Episode 2: The CLEAR study, 4-year follow-up data
Presented by Prof Emmanuel Seront (UCL Louvain) and Prof Christof Vulsteke (Maria Middelares Gent)
In the primary analysis of the CLEAR study, the combination of lenvatinib and pembrolizumab (len-pem) demonstrated a statistically significant enhancement in PFS and OS when compared to sunitinib among patients with advanced renal cell carcinoma (aRCC). The recently available four-year follow-up data further substantiate the robustness of these findings. The overall response rate achieved with len-pem is very high (71%). In terms of PFS, the len-pem cohort exhibited a median duration of 23.3 months, whereas the sunitinib group showed a significantly shorter median PFS of 9.2 months (HR 0.42; 0.34-0.52). Considering the two-year duration of IO therapy, it is reasonable to anticipate a decline in PFS post-cessation of IO treatment. An additional positive aspect is the low incidence of primary progressive disease, recorded at only 5%, indicating that a minority of patients will experience initial disease progression—a pivotal consideration in the assessment of treatment efficacy.
A recurring observation across IO-TKI studies is the progressive increase in OS HR with each subsequent follow-up analysis. This phenomenon contrasts with findings from studies involving immune checkpoint inhibitors only (IO-IO studies), where an immediate response is observed in only 40% of patients, of whom 56% exhibit a sustained and durable response. Notably, in the IO-TKI studies, the initial response rate starts at 70%, indicating a higher likelihood of losing patients over time. Consequently, there is a growing apprehension regarding the optimal course of action with extended follow-up periods. The dilemma arises in deciding between the continuation of TKI therapy, which is associated with toxicities and potential impacts on quality of life, or exploring the possibility of incorporating more effective immune checkpoint inhibitors.
Notwithstanding, Prof Vulsteke affirms the efficacy of the IO-TKI combination as a highly active regimen that demonstrates significant efficacy. In situations demanding rapid responses, such as an impending vascular crisis, the IO-TKI combination presents a notable advantage, with a 71% response rate, compared to the 40% response rate associated with an IO-IO regimen. In scenarios where durability or the presence of sarcomatoïd features is a primary consideration, an IO-IO regimen might be more suitable. This consideration is particularly relevant for the intermediate and poor-risk population.
In the IMDC favourable risk group, the optimal approach remains less clear. While an IO-TKI combination leads to an increased overall response rate, it is accompanied by increased toxicity. Currently, there is minimal disparity in OS outcomes. The experts concur that many patients in this group may derive greater benefit from either sunitinib or cabozantinib alone, underscoring the complexity of treatment decisions in this specific risk category.
Although the stratification of the risk profile using the IMDC risk calculator appears straightforward, practical application often necessitates a nuanced clinical intuition. It is noteworthy that these criteria were not originally designed to serve as predictive tools, and as such, their application is flexible in alignment with clinical preferences and patient-specific considerations.
References:
Choueiri TK et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol 2023;24(3):228-38.S1340.