Clinical Trial Review: CLEAR
Panelists discuss how the CLEAR trial showed pembrolizumab plus lenvatinib achieved the highest objective response rate (71%) and progression-free survival (23.3 months) among frontline regimens, though requiring careful patient selection due to lenvatinib's challenging toxicity profile at the full 20 mg dose.
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The CLEAR trial established pembrolizumab plus lenvatinib as the immunotherapy-tyrosine kinase inhibitor combination with the highest objective response rate (71% vs 37% for sunitinib) and complete response rate (18%) among first-line regimens. Tykodi presents the impressive efficacy data with a 49.8-month median follow-up, including the highest progression-free survival (23.3 vs 9.2 months) and primary progression rate of only 5%. Despite a robust HR of 0.79 for overall survival, median survival times were similar (53.7 vs 54.3 months), reflecting effective subsequent therapies in the control arm.
Post hoc analysis of responding patients reveals 3 distinct categories: complete responders (65 patients), very good partial responders with greater than or equal to75% target lesion regression (59 patients), and standard partial responders with 30% to 75% regression (129 patients). Duration of response varied significantly: complete responders (43.7 months), near-complete responders (30.5 months), and other partial responders (17.2 months). Complete responders demonstrated specific characteristics: younger age, lymph node-predominant metastases, rare bone/brain involvement, and nearly universal prior nephrectomy.
The regimen's challenge lies in lenvatinib's demanding 20 mg starting dose, requiring careful patient selection and experienced toxicity management. Most practitioners report universal dose reductions, though Rini advocates starting at full dose with intensive monitoring support. The combination appeals to physicians prioritizing maximum tumor shrinkage and highest complete response rates, particularly for patients who can tolerate aggressive tyrosine kinase inhibitor dosing. Patient selection becomes critical, favoring robust individuals without significant cardiovascular comorbidities who can benefit from the highest response rates available in first-line clear cell renal cell carcinoma treatment.
