Metastatic Clear Cell Renal Cancer Research Articles

Early response assessment to targeted therapy in metastatic clear cell renal cancer using 68Ga-PSMA-11 PET/CT and comparison with CECT: a feasibility study

Early response assessment to targeted therapy in metastatic clear cell renal cancer using 68Ga-PSMA-11 PET/CT and comparison with CECT: a feasibility study

A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR)

BackgroundDespite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer.MethodsThis is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS).DiscussionOur prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients.Trial registrationClinicalTrials.gov: NCT06059014.

2/1 dose schedule of sunitinib is superior than the 4/2 regimen for the first-line therapy of clear cell metastatic renal cell carcinoma - An Indian experience.

Sunitinib remains the first-line treatment for favorable risk metastatic clear cell renal cell cancer (mccRCC). It was conventionally given in the 4/2 schedule; however, toxicity necessitated trying the 2/1 regimen. Regional variations in treatment response and toxicity are known, and there is no data from the Indian subcontinent about the outcomes of the alternative dosing schedule. Clinical records of all consecutive adult patients who received sunitinib as first-line therapy for histologically proven mccRCC following cytoreductive nephrectomy from 2010-2018 were reviewed. The primary objective was to determine the progression-free survival (PFS), and the secondary objectives were to evaluate the response rate (objective response rate and clinical benefit rate), toxicity, and overall survival. A list of variables having a biologically plausible association with outcome was drawn and multivariate inverse probability treatment weights (IPTW) analysis was done to determine the absolute effect size of dosing schedules on PFS in terms of "average treatment effect on the treated" and "potential outcome mean." We found 2/1 schedule to be independently associated with higher PFS on IPTW analysis such that if every patient in the subpopulation received sunitinib by the 2/1 schedule, the average time to progression was estimated to be higher by 6.1 months than the 4/2 schedule. We also found 2/1 group to have a lower incidence than the 4/2 group for nearly all ≥ grade 3 adverse effects. Other secondary outcomes were comparable between both treatment groups. Sunitinib should be given via the 2/1 schedule in Indian patients.

Dynamic partitioning of branched-chain amino acids-derived nitrogen supports renal cancer progression

Metabolic reprogramming is critical for tumor initiation and progression. However, the exact impact of specific metabolic changes on cancer progression is poorly understood. Here, we integrate multimodal analyses of primary and metastatic clonally-related clear cell renal cancer cells (ccRCC) grown in physiological media to identify key stage-specific metabolic vulnerabilities. We show that a VHL loss-dependent reprogramming of branched-chain amino acid catabolism sustains the de novo biosynthesis of aspartate and arginine enabling tumor cells with the flexibility of partitioning the nitrogen of the amino acids depending on their needs. Importantly, we identify the epigenetic reactivation of argininosuccinate synthase (ASS1), a urea cycle enzyme suppressed in primary ccRCC, as a crucial event for metastatic renal cancer cells to acquire the capability to generate arginine, invade in vitro and metastasize in vivo. Overall, our study uncovers a mechanism of metabolic flexibility occurring during ccRCC progression, paving the way for the development of novel stage-specific therapies.

Coordinated Pembrolizumab and High Dose IL-2 (5-in-a-Row Schedule) for Therapy of Metastatic Clear Cell Renal Cancer.

The ligation of the interleukin-2 (IL-2) receptor and immune checkpoint blockade may each alter lymphocytes, thereby inducing regression in various cancers. Single agent objective response rates of 14% to 25% have been reported for usual schedule 14-dose-in-a-row IL-2 therapy of metastatic clear cell renal cancer (ccRCC), with a notable subset of responses being durable. Pembrolizumab yielded a 33% response rate in patients with metastatic ccRCC. This study addressed the safety and feasibility of the combination of IL-2 and pembrolizumab in the treatment of metastatic ccRCC. Subjects were treated with four 9-week blocks of therapy, receiving pembrolizumab every 3 weeks in all blocks and receiving 4 courses of 5-planned-doses high dose IL-2 in each of blocks 2 and 3. Safety was monitored by a Pocock boundary of study suspension and re-evaluation if exceeding a 15% dose limiting toxicity rate at α=0.05. The Simon 2-stage design tested for an alternative hypothesis response rate of at least a 45% vs. a null hypothesis rate of less than 20%, with α=0.10 and 90% power RESULTS: No accrual suspension for safety was triggered. The objective response rate was 70% (19/27, 95% CI: 0.50-0.86). Nine patients responded after pembrolizumab alone and ten responded after the addition of IL-2. At a minimum follow-up of 23 months, 9 of the responding patients had no disease progression requiring additional treatment. The combination of 5-planned-dose-schedule high dose IL-2 and pembrolizumab is feasible, with a high response rate, justifying further exploration of this dual immune treatment of metastatic ccRCC.

