Multicenter randomized trial of deferred cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma receiving checkpoint inhibitors: the NORDIC-SUN-Trial

Around 20% of patients with Renal Cell Carcinoma (RCC) have synchronous metastatic disease at diagnosis, i.e. are diagnosed with a primary kidney tumor and metastases simultaneously. Patients presenting with metastatic disease at primary diagnosis have the worst prognosis due to underlying aggressive tumor biology and are often clinically challenging due to symptoms from either the primary tumor or the metastases [1, 2]. The critical question is whether the primary kidney tumor should be removed in patients with de novo, synchronous, mRCC.

In the clinic, mRCC patients are stratified into ‘favorable’, ‘intermediate’, and ‘poor’ prognostic risk groups according to 0, 1–2, or 3–6 international metastatic renal cell carcinoma database consortium (IMDC) risk factors, respectively, with the majority (95%) of de novo synchronous mRCC patients belonging to the intermediate or poor risk group [2, 3].

Despite the improvements that targeted treatment and checkpoint immunotherapies have brought to mRCC, response rates are still overall poor across patients (reviewed in [4]). Surgical resection of the primary tumor (cytoreductive nephrectomy, CN) upon metastatic spread at diagnosis is currently recommended following systemic therapy for patients with a good general health condition, few IMDC risk factors (maximum of three), and a response to systemic therapy [5, 6]. The concept is that CN combined with systemic therapy may result in no evidence of disease and eliminate a potential source of immunosuppressive or tumor-promoting growth factors [7‐9]. On the other hand, if performed initially, there is a risk for operated patients never to receive or benefit from systemic therapy due to complications following CN or rapid tumor progression, due to having their commencement of systemic treatment delayed because of surgery complications, or due to hampering of the immune response following antibiotic treatment after surgery [10]. Recently, a post hoc analysis from the JAVALIN renal 101 phase 3 trial indicated that CN may improve OS in synchronous metastatic patients receiving tyrosine kinase inhibitor and immunotherapy (TKI-IO) treatment [11].

In the era of targeted TKI therapy two randomized trials, CARMENA [12] and SURTIME [13], have questioned the role and timing of CN in synchronous mRCC patients with results pointing towards an improved benefit upon a deferred approach [13]; except for poor risk patients [7]. The deferred CN approach ensures systemic therapy for all patients, avoids systemic treatment delay, and spares surgery in patients with progressive tumors [12]. Furthermore, baseline IMDC risk features are dynamic [14, 15] and the administration of systemic therapy may change deviant blood measures and performance status of the patient, and thus change the IMDC risk score, possibly increasing surgery eligibility. However, both studies investigating the CN and TKI combinatorial effect were underpowered and performed in a previous treatment era, and thus the effect of CN in synchronous mRCC needs to be further verified in the present checkpoint immunotherapy (IO) era. Retrospective analyses have reported benefits of CN in IO-treated patients [16], however as CN only is performed in patients with a good performance status the results may be biased. To test the effect of CN in IO-treated mRCC patients the randomized prospective trial; Deferred Cytoreductive Nephrectomy in Synchronous Metastatic Renal Cell Carcinoma: The NORDIC-SUN-Trial (NCT03977571), described here, has been initiated. We aim to test the effect of deferred CN in mRCC patients receiving combination IO (IO-IO) or TKI-IO, which is currently used as standard treatment for IMDC intermediate- and poor-risk mRCC patients. Concurrently, the PROBE trial (NCT04510597) is recruiting in the US, also trying to answer this clinical question, thereby underlining its importance in the management of primary metastatic RCC.

There is a pressing need in renal cancer patient management for reliable and clinically accessible biomarkers to predict treatment response and surgery benefit to tailor the right treatment for the individual patient hereby minimizing negative consequences to patients while assuring optimal usage of health expenses.

Immunotherapy executes its antitumor probabilities by activating the patient's own immune system. However, only little is known about the immunomodulatory and biological effects of nivolumab combined with ipilimumab, as well as the new treatment combination of TKI-IO therapy in mRCC, with the IO-IO therapy having no effect in 20% of patients with their best objective response being progressive disease [17]. Consequently, we have an urgent need for biomarkers to assure we treat the right patients. Recent studies have indicated that the treatment response may be impacted by the composition of the immune T cells as well as the microbiota (reviewed in [18]). Moreover, circulating tumor DNA (ctDNA) presents a promising sensitive tool for prognostication, detection of relapse, and monitoring of treatment response as it captures intra- and inter-tumor heterogeneity, and correlates with tumor burden [19, 20]. RCC is genetically a multistep process (loss of 3p on the one allele, followed by mutations on the other allele in VHL, PBRM1, BAP1, SETD2, and subsequently loss of 9p and 14q), with increasing tumor aggressiveness by an increasing number of genetic events [21]. Thus, mapping the genetic events may predict which patients would benefit, or not benefit, from surgery and treatment. The present trial will integrate a comprehensive translational research program with various specimen sampling for biomarker analysis using fresh frozen tumor tissue, blood samples and rectal swabs, to personalize renal cancer treatment in the future.

