Jason S. Simon

Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma

BACKGROUND Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment. METHODS A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety. RESULTS The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%). CONCLUSIONS Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).

Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma

Purpose: Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating prospective mRCC trial. Experimental Design: Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs. <5% tumor membrane staining), tumor gene expression (Affymetrix U219), serum chemokines, and safety were assessed. Results: In 91 treated patients, median overall survival [95% confidence interval (CI)] was 16.4 months [10.1 to not reached (NR)] for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0 to NR) for 10 mg/kg, and NR for treatment-naïve patients. Median percent change from baseline in tumor-associated lymphocytes was 69% (CD3+), 180% (CD4+), and 117% (CD8+). Of 56 baseline biopsies, 32% had ≥5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included upregulation of IFNγ-stimulated genes (e.g., CXCL9). Median increases in chemokine levels from baseline to C2D8 were 101% (CXCL9) and 37% (CXCL10) in peripheral blood. No new safety signals were identified. Conclusions: Immunomodulatory effects of PD-1 inhibition were demonstrated through multiple lines of evidence across nivolumab doses. Biomarker changes from baseline reflect nivolumab pharmacodynamics in the tumor microenvironment. These data may inform potential combinations. Clin Cancer Res; 22(22); 5461–71. ©2016 AACR.

Programmed death-ligand 1 (PD-L1) expression in various tumor types

Meeting abstracts Programmed cell death-1 (PD-1) is a co-inhibitory receptor expressed on lymphoid and non-lymphoid-derived cells that negatively regulates peripheral T-cell responses. PD-L1, the major PD-1 ligand, is expressed on various tumors and is being investigated as a possible predictive

Peripheral and tumor immune correlates in patients with advanced melanoma treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) monotherapy or in combination with ipilimumab

Peripheral and tumor immune correlates in patients with advanced melanoma treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) monotherapy or in combination with ipilimumab Michael A Postow, Diana M Cardona, Janis M Taube, Robert A Anders, Clive R Taylor, Jedd D Wolchok, Margaret K Callahan, Michael A Curran, Alexander M Lesokhin, Joseph F Grosso, Christine E Horak, John Cogswell, Jason S Simon, Ashok K Gupta, Mario Sznol

Assessment of programmed death‐ligand 1 expression and tumor‐associated immune cells in pediatric cancer tissues

Programmed death 1 (PD‐1) signaling in the tumor microenvironment dampens immune responses to cancer, and blocking this axis induces antitumor effects in several malignancies. Clinical studies of PD‐1 blockade are only now being initiated in pediatric patients, and little is known regarding programmed death‐ligand 1 (PD‐L1) expression in common childhood cancers. The authors characterized PD‐L1 expression and tumor‐associated immune cells (TAICs) (lymphocytes and macrophages) in common pediatric cancers.

Abstract 249: Assessment of PD-L1 expression and tumor-associated lymphocytes in pediatric cancer tissues

