Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma (mRCC
PUBLISHED: 2015-11-30  681 total views, 2 today

Toni k. Choueiri1, Mayer n. Fishman2, Bernard Escudier3, David f. Mcdermott4, Arriet Kluger5, Walter m. Stadler6, Jose luis Perez-gracia7, Douglas Mcneel8, Brendan Curti9, Michael r. Harrison10, Elizabeth r. Plimack11, Leonard Appleman12, Lawrence Fong13, Charles g. Drake14, Tina c. Young15, Petra Ross-macdonald15, Jason s. Simon15, Dana Walker15, Mario Sznol5

1oncology, Dana-Farber Cancer Institute, Boston, MA, USA, 2Tampa, H. Lee Moffitt Cancer Center & Research Institute, 3Villejuif, Institut Gustave Roussy, 4Dana-Farber/Harvard Cancer Center, Beth Israel Deaconess Medical Center, 5New Haven, Yale Cancer Center, 6Chicago, University of Chicago Medicine, 7Pamplona, University Clinic of Navarra, 8Department of Medicine, University of Wisconsin-Madison, 9Providence Portland Medical Center, Providence Cancer Center, 10Durham, Duke University Medical Center, 11Philadelphia, Fox Chase Cancer Center, 12Pittsburgh, University of Pittsburgh Medical Center (UPMC) Cancer Pavilion, 13San Francisco, University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, 14Baltimore, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 15Princeton, Bristol-Myers Squibb

 

Objective:This prospective biomarker study in patients (pts) with mRCC treated with the programmed death-1 (PD-1) inhibitor antibody nivolumab assessed baseline (BL) and changes in serum chemokines, tumor T cell infiltrates (TIL), gene expression, T cell repertoire (TCR), and other biomarkers potentially associated with clinical outcomes (NCT01358721). Method: Pts treated with 1–3 prior therapies received nivolumab 0.3, 2, or 10mg/kg IV Q3W; treatment-naïve pts received 10mg/kg IV Q3W. Biopsies were obtained at BL and cycle 2 day 8. Overall survival (OS) parameters were estimated by Kaplan-Meier method. Tumor PD-L1 expression was measured by immunohistochemistry (28-8 antibody; Dako). PD-L1 positivity was defined as ≥ 5% tumor membrane staining in ≥ 1 biopsy; tumor burden response as ≥ 20% reduction. Gene expression data were obtained on Affymetrix U219. Result: 91 pts were treated. Of 56 evaluable BL biopsies, 32% were PD-L1+. Median OS (95% CI) was 16.4 mo (10.1–not reached [NR]) for 0.3mg/kg, NR for 2mg/kg, 25.2 mo (12.0–NR) for 10mg/kg, and NR for treatment-naïve pts. 1-yr and 2-yr OS rates (95%CI) were 75% (64–83) and 58% (46–68), respectively. OS by PD-L1 status is summarized (table). Pts with tumor burden response (n=13) had ≥ 1.3-fold differential BL expression of 311 genes (P<0.01, false discovery rate < 16%). Cell-mediated immune transcripts were elevated, including effector cell markers GZMB, NKG7, and CD7, NK/CD8-activating ligand MICB, inflammasome component AIM2, and activated macrophage marker IL-1a. Analysis of association between OS and serum chemokine levels, TCR and TIL is ongoing. PD-L1+n = 18PD-L1–n = 38Median OS, mo(95% CI) Overall NR23.4 (13.1–33.3) Previously treated NR22.3 (12.0–27.0) Treatment-naïve NR33.3 (2.0–NR)OS rate(95%CI) 1-yr71 (44–87)71 (52–83)2-yr64 (37–82)48 (30–64). Conclusion:Association of immune markers at BL with subsequent tumor burden response suggests that infiltrating immune activating cells may mediate response to nivolumab in mRCC pts. Consistent with the randomized phase II study of nivolumab in mRCC, OS appears longer in PD-L1+ pts but promising in both PD-L1+ and PD-L1– pts, especially when treatment-naïve. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2015 ASCO Annual Meeting. All rights reserved.

 

Key Words: Nivolumab, Immunomodulatory activity, Renal cell carcinoma


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