CLEAR Benefit Found For Lenvatinib–Pembrolizumab In Advanced RCC

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Advanced renal cell carcinoma (RCC) patients given lenvatinib plus pembrolizumab as a first systemic therapy achieved significantly longer progression-free survival (PFS) than those given sunitinib monotherapy, the CLEAR investigators say. 

The findings have been published in The New England Journal of Medicine to coincide with their presentation at the 2021 Genitourinary Cancers Symposium. 

Robert Motzer, from Memorial Sloan Kettering Cancer Center in New York, USA, and co-authors explain that while the combination of lenvatinib and everolimus also offered a significant PFS benefit compared with sunitinib, only the pembrolizumab combination also achieved an overall survival (OS) benefit. 

This “confirms that an immune-checkpoint inhibitor–kinase inhibitor combination therapy is important in the first-line treatment of patients with advanced renal cell carcinoma”, they say. 

Median PFS was 23.9 months for the 355 patients who were randomly assigned to receive lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks and 14.7 months for the 357 patients given lenvatinib 18 mg/day plus everolimus 5 mg/day. 

By contrast, the 357 patients who received sunitinib 50 mg/day on a 4-weeks on, 2-weeks off schedule achieved a median PFS of just 9.2 months, resulting in hazard ratios (HRs) for progression or death of 0.39 and 0.65 in favour of the pembrolizumab and everolimus combinations, respectively. 

Further analysis showed that both the lenvatinib combinations were significantly better than sunitinib across all subgroups assessed including by MSKCC and IMDC classifications. The majority of patients had intermediate or favourable scores for both the MSKCC prognosis and the IMDC risk classifications. 

Median OS was not reached in any of the treatment arms but there was a significant difference between the lenvatinib plus pembrolizumab versus sunitinib arms with a HR of 0.66, whereas OS appeared comparable for the everolimus combination and sunitinib. 

And the OS benefit with lenvatinib plus pembrolizumab was found for most subgroups, including patients whose tumours were positive or negative for PD-L1, albeit not for those meeting the IMDC criteria for favourable risk. 

Median duration of response was 25.8 months with the pembrolizumab combination, 16.6 months with the everolimus combination and 14.6 months with sunitinib; this reflected the longer median duration of treatment with the pembrolizumab combination, at 17.0 months versus 11.0 and 7.8 months, respectively. 

Grade 3 or more severe adverse events of any cause were reported for 82.4% of patients receiving lenvatinib plus pembrolizumab, 83.1% of those given lenvatinib plus everolimus and 71.8% of sunitinib-treated patients. 

Adverse events of any grade led to discontinuation of one or both treatments in 37.2% of patients given the pembrolizumab combination and 27.0% of those given the everolimus combination, versus 14.4% of sunitinib-treated patients. The corresponding rates of dose reduction were 78.4%, 73.2% and 50.3%. 

“The safety profile of each combination therapy was consistent with that of each component as a single agent”, the researchers observe. 

Alain Ravaud, from Hospital Saint-André in Bordeaux, France, writes in an editorial accompanying the study that the CLEAR findings add to “existing evidence of positive outcomes” for PD-1 inhibitors plus ipilimumab or axitinib in advanced RCC. 

He suggests that treatment choices might differ depending on whether patients have rapid progression – which would favour use of a PD-1 inhibitor plus VEGFR tyrosine kinase inhibitor – or slower progression and favourable metastatic sites, such as the lung, which might allow physicians to consider toxicity and other distinguishing features between regimens. 

“What is needed at this point are biomarker-driven studies”, the editorialist proposes. 

“In pivotal studies, certain patient characteristics have been identified as predictive of differences in treatment efficacy with antiangiogenic drugs or immune-checkpoint inhibitors; even molecular biologic approaches (e.g., with transcriptomics or gene signatures) have been used to identify distinct groups”, he notes. 

References  

Motzer R, Alekseev B, Rha S-Y, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med; Advance online publication 13 February 2021. DOI: 10.1056/NEJMoa2035716  

Ravaud A. A step ahead in metastatic renal cell carcinoma. N Engl J Med; Advance online publication 13 February 2021. DOI: 10.1056/NEJMe2101777