A single center open-label uncontrolled study to investigate tumour response and vascularization changes in neoadjuvant therapy with BAY 43-9006 single agent therapy in patients with operable renal cell cancer

e16058 Background: Preclinical data suggest there are synergistic effects of radiation therapy (RT) and check point inhibitors in anticancer immunity. The primary objective of this study was to explore the immunomodulatory activity of RT alone or in combination with Pembrolizumab (pembro) in solid tumors including renal cell cancer (RCC) patients (pts). Methods: RCC pts who progressed after at least one front-line therapy were eligible. Pts were treated with either RT (8Gy x 1 or 4Gy x 5) followed by (f/b)pembro or 1 dose pembro f/b RT f/b pembro. Pre- and post RT tumor biopsy was obtained to evaluate PD-L1 expression (assay by QualTeck). Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Treatment response was measured based on modified RECIST criteria. Results: Twelve RCC patients were enrolled including 2 with non-clear cell subtype. One pt was not evaluable since pt quickly deteriorated and was taken off study. As of January 13, 2017, 2 pts are still on active treatment. Two pts had partial response (18%) and were on study for at 54 and 63 weeks. One responder was treated with 8 Gy f/b pembro while 1 was treated with 1 dose pembro f/b RT f/b pembro. Five pts had stable disease of 18 to 45 weeks and 4 pts (36%, non-responders) had progression in 9 weeks. For adverse events, 1 pt developed grade 3 pneumonitis after 10 cycles of pembro (RT to adrenal mets). Grade 3 AEs include Fatigue, Nausea, Hyperglycemia, Lymphopenia, thrombocytopenia and AST elevation (post RT for liver mets). PDL1 expression and tumor infiltrating lymphocytes presence after RT showed various patterns. Preliminary flow cytometry showed persistent higher numbers of monocytes in non-responders comparing with responders. CD4+, CD8+ and NK cells and other markers are under analyzed and the results will be presented. Conclusions: The combination of RT (8Gy or 20Gy) with pembro is feasible and tolerated, and demonstrates clinical activity. The AE profile is similar to single agent pembro. Monocytes, T and NK cell kinetics are being examined. (ClinicalTrials.gov ID: NCT02318771) Clinical trial information: NCT02318771.

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Phase II Study of Erlotinib in Patients With Locally Advanced or Metastatic Papillary Histology Renal Cell Cancer: SWOG S0317

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.8821 ◽

2009 ◽

Vol 27 (34) ◽

pp. 5788-5793 ◽

Cited By ~ 69

Author(s):

Michael S. Gordon ◽

Michael Hussey ◽

Raymond B. Nagle ◽

Primo N. Lara ◽

Philip C. Mack ◽

...

Keyword(s):

Overall Survival ◽

Treatment Failure ◽

Disease Control ◽

Survival Time ◽

Renal Cell Cancer ◽

Renal Cell ◽

Cell Cancer ◽

Single Agent ◽

Locally Advanced ◽

Tumor Type

Purpose Patients with advanced papillary renal cell cancer (pRCC) have poor survival after systemic therapy; the reported median survival time is 7 to 17 months. In this trial, we evaluated the efficacy of erlotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in patients with advanced pRCC, a tumor type associated with wild-type von Hippel Lindau gene. Patients and Methods Patients with histologically confirmed, advanced, or metastatic pRCC were treated with erlotinib 150 mg orally once daily. A RECIST (Response Evaluation Criteria in Solid Tumors) response rate (RR) of ≥ 20% was considered a promising outcome. Secondary end points included overall survival and 6-month probability of treatment failure. Results Of 52 patients registered, 45 were evaluable. The overall RR was 11% (five of 45 patients; 95% CI, 3% to 24%), and the disease control rate was 64% (ie five partial response and 24 stable disease). The median overall survival time was 27 months (95% CI, 13 to 36 months). Probability of freedom from treatment failure at 6 months was 29% (95% CI, 17% to 42%). There was one grade 5 adverse event (AE) of pneumonitis, one grade 4 thrombosis, and nine other grade 3 AEs. Conclusion Although the RECIST RR of 11% did not exceed prespecified estimates for additional study, single-agent erlotinib yielded disease control and survival outcomes of interest with an expected toxicity profile. The design of future trials of the EGFR axis in pRCC should be based on preclinical or molecular data that define appropriate patient subgroups, new drug combinations, or potentially more active alternative schedules.

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Re: Michael B. Atkins, Elizabeth R. Plimack, Igor Puzanov, et al. Axitinib in Combination with Pembrolizumab in Patients with Advanced Renal Cell Cancer: A Non-randomised, Open-label, Dose-finding, and Dose-expansion Phase 1b Trial. Lancet Oncol 2018;19:405–15

European Urology ◽

10.1016/j.eururo.2018.04.015 ◽

2018 ◽

Vol 74 (2) ◽

pp. e50 ◽

Cited By ~ 1

Author(s):

Vincenzo Di Nunno ◽

Matteo Santoni ◽

Francesco Massari

Keyword(s):

Renal Cell Cancer ◽

Renal Cell ◽

Cell Cancer ◽

Dose Finding ◽

Open Label ◽

Expansion Phase ◽

Label Dose ◽

Phase 1B ◽

Advanced Renal Cell Cancer

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CNTO328 (Anti-IL-6 mAb) treatment and hemoglobin (Hb) levels in renal cell cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e20648 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e20648-e20648 ◽

