ASCO 2019: Safety and Efficacy of Nivolumab plus Ipilimumab in Patients with Advanced Renal Cell Carcinoma with Brain Metastases: Interim Analysis of CheckMate 920

Chicago, IL (UroToday.com) The landscape of systemic therapy for metastatic renal cell carcinoma (mRCC) is rapidly changing. Beyond the addition of immune checkpoint inhibitor combinations (nivo/ipi) and additional tyrosine kinase inhibitors (TKIs) such as cabozantinib, there are now combination therapies that are demonstrating excellent responses rates in the first line. In the phase 3 CheckMate 214 trial,1 the combination of nivolumab plus ipilimumab (N+I) demonstrated superior objective response rate (ORR) and overall survival (OS) vs. sunitinib (S) in previously untreated pts with International Metastatic RCC Database Consortium (IMDC) intermediate/poor (I/P)-risk, clear-cell, advanced RCC.   The recent data from KEYNOTE‑426 has led to the approval of axinitib/pembrolizumab in the first line for mRCC, and as can be expected from this combination, seems to have efficacy for good, intermediate and poor risk patients. 

However, those previous clinical trials of patients (pts) with advanced or metastatic RCC (aRCC), including CheckMate 214,1 have mostly excluded patients with brain metastases. Brain metastases represent a subset of patients with poor prognosis – and often have been included due to low historical antitumor activity in the targeted therapy era. However, antitumor activity in patients with brain metastases has been observed in patients with melanoma treated with NIVO 1 mg/kg + IPI 3mg/kg and patients with non-small cell lung cancer treated with NIVO 240 mg + IPI 1mg/kg. Hence, it would appear that immune checkpoint inhibitors may have antitumor activity that is able to cross the blood-brain barrier. 

CheckMate 920 is an ongoing, phase 3b/4 clinical trial of NIVO + IPI treatment in patients with aRCC with a high unmet medical need. This includes a cohort of patients with asymptomatic brain metastases. 

The full study protocol is below: 
ASCO 2019 CheckMate 920 study design

Patients with previously untreated aRCC of any histology, with asymptomatic brain metastases (not on corticosteroids or receiving radiation), and Karnofsky performance status ≥70% were assigned to treatment with NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks for 4 doses, followed by NIVO 480 mg every 4 weeks. They were treated until disease progression, unacceptable toxicity, or for a maximum of 2 years. The primary endpoint of the study was the incidence of high-grade immune-mediated adverse events (IMAEs). Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 per investigator. Exploratory endpoints included additional safety analyses and overall survival (OS). 

A total of 28 patients were enrolled in the brain metastases cohort. 15 patients received all 4 Nivo/ipi doses so far, the median number of doses received is 3.2. The demographics of the group are below: 
ASCO 2019 CheckMate 920 baseline demographic

As expected, most were favorable/intermediate risk, majority had ccRCC, and 14% had sarcomatoid features. 

With a minimum follow-up of 6.5 months, 14 patients have experience treatment-related Grade 3-4 adverse events (50%), and 7 have discontinued therapy as a result (25%). The most common grade 3-4 AE is lipase elevation, fatigue, diarrhea, nausea, and decreased appetite. Immune-mediated side effects are listed below: 
ASCO 2019 CheckMate 920 immune mediated AEs

Looking at oncologic secondary outcomes, ORR by RECIST v1.1 per investigator in all treated subjects was 28.6% (95% CI 13.2–48.7).  No CR’s were reported – all were partial responses. Among patients with sarcomatoid features, 2 of 4 had partial responses. Median PFS in all treated subjects was 9.0 months (95% CI 2.9–not estimable [NE]). Median OS has not yet been reached (95% CI 13.1–NE).  
ASCO 2019 CheckMate 920 PF survival

In a patient population that has often had minimal response to prior targeted therapies, and are often excluded from clinical trials, it would appear that NIVO + IPI treatment showed an acceptable safety profile consistent with previous reports of this dosing regimen. More importantly, they demonstrate an encouraging antitumor activity. This may become a viable option for these patients – and may warrant inclusion in future studies.

Clinical trial information: NCT02982954 

Presented by: Hamid Emamekhoo, MD, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology)  at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References: 
  1. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, Plimack ER, Barthélémy P, Porta C, George S, Powles T, Donskov F, Neiman V, Kollmannsberger CK, Salman P, Gurney H, Hawkins R, Ravaud A, Grimm MO, Bracarda S, Barrios CH, Tomita Y, Castellano D, Rini BI, Chen AC, Mekan S, McHenry MB, Wind-Rotolo M, Doan J, Sharma P, Hammers HJ, Escudier B; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290. doi: 10.1056/NEJMoa1712126. Epub 2018 Mar 21. 
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