Kidney Cancer Journal | Volume 3, Issue 2

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) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status. Results: A total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were < 9.0, 9.0–12.9, 12.9–22.8, and > 22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p  < 0.001). Furthermore, EVE trough levels were higher in men than women (19.4 versus 15.4 ng/mL, p  = 0.01). Risk of grade 2 + triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.08; p  = 0.02 and OR = 2.63; p  = 0.002). Risk of grade 2 + rash was increased in Q2 and Q4 vs Q1 (OR = 2.99; p  = 0.01 and OR = 2.90; p  = 0.02). There was also an increased risk of any grade 3 + tox in Q2 vs Q1 (OR = 1.71; p  = 0.05). Conclusions: We identified significant gender and age-related differences in EVE trough levels in patients receiving adjuvant treatment for RCC. Furthermore, our analysis identified significant associations between EVE exposure and probability of toxicity.

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 hundred and fifty-five patients were captured in the registry including N = 255 COMM patients and N = 200 ACAD patients. Initial analysis of COMM patients showed a median PFS of 6.24 months [95% CI, 5.4, 7.5], 3.88 months [95% CI, 3.0, 4.8], and 3.35 months [95% CI 2.9, 4.4] with first, second, and third line systemic therapy. ACAD patients had longer median PFS estimates of 11.3 months [95% CI, 7.5, 13.6], 4.4 months [95% CI, 2.7, 8.9], and 5.22 months [95% CI, 2.7, 6.3] respectively. Median OS was 12.06 months [95% CI 8.7, 15.4] among COMM patients and 36.73 months [95% CI 26.2 42.2) among ACAD patients. Differences persisted with inclusion of well-established prognostic models and predictive factors such as treatment exposures. Conclusions: There may be differences between outcomes for mRCC patients in community versus academic settings; however rselection most likely plays a role and we need further studies to determine reasons for these potential disparities. A prospective metastatic renal cell carcinoma (MaRCC) registry has been accrued encompassing sixty academic and community treatment sites across the United States rwith the goal of examining real-world treatment patterns and outcomes; MaRCC may shed further light on any potential outcomes differences. 

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
Clinicaltrials.gov 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.