Cited By ~ 1

Author(s):

M. Schipperus ◽

M. Cornfeld ◽

B. Rijnbeek ◽

B. Berns ◽

J. Rossi

Keyword(s):

Renal Cell Cancer ◽

Renal Cell ◽

Iron Homeostasis ◽

Tumor Response ◽

Cell Cancer ◽

Median Number ◽

Open Label ◽

Anemia Of Chronic Disease ◽

Potent Inducer ◽

The Difference

e20648 Background: CNTO328 is a chimeric monoclonal antibody against the inflammatory cytokine, IL-6, which is currently being studied in hematologic and solid malignancies. IL-6 is a potent inducer of hepatic production of hepcidin, which is the key regulator of iron homeostasis and causes anemia by blocking iron export from enterocytes and macrophages. Hepcidin is an important factor in the pathogenesis of ‘anemia of chronic disease‘. CNTO328 treatment has previously been shown to produce profound Hb increases in Castleman's disease, a disorder caused by deregulated IL-6 production. We subsequently conducted this retrospective review to assess whether CNTO328 treatment is associated with an increase in Hb level in renal cell cancer patients (pts). Methods: All laboratory results for pts with metastatic renal cell carcinoma in this open label phase 2 study were reviewed. Pts were treated with CNTO328 (6 mg/kg) IV infusions Q2 weeks and were evaluated for tumor response and markers of pharmacodynamic effect. The difference in Hb levels from baseline to end of study was calculated. Results: Twenty pts (19 males) with a median age of 62 yrs (range 50–77) were studied. The median number of infusions was 6 (1–13). Of 18 pts evaluable for tumor response, 11 (61%) had SD and 7 (39%) had PD. The median baseline Hb was 13.6 g/dL (10.8–17.1). Nineteen pts were evaluable for Hb response. No pts received ESAs or transfusions. Treatment with CNTO328 resulted in a sustained Hb increase in 16 of the 19 pts (84%), with 13 (68%) achieving a max Hb increase of ≥ 1 g/dL (median 1.9; range 1.0–3.5). Hb responses were early (by day 8) and independent of tumor response. No Hb overshoot or thromboembolic events were observed. A trend toward decreased platelet and neutrophil counts was observed. Conclusions: Though pts were not anemic at baseline, our results suggest that CNTO328 leads to sustained increase in Hb levels, not correlated with tumor response. This increase in Hb is presumably due to the reduction of hepcidin via IL-6 blockade and targeting the hepcidin pathway may lead to new therapies for anemia of cancer. This hypothesis warrants further evaluation with prospective mechanistic studies. [Table: see text]

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An exploratory study to investigate the immunomodulatory activity of radiation therapy in combination with pembrolizumab in patients with renal cell cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.518 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 518-518

Author(s):

Jianqing Lin ◽

Jean H. Hoffman-Censits ◽

William Kevin Kelly ◽

Madalina Tuluc ◽

Colette Shaw ◽

...

Keyword(s):

Flow Cytometry ◽

Radiation Therapy ◽

Renal Cell Cancer ◽

Renal Cell ◽

Nk Cell ◽

Synergistic Effects ◽

Cell Cancer ◽

Single Agent ◽

Clinical Activity ◽

Immunomodulatory Activity

518 Background: Preclinical data suggest there are synergistic effects of radiation therapy (RT) and check point inhibitors in anticancer immunity. The primary objective of this study was to explore the immunomodulatory activity of RT alone or in combination with Pembrolizumab (pembro) in solid tumors including renal cell cancer (RCC) patients (pts). Methods: RCC pts who progressed after at least one front-line therapy were eligible. Pts were treated with either RT (8Gy x 1 or 4Gy x 5) followed by (f/b) pembro or 1 dose pembro f/b RT f/b pembro. Pre- and post RT tumor biopsy was obtained to evaluate PD-L1 expression (assay by QualTeck). Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Treatment response was measured based on modified RECIST criteria. Results: 12 RCC patients were enrolled including 2 with non-clear cell subtype. One pt was not evaluable since pt quickly deteriorated and was taken off study. As of September 30, 2016, 5 pts were still on study with 3 pts having partial response (27.2%, responders) and were on study for at least 9.8 months. 2 responders were treated with 8 Gy f/b pembro while 1 was treated with pembro f/b RT f/b pembro. Six pts (54.5%, non-responders) had PFS between 2 – 4 m and were off study. For adverse events, 1 pt developed grade 4 pneumonitis after 10 cycles of pembro (RT to adrenal mets). Grade 3 AEs include fatigue, nausea, hyperglycemia, lymphopenia, thrombocytopenia, and AST elevation (post RT for liver mets). PDL1 expression and tumor infiltrating lymphocytes presence after RT showed various patterns. Preliminary flow cytometry showed persistent higher numbers of monocytes in non-responders compared with responders. CD4+, CD8+, and NK cells and other markers are under-analyzed and the results will be presented. Conclusions: The combination of RT (8Gy or 20Gy) with pembro is feasible and tolerated, and demonstrates clinical activity. The AE profile is similar to single agent pembro. Monocytes, T, and NK cell kinetics are being examined. Clinical trial information: NCT02318771.

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