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Lenvatinib/pembrolizumab effective in all-comer RCC population, independent of biomarker status


Results from an exploratory analysis of the KEYNOTE-146/study 111 trial shared during the 2022 ASCO Genitourinary Cancers Symposium showed the combination of lenvatinib (Lenvima) plus pembrolizumab (Keytruda) was effective in patients with advanced renal cell carcinoma (RCC), regardless of their biomarker status.1

Chung-Han Lee, MD, PhD

Chung-Han Lee, MD, PhD

Although the study results were “disappointing from a biomarker development standpoint,” according to lead study author Chung-Han Lee, MD, PhD, assistant attending physician, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, the results confirm the effectiveness of the regimen across various lines of treatment.

“We know that even without biomarker stratification, this regimen already has high response rates and a fairly long progression-free survival,” see Lee. “[Providers] don't necessarily need to do extra steps in order to make a decision about whether or not they would offer this type of treatment to their patients.”

The primary objective of the analysis was to identify if there was an association between patient outcomes and gene expression signatures generated via RNA sequencing and DNA variants for individual genes of interest via whole exome sequencing. As of now, Lee explained, the field is in its infancy stages in learning if there are good predictive biomarkers to stratify patients to different treatment modalities.

“What we’ve done already is we’ve looked at various genomic and gene expression biomarkers in various settings. A lot of this comes from analysis of both phase 2 and phase 3 studies. Perhaps the most informative (data) recently has been looking within the first-line space,” he said. “And what they've demonstrated is there are specific gene expression patterns that have correlated with superior outcomes. However, where we really are lacking is the ability to translate this into clinical practice and having this type of information guide some of the clinical choices that we're making.”

In the past, providers have been able to analyze the genomics of patients who were naive to immunotherapy and identify those high levels of HLA diversity were linked to an increased odds of response to lenvatinib plus pembrolizumab.

In this exploratory analysis, Lee said, the study authors were interested in seeing if this could be translated in patients who have been pretreated with immunotherapy.

“We're trying to understand whether or not treatment-naive tissue, can be predictive of outcomes for people who've already had multiple lines of systemic therapy,” he explained. “So, we're trying to answer … whether or not there were good predictive biomarkers in the space and whether or not we could use older tissue? Or do the treatments that people have, potentially have an impact on whether or not some of the things that have worked can still continue to work?”

The phase 1b/2 KEYNOTE-146/study 111 trial comprised 147 patients (median age, 60 years; 78.2% male; 86.5% White), of which 80 (median age, 62 years; 75% male; 92.5% White) had available RNA sequencing and 60 had available whole exome sequencing (median age, 63.5 years; 78.3% male; 90% White).

A significant proportion of patients (71.4%) in the overall population had received prior anti–PD-1/PD-L1 therapy, as did patients in the RNA-sequencing population (87.5%) and whole exome sequencing population (88.3%). Few patients in the overall population, RNA-sequencing and whole exome sequencing population were treatment naïve (15.6%; 12.5%; 11.7%, respectively).

The findings showed that the objective response rate was similar among the 3 patient subgroups — 63.9% in the overall population, 66.2% in those with evaluable RNA sequencing and 68.3% in those with evaluable whole exome sequencing.

Moreover, the median PFS was also similar across the 3 groups. The median PFS in the overall population was 14.1 months (95% CI, 11.7-18.6), and 17.7 months in both the RNA-sequencing evaluable group (95% CI, 11.1-19.8) and the whole exome sequencing-evaluable group (95% CI, 11.7-22.1). The data also showed similar objective response rates across selected DNA variants including SETD2, BAP1, PBRM1 and VHL.

As for next steps, Lee noted that more analyses are warranted.

“It really is going to be looking to see whether or not we can get tissue that is closer to the time of systemic therapy and doing an analysis to see whether or not that is going to end up being predictive,” he concluded. “We certainly also want to see our ability to understand what are the changes that happened to the tumor as (a patient) gets treatment, because that may be very informative in terms of what the subsequent therapies you should think about.


1. Lee CH, Rasco DW, Rao A, et al. Association between biomarkers and clinical outcomes of lenvatinib + pembrolizumab in advanced renal cell carcinoma (RCC): Results from Study 111/KEYNOTE-146. J Clin Oncol. 2022;40(suppl 6):375. doi: 10.1200/JCO.2022.40.6_suppl.375.

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