PD-1 signaling in the tumor microenvironment dampens immune responses to cancer and blocking this axis induces anti-tumor effects in several malignancies. Some studies have demonstrated increased efficacy of PD-1 blockade when tumor cells express PD-L1. Clinical studies of PD-1 blockade have not yet been conducted in pediatric patients and little is known regarding PD-L1 expression in common childhood cancers. We characterized PD-L1 expression and Tumor Associated Immune Cells (TAIC, lymphocytes and macrophages) in common pediatric cancers. Whole slide sections (n = 91) and tissue microarrays (n = 365) were evaluated by IHC for PD-L1 expression using the 28-8 anti-PD-L1 mAb in an automated Dako assay. PD-L1 expression was considered positive when at least 1% of tumor cells analyzed demonstrated plasma membrane staining. TAIC were also assessed for expression of PD-L1, and a subset of 60 tumors were assessed for CD3, CD4, CD8, CD45RO, PD-1, and FoxP3 expression on TAIC. Nine percent (N = 40) of evaluable tumors expressed PD-L1. Highest frequency histotypes comprised non-Hodgkin lymphoma (80%, 8/10), glioblastoma multiforme (30%, 6/20), and neuroblastoma (14%, 17/118). No PD-L1 staining was observed in Ewing sarcoma (0/20) or medulloblastoma (0/40). Despite a relatively low frequency of PD-L1+ pediatric cancers, the majority contained TAIC (73%, 334/456). Of these TAIC+ tumors, 73% of samples contained lymphocytes only, 25% contained lymphocytes and macrophages and 3% contained macrophages only. Twenty-one percent of TAIC+ samples demonstrated PD-L1 expression on TAIC, mostly comprising PD-L1 expression on macrophages (65%, 60/92), while lymphocytes expressed PD-L1 in only 7% (22/324). Taken together, PD-L1 was expressed in tumor and/or TAIC in 20% (90/456). Sixty samples were further analyzed to characterize TAIC, with 77% of the samples demonstrating infiltration of CD8+ T cells, most of which expressed CD45RO. Fox-P3 and PD-1 were expressed in 42% and 47% of the samples respectively. In summary, this provides the most comprehensive analysis of PD-L1 expression in pediatric associated cancer to date. Results show that a subset of pediatric cancers demonstrate tumor associated PD-L1 expression, while a much larger fraction demonstrate infiltration with tumor associated lymphocytes. Further preclinical and clinical investigation will define the predictive nature of PD-L1 expression in childhood cancers, but available data is not sufficient to exclude enrollment to clinical trials based on PD-L1 status. Citation Format: Robbie G. Majzner, Jason S. Simon, Joseph F. Grosso, Daniel Martinez, Bruce Pawel, Mariarita Santi-Vincini, Melinda S. Merchant, Poul Sorensen, Crystal L. Mackall, John M. Maris. Assessment of PD-L1 expression and tumor-associated lymphocytes in pediatric cancer tissues. [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 249. doi:10.1158/1538-7445.AM2015-249

Peripheral blood and tumor biomarkers in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab

Background Programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptors are immune checkpoint receptors involved in tumor immune evasion. Nivolumab and ipilimumab are fully human monoclonal PD-1 and CTLA-4 blocking antibodies, respectively, and have shown clinical antitumor activity as monotherapy. In a multicohort, phase 1 study with melanoma patients (pts), nivolumab/ipilimumab combination produced objective response rates (ORRs) of up to 53% (NCT01024231). We evaluated putative predictive biomarkers for nivolumab and ipilimumab monotherapy in the combination setting, including tumor PD-L1 expression, absolute lymphocyte count (ALC), peripheral blood (PB) myeloid-derived suppressor cells (MDSCs), and pharmacodynamic changes in T-cell phenotype. Methods An automated immunohistochemistry assay (developed by Dako) using the 28-8 PD-L1 antibody was used to evaluate tumor PD-L1 membrane expression in archival FFPE specimens. ALC was measured in serial PB samples. Flow cytometry was used to characterize changes in percentage, number, and phenotype of activated CD4 + and CD8 + T cells and MDSC. Results Using a cut-off of 5% tumor cell membrane staining, 37% of pts (13/35) exhibited PD-L1 expression. Nine of 22 pts (41%) with PD-L1 negative tumors and 6/13 pts (46%) with PD-L1 positive tumors achieved an OR. ALC increase vs baseline was not observed, but phenotypic changes in PB T-cell subsets (increases in percentage of CD4 and CD8 expressing HLA-DR, ICOS, and/or Ki67) were evident. Six of 14 pts (43%) with low ALC (<1.0 at wk 6-7) achieved an OR, vs 15/38 pts (39%) with ALC ≥1.0 at wk 6-7. Lower pretreatment percent MDSC correlated with higher ORR (P<0.05). Conclusions ORRs with nivolumab/ipilimumab combination in this small pt subset were not associated with PD-L1 expression or ALC, in contrast to prior observations with nivolumab or ipilimumab monotherapy, respectively. Compared with either therapy alone, the combination may induce an immune response with distinct characteristics. PB and tumor biomarkers, and their relationship to clinical activity patterns, will be further investigated in this study and in phase 2/3 randomized studies.

Markers of inflammation are associated with clinical outcomes in patients with metastatic renal cell carcinoma treated with nivolumab

Meeting abstracts In previously treated patients with metastatic renal cell carcinoma (mRCC), the programmed death-1 (PD-1) inhibitor antibody nivolumab demonstrated objective response rates of 20%–22% and median overall survival (OS) of 18.2– 25.5 months[[1][1]]. An exploratory biomarker

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