Lenvatinib + pembrolizumab shows CLEAR survival benefit over sunitinib in advanced RCC

The combination therapy of lenvatinib plus pembrolizumab significantly improves survival outcomes compared with the standard-of-care treatment of sunitinib in the first-line setting for advanced renal cell carcinoma (RCC), according to the CLEAR* study presented at the 2021 ASCO GU Cancer Symposium.

The primary endpoint of progression-free survival (PFS) in patients receiving lenvatinib + pembrolizumab was more than double of those treated with sunitinib alone (median, 23.9 vs 9.2 months; hazard ratio [HR], 0.39; p<0.001). [ASCO GUCS 2021, abstract 269; N Engl J Med 2021;doi:10.1056/NEJMoa2035716]

Furthermore, overall survival (OS) was also significantly longer in the lenvatinib + pembrolizumab arm vs the sunitinib arm (median, not reach for both; HR, 0.66; p=0.005).

Lenvatinib represents a VEGFR TKI** whereas pembrolizumab is an anti-PD-1*** monoclonal antibody — each of which has shown activity as monotherapies for RCC treatment.

“A combination of two modes of action, such as an anti–PD-1 drug and a VEGFR TKI, has a greater chance of achieving control of the disease early on, as measured by PFS, than do combinations of immune-checkpoint inhibitors only,” wrote Dr Alain Ravaud from Hospital Saint-André, University Hospital Center Bordeaux, Bordeaux, France, in a linked editorial. [N Engl J Med 2021;doi: 10.1056/NEJMe2101777]

CLEAR marks the third RCC trial which showed a significant survival benefit with upfront therapy of a immunotherapy-TKI combination over sunitinib — following pembrolizumab plus axitinib in KEYNOTE-426 and nivolumab plus cabozantinib in CheckMate 9ER.

“This trial is a step forward in that it provides data that will assist in determining which combination of anti–PD-1 drug and VEGFR TKI may be effective as an alternative to nivolumab and ipilimumab for some patients,” Ravaud stated. 

“Rapid progression of the disease, especially in symptomatic patients and in patients who have involvement of an unfavourable metastatic site (eg, liver or large mediastinal lymph nodes) requiring a rapid response to treatment, favours combining two modes of action,” he explained.

Advantage of immunotherapy + TKI

In the phase III, multicentre CLEAR study, 1,069 patients with advanced RCC were randomized 1:1:1 to receive oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg Q3W, lenvatinib 18 mg once daily plus oral everolimus 5 mg once daily, or oral sunitinib 50 mg once daily (following a 6-week cycle with 4 weeks “ON” and 2 weeks “OFF”).

The third arm of lenvatinib + everolimus similarly led to a significantly longer PFS than sunitinib alone (median, 14.7 vs 9.2 months; HR, 0.65; p<0.001). However, no significant improvement was seen for OS (HR, 1.15; p=0.30).

“The finding of an OS benefit of lenvatinib in combination with pembrolizumab but not in combination with everolimus confirms that an immune-checkpoint inhibitor–kinase inhibitor combination therapy is important in the first-line treatment of patients with advanced RCC,” according to the investigators.

Improvement in overall response rate (ORR), nonetheless, reached significance with both the lenvatinib + pembrolizumab combination, as was with lenvatinib + everolimus, compared with sunitinib (71.0 percent and 53.5 percent vs 36.1 percent; p<0.001). Complete response rate in the lenvatinib + pembrolizumab was quadrupled compared with the sunitinib arm (16.1 percent vs 4.2 percent). The corresponding rate in the lenvatinib + everolimus was 9.8 percent.

Consistent safety profile

“The safety profiles of lenvatinib plus pembrolizumab/everolimus were consistent with each drug's known profile and manageable, as needed, through dose modifications,” reported lead author Dr Robert Motzer of Memorial Sloan Kettering Cancer Center in New York, New York, US.

Treatment-emergent or worsening adverse events (AEs) of grade ≥3 occurred in 82.4 percent of the patients treated with lenvatinib + pembrolizumab, 83.1 percent in the lenvatinib + everolimus arm, and 71.8 percent in the sunitinib arm. The most common grade ≥3 AEs occurring in at least 10 percent of patients in any treatment group included hypertension, diarrhoea, and increased lipase levels.

“Interruption or dose reduction of lenvatinib after initiation of treatment is a common strategy (irrespective of indication) to maximize therapeutic benefit while reducing the risk of toxic effects,” according to Motzer and co-authors.

AEs leading to dose reduction of lenvatinib occurred in 68.8 percent of patients receiving lenvatinib + pembrolizumab, while dose reduction of everolimus, lenvatinib, or both was required in 73.2 percent of patients on lenvatinib + everolimus.

“Overall, interruptions and reductions were effectively used in this trial, which allowed patients to continue to receive life-prolonging therapy for a longer period,” noted the investigators.

“Although the combination of lenvatinib and pembrolizumab was associated with some notable side effects, these AEs are often adequately managed with medical therapy if they are diagnosed early during patient visits,” they added.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” Motzer concluded.

 

*CLEAR: A multicentre, open-label, randomized, phase 3 trial to compare the efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib alone in first-line treatment of subjects with advanced renal cell carcinoma
**VEGFR TKI: Vascular endothelial growth factor receptor tyrosine kinase inhibitor
***PD-1: Programmed cell death 1