KEYNOTE-564, CheckMate 9ER, and More: Where Do We Stand With Advanced and Metastatic RCC?

Thomas Powles, MBBS, MRCP, MD, Barts Cancer Centre, gives his expert, unique feedback on some of the landmark kidney cancer clinical data presented during oral sessions at the American Society of Clinical Oncology Genitourinary Cancer Symposium 2024, including what to make of the long-term KEYNOTE-564 analysis, the future of adjuvant treatment approaches, and how the frontline combination options should be compared moving forward for advanced disease.

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What are your overall thoughts on KEYNOTE-564? Are these results as monumental as they seem?

Dr. Powles: I believe it is a topic currently under debate within the community. I view the data as groundbreaking. We have achieved a milestone with the introduction of overall survival data, marking a significant shift. Previously, while demonstrating statistically significant and clinically meaningful disease-free survival, we lacked overall survival data. Even in the initial stages, the trend was positive, with an OS ratio of 0.53 at the first data cut. Though the absolute difference in events was relatively small due to the limited number of events, the trend was evident.

So, when these recent data emerged, it was not surprising that we achieved overall survival, given the previous trends. However, it is undeniably significant that we now have statistically significant overall survival results. This changes the conversation with patients. Previously, we discussed reducing cancer recurrence risk by approximately 40%, without certainty on prolonged survival. Now, with these results, we can confidently say there is a substantial increase in the likelihood of prolonged survival. Consequently, I anticipate more patients opting for this treatment, likely increasing from 50% to around 70%.

How do we better select patients for adjuvant pembrolizumab, and how does this study open the door for investigating other adjuvant treatment approaches?

Dr. Powles: Patient selection for adjuvant therapy has been a challenge. During Dr. Choueiri’s presentation, questions arose regarding overtreatment of patients unlikely to relapse. However, even with this, more patients remain alive overall, emphasizing the need to identify higher-risk groups more effectively. It is imperative to avoid treating low-risk patients unnecessarily.

Enhancing patient selection requires exploring tools like circulating and tissue-based biomarkers to identify those at higher risk of relapse. This study marks the initial step in a journey toward refining patient selection. I believe in the future, we will develop biomarkers to tailor treatment more precisely. Those urging caution in interpreting the data are essentially advocating for better patient identification, a crucial aspect. Early intervention with immunotherapy in at-risk patients is vital, given the challenges encountered during treatment journeys. While not all patients receive all available therapies, identifying and treating those at risk early can be curative, particularly in the adjuvant setting. As the dialogue shifts from speculation to certainty regarding survival benefits, it is essential for the medical community to consider the implications for patient care carefully.

In the upfront setting, how does the nivo/cabo data from CheckMate 9ER fair in previously untreated advanced kidney cancer, and how does this regimen compare to other options?

Dr. Powles: To me, the various regimens appear similar. Instead of fixating on the choice between specific combinations like nivo/cabo versus len/pembro, we should emphasize managing toxicity and optimizing patient care throughout the treatment journey. Questions surrounding when to discontinue treatment or manage adverse events are paramount. The choice between these regimens seems less critical than ensuring optimal use of whichever is selected. Each combination has its nuances; for instance, nivo/ipi may offer less immediate disease control, while VEGF-TKIs pose long-term challenges. However, overall survival outcomes are comparable across these regimens. Hence, my advice to the clinical community is to select one regimen and administer it effectively, backed by a knowledgeable team providing comprehensive support.

Do you believe the research into these combination approaches should focus less on survival outcomes and more on TRAEs and PROs moving forward?

Dr. Powles: I do. Questions surrounding treatment duration, toxicity management, and patient-reported outcomes are more pertinent than comparing survival outcomes between these combinations. We need clarity on when to cease or modify treatment based on adverse events and how to manage patients experiencing toxicity while exhibiting positive treatment responses. These questions hold more significance than comparing survival data across regimens.