CLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancer
Combining the multi-kinase inhibitor lenvatinib with pembrolizumab more than doubled the time to progression compared with sunitinib in advanced clear-cell kidney cancer and improved survival, with 71% of patients responding.
Open-label phase 3 trial of 1,069 patients with untreated advanced clear-cell renal cell carcinoma randomised to lenvatinib plus pembrolizumab, lenvatinib plus everolimus, or sunitinib. Primary endpoint was PFS by independent review.
Median PFS was 23.9 vs 9.2 months (HR 0.39) for lenvatinib plus pembrolizumab, with OS HR 0.66 and an objective response rate of 71.0% vs 36.1%. Alongside KEYNOTE-426 (axitinib plus pembrolizumab), CheckMate 9ER (cabozantinib plus nivolumab) and CheckMate 214 (nivolumab plus ipilimumab), it established immunotherapy-based combinations as universal first-line therapy for advanced kidney cancer.
- Median PFS 23.9 vs 9.2 months; HR 0.39 (95% CI 0.32-0.49).
- Overall survival HR 0.66 (95% CI 0.49-0.88) at the primary analysis; subsequent follow-up showed median OS about 53.7 vs 54.3 months with HR 0.79, as sunitinib patients received later immunotherapy.
- Objective response 71.0% vs 36.1%; complete response 16.1% vs 4.2%.
- Benefit across all IMDC risk groups, including favourable risk.
- Grade 3 or higher adverse events 82.4% vs 71.8%; hypertension, diarrhoea and proteinuria led to frequent lenvatinib dose reductions.
Patients with newly diagnosed advanced clear-cell kidney cancer should receive an immunotherapy-based combination; lenvatinib plus pembrolizumab gives the highest response rate and longest PFS of the available options, at the cost of more side effects requiring dose adjustment. Sunitinib alone is no longer an appropriate standard. Choosing among the combinations depends on risk group, symptoms, comorbidity and the value placed on treatment-free survival, which favours nivolumab plus ipilimumab in intermediate and poor risk.
- Open-label; no head-to-head comparison among the immunotherapy combinations.
- The OS advantage narrowed with longer follow-up because of subsequent immunotherapy in the sunitinib arm.
- High rates of dose reduction and discontinuation of lenvatinib; the 20 mg starting dose is debated.
- Non-clear-cell histologies were excluded.
Pages like this
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