Citations

Abstract Background: Previous data on the relationship between PD-L1 expression and activity of anti-PD-1 and anti-PD-L1 antibodies have been conflicting. MK-3475, a humanized monoclonal IgG4 antibody against PD-1, has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated tumor PD-L1 expression and its relationship with outcomes in a phase I clinical trial of MK-3475. We also evaluated T cell activation as a pharmacodynamic marker of MK-3475 activity. Methods: 135 MEL pts received MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W. Tumor response was assessed by RECIST 1.1 per independent central review, including requirement for a confirmatory CT scan. Pretreatment biopsy was required. Serial blood samples were collected before infusion at the start of cycles 1-5 (Q2W dosing) or 1-4 (Q3W dosing). Tumor PD-L1 expression was assessed by IHC. A preliminary cutoff of 1% of stained cells was used to define PD-L1 positivity. Absolute CD4+ and CD8+ T cell counts and the percentage of activated (HLA-DR as marker) CD4+ and CD8+ T cells in peripheral blood were assessed by multiplex flow cytometry (n = 101). Results: Median PFS was 36 weeks, 6-month overall survival (OS) rate was 89%, and 12-month OS rate was 81%. Median duration of response and OS were not reached. In the 116 pts with measurable disease, ORR was 41%. PFS and response rate were significantly associated with tumor PD-L1 expression (Table). At week 6, a statistically significant percent increase from baseline in the percentage of activated (HLA-DR+) CD4+ and CD8+ T cells was observed at all doses (pooled mean percent change [SE], +24.0% [4.7%] for HLA-DR+/CD8+, +17.5% [2.7%] for HLA-DR+/CD4+). Conclusions: Tumor PD-L1 expression levels were associated with tumor response and PFS in MEL pts treated with MK-3475; activity was also observed in pts with low PD-L1 expression. As assessed by HLA-DR expression, post-treatment T cell activation in the circulating pool was increased at all doses tested. Patients WithMeasurable Disease and Interpretable PD-L1 IHC ResultsPatients With InterpretablePD-L1 IHC Results and PFS and OS Data PD-L1 TumorExpressionNORR, n (%)NPFS at 6 months, % (95% CI)Median PFSOS at 6 months, % (95% CI)Median OSPositive (membrane staining in ≥1% of cells)5529 (53)6058 (47-72)10.6 mo93(87-100)Not reachedNegative (membrane staining in <1% of cells)161* (6)2232 (16-64)2.9 mo75(58-97)Not reachedHR (95% CI) for PD-L1-positive vs negative____0.54(0.28-1.05)_0.67(0.25-1.83)One-sidedP value(PD-L1 association test)_<0.004 (logistic regression)__0.034(Cox regression)_0.220(Cox regression)*IPI-pretreated patient who received MK-3475 10 mg/kg Q2W. Citation Format: Adil I. Daud, Omid Hamid, Antoni Ribas, F. Stephen Hodi, Wen-Jen Hwu, Richard Kefford, Jedd Wolchok, Peter Hersey, Jeffrey S. Weber, Richard Joseph, Tara C. Gangadhar, Roxana S. Dronca, Amita Patnaik, Hassane Zarour, Anthony M. Joshua, Kevin Gergich, Dianna Wu, Jared K. Lunceford, Kenneth Emancipator, Marisa Dolled-Filhart, Nicole Li, Scot Ebbinghaus, S. Peter Kang, Caroline Robert. Antitumor activity of the anti-PD-1 monoclonal antibody MK-3475 in melanoma(MEL): Correlation of tumor PD-L1 expression with outcome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT104. doi:10.1158/1538-7445.AM2014-CT104

Abstract Immune checkpoint blockade therapies have demonstrated promising therapeutic effects; however, clinical outcomes are variable, with only a subgroup of cancer patients achieving durable complete responses. New therapeutic strategies, including local administration of immunomodulatory antibodies, have been considered as better routes for improving the overall efficacy of antibody-based therapy. Clin Cancer Res; 21(5); 944–6. ©2014 AACR. See related articles by Mangsbo et al., p. 1115, and Dai et al., p. 1127

Cardiac metastasis in renal cell carcinoma is a very rare entity, with only a few previously reported cases. In this series, we report two cases of ventricular metastases from renal cell carcinoma without vena cava or right atrial involvement. The first case involves an initially isolated inoperable metastasis to the left ventricle, which was treated with systemic targeted therapy with favorable local response. Our second case illustrates a patient with an isolated cardiac metastasis in the interventricular septum with extension into the right ventricle, which has also remained stable in size on systemic targeted therapy. Although anti-angiogenic agents such as tyrosine kinase inhibitors have transformed the treatment of metastatic renal cell carcinoma in recent years, their efficacy and safety in treating patients with metastatic disease in highly vascular organs such as the heart are currently unknown, with no prior reports on this topic. We describe our novel management of these unique cases and discuss the current medical and surgical approaches to treating cardiac metastases from renal cell carcinoma.

