ASCO GU 2019: Final analysis from the NIVOREN GETUG AFU 26 study — Safety and Efficacy of Nivolumab in Metastatic Renal Cell Carcinoma

San Francisco, CA (UroToday.com) Immune checkpoint inhibitors have changed the treatment paradigm of metastatic renal cell carcinoma (mRCC), both in the front line and second line settings. Nivolumab, a humanized IgG4 anti-PD-L1 monoclonal antibody, is approved in both settings, based on CheckMate 214 (in combination with ipilimumab) in the first line, and CheckMate 025 in the second line.1,2 NIVOREN GETUG AFU 26 is a French multicenter prospective study to evaluate the safety and efficacy of nivolumab in a real-world setting. A total of 729 patients were enrolled between February 2016 and June 2017. These patients had failed at least 1 line of VEGF/VEGFR inhibition and patients with a performance status of 0-2 were allowed. During GU ASCO 2018, interim results of the first 528 patients were reported, with an 18.5% confirmed overall response rate, with 0.4% complete responses and 18.1% partial responses. The median PFS at that time was 4 months and median overall survival was 18.6 months. This abstract, presented at ASCO GU 2019, provides an update to that data.

720 patients were included in the final analysis. In terms of patient characteristics, all patients had clear cell mRCC. The majority of patients were men (77.4%), had prior nephrectomy (84.7%), and had an ECOG of 0 (85%). 22.4% of patients had already received two prior lines of therapy, and the majority of patients were intermediate and poor risk (81.7%). 12.3% of patients were found to have brain metastases per study screening protocol. 
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After a median of 20.9 months, the median duration of treatment was 5.2 months with 15% of patients still on treatment. The confirmed ORR was 21%, with the majority of those being partial responses and only 1.3% complete response. The median progression-free survival was 3.2 months and the 12-month survival rate was 69%. The curve begins to flatten out after 6 month – 6 month PFS was 35% and 12 month PFS was 23.8%.
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Interestingly, 47% of patients were treated beyond progression. 59% of patients received an additional line of therapy and 22% died without any further therapy. In terms of overall survival, the median OS was 24.5 months with 69% of patients alive at one year and upon subgroup analysis, there was no difference in OS between the number of prior lines of therapy or presence of brain metastases. However, patients with poor performance status, prior everolimus, and poor renal function did have worse median OS. 
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OS correlated nicely with IMDC criteria with a median OS of 32 months, 25 months, and 10 months for favorable, intermediate, or poor risk disease, and separated out nicely even when broken down to the individual number of IMDC risk factors.
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The best response was correlated with overall survival, with a median OS of 28.4 months for patients with stable disease and 13 months for those with initial progressive disease. PFS correlated with best response as well, with a median PFS of 27.8 months for those with a PR/CR. 
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In terms of safety, 17.9% of patients had a grade 3/4 event and 6 (0.008%) patients had grade 5 toxicity which confirms the safety signals seen in CheckMate 025.  Of note, patients who had a grade 3 or high treatment-related event had longer progression-free survival (HR 0.69 [0.55-0.87]). 
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This study confirms prior clinical trials in a real-world setting that nivolumab is active and safe in patients with clear cell RCC. In addition to the primary and secondary outcomes, two interesting points are described in this abstract. First, oncologists frequently treat beyond progression with nivolumab. Second, this study’s results bring to light what many oncologists have suspect regarding the relationship between response and immune toxicity, showing that patients who have some off-target effect of therapy may derive more benefit than those without any immune-mediated side effects. 

Presented by: Laurence Albiges, MD, PhD, Head, Genitourinary Unit, Gustave Roussy Institute, Villejuif, France
Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

References:
  1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2018;378:1277-90.
  2. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2015;373:1803-13
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