Panel Discussion on OS Data From KEYNOTE-564 Study and Post-Relapse Treatment Selection

A roundtable discussion, moderated by Rana McKay, MD, discussed the latest updates in frontline treatment for renal cell carcinoma, including how data from the American Society of Clinical Oncology Genitourinary Cancers Symposium 2024 alters the treatment paradigm. Dr. McKay was joined by Nizar Tannir, MD; Hans Hammers, MD; and Katy Beckermann, MD.

In the third segment of the roundtable series, the panel discussed the groundbreaking OS results from the KEYNOTE-564 study and implications for their practice.

Watch the next segment in this series.

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Dr. McKay: We have spent a lot of time discussing our current position in treatment selection, including topics like metastasectomy and cytoreductive nephrectomy. Let us delve into the data presented. There was a substantial amount discussed, so we will go through it step by step. Let us start with localized treatment. I believe the most significant data presented during the entire meeting was from the KEYNOTE-564 trial.

Dr. Beckermann, perhaps you could begin by providing an overview of the study and its primary data.

Dr. Beckermann: It was indeed exciting to review the data from the KEYNOTE-564 trial today. This marks the first adjuvant trial in years to offer both disease-free survival (DFS) and overall survival (OS) data. It is truly an exciting prospect for our patients as we strive to cure more individuals. Our primary goal is always to enhance patient outcomes, and utilizing immunotherapy in an earlier treatment setting aligns with this objective. The observed separation in survival curves was particularly compelling, indicating a clear signal of efficacy. There were extensive discussions following this presentation, and I look forward to hearing insights from my colleagues here.

Dr. Pedro Barata provided an insightful discussion on the multifactorial challenges encountered, highlighting the complexity in patient selection for adjuvant treatment. Moving forward, it is crucial that we design trials with a focus on minimal-risk disease or gain a better understanding of tissue biology to effectively identify suitable candidates. Nevertheless, I commend the entire team for achieving positive outcomes in both DFS and OS, and I am eager to further our understanding in this area.

Dr. McKay: Absolutely, this is a landmark moment not only in genitourinary medical oncology but also across all malignancies. It represents the first positive adjuvant trial demonstrating an improvement in OS with immune checkpoint inhibitors. How do you interpret this data, and how will we implement it in practice?

Hans Hammers: One critical aspect to consider is the design of the study. For instance, in the landmark melanoma trials, access to pembrolizumab was ensured for all participants, regardless of their allocation to the placebo arm. Unfortunately, this wasn’t the case in the KEYNOTE-564 study. Less than 50% of patients in the control arm received immune checkpoint inhibitors upon progression. This discrepancy raises questions regarding the real-world applicability of the observed survival benefits, especially when comparing outcomes between different regions. Additionally, in societies with widespread access to immunotherapy, the OS benefit may not be as pronounced, given the potential curative effects of immunotherapy across disease stages. Therefore, it’s premature to universally recommend adjuvant immunotherapy without further data clarification. We need a comprehensive understanding of patient selection criteria to optimize treatment outcomes.

Dr. McKay: Indeed, the historical context is vital. Before immune checkpoint inhibitors, median survival was considerably shorter. However, with the advent of these agents, we have seen substantial improvements. Yet, we must scrutinize the data rigorously, especially regarding the percentage of patients receiving treatment in both arms. This scrutiny will be pivotal in determining the true clinical significance of the observed OS benefit.

Dr. Hammers: Absolutely. Another intriguing aspect is the subset of patients who received post-treatment surgical or radiation interventions. Understanding the characteristics of these patients, such as whether they had oligometastatic disease or local recurrences, will provide valuable insights into treatment strategies moving forward.

Dr. Tannir: Approximately 25% to 30% of patients received some form of local therapy post-treatment. Dr. Toni Choueiri highlighted that among these patients, some with favorable risk profiles experienced relapse, necessitating further intervention. However, concerns arise when patients relapse while on adjuvant pembrolizumab therapy, as observed in clinical practice. This prompts questions about the subsequent management of these patients and whether they should be considered for more aggressive therapeutic approaches.

Dr. McKay: Determining the appropriate course of action for patients experiencing relapse during or shortly after adjuvant pembrolizumab therapy is indeed challenging. Currently, we lack a standardized definition for immune checkpoint inhibitor resistance in RCC. We must establish clear criteria to guide treatment decisions and incorporate this knowledge into future studies.

Dr. Hammers: Agreed. It is essential to manage patient expectations regarding treatment outcomes accurately. Additionally, exploring alternative immune checkpoint inhibitors, such as CTLA-4 inhibitors, may offer viable options for patients who exhibit resistance to PD-1 therapy. While these alternatives may not benefit the majority of patients, they could prove effective in select cases, thereby expanding our therapeutic repertoire.

Dr. Beckermann is exploring ongoing trials on novel modalities, such as ADA inhibitors, that may hold promise for enhancing treatment efficacy in RCC. As PD-1 remains a foundational component of our treatment approach, we must continue investigating complementary therapies to optimize patient outcomes.

PD-1 therapy has revolutionized RCC treatment, but it is evident that a singular approach may not suffice for all patients. By integrating additional modalities and refining our patient selection criteria, we can continue advancing treatment strategies in RCC.