Objective To determine renal function eligibility for cisplatin‐based chemotherapy using our experience with radical cystectomy ( RC ) patients. Patients and Methods Using the M ayo C linic C ystectomy R egistry, we identified 768 patients treated with RC without neoadjuvant chemotherapy for urothelial carcinoma from 1980–2005. Glomerular filtration rate ( GFR ) was estimated using the C hronic K idney D isease E pidemiology C ollaboration ( CKD‐EPI ) equation and a value of ≥60 mL/min was considered eligible for cisplatin‐based chemotherapy. Factors associated with change in GFR (from preoperative to 3‐month postoperative) were assessed using linear regression. Results The median age was 68 years, while the median GFR was 60 mL/min both preoperatively and 3 months after RC . Overall, 405 (53%) patients had a GFR of <60 mL/min before surgery and 387 (50%) had a GFR of <60 mL/min at 3 months after RC . Patients with hydronephrosis (209 patients) had significantly lower preoperative GFRs than with patients without hydronephrosis (median 52 vs 62 mL/min, respectively; P < 0.001). Among the 363 patients with a GFR of ≥60 mL/min before RC , 91 (25%) had a decline in renal function to a GFR of <60 mL/min at 3 months after RC . In multivariable analyses, older age ( P < 0.001), higher preoperative GFR ( P < 0.001) and continent urinary diversion ( P = 0.011) were significantly associated with a negative change in GFR after RC . Conclusions Our results suggest that nearly half of patients undergoing RC are not eligible to receive perioperative cisplatin‐based chemotherapy based on renal function status. About a quarter of patients eligible for cisplatin before surgery are no longer eligible after RC . Certain patient characteristics and surgical factors are more likely to experience a negative change in GFR after RC and should be counselled accordingly.

Objective To evaluate carbonic anhydrase IX ( CAIX ) expression as an independent prognostic marker for clear cell renal cell carcinoma ( ccRCC ). With recent smaller studies showing conflicting results, we aimed to update our initial analysis in 2007 with an additional 5‐year follow‐up. Patients and Methods We provided long‐term follow‐up of the same cohort used in our 2007 study (730 patients with unilateral, sporadic ccRCC treated surgically between 1990 and 1999). Associations of CAIX expression with RCC death and distant metastases were evaluated using C ox proportional hazards regression models. Results CAIX was expressed in 708 (97.0%) of the specimens; 163 tumours (22.3%) had low (≤85%) expression and 567 (77.7%) high (>85%) expression. There were 483 deaths and 265 RCC ‐specific deaths. The median follow‐up for the 247 patients still under observation was 13.8 years. Univariately, low CAIX expression was associated with an increased risk of RCC death vs high expression (hazard ratio 1.62; P < 0.001). Low CAIX expression was not statistically significantly associated with RCC death or distant metastases after adjusting for nuclear grade or coagulative tumour necrosis. Conclusion After additional long‐term follow‐up of our large cohort, our results continue to suggest that CAIX is not an independent prognostic marker for ccRCC .

SummaryWe have observed T helper type 2 (Th2) polarization of systemic immunity in patients with metastatic malignant melanoma. We hypothesized that similar changes in systemic immunity occur with ageing and may be permissive for the development of melanoma. We analysed the peripheral blood of 389 healthy blood donors. All subjects were profiled for peripheral blood T cell and B cell subsets, and 58 of these subjects were profiled for antigen-specific cytotoxic T cell subsets [cytomegalovirus (CMV), influenza and melanoma antigen recognized by T cells 1 (MART-1)]. Ninety-five separate healthy subjects underwent profiling of 42 plasma cytokines. Ageing was associated positively with CD4+CD294+ Th2 cells, and associated negatively with CD3+ T cells, cytotoxic T cells and T helper cells. Ageing was also associated negatively with CMV-, influenza- and MART-1-specific naive and CD8+ T cells. There were significant increases in plasma monocyte chemotactic protein 1 (MCP-1) (CCL1) and regulated upon activation normal T cell expressed and secreted (RANTES) (CCL5) with age. We observed differences in cytokine profiles between males and females; specifically, women had higher levels of sCD40L and PDGF-AA. In summary, we demonstrated in healthy blood donors that ageing was associated with an increase in cellular Th2 bias and a decline in total numbers of T cells. Additionally, there was an increase in MCP-1 and RANTES with ageing. Women had higher levels of sCD40L and PDGF-AA than men.