Imagine a world where cancer doesn't just disappear after surgery—it stays gone for years, giving patients a real shot at long-term remission. That's the groundbreaking potential we're talking about with adjuvant pembrolizumab in clear cell renal cell carcinoma (ccRCC). But here's where it gets controversial: Is this immunotherapy a game-changer for everyone, or are there hidden risks we haven't fully explored? Stick around to dive into the latest findings that could reshape how we treat this aggressive kidney cancer.
Adjuvant pembrolizumab, the drug behind the brand Keytruda, has been showing lasting positive effects in patients with ccRCC who face a higher chance of the disease coming back. For those new to this, ccRCC is the most common type of kidney cancer, and 'adjuvant' means using the treatment after surgery to prevent recurrence. The good news from a major study called KEYNOTE-564 is that these benefits hold steady over time, with no unexpected safety issues popping up in the long run.
After tracking patients for an average of 69.5 months—ranging from about 5 to over 7 years—with data cut off on September 25, 2024, the study revealed that pembrolizumab significantly improved key outcomes compared to a placebo. Disease-free survival (DFS), which measures how long patients live without the cancer returning or progressing, was still not reached (meaning many were still doing well) in the pembrolizumab group of 496 patients. In contrast, the placebo group of 498 patients had a median DFS of just over 68 months. The hazard ratio (HR), a way to quantify the difference, was 0.71, showing a clear advantage for the immunotherapy. To put this in perspective, imagine DFS as the patient staying in remission—pembrolizumab helped them stay cancer-free longer, with estimated rates at 2, 3, 4, 5, and 6 years being 78.2%, 72.5%, 65.0%, 60.9%, and 58.5% respectively. For placebo, these rates were lower: 67.2%, 62.8%, 56.5%, 52.2%, and 48.7%.
Even better, overall survival (OS), which tracks how long patients live regardless of cancer recurrence, was also improved. The median OS wasn't reached in either group, but the HR of 0.66 indicated pembrolizumab's edge. Survival rates at those same time points were 96.3%, 93.9%, 91.2%, 87.7%, and 86.1% for pembrolizumab versus 93.9%, 89.5%, 86.0%, 82.3%, and 79.4% for placebo. This means patients on the drug were not only avoiding recurrence but living longer overall—a huge win for quality of life.
And this is the part most people miss: The treatment didn't just help in general; it consistently worked across different patient groups, including those with varying risk levels and even those with sarcomatoid features, which are aggressive cancer traits that make the disease harder to treat. For instance, in intermediate-high risk patients without distant metastases (M0 intermediate-high), the DFS HR was 0.75; for high-risk M0 patients, it was 0.61; and for those who'd had metastases removed but were now cancer-free (M1 NED), it dropped to 0.48. Even with sarcomatoid features, the HR was 0.56, compared to 0.75 without them. OS benefits followed suit, with notable improvements in intermediate-high risk (HR 0.71), high risk (HR 0.86), and M1 NED (HR 0.36) subgroups. Think of it like customizing a treatment plan—pembrolizumab seemed to adapt to different risk profiles, keeping survival curves separated early and sustaining that gap.
Beyond DFS and OS, pembrolizumab extended distant metastasis-free survival (DMFS), meaning it delayed cancer spreading to other organs, with a median not reached versus 80.7 months for placebo (HR 0.73). Time to recurrence was also prolonged, at a median not reached versus 80.9 months (HR 0.69). When cancer did return, patients in both groups received follow-up treatments at similar rates: about 64% in the pembrolizumab arm and 68% in the placebo arm got some systemic therapy, while 16-19% received no further treatment. Interestingly, more in the pembrolizumab group opted for surgery or radiation alone (19.3% vs. 13.3%), and fewer needed additional anti-PD(L)1 therapies (28.7% vs. 48.2%), suggesting the initial adjuvant approach might have set them up for success.
Now, let's talk about the study itself to understand the groundwork. KEYNOTE-564 was a randomized, double-blind, placebo-controlled phase 3 trial, the gold standard for testing new treatments. It included adults aged 18 and up with confirmed ccRCC who hadn't had systemic therapy for advanced disease. Eligibility focused on those at intermediate-high or high risk of recurrence, or those who'd had metastases removed and were now free of detectable disease (NED), all within 12 weeks of surgery like nephrectomy or metastasectomy. Patients were randomly split 1:1 to get pembrolizumab intravenously at 200 mg every 3 weeks for about a year (up to 17 cycles) or matching placebo. Treatment stopped if cancer recurred, side effects became unbearable, or the patient chose to quit. To ensure fairness, they accounted for factors like metastasis stage (M0 vs. M1 NED), performance status (how well patients could do daily activities), and geographic region.
The main goal was DFS, with OS and safety as secