Toni K. Choueiri

Outcomes of Metastatic Chromophobe Renal Cell Carcinoma (chrRCC) in the Targeted Therapy Era: Results from the International Metastatic Renal Cell Cancer Database Consortium (IMDC)

Background: Treatment outcomes are poorly characterized in patients with metastatic chromophobe renal cell cancer (chrRCC), a subtype of renal cell carcinoma. Objective: This retrospective series aims to determine metastatic chrRCC treatment outcomes in the targeted therapy era. Methods: A retrospective data analysis was performed using the IMDC dataset of 4970 patients to determine metastatic chrRCC treatment outcomes in the targeted therapy era. Results: 109/4970 (2.2%) patients had metastatic chrRCC out of all patients with mRCC treated with targeted therapy. These patients were compared with 4861/4970 (97.8%) clear cell mRCC (ccRCC) patients. Patients with metastatic chrRCC had a similar OS compared to patients with ccRCC (23.8 months (95% CI 16.7 – 28.1) vs 22.4 months (95% CI 21.4 – 23.4), respectively (p = 0.0908). Patients with IMDC favorable (18%), intermediate (59%) and poor risk (23%) had median overall survivals of 31.4, 27.3, and 4.8 months, respectively (p = 0.028). Conclusions: To the authors’ knowledge, this is the largest series of metastatic chrRCC patients and these results set new benchmarks for survival in clinical trial design and patient counseling. The IMDC criteria risk categories seem to stratify patients into appropriate favourable, intermediate, and poor risk groups, although larger patient numbers are required. It appears that outcomes between metastatic chrRCC and ccRCC are similar when treated with conventional targeted therapies. Patients with metastatic chrRCC can be treated with tyrosine kinase inhibitors and enrolled in clinical trials to further measure outcomes in this rare patient population.

Enrichment of FGFR3-TACC3 Fusions in Patients With Bladder Cancer Who Are Young, Asian, or Have Never Smoked

PurposeFGFR3-TACC3 (fibroblast growth factor receptor 3–transforming acidic coiled coil-containing protein 3) fusions have recently been identified as driver mutations that lead to the activation of FGFR3 in bladder cancer and other tumor types and are associated with sensitivity to tyrosine kinase inhibitors. We examined the clinical and molecular characteristics of patients with FGFR3-TACC3 fusions and hypothesized that they are enriched in a subset of patients with bladder cancer.Materials and MethodsWe correlated somatic FGFR3-TACC3 fusions with clinical and molecular features in two cohorts of patients with bladder cancer. The first cohort consisted of the muscle-invasive bladder cancer (MIBC) data set (n = 412) from The Cancer Genome Atlas. The second cohort consisted of patients with MIBC or high-grade non-MIBC at the Dana-Farber Cancer Institute that had targeted capture sequencing of a selected panel of cancer genes (n = 356). All statistical tests were two sided. The clinical response of one pat...

Transforming the Perioperative Treatment Paradigm in Non-Metastatic RCC—A Possible Path Forward

In 2017, there is no adjuvant systemic therapy proven to increase overall survival in non-metastatic renal cell carcinoma (RCC). The anti-PD-1 antibody nivolumab improves overall survival in metastatic treatment refractory RCC and is generally tolerable. Mouse solid tumor models have revealed a benefit with a short course of neoadjuvant PD-1 blockade compared to adjuvant therapy. Two ongoing phase 2 studies of perioperative nivolumab in RCC patients have shown preliminary feasibility and safety with no surgical delays or complications. The recently opened PROSPER RCC trial (A Phase 3 RandOmized Study Comparing PERioperative Nivolumab vs. Observation in Patients with Localized Renal Cell Carcinoma Undergoing Nephrectomy; EA8143) will examine if the addition of perioperative nivolumab to radical or partial nephrectomy can improve clinical outcomes in patients with high risk localized and locally advanced RCC. With the goal of increasing cure and recurrence-free survival (RFS) rates in non-metastatic RCC, we are executing a three-pronged, multidisciplinary approach of presurgical priming with nivolumab followed by resection and adjuvant PD-1 blockade. We plan to enroll 766 patients with clinical stage ≥T2 or node positive M0 RCC of any histology in this global, randomized, unblinded, phase 3 National Clinical Trials Network study. The investigational arm will receive two doses of nivolumab 240 mg IV prior to surgery followed by adjuvant nivolumab for 9 months. The control arm will undergo the current standard of care: surgical resection followed by observation. Patients are stratified by clinical T stage, node positivity, and histology. The trial is powered to detect a 14.4% absolute benefit in the primary endpoint of RFS from the ASSURE historical control of 55.8% to 70.2% at 5 years (HR = 0.70). The study is also powered to detect a significant overall survival benefit (HR 0.67). Key safety, feasibility, and quality of life endpoints are incorporated. PROSPER RCC exemplifies team science with a host of planned correlative work to investigate the impact of the baseline immune milieu and changes after neoadjuvant priming on clinical outcomes.

Abstract 1306: Biomarker results from a clinical trial of nivolumab in patients (pts) with metastatic renal cell carcinoma (mRCC) (CA209-009): Gene expression, serum profiling for immune markers, and multiplex tissue immunohistochemistry (IHC)

Background. A prospective study of the programmed death-1 (PD-1) inhibitor nivolumab, which shows clinical activity in mRCC (Motzer RJ, et al. JCO, 2014), reported changes in serum chemokines (CXCL9, CXCL10) and tumor T cell infiltrates consistent with PD-1 inhibition (Choueiri TK, et al. ASCO 2014; abstract 5012). Here we expand on these findings to report on immune biomarkers in tumor biopsies and peripheral blood. Methods. Ninety-one eligible pts who had RCC with a clear cell component and measurable disease received nivolumab intravenously on day 1 of each 3 week treatment cycle. Previously treated pts were randomized to 0.3 (n = 22), 2 (n = 22), or 10 mg/kg (n = 23) nivolumab; treatment-naive pts (n = 24) received 10 mg/kg. IHC was performed on tumor biopsies obtained at baseline (BL) and at cycle 2 day 8 (C2D8) to quantify cells bearing T cell markers (CD3/CD4/CD8/FoxP3/PD1); matched specimens were available for 53 pts. Gene expression (18,562 loci; Affymetrix) was analyzed in biopsies and peripheral whole blood obtained at BL and on treatment. Pharmacodynamic effects on transcription were evaluated for connection to immune cell lineages (Abbas AR, et al. Genes and Immunity, 2005) and for biological impact (MetaCore). Serum at BL and time points through C4D1 was analyzed for markers of inflammation (53 analytes; Myriad RBM) and antibodies against tumor antigens (30 antigens; Serametrix). Results. IHC (n = 53 pairs) revealed a significant (P 1.3-fold; P 1.2-fold, P 30%. By C4D1, 22/61 (36%) pts demonstrated increased seroconversion against ≥ 5 tumor antigens. Conclusions. In this first biomarker-based study of an immune checkpoint inhibitor in mRCC, immunomodulatory effects consistent with PD-1 inhibition were seen in peripheral blood and the tumor microenvironment. Ongoing phase 3 studies will provide additional evidence of the effect of nivolumab on these biomarkers (NCT01668784, NCT02231749). Citation Format: Toni K. Choueiri, Mayer N. Fishman, Bernard Escudier, Walter M. Stadler, Scott Chasalow, Petra Ross-Macdonald, Maria Jure-Kunkel, Mario Sznol, Jason S. Simon. Biomarker results from a clinical trial of nivolumab in patients (pts) with metastatic renal cell carcinoma (mRCC) (CA209-009): Gene expression, serum profiling for immune markers, and multiplex tissue immunohistochemistry (IHC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1306. doi:10.1158/1538-7445.AM2015-1306