Pedro C. Barata, MD, MSc, explains how the favorable efficacy and tolerability of lenvatinib and pembrolizumab observed in the CLEAR trial helps provide a standard of care in this patient population.
Pedro C. Barata, MD, MSc, assistant professor of medicine at Tulane University School of Medicine, discusses the efficacy and tolerability of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) for patients with clear cell renal cell carcinoma (RCC).
In the phase 3 CLEAR trial (NCT02811861), lenvatinib/pembrolizumab was investigated in comparison to sunitinib (Sutent) as therapy for patients with RCC. The results of this trial led to lenvatinib/pembrolizumab becoming one of the standard-of-care frontline IO/TKI (immunotherapy/tyrosine kinase inhibitor) regimens in this patient population.
At the time of primary analysis, the objective response rate (ORR) with lenvatinib/pembrolizumab was 71.0%, with a best response of complete response (CR) in 16.1% of patients determined by an independent review committee. Barata says the confirmed CR rate was lower in the investigator analysis but was still significant. Progression-free survival (PFS) was close to 2 years, and overall survival (OS) favored lenvatinib/pembrolizumab with a HR of 0.66 for a greater than 30% improvement in OS. This trial established lenvatinib/pembrolizumab as a standard of care and confirmed that IO/TKI therapy is superior to TKI monotherapy for the majority of patients with advanced RCC.
Barata explains that the 20 mg dose of lenvatinib was high and led to some significant adverse events (AEs), however, the combination was tolerable overall when managed with dose reductions and discontinuations. He adds that oncologists are getting better at dealing with AEs associated with IO/TKI combinations by recognizing and preemptively acting to manage toxicities.
0:08 | What's important about these data, among other things, is lenvatinib/pembrolizumab is established as a new standard of care due to the efficacy end points; ORR [was] very close to 70%, [so] we had a very high ORR. Originally, it was right around 16% [by] independent review; I know it dropped to about 10% or so in the investigator analysis, but to be fair, [it reached] double digits once again with these IO/TKI combinations. In addition to that median PFS [was] very close to 2 years, and OS was definitely favoring the combination compared with sunitinib and in the ballpark of what we really would expect with risk reduction around 30%, survival favoring the combination of lenvatinib/pembrolizumab.
1:05 | The combination was tolerable. It is true that we did have…some [AEs], kind of expected from combining a higher dose of the TKI lenvatinib with pembrolizumab. Nonetheless, you can manage them with other dose reductions or even dose discontinuation if you will. Again, as we're getting better at least dealing with [AEs] from these medications, we're becoming more professional at dealing with [AEs] and preemptively acting on them. And so, I would argue it is a very active strategy [that] established lenvatinib/pembrolizumab as a new standard of care, as other combinations are, and again reminds us that TKI monotherapy is no longer an acceptable approach for most patients who come to us with untreated advanced RCC.