The Emerging Role of Combination Angiogenesis Inhibitors and Immune Checkpoint Inhibitors in the Treatment of Metastatic Renal Cell Cancer

The advent of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) a decade ago revolutionized the treatment paradigm in advanced metastatic clear cell renal cell carcinoma (RCC) with improved survival rates compared to the pre-TKI era. Monotherapy with VEGF TKIs has remained first-line. However, sequencing of different TKIs, mammalian target of rapamycin (mTOR) inhibitors, or immune checkpoint inhibitors (ICIs) has been the subject of controversy in the treatment landscape of metastatic RCC. First-line treatment further evolved with the approval of nivolumab plus ipilimumab in intermediate-and poor-risk patients based on an overall survival (OS) benefit demonstrated in the CheckMate214 trial 

What Comes After Immuno-Oncology Therapy for Kidney Cancer?

The treatment landscape of advanced renal cell carcinoma (RCC) is rapidly evolving. Immune checkpoint inhibitors (ICI) have now become the preferred first line treatment with the approval of nivolumab and ipilimumab combination in intermediate to poor risk patients. Combination/s of ICI with vascular endothelial growth factor (VEGF) inhibitors will also be approved in future. The optimal treatment of patients who progress on ICI-based therapies is not well defined as of yet. In this review, we discuss the data regarding various treatment options available in this space, their limitations, and also provide our opinion regarding treatment selection.

Sunitinib Dose Escalation in Metastatic Renal Cell Carcinoma

Background and objective: Sunitinib has been a standard treatment for patients with metastatic renal cell carcinoma (mRCC) since 2006. However, almost all patients will eventually progress. Besides well described mechanisms of primary or secondary resistance, insufficient drug exposure may lead to disease progression. The aim of this study was to identify patients in whom sunitinib dose escalation was performed and to analyse safety and efficacy of this strategy in clinical practice. Methods: A single-centre retrospective study on dose escalation in mRCC patients who were treated with sunitinib at the Medical University of Vienna between January 2011 and May 

Everolimus Exposure as a Predictor of Toxicity in Renal Cell Cancer Patients in the Adjuvant Setting: Results of a Pharmacokinetic Analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT01120249)

Background: S0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity. Methods: Patients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) 

miR-22 Regulates Invasion, Gene Expression and Predicts Overall Survival in Patients with Clear Cell Renal Cell Carcinoma

Background: Clear cell renal cell carcinoma (ccRCC) is molecularly diverse and distinct molecular subtypes show different clinical outcomes. MicroRNAs (miRNAs) are essential components of gene regulatory networks and play a crucial role in progression of many cancer types including ccRCC. Objective: Identify prognostic miRNAs and determine the role of miR-22 in ccRCC. Methods: Hierarchical clustering was done in R using gene expression profiles of over 450 ccRCC cases in The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis was performed to identify prognostic miRNAs in the TCGA dataset. RNA-Seq was performed to identify miR-22 target genes in primary 

Real-World Data from a Metastatic Renal Cell Carcinoma Community-Academic Registry: Comparative Outcomes of Progression Free Survival and Overall Survival

Background: No studies have looked at comparative outcomes in the treatment of metastatic renal cell carcinoma (mRCC) between academic and community practice settings. Methods: We created a joint academic (ACAD) and community (COMM) retrospective registry of patients treated for mRCC. This registry represents a collaboration of an academic research network (Duke Oncology Network; Durham, NC) and a community-based oncology network (ACORN Research; Memphis, TN) of multiple member practices. We compared progression free survival and overall survival between these centers. We included patients diagnosed with mRCC after January 1, 2007 and before February 7, 2011. Results: Four 

Clinical Trials Corner

A Phase 3b, Randomized, Double-blind Study of Nivolumab Combined with Ipilimumab Versus Nivolumab Monotherapy for Patients With Previously Untreated Advanced Renal Cell Carcinoma and Intermediate- or Poor-Risk Factors

Status: Recruiting identifier: NCT03873402
Sponsor: Bristol-Myers Squibb
Enrollment: 418

Rationale: The CheckMate-025 trial, evaluating nivolumab versus everolimus in patients with metastatic RCC progressed after antiangiogenesis therapy, established an overall survival benefit with the use of nivolumab; the objective response rate (ORR) for nivolumab in that trial was 25%. Subsequently the combination of nivolumab and ipilimumab was compared to sunitinib in the CheckMate-214 trial in patients with newly diagnosed metastatic RCC with intermediate- to poor-risk disease by International Metastatic RCC Database Consortium (IMDC) criteria; the study demonstrated a median overall survival advantage with nivolumab plus ipilimumab compared to sunitinib (not reached versus 26.0 months; hazard ratio (HR)= 0.63; p<0.001). The ORR for the combination was 42%. The combination of nivolumab plus ipilimumab led to 46% Grade 3 and higher adverse events (AEs); 35% of patients in the nivolumab plus ipilimumab group required treatment with high-dose glucorticoids due to immune-related AEs. Pembrolizumab was also studied as monotherapy, in patients with previously untreated advanced RCC, in the KEYNOTE-427 trial. In this single arm study, the ORR was 33.6%. Nivolumab has not been studied in the first-line setting, and increased toxicity is observed with the combination of nivolumab plus ipilimumab, driving the design of this trial.

Study Design: This Phase 3b study enrolls patients with newly diagnosed advanced or metastatic RCC, who have not previously received any systemic therapy for RCC, who have histologically confirmed predominantly clear cell subtype RCC; patients with clear cell disease with sarcomatoid features are also included. Patients must have intermediate or poor risk disease based on the International Metastatic RCC Database Consortium (IMDC) criteria. They cannot have received any immune checkpoint or T-cell co-stimulation therapy. Patients will be randomized to receive, in a double-blinded manner, either nivolumab and ipilimumab or nivolumab and placebo.

Endpoints: The primary endpoint of the trial is progression-free survival (PFS) and ORR. Secondary endpoints include overall survival, disease control rate (DCR), duration of response (DOR), time to objective response (TTR), as well as AEs.

Comments: This multi-center international trial asks an important question regarding the role of intensification of immune checkpoint inhibition in the treatment of intermediate- and poor-risk advanced RCC. While treatment of advanced RCC now involves several options for dual therapy, including nivolumab plus ipilimumab and pembrolizumab plus axitinib, both of which have demonstrated improvement in overall survival in comparison to sunitinib, these combination approaches come with increased toxicity that can be discouraging to the patient as well as the practicing oncologist. While the KEYNOTE-427 trial (Cohort A) did show an impressive ORR of ~34%, this was a single-arm trial. This randomized, double blind trial has the potential to address the true benefit of combination immune checkpoint inhibition versus anti-PD-1 therapy alone, as well as to better assess the true toxicity of the combination versus nivolumab alone. Ultimately, this study could provide oncologists the option to treat with anti-PD-1 therapy alone in the first-line setting in intermediate- and poor-risk patients, though the study will require some time to mature in order to evaluate the results meaningfully.