EIKCS 2021: Designing Biomarker-Driven Trials: Opportunities and Challenges

(UroToday.com) The treatment landscape in the first-line therapy of metastatic renal cell carcinoma (mRCC) has rapidly evolved over the past 3 years. In spite of all these changes, more changes are coming. In a presentation at the European International Kidney Cancer 2021 Virtual Annual Meeting, Dr. Vano discussed biomarker-driven trials.

He first argued for the rationale of biomarker-driven trials based on the rationale that metastatic kidney cancer represents an incurable disease and current therapies have significant toxicity. He further emphasized that, based on drug development over the past two decades, there are many treatment options in mRCC that improve survival.


As a result of general improvements in care as well as the ability to sequence many lines of therapy, survival has broadly increased: for example, patients receiving sunitinib in the pivotal SUN trial (published in 2009) had a median overall survival of 26 months while those receiving sunitinib in the control arm of the recently published CLEAR trial had a median overall survival of 38 months.

Given all these treatment options, we need biomarkers of treatment efficacy. Dr. Vano first emphasized that wile PD-L1 expression provides informative data regarding benefit comparing immunotherapy-based regimes to TKI alone, it is not useful to guide treatment decision making between TKI-IO vs IO/IO regimes.

In contrast, he suggested that “one of the best biomarkers” is a gene expression signature. One example of such a signature was derived from an ancillary analysis of the JAVELIN trial. This 26-gene signature provides predictive ability for patients treated with avelumab and axitinib, but not among patients receiving nivolumab + ipilimumab. Further work is needed to assess its ability among patients undergoing other Tyrosine Kinase Inhibitors (TKI)/IO regimes. 

A second example of a gene expression signature comes from the Nivoren trial, in which the angiogenesis and immune signatures were combined to identify four clusters, which are associated with prognosis. These clusters could allow better identification of responders to either nivolumab, nivolumab + ipilimumab or TKI. ccrcc1 “immune-low” and ccrcc4 “immune-high” tumors have been associated with the poorest outcomes, whereas ccrcc2 “angio-high” and ccrcc3 “normal-like” tumors have been associated with the best outcomes.


Based on these data, they designed the BIONIKK trial, an open-label, phase II biomarker-driven randomized trial. Patients with ccrcc1 and ccrcc4 signatures were randomized to nivolumab versus nivolumab + ipilimumab, whereas those with ccrcc2 and ccrcc3 signatures were randomized to receive nivolumab + ipilimumab versus TKI.


Among patients with the ccrcc1 signature, objective response rates were higher among those who received combination therapy with nivolumab + ipilimumab (39.4%; 6.1% complete response rate) than those who received nivolumab alone (20.7%; 0% complete response rate) whereas, among those with a ccrcc4 signature, objective response rates were 50.3% in those receiving the combination approach (11.8% complete response rate) as compared to 50% in those receiving nivolumab alone (7.1%). In patients with the ccrcc2 signature, objective response rates were 48.3% in the nivolumab + ipilimumab arm (13.8% complete response rate) and 53.8% in the TKI arm (0% complete response rate) whereas, among patients with the ccrcc3 signature, 25% receiving nivolumab + ipilimumab had objective responses (0% complete response rate) and 0% receiving TKI had an objective response.  


These are the first randomized data based on molecular risk group assessment to guide first-line therapy in metastatic ccRCC. In particular, among patients with the ccrcc4 signature, use of combination therapy may not be required based on relatively little difference in response rate. Patients with the ccrcc2 signature may be most appropriate for IO-TKI combinations given the benefit seen with TKI monotherapy. Notably, ancillary analyses of CheckMate-009 demonstrate that the ccrcc4 signature is associated with response to IO therapy, but resistance to TKI therapy.

As a word of caution, he emphasized that the BIONIKK trial had a 35% screen failure rate due to need for frozen tumors. There are further challenges in identifying the risk biomarkers and the right study design to provide actionable results. However, this field of research holds, in Dr. Vano’s view, a lot of opportunities in spite of these challenges.


Presented by: Yann-Alexandre Vano, MD, Hôpital Européen Georges Pompidou, Paris, France

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the 2021 European International Kidney Cancer Symposium (EIKCS), April 23-24, 2021

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