KEY TAKEAWAYS
- Phase 3 trial CLEAR aimed to demonstrate that lenvatinib plus pembrolizumab is an effective first-line treatment for advanced clear cell RCC.
- Patients enrolled in the lenvatinib plus pembrolizumab arm with a confirmed complete response or >75% target-lesion reduction by 6 months had a 24-month OS probability of ≥91.7%.
- Patients with an intermediate/poor IMDC risk classification had longer median progression-free survival and a higher ORR with lenvatinib plus pembrolizumab versus sunitinib.
- Landmark analyses showed that tumor response by 6 months correlated with longer OS, and patients with no progression by 6 months had lower probabilities of death in both treatment arms.
- While the study’s results were exploratory and not powered/stratified, the findings suggest that the extent of tumor shrinkage can predict survival in advanced/metastatic RCC.
In the case of advanced/metastatic renal cell carcinoma (RCC), a disease with a notoriously low survival rate, the degree to which the tumor shrinks has been recognized as a predictor of survival. Therefore, to evaluate the efficacy and survival outcomes in certain subgroups, we will do an exploratory analysis of overall survival (OS) by tumor response by 6 months.
An open-label, randomized, multicenter phase 3 trial (CLEAR) was conducted to determine the best first-line therapy for patients with advanced clear cell RCC.
Participants were assigned to receive either 4 weeks of lenvatinib 50 mg orally daily with pembrolizumab 200 mg intravenously once every 3 weeks, 4 weeks of lenvatinib + everolimus (not included in this analysis), or sunitinib 50 mg orally daily for 4 weeks on therapy/2 weeks of no treatment. They performed landmark analyses to determine whether or not tumor regression and disease progression by 6 months were associated with OS. In addition, target kidney lesion existence and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk subgroup were used to evaluate progression-free survival, response duration, and objective response rate (ORR).
An external review panel determined the effectiveness according to the Response Assessment Criteria in Solid Tumors, version 1.1. Patients enrolled in the lenvatinib + pembrolizumab arm who achieved a complete response or >75% target-lesion reduction by 6 months had a 24-month OS probability of 91.7%, according to landmark analyses by tumor shrinkage. In addition, patients who experienced no illness advancement after 6 months had lower mortality probabilities in both treatment groups, according to a landmark analysis comparing disease progression.
With lenvatinib + pembrolizumab, patients with an intermediate/poor IMDC risk classification had a higher ORR (72.4% vs. 28.8%) and longer median progression-free survival (22.1 vs. 5.9 mo). Similarly, lenvatinib plus pembrolizumab fared better in individuals who were IMDC-favorable and those who had or did not have target kidney lesions. Inadequacies include a lack of statistical power and a need for more stratification in data analysis. According to landmark analyses, tumor remission by 6 months was associated with longer OS in patients with advanced RCC treated with a combination of lentivizumab and pembrolizumab rather than sunitinib alone.
Source: https://pubmed.ncbi.nlm.nih.gov/36720658/
Clinical trial: https://clinicaltrials.gov/ct2/show/NCT02811861
Grünwald, V., Powles, T., Kopyltsov, E., Kozlov, V., Alonso-Gordoa, T., Eto, M., Hutson, T., Motzer, R., Winquist, E., Maroto, P., Keam, B., Procopio, G., Wong, S., Melichar, B., Rolland, F., Oya, M., Rodriguez-Lopez, K., Saito, K., McKenzie, J. and Porta, C. (2023). Survival by Depth of Response and Efficacy by International Metastatic Renal Cell Carcinoma Database Consortium Subgroup with Lenvatinib Plus Pembrolizumab Versus Sunitinib in Advanced Renal Cell Carcinoma: Analysis of the Phase 3 Randomized CLEAR Study. European Urology Oncology. doi:https://doi.org/10.1016/j.euo.2023.01.010.
