients with advanced renal cell carcinoma (RCC), and maintains or improves patients’ health-related quality of life (HRQoL), new data from the CLEAR trial have shown.

In a post hoc exploratory analysis, the lenvatinib/pembrolizumab combination demonstrated significantly improved PFS vs sunitinib in subgroups of patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate/poor risk disease (median, 22.1 months vs 5.9 months; hazard ratio [HR], 0.36; 95 percent confidence interval [CI], 0.28 to 0.47) as well as those with IMDC favourable risk disease (median, 28.1 months vs 12.9 months; HR, 0.41; 95 percent CI, 0.28 to 0.62). [Grünwald V, et al, ASCO 2021, abstract 4560]

OS was also significantly improved with lenvatinib/pembrolizumab vs sunitinib in patients with IMDC intermediate/poor risk disease (median, not evaluable in both groups; HR, 0.58; 95 percent CI, 0.42 to 0.80). In the IMDC favourable risk subgroup, the small number of events was inadequate for evaluation of OS (HR, 1.15; 95 percent CI, 0.55 to 2.40).

ORR also favoured lenvatinib/pembrolizumab vs sunitinib in the IMDC intermediate/poor risk (72.4 percent vs 28.8 percent) and favourable risk (68.2 percent vs 50.8 percent) subgroups.

The PFS, OS and ORR benefits of lenvatinib/pembrolizumab vs sunitinib were observed in patients with target kidney lesions (median PFS, 22.1 months vs 7.5 months; HR, 0.40; 95 percent CI, 0.25 to 0.65) (OS HR, 0.44, 95 percent CI, 0.26 to 0.77) (ORR, 71.8 percent vs 27.0 percent; odds ratio [OR], 10.55; 95 percent CI, 4.54 to 24.52), as well as those without target kidney lesions (median PFS, 25.8 months vs 9.4 months; HR, 0.38; 95 percent CI, 0.30 to 0.49) (OS HR, 0.76; 95 percent CI, 0.54 to 1.09) (ORR, 70.8 percent vs 38.5 percent; OR, 3.87; 95 percent CI, 2.66 to 5.37).

The CLEAR investigators also performed a 6-month landmark analysis of OS by depth of response in the lenvatinib/pembrolizumab group. Notably, all patients who achieved complete response with lenvatinib/pembrolizumab at 6 months were alive at 2 years. The 2-year OS rate was similar, at 91.7 percent, among patients who achieved >75 percent reduction in target lesions at 6 months with lenvatinib/pembrolizumab.

In another analysis, HRQoL and disease-related symptoms were shown to be similar or better among patients treated with lenvatinib/pembrolizumab vs sunitinib, and similar or worse in those treated with lenvatinib/everolimus vs sunitinib. [Motzer RJ, et al, ASCO 2021, abstract 4502]

At mean follow-up (week 46), overall changes in HRQoL from baseline favoured lenvatinib/pembrolizumab vs sunitinib, with significant between-group differences in physical functioning, fatigue, dyspnoea, and constipation favouring lenvatinib/pembrolizumab. Overall changes in HRQoL from baseline also favoured the lenvatinib/everolimus vs sunitinib group at 46-week mean follow-up, with significant differences in pain, appetite loss, and diarrhoea favouring lenvatinib/everolimus. There were no significant differences for both lenvatinib/pembrolizumab and lenvatinib/everolimus vs sunitinib in 14 of 18 HRQoL scale comparisons.

Median time to first deterioration (TTD) favoured lenvatinib/pembrolizumab vs sunitinib for physical functioning, dyspnoea, appetite loss, and European Quality of Life 5-Dimension 3-Level System visual analogue scale. Time until definitive deterioration favoured lenvatinib/pembrolizumab vs sunitinib for global health status/QoL, physical/role/ emotional/social functioning, fatigue, nausea and vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, and diarrhoea. No significant differences in 15 of 19 TTD scale comparisons were observed for both lenvatinib/pembrolizumab and lenvatinib/everolimus vs sunitinib.