Perioperative therapy in renal cancer in the era of immune checkpoint inhibitor therapy

Abstract

Purpose of reviewImmune checkpoint inhibitor (ICI) combination therapy has revolutionized therapy of metastatic renal cancer. The success of immunotherapy has renewed an interest to study these agents in adjuvant and neoadjuvant settings and prior to cytoreductive nephrectomy. This narrative review will give an overview of ongoing trials and early translational research outcomes.Recent findingsIn nonmetastatic renal cell carcinoma (RCC), five phase 3 adjuvant and neoadjuvant trials with ICI monotherapy or combinations are ongoing with atezolizumab (IMmotion 010; NCT03024996), pembrolizumab (KEYNOTE-564; NCT03142334), nivolumab (PROSPER; NCT03055013), nivolumab with or without ipilimumab (CheckMate 914; NCT03138512) and durvalumab with or without tremelimumab (RAMPART; NCT03288532). Phase 1b/2 neoadjuvant trials demonstrate safety, efficacy and dynamic changes of immune infiltrates and provide rationales for neoadjuvant trial concepts as well as prediction of response to therapy. In primary metastatic RCC, two phase 3 trials investigate the role of deferred cytoreductive nephrectomy following pretreatment with ICI combination (NORDICSUN; NCT03977571 and PROBE; NCT04510597).SummaryThe outcomes of the major phase 3 trials are awaited as early as 2023. Meanwhile, translational data from phase 1b/2 studies enhance our understanding of the tumour immune microenvironment and its dynamic changes.

Primary Renal Tumour Response in Patients Treated with Nivolumab and Ipilimumab for Metastatic Renal Cell Carcinoma: Real-world Data Assessment

“…Meanwhile, immune checkpoint inhibitor (ICI)-based combination therapy has become the standard first-line treatment for International Metastatic RCC Database Consortium (IMDC) intermediate- and poor-risk patients [5] . Consequently, the recent evidence and recommendations from CARMENA and SURTIME have been superseded, and up to 30% of metastatic renal cell carcinoma (mRCC) patients were treated with their primary in place in the pivotal ICI combination therapy trials [6] . With up to 16% of complete response (CR) rates at metastatic sites [7] , patients are increasingly being offered deferred CN to achieve surgical complete remissions.…”

“…With up to 16% of complete response (CR) rates at metastatic sites [7] , patients are increasingly being offered deferred CN to achieve surgical complete remissions. In a retrospective analysis involving 20 patients who underwent deferred CN following ICI therapy, 10% had a complete pathological response in the primary [8] , and currently two randomised controlled trials investigate the role of deferred CN in this setting [6] . We retrospectively analysed, within the context of a clinical audit, safety and oncological outcome data from three European referral centres of patients with treatment-naïve mRCC who received first-line nivolumab and ipilimumab with the primary in place ( Supplementary material ).…”

“…In addition, deferred CN leads to NED in those with a CR at metastatic sites. As a legacy of CARMENA and SURTIME [4] , two phase 3 randomised controlled trials are investigating deferred CN versus no CN after ICI combination therapy (NORDICSUN [NCT03977571] and PROBE trial [NCT04510597]) [6] . Finally, treatment with the primary tumour in place seems to be safe.…”

Cytoreductive Nephrectomy: Still Necessary in 2021

“…Two phase 3 RCTs are currently investigating the role of deferred CN versus no CN after pretreatment in this population. Interestingly, both trials no longer include an upfront CN arm and randomise patients after a clinical benefit has been achieved following at least 3 mo of pretreatment [13] . PROBE (NCT04510597) is evaluating whether deferred CN after an objective response or stable disease at metastatic sites following systemic therapy adds a survival benefit to systemic therapy alone.…”

Editorial: Standard and future in the treatment of renal cell carcinoma

“…The perioperative setting is a treatment space defined by several variables. Kuusk et al [8] addresses this clinical space which has been changed by the CARMENA and SURTIME trials which postponed cytoreductive nephrectomy as the first treatment option in metastatic patients. These trials have been performed with TKIs, which are no longer standard of care.…”