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RCC Outcomes Optimization

CE / CME

Optimizing Outcomes for Patients With RCC

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: April 07, 2023

Expiration: April 06, 2024

Katy Beckermann
Katy Beckermann, MD, PhD
CME/CE Information

Activity

Progress
1
Course Completed

Trials of Tyrosine Kinase Inhibitors as Adjuvant Treatment in RCC

Numerous adjuvant clinical trials have been performed with various TKIs, including sunitinib, sorafenib, pazopanib, and axitinib all compared with placebo in patients who underwent nephrectomy with curative intent and had staging or other risk factors that were concerning for recurrence.1-7 Of note, only 1 trial—the S‑TRAC trial of sunitinib vs placebo—yielded positive results; it was positive for DFS but did not show an overall survival (OS) benefit.2,3 Researchers have continued investigations to improve on this data and increase the chance for cure for patients who are undergoing nephrectomy and have the risk of recurrence. 

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KEYNOTE-564: Adjuvant Pembrolizumab vs Placebo for ccRCC

Checkpoint inhibition is the backbone of therapy in the frontline setting for metastatic clear cell RCC. A logical next step is to investigate if checkpoint inhibition could be used in the adjuvant setting. The phase III KEYNOTE‑5648,9 study randomized nearly 1000 patients to receive either adjuvant pembrolizumab (a PD-1 inhibitor) or placebo. The primary endpoint was DFS, and the secondary endpoint was OS. 

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KEYNOTE-564: Eligibility Criteria

The KEYNOTE-5648,9 study tried to identify those with high risk of recurrence. Patients were eligible for this study if they had intermediate- to high-risk disease including pT2 with grade 4 or sarcomatoid differentiation, pT3 or pT4 any grade, or any pT with node‑positive disease, as well as M1 NED with resection 1 year from nephrectomy.

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KEYNOTE-564 30-Mo Follow-up: DFS (Primary Endpoint)

The 30-month follow‑up for DFS showed 78.3% of patients who received pembrolizumab with DFS at 24 months vs 67% who received placebo (HR: 0.63; 95% CI: 0.50-0.80; P <.0001).8,9 

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KEYNOTE-564 30-Mo Follow-up: DFS by Recurrence Risk

A subgroup analysis was performed that looked at DFS by recurrence risk: intermediate-high risk, high risk, and M1 NED. This subgroup analysis was not powered for this comparison, but as the risk of recurrence increases, there is a larger separation of the curves for adjuvant pembrolizumab vs placebo.8,9 The 24-month DFS rate for pembrolizumab vs placebo was 81.1% vs 72.0% in the intermediate-high‒risk group, 48.7% vs 35.4% in the high-risk group, and 78.4% vs 37.9% in the M1 NED group.

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KEYNOTE-564 Subgroup Analysis: DFS by UISS Risk Group and Disease Stage

At the 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, results of another subgroup analysis of different risk assessments were reported: the UCLA Integrated Staging System, the American Joint Committee on Cancer staging system, and the TNM staging system. Some groups are quite small, but the trend tends to favor pembrolizumab in this adjuvant trial across subgroups.10 

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KEYNOTE-564 30-Mo Follow-up: Overall Survival

We hope that an improvement in DFS will translate to an improvement in OS. After 30 months of follow-up, only 66 OS events have occurred between the 2 groups. It is too early to make any conclusions on clinical implications from this, but we will continue to look forward to seeing what that future data show.9

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Trials of Immunotherapy in Nonmetastatic RCC

Three other clinical trials also are assessing if checkpoint inhibition in the adjuvant or neoadjuvant setting could help increase the chance for cure and improve DFS. PROSPER11 looked at both a neoadjuvant and adjuvant design and compared nivolumab (PD-1 inhibitor) with observation in patients with planned nephrectomies. The IMmotion trial12 was adjuvant only, and instead of PD‑1 inhibition, as in the KEYNOTE-564 trial, it looked at atezolizumab, which is a PD‑L1 inhibitor. Lastly, CheckMate 91413 looked at the combination of a PD‑1 inhibitor and a CTLA-4 inhibitor using nivolumab and ipilimumab in the adjuvant setting. All of these studies have slightly different inclusion criteria and approaches (eg, histology, adjuvant only vs neoadjuvant/adjuvant). 

IMmotion12 and CheckMate 91413 have both been published and did not show DFS or OS benefits. PROSPER11 results have been orally presented and, similarly, did not show DFS or OS improvement. Numerous conversations are happening in the field about why this might be the case. 

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Who Should Get Adjuvant Treatment?

Based on the available evidence in this setting, clinically, when I see a patient who has T3 high risk, T4, lymph node positive, or M1 NED and is within 1 year of surgical resection, I consider adjuvant therapy. It is certainly an individualized patient decision that involves consideration of patient comorbidities, goals, and a thorough consenting process to ensure that the patient understands the risks with treatment, such as potentially irreversible irAEs. 

You are discussing adjuvant therapy for RCC with your fellow in clinic and are reviewing the phase III KEYNOTE-564 study of pembrolizumab vs placebo as adjuvant therapy in clear cell RCC. Which of the following patient populations would you tell her had the largest absolute difference in 24-month disease-free survival (DFS) with pembrolizumab vs placebo?

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