ASCO GU 2019: Phase II Trial of Nivolumab Plus Ipilimumab in Patients with SMARCB1 Deficient Kidney Malignancies

San Francisco, CA ( Last year, CheckMate 214 reported a significant overall survival (OS) benefit for intermediate and poor risk mRCC patients with combination nivolumab plus ipilimumab vs sunitinib1.  Given these encouraging outcomes, the search for additional applications of this combination therapy is ongoing. The potent tumor suppressor SMARCB1 (also known as INI-1, hSNF5, or BAF47) is inactivated in all cases of renal medullary carcinoma and renal cell carcinoma unclassified with medullary phenotype, as well as most malignant rhabdoid tumors of the kidney.  Although rare, these kidney malignancies are highly lethal and often occur in young patients. Indeed, the role of immune checkpoint inhibitor therapy remains to be prospectively defined in tumors harboring SMARCB1 defects. Other than a case report noting the efficacy of single-agent nivolumab in a patient with renal medullary carcinoma2, there were no durable responses in subsequent cases3.  Dr. Msaouel highlighted their trial design assessing the combination of anti-PD1 (nivolumab) with anti-CTLA4 (ipilimumab) immune checkpoint inhibitor therapy for these aggressive tumors. They hypothesize that combination therapy will lead to more potent antitumor responses (objective response rate) compared to those reported with single-agent nivolumab for patients with SMARCB1 deficient kidney malignancies.

This single-arm phase II trial will test the efficacy of nivolumab plus ipilimumab in up to 30 patients with SMARCB1-negative renal medullary carcinoma, renal cell carcinoma unclassified with medullary phenotype, and adult-onset kidney malignant rhabdoid tumors. The trial schema is as follows:

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*Continued maintenance Nivo every 2 weeks until disease progression on unacceptable treatment-related toxicity

Any number of prior therapies is allowed and patients are eligible regardless if they’ve had a prior nephrectomy. Patients must not have had prior treatment with either anti-PD(L)1 or anti-CTLA-4 checkpoint inhibitors. Patients will be treated with ipilimumab1 mg/kg + nivolumab 3 mg/kg every 3 weeks x4 doses followed by maintenance nivolumab480 mg every 4 weeks for up to two years. Ongoing monitoring for safety and futility will be implemented using cohorts of 10 patients each. The primary endpoint is objective response rate and the trial objective is to achieve a similar or greater objective response rate compared with the historical objective response rate of 29% achieved at the MD Anderson Cancer Center using conventional cytotoxic chemotherapies. Secondary endpoints include progression-free survival, overall survival, and disease control rate. To evaluate potential biomarkers for treatment response, correlative analyses will be performed in tumor tissue and peripheral blood samples obtained at:

  1. Pre-treatment (baseline) up to 6 weeks (42 days) prior to initiation of treatment on Day 1
  2. After completion of the combination therapy (nivolumab plus ipilimumab) phase
  3. Upon disease progression.

At the time of the abstract submission, two patients have been enrolled in this study. Clinical trial information: NCT03274258

Presented by: Pavlos Msaouel, MD, Ph.D., The University of Texas MD Anderson Cancer Center, Houston, Texas

Written By: Gina B. Carithers Founder and Publisher

Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter:@zklaassen_md @ the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med2018;378(14):1277-1290.
2. Beckermann KE, Jolly PC, Kim JY, et al. Clinical and immunologic correlates of response to PD-1 blockade in a patient with metastatic renal medullary carcinoma. J Immunother Cancer2017 Jan 17;5:1.
3. Sodji Q, Klein K, Sravan K, et al. Predictive role of PD-L1 expression in the response of renal medullary carcinoma to PD-1 inhibition.