The deferred CN approach enables all patients to be treated with systemic therapy, restricting only patients benefitting from the therapy to receive surgery. However, current data are derived during the TKI era and only point towards a survival benefit for CN in the subgroup patients with a maximum of 3 IMDC risk factors. In this trial we aim to describe the effect of deferred CN in a contemporary patient population treated with IO-IO or TKI-IO therapy.

Furthermore, the genomic landscape of the tumor, tumor microenvironment composition, peripheral immune subsets and the microbiome may be of great importance to the efficacy of treatment and to select candidates for surgery. To facilitate this, we will collect patient specimens longitudinally during the trial.

The aim of this study is to conduct an open, randomized, multicenter comparison trial, evaluating the effect of deferred CN compared with no surgery, following initial nivolumab combined with ipilimumab or a TKI-IO-combination, in synchronous mRCC patients with ≤ 3 IMDC risk features and absence of progressive disease at metastatic sites.

The primary endpoint is overall survival (OS) compared between synchronous mRCC patients receiving a deferred CN and patients not receiving surgery.

NORDIC-SUN is a multicenter open label randomized trial investigating the impact of CN in synchronous mRCC following 3 or 6 months of immunotherapy-based first-line treatment. Patients will be stratified by 1:1 allocation into Arm A (deferred CN) and Arm B (no surgery) based on criteria of surgical resectability, ≤ 3 IMDC risk features, and absence of progressive disease at metastatic sites. The remaining patients not eligible for randomization, referred to as Arm C, will be described, but are not a part of the main analysis.

The study design is outlined in Fig. 1.

The trial will include 400 mRCC patients with synchronous disease. Participating centers will be University Hospitals in Denmark and the Nordic Countries, and possibly a few European sites. The coordinating center, which includes a data manager, is placed at Aarhus University Hospital, Denmark, managing the trial in close collaboration with the PI and the steering committee. Collaborating centers report to the coordinating center.

Patients are randomized 1:1 into the two treatment arms:

Patient eligible for surgery is randomized by a local project nurse using a computer-generated allocation sequence and is not blinded due to the circumstances; surgery versus no surgery. In Arm A patients are treated according to standard protocol with first-line IO-IO or TKI-IO combination treatment followed by a CN. In Arm B patients are receiving standard IO-IO or a TKI-IO combination first-line treatment (Fig. 1). Patients will be stratified by treatment choice (IO-IO vs TKI-IO).

The remaining patients, referred to as Arm C, not eligible for randomization due to > 3 IMDC risk factors, progressive disease at metastatic sites, poor performance or a non resectable tumor will undergo three months of nivolumab or a TKI-IO combination and then be evaluated again after another 3 months. If still not eligible for randomization, the patients will continue nivolumab maintenance and TKI-IO combination and be followed on survival.

Patients included in the NORDIC-SUN trial are stratified according to institution, treatment choice, number of IMDC risk factors, and combined elevated neutrophil–lymphocyte ratio and hyponatremia.

All patients will receive systemic IO-IO or TKI-IO immediately after inclusion. After three months of nivolumab combined with ipilimumab or a TKI-IO combination, the patient will be discussed for resectability at the multidisciplinary meeting (MDT), whether the patient is eligible for CN. Patients with ≤ 3 IMDC risk factors and deemed suitable for CN including an acceptable performance status and absence of progression at metastatic sites will then undergo randomization. Patients deemed not suitable for surgery or have > 3 IMDC risk features at the 3 month evaluation continue systemic therapy for 3 months, followed by a 2nd evaluation 6 months after inclusion. Patients with ≤ 3 IMDC risk factors and deemed suitable for CN at 2nd evaluation will then undergo randomization. Patients deemed not suitable for surgery or have > 3 IMDC risk features at the 6 month evaluation continue systemic therapy (Arm C). Nivolumab may continue until unacceptable toxicity or total treatment length of two years from inclusion. Allocating patients to Arm C promotes participant retention, securing outcome data of patients not randomized.

Inclusion began right before the Corona epidemic set in. The study was therefore paused and has now been re-initiated in January 2023. Presently, 40 patients are included (10% accrual) and the study will continue until full accrual (400 patients) have been reached in 2026, with a follow-up period of additional three years. The primary endpoint is expected to be reached and ready for publication in 2029.

All patients will have blood samples collected at baseline, week 12, and week 24. Rectal swabs are taken as a proxy for stool samples at baseline and week 12. At baseline, a fresh frozen tumor core biopsy is seeked to be obtained and for Arm A biopsies from the nephrectomy specimen will be fixed and stored according to the Danish Cancer Biobank for future analyses. All samples will be anonymously labeled with a pseudo patient study identifier. See Fig. 1.

Blood, tissue, and fecal swab samples collected during the trial will be stored in the Bio- and Genome Bank, Denmark. Residual blood and tissue biopsies as well as clinical and sequencing data will be transferred to the Renal Cancer Research Biobank at Aarhus University Hospital for future research, where it will be saved and stored in a pseudonymized form.

Any protocol modifications will be reported timely to the relevant authorities, investigators/centers, and if necessary, patients. No protocol modification is effected before the necessary approval have been given. Results from the NORDIC-SUN trial will be published in peer-reviewed scientific journals.