ESMO 2018: Brain Metastases Response to Nivolumab in Patients with Renal Cell Carcinoma: Prospective Analysis from the GETUG-AFU 26 (NIVOREN) Trial

Munich, Germany (UroToday.com) The cumulative incidence of brain metastases after a patient has been diagnosed with renal cell carcinoma (RCC) is 10% at 5 years¹. In a cohort of 138 patients with metastatic renal cell carcinoma (mRCC) who underwent treatment for their brain metastases, median overall survival was 10.7 months and 5 year overall survival was 12%². In another cohort of patients from Europe, median survival was 7 months, with negative prognostic factors being lack of nephrectomy, left side and temporal location of brain metastases, the presence of fever or weight loss, ESR > 50 mm/hr, and time from initial diagnosis to brain metastases ≤ 18 months³. Because RCC may be resistant to radiation, these patients often have poor prognosis.

Nivolumab is a PD-1 monoclonal antibody which has demonstrated activity for mRCC in the second line based on results from Checkmate 025⁴. After the approval of nivolumab for patients with mRCC, NIVOREN GETUG-AFU 26 study (NCT03013335) was initiated – this is a French multicenter prospective study which evaluates the safety and efficacy of nivolumab in the real world setting. In the first analysis of GETUG-AFU 26 at GU ASCO 2018, 729 patients had been enrolled and the median duration of treatment was 4.1 months, with 31.4% of patients still on therapy⁵. 170 patients at that time had died and the 12-month overall survival rate was 66.4%.

At this time, literature regarding the efficacy of nivolumab from brain mets exists for melanoma and lung cancer. In an abstract presented at ASCO 2017, Tawbi et al found that nivolumab was active against brain metastases in patients with metastatic melanoma, with an objective response rate of 55% (41/75) and median time of response of 2.8 months⁶. This study examines the efficacy of nivolumab for mRCC brain mets.

This is a real world study examining patients with advanced RCC who were treated with nivolumab after progression on VEGFR directed therapies. There were two cohorts in this study – cohort A had patients who had not received any prior brain directed therapy (surgery, radiation, steroids), and cohort B had patients who had prior focal therapy. We report here the outcomes for cohort A. These patients were notably asymptomatic, without significant edema, and did not receive any steroids. This data has never been reported before in a prospective manner and we have a paucity of clinical trial data in this space due to the exclusion of many patients with brain metastases in clinical trials, both treated and untreated.

In the NIVOREN study, out of the 729 patients, 73 patients had brain metastases, which is consistent with the estimates of the incidence of brain mets in this population as described earlier. 39 of these patients met criteria for cohort A and 34 were in cohort B. The median follow up was 16.1 months.

ESMO 2018 NIVOREN study population2

Most of these patients had intermediate or poor risk disease and the majority had only one brain metastasis. The median sum of diameters of metastatic disease was 11 mm. Of note, there were 5 patients in cohort A who had previously received stereotactic radiosurgery on non-target lesions and had untreated lesions at baseline and thus were included in cohort A.

In terms of response, 4 of the 39 patients responded (11.8%), all of which were complete responses. 15/39 patients had stable disease (44%), 15 had progressive disease (44%).

This is the first prospective study which reports the efficacy of nivolumab for patients with untreated brain metastases. The response rate was lower than what has been seen in melanoma and lung cancer brain metastases – however, it is not too disparate from the overall response rate to nivolumab seen for the entire cohort of patients in NIVOREN, which was 18.5%. Prior prospective studies had reported lower intracranial rates but the discussant notes that prior studies excluded patients who had brain edema – these patients could have a more inflamed tumor microenvironment and may actually respond better to immunotherapy, but it could have also been a random finding given small numbers. The blood-brain barrier is thought to be disrupted in mRCC with brain metastases so delivery of drug was not thought of as the major barrier. Ultimately, this study demonstrates that there is still a great unmet need for patients with mRCC and brain metastases.

Presented by: Ronan Flippot, MD, Department of Medical Oncology, Gustave Roussy Institute, Villejuif, France

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University @TheRealJasonZhu at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23, 2018, Munich Germany

References:
1. Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002;94:2698-705.
2. Shuch B, La Rochelle JC, Klatte T, et al. Brain metastasis from renal cell carcinoma: Presentation, recurrence, survival and implications for systemic therapy. Journal of Clinical Oncology 2008;26:5097-.
3. Culine S, Bekradda M, Kramar A, Rey A, Escudier B, Droz JP. Prognostic factors for survival in patients with brain metastases from renal cell carcinoma. Cancer: Interdisciplinary International Journal of the American Cancer Society 1998;83:2548-53.
4. 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.
5. Albiges L, Negrier S, Dalban C, et al. Safety and efficacy of nivolumab in metastatic renal cell carcinoma (mRCC): Results from the NIVOREN GETUG-AFU 26 study. Journal of Clinical Oncology 2018;36:577-
6. Tawbi H, Forsyth P, Algazi A, Hamid O, Hodi S, Moschos S. Efficacy and safety of nivolumab plus ipilimumab in patients with melanoma metastatic to the brain: Results of the phase II study CheckMate 204. J Clin Oncol 2017;35:9507abstr.

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