RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse

TPS4595 Background: Bempegaldesleukin (NKTR-214) is a CD122-preferential IL-2 pathway agonist that stimulates proliferation and activation of tumor antigen-specific CD8+ T cells and natural killer cells within the tumor microenvironment and increases PD-1/PD-L1 expression. These properties make bempegaldesleukin (NKTR-214) a potentially promising agent for combination therapy with checkpoint inhibitors that target and inhibit the PD-1/PD-L1 pathway. In phase 1 studies, NKTR-214 plus nivolumab demonstrated encouraging objective response rates (ORR) in first-line renal cell carcinoma (RCC) and an acceptable safety profile. Immunotherapy with NKTR-214 plus nivolumab may lead to greater clinical benefit than tyrosine kinase inhibitors (TKIs), standard-of-care agents, in this patient population. Methods: This multicenter, randomized, open-label phase 3 study (NCT03729245) will evaluate the efficacy and safety of bempegaldesleukin (NKTR-214) plus nivolumab compared with investigator’s choice of TKI (sunitinib or cabozantinib) in patients with previously untreated advanced or metastatic RCC with clear cell component. Exclusion criteria include active brain metastasis and autoimmune disease. Approximately 600 patients will be randomized in a 1:1 ratio, stratified by PD-L1 status (≥1% vs < 1% or indeterminate), International Metastatic RCC Database Consortium prognostic score (1-2 [intermediate risk] vs 3-6 [poor risk]); and TKI (sunitinib or cabozantinib; cabozantinib percentage to be capped at 50%). Combination therapy will consist of bempegaldesleukin (NKTR-214) 0.006 mg/kg intravenously (IV) every 3 weeks (Q3W) plus nivolumab 360 mg IV Q3W until progression or death or maximum of 2 years. TKI therapy will consist of sunitinib 50 mg orally once daily (QD) for 4 weeks followed by 2 weeks off or cabozantinib 60 mg orally QD. Primary objectives are ORR by blinded independent central radiology (BICR) assessment and overall survival. Secondary objectives are progression-free survival by BICR, safety, predictive value of PD-L1 expression, and quality of life. Enrollment is ongoing. Clinical trial information: NCT03729245.

Download Full-text

Cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) (CaNI) for advanced renal cell carcinoma with variant histology (aRCCVH).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps4592 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS4592-TPS4592

Author(s):

Bradley Alexander McGregor ◽

Wanling Xie ◽

Mehmet Asim Bilen ◽

David A. Braun ◽

Wenxin Xu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Phase Iii ◽

Cancer Center ◽

Prior Therapy ◽

Variant Histology

TPS4592 Background: Despite advances in therapy of clear cell renal cell carcinoma, outcomes for patients with aRCCVH remain poor and these patients have typically been excluded from pivotal phase III studies. COSMIC-313 (NCT03937219) exploring C/N/I vs N/I excludes those with aRCCVH. Given responses seen with C as well as N/I in aRCCVH, there is reason to explore this triplet combination in this population. Methods: NCT04413123 is single arm phase 2 trial multi-institutional study involving Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Winship Cancer Institute, Karmanos Cancer Center, University of California in San Diego and University of Texas Southwestern. The primary objective is to assess the objective response rate (ORR) by investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 of C in combination with N/I in aRCCVH. Key secondary endpoints are progression-free survival (PFS), overall survival (OS) and toxicity by Common Terminology Criteria for Adverse Events (CTCAE) version 5. Mandatory pretreatment biopsy (unless medically infeasible) is required for correlative analysis to define the composition and transcriptional states of tumor and immune cells within the aRCCVH microenvironment in addition to determining the number and state of tumor-infiltrating T cell clones in aRCCVH and relation to response. Any variant histology is allowed, including clear-cell RCC with over 80% sarcomatoid features. Patients may be treatment naïve or received prior therapy including up to one anti-vascular endothelial growth factor agent not including C; prior therapy with immune checkpoint inhibitors is exclusionary. All International Metastatic RCC Database Consortium risk classifications are allowed; patients should have adequate organ function with performance status 0-1. C will be administered at a starting dose of 40 mg daily. N will be dosed at 3 mg/kg with I 1 mg/kg every 3 weeks followed by maintenance N 480 mg IV every 4 weeks and will be continued until progressive disease or unacceptable toxicity. C can be reduced to. 20 mg daily or 20 mg every other day as needed for toxicity. Dose reductions of N or I are not permitted but delays up to 12 weeks are allowed; N may be continued without I if toxicity can be directly attributed to I. Radiographic imaging is performed at baseline with first scheduled assessment at 12 weeks then every 8 weeks thereafter. A one-stage design is employed to enroll 40 eligible patients, which provides 93% power at 1-sided alpha of 0.09 to distinguish an ORR of 40% versus 20%. 12 or more responses are required to deem treatment promising. Seven of the planned 40 patients have been enrolled as of 2/1/2021. Clinical trial information: NCT04413123.

Download Full-text