ASCO 2020: A Phase III, Randomized, Placebo-Controlled Trial of Nivolumab or Nivolumab plus Ipilimumab in Patients with Localized Renal Cell Carcinoma at High-Risk of Relapse after Radical or Partial Nephrectomy (CheckMate 914)

( Surgical excision is the standard of care for patients with non-metastatic renal cell carcinoma (RCC). Depending on the tumor stage, rates of recurrence vary widely. Relatively high rates of recurrence in patients with pathological stage 3 renal cell carcinoma have prompted interest in the use of adjuvant therapy to decrease this risk. Following the introduction of tyrosine kinase inhibitors (TKIs) for the treatment of patients with metastatic kidney cancer, they were examined in the adjuvant setting. While the ASSURE trial (examining sorafenib or sunitinib), the ATLAS trial (examining axitinib), the PROTECT trial (examining pazopanib), and the SORCE trial (examining sorafenib) demonstrated no benefit in disease-free survival with the use of adjuvant TKIs, the S-TRAC trial (examining sunitinib) did find benefit. A meta-analysis of these data, as well as expert interpretation, has suggested no benefit, and thus, this approach is not widely used.

However, the need for efficacious adjuvant therapy remains. The CheckMate 214 demonstrated a significant survival benefit in the first-line use of nivolumab plus ipilimumab (NIVO+IPI) for patients with advanced/metastatic RCC, with a manageable safety profile. Further, early evidence suggests potential clinical activity for anti-PD-L1 monotherapy in patients with advanced RCC. These data set the stage for assessment of the role of adjuvant immunotherapy in patients at high risk for recurrence following nephrectomy.

In the Genitourinary Cancer—Kidney and Bladder Poster Session at the 2020 American Society of Clinical Oncology Virtual Annual Meeting, Dr. Axel Bex and colleagues presented the design of the Phase III, double-blind CheckMate 914 study which will evaluate NIVO and NIVO+IPI vs. placebo in pts with a high risk of relapse after nephrectomy.

As registered with (NCT03138512), the CheckMate 914 trial is comprised of patients who underwent radical or partial nephrectomy with negative surgical margins at least four weeks and less than 12 weeks prior to randomization with a targeted accrual of 1,600 patients.

Key pathologic inclusion criteria include:

1. Predominantly clear cell histology

2. Pathologic TNM stage T2a (with high-grade disease, grade 3 or 4), T2b (any grade), T3 (any grade), or T4 (any grade) N0M0, or any patient with pN1M0 disease, regardless of primary tumor stage or grade

3. Tumor tissue obtained ≤ 3 months pre-enrollment

Other key inclusion criteria include Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and no clinical or radiological evidence of macroscopic residual disease or distant metastases post-nephrectomy.

Key exclusion criteria include the following:

1. Conditions requiring corticosteroid or immunosuppressive systemic treatment

2. Autoimmune disease

3. Prior treatment with drugs specifically targeting T-cell co-stimulation or checkpoint pathways

4. Prior systemic treatment for RCC

This trial is designed with two parts. In the first (part A), patients are randomized in a 1:1 fashion to NIVO+IPI or placebo. In the second (part B), patients are randomized in a 1:1:2 fashion to NIVO+IPI, placebo, or NIVO alone. Randomization is stratified according to TNM staging and surgical approach (partial vs. radical nephrectomy).

All treatments are given for 24 weeks or until disease recurrence, unacceptable toxicity, or withdrawal of consent.

checkmate 914 study design

The primary outcome is disease-free survival according to blinded independent central review. This will be analyzed separately for each part A with the expected completion of part A in August 2022 and of part B in July 2024. (part A: NIVO+IPI vs. placebo; part B: NIVO vs. placebo). Key secondary outcomes include overall survival.

Presented by: Axel Bex, MD, PhD, Consultant Clinical Lead Specialist, Centre for Kidney Cancer, Associate Professor UCL Division of Surgical and Interventional Science, The Royal Free London NHS Foundation Trust

Co-Authors: Paul Russo, Yoshihiko Tomita, Viktor Grünwald, Luz-Margarita Ramirez, Brent M. McHenry, Robert J. Motzer

Written by: Christopher J.D. Wallis, MD, PhD, Urologic Oncology Fellow, Vanderbilt University Medical Center, Nashville, Tennessee, Twitter: @WallisCJD, at the 2020 American Society of Clinical Oncology Virtual Annual Meeting (#ASCO20), May 29th-May 31st, 2020
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