First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma: What Are the Most Appropriate Combination Therapies?

Simple SummaryFirst-line treatment options for metastatic clear cell renal cell carcinoma have significantly increased. The current recommended therapeutic strategy is based on a combination, but monotherapy remains an alternative. However, the choice of the type of combination, i.e., dual immunotherapy or immunotherapy combined with an antiangiogenic drug, has not been clearly standardized. A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. This review summarizes all recent data from the main combinations evaluated in first-line treatment and discusses the choice of drugs according to the patient’s profile and the benefit/risk balances of each combination.The development of antiangiogenic treatments, followed by immune checkpoint inhibitors (ICI), has significantly changed the management of metastatic clear cell renal cell cancer. Several phase III trials show the superiority of combination therapy, dual immunotherapy (ICI-ICI) or ICI plus tyrosine kinase inhibitors (TKI) of the vascular endothelium growth factor (VEGF) over sunitinib monotherapy. The question is therefore what is the best combination for a given patient? A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. However, several issues remain unresolved and require further investigation, such as the PD-L1 status, the relevance of possible options based on the patient’s profile, and consideration of second-line and subsequent treatments.

Multiparametric MRI for assessment of early response to neoadjuvant sunitinib in renal cell carcinoma.

To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI. Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival. 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001). Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS. EudraCtNo: 2005-004502-82.

Sunitinib in metastatic clear cell renal cancer (CCRC): A real life Chilean single institution experience.

e16562 Background: The introduction of biologic and immunologic therapy has produced a profound change in the management of metastatic CCRC but there is no definitive indication on drug selection and therapeutic sequences based on efficacy, toxicity, costs and access. Methods: We report 50 consecutive stage IV CCRC patients treated at our Institution from 12/2007 to 11/2020 with sunitinib at recommended dosage. Median age at stage IV diagnoses was 62.5 months (39 to 79). Sex distribution was 5 women (10%) and 45 (90%) men. Under MSKCC criteria 35 patients were medium + high risk (70%) and 15 (30%) low risk. Results: On an intent to treat basis the complete + partial response rate was 56% (28/50) for the entire group , 45.7% (16/35) for the high-risk group and 80% (12/15) for the low-risk group. Actuarial 5 year survival was 24% for the entire group, 11.4% for the high-risk group and 53.3% for the low -risk group. We explored the effect of metastases-free time on survival. We found that 15 patients were metastatic at the moment of initial diagnoses versus 26 patients who developed metastatic disease at 12+ months after primary tumor diagnoses. Mean survival was 32.7 months (1 - 97) for the first group and 49.5 months (6 - 156) for the second group (p&lt;0.5). Subsequent therapies consisted of pazopanib (25 patients), axitinib (17 patients), everolimus (9 patients), nivolumab (6 patients) and cabozantinib (1 patient). Secondary reactions consisted of emesis (20%), diarrhea (16%), asthenia (14%), skin dispigmentation (12%), mucositis (10%), disgeusia (10%), dermatitis (10%), neutropenia (8%), hand and foot syndrome (4%). Conclusions: Sunitinib is a good choice in low-risk metastatic CCRC and we adopted this regimen as standard therapy in this group of patients at our Institution.

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial

BackgroundThe use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. ObjectiveTo evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. Design, setting, and participantsIMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. InterventionPatients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. Outcome measurements and statistical analysisThe secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. Results and limitationsFifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19–37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6–13.7) mo. The median event follow-up duration was 19.4 (12.9–21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. ConclusionsThe atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. Patient summaryPatients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.

Second-Line Therapies in the Changing Landscape of First-Line Therapies for Metastatic Clear Cell Renal Cell Cancer.

In recent years, first-line therapies for metastatic renal cell carcinoma (mRCC) have shifted to a combination of immune checkpoint inhibitors or a combination of antiangiogenesis tyrosine kinase inhibitors (TKIs) and immunotherapy. This has led to a need to address standard-of-care treatment in the second-line setting. Our review presents an analysis of current and upcoming data to guide treatment decisions. After progression on nivolumab plus ipilimumab, current data favor monotherapy TKI with cabozantinib or axitinib. Current literature for second-line therapy given after combination TKI plus immunotherapy shows the strongest evidence for either single-agent cabozantinib or combination everolimus with lenvatinib. Investigations are ongoing for the role of TKIs with immunotherapy in the second-line setting. Novel agents, such as HIF2α inhibitors, are currently being studied as single agents and in combination with other treatment modalities in efforts to improve patient outcomes in mRCC.

Biomarkers of Prognosis and Efficacy of Anti-angiogenic Therapy in Metastatic Clear Cell Renal Cancer.

In the last decades, the prognosis of metastatic renal cell carcinoma (mRCC) has remarkably improved following the advent of the “targeted therapy” era. The expanding knowledge on the prominent role played by angiogenesis in RCC pathogenesis has led to approval of multiple anti-angiogenic agents such as sunitinib, pazopanib, axitinib, cabozantinib, sorafenib, and bevacizumab. These agents can induce radiological responses and delay cancer progression for months or years before onset of resistance, with a clinically meaningful activity. The need for markers of prognosis and efficacy of anti-angiogenic agents has become more compelling as novel systemic immunotherapy agents have also been approved in RCC and can be administered as an alternative to angiogenesis inhibitors. Anti PD-1 monoclonal antibody nivolumab has been approved in the second-line setting after tyrosine kinase inhibitors failure, while combination of nivolumab plus anti CTLA-4 monoclonal antibody ipilimumab has been approved as first-line therapy of RCC patients at intermediate or poor prognosis. In this review article, biomarkers of prognosis and efficacy of antiangiogenic therapies are summarized with a focus on those that have the potential to affect treatment decision-making in RCC. Biomarkers predictive of toxicity of anti-angiogenic agents have also been discussed.

Abstract 201: The mechanism of vascular mimicry in clear cell renal cell cancer

Abstract Although anti-angiogenic drugs were used as first-line treatment in metastatic clear cell renal cell cancer (ccRCC), some patients with metastatic ccRCC still had limited survival benefit from anti-angiogenic therapy. The main reason was resistance to anti-angiogenesis treatment. Tumor blood vessel could be divided into endothelial cell-derived or tumor cell-derived vessels. Tumor cell-derived vascular channel was called as tumor vascular mimicry (VM). PAS-CD34 staining in ccRCC tissues revealed that the expression status of VM was different in ccRCC patients. And the progression-free survival and overall survival were significantly shorter in ccRCC patients with high VM expression level. To explore the effect of VM on the resistance to anti-angiogenesis treatment and the molecular mechanism of VM, we successfully established a three-dimensional culture model for the formation of tumor cell-derived vessel-like structures. We found the formation of blood vessel-like structures in kidney cancer cells was not affected by the anti-angiogenic drug, such as Sunitinib, suggesting that VM was closely associated with resistance to anti-angiogenic therapy. Moreover, we had discovered the “molecular signature of vascular mimicry in renal cancer”. Using this signature, 531 ccRCC patients in TCGA could be divided into two groups with different prognosis. More importantly, we found that HGF/c-MET signaling pathway regulated the expression of Serpinb2 through the downstream AKT pathway, and thus affected the formation of vascular mimicry in SN12C, 786-O cells. In addition, we also had found that HGF could promote the formation of blood vessel-like structure in lung and bladder cancer cells, and the " molecular signature of vascular mimicry in renal cancer " also could differentiate patients with renal papillary carcinoma, bladder cancer, endometrial cancer, lung adenocarcinoma cancer, and pancreatic cancer. These finding suggested that the molecular mechanism of vascular mimicry in renal cancer was universal, to some extent. This project partially elucidated the molecular mechanism of vascular mimicry in renal cancer and its clinical significance, laying a theoretical foundation for the development of more effective anti-angiogenic drugs. Citation Format: Jun-Ping Yang, Xing-Si Peng, Chao-Nan Qian. The mechanism of vascular mimicry in clear cell renal cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 201.

Overall responses with coordinated pembrolizumab and high dose IL-2 (5-in-a-row schedule) for therapy of metastatic clear cell renal cancer: A single center, single arm trial.

657 Background: Ligation of IL-2 receptor or blockade of PD-1 receptor may change lymphocytes to induce regression of cancers with diverse histology or site of origin. Single agent objective response rates of 14-25% have been reported for IL-2 therapy of metastatic clear cell RCC (ccRCC). A response rate of 33% was observed in pembrolizumab treated ccRCC patients. Nivolumab treated ccRCC patients were observed to have early intratumoral migration of lymphocytes. A case report of IL-2 induced major regression right after no change on nivolumab therapy suggested that combining the two means of lymphocyte stimulation could be effective. Other trials combining IL-2 receptor agonists (NKTR-214) and PD-1 blockade have also reported regression of ccRCC. Distinctive attributes of high dose IL-2 therapy are the required inpatient stay and the durability of the complete responses. Methods: This single-institution, single arm study addresses the safety and feasibility of the combination of IL-2 and pembrolizumab in the treatment of metastatic ccRCC. Subjects are treated on four nine-week blocks, as follows: Pembrolizumab is given on weeks 1, 4, and 7 of each block. Patients are admitted for 5 doses of high dose IL-2 (given over ~ 33 hours/3 days) on weeks 2, 3, 5, and 6 of blocks 2 and 3. Safety is monitored by a Pocock boundary of .05 likelihood of 0.15 dose limiting toxicity rate. The Simon 2-stage alternative hypothesis for the sample size was a 45+% major response rate vs null hypothesis &lt; 20%, at alpha = 0.10, 90% power. Results: No accrual stop for safety was triggered. Thirteen of the first 18 patients responded, substantially exceeding the requirement of 8+/24 combination-treated patients to reject the null. Seven patients responded after receiving pembrolizumab alone, six after starting combination therapy in block 2. Accrual is completed; at 27. Kaplan-Meier analysis projects ORR of 69%, with ORR 90%-lower confidence bound of 55%. Conclusions: The combination of high dose IL-2 and pembrolizumab is feasible, with a high response rate, justifying further exploration of this dual immune treatment of metastatic ccRCC. Clinical trial information: NCT02964078.

The efficacy and safety of sunitinib given on an individualised schedule as first-line therapy for metastatic renal cell carcinoma: A phase 2 clinical trial

BackgroundSunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient. Materials and methodsIn a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria. ResultsThe null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6–16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18–20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration. Conclusions: Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. Clinicaltrials.gov identifierNCT01499121.

P112 - VEGF tyrosine kinase inhibitors after bevacizumab and atezolizumab in metastatic clear cell renal cancer

P112 - VEGF tyrosine kinase inhibitors after bevacizumab and atezolizumab in metastatic clear cell renal cancer

Novel Agents and Drug Development Needs in Advanced Clear Cell Renal Cancer.

The treatment of metastatic clear cell renal cancer is changing rapidly, with the focus switching from vascular endothelial growth factor-targeted therapies to immune checkpoint inhibitors and novel combinations. Specifically, recent data with programmed death ligand inhibitors is revolutionizing the standard approach to metastatic renal cell carcinoma. However, there is speculation around a number of newer potentially therapeutic targets, such as indoleamine 2,3-dioxygenase, transforming growth factor-β, interleukin-10, and adenosine. In this article, we review novel treatments, promising combinations, and consideration in both trial design and clinical application of therapeutics that will influence practice in the future.

Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma

Cytoreductive nephrectomy (CN) has been the standard of care in patients with metastatic clear-cell renal cancer who present with the tumour in place. The CARMENA trial compared systemic therapy alone with CN followed by systemic therapy. This article outlines the new guidelines based on these data. Patient summaryThe CARMENA trial demonstrates that immediate cytoreductive nephrectomy should no longer be considered the standard of care in patients diagnosed with intermediate and poor risk metastatic renal cell carcinoma when medical treatment is required. However, the psychological burden poor risk patients experience hearing that removal of their primary tumour will not be beneficial, should be carefully considered.

Prospective single center trial of next-generation sequencing analysis in metastatic renal cell cancer: the MORE-TRIAL.

Aim:Targeted therapies have substantially improved the survival of patients with metastatic clear cell renal cell cancer. No prognostic or predictive biomarkers are available. Comprehensive genetic profiling offers the opportunity to define prognostic and predictive signatures aiming at a more personalized approach to treatment.Methods:In this prospectively conducted cohort study, tumor tissue and liquid biopsies are sampled at baseline and upon first and second progression under systemic treatment. Samples will be analyzed by whole-exome sequencing to generate prognostic and predictive patterns for systemic therapies.Discussion:This study is aiming at exploring genetic profiles with prognostic and predictive value in metastatic renal cell cancer patients. Clonal evolution facilitating resistance to systemic treatment will be investigated by repeat biopsies.

Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment. High-dose interleukin-2 (HDIL-2) therapy remains a reasonable treatment option in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and have minimal comorbid conditions. In the near future, these agents are likely to be surpassed by cabozantinib and by combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab. Independent review has recently confirmed superiority of first-line cabozantinib over sunitinib in a phase 2 trial of 157 patients with intermediate or poor risk mccRCC (progression-free survival [PFS] 8.6 vs 5.3months, hazard ratio [HR] 0.48, p = 0.0008). In a separate study of 1096 patients treated with either upfront sunitinib or the combination of nivolumab and ipilimumab, those with intermediate and poor risk had significant improvement in both PFS (11.6 vs 8.4months, HR 0.82, p = 0.0331) and OS (not reached vs 26months, p < 0.0001). Responses were greater in patients with positive programmed death receptor ligand-1 (PD-L1) tumor staining, and pending regulatory approval may become standard of care in untreated patients with intermediate to poor risk disease with positive PD-L1 status. This likely represents the beginning of additional novel immunotherapy combinations for the first-line treatment of mccRCC.

926TiP - Phase Ib/II trial of interleukin-2 (IL-2) and nivolumab in metastatic clear cell renal cell cancer (RCC)

926TiP - Phase Ib/II trial of interleukin-2 (IL-2) and nivolumab in metastatic clear cell renal cell cancer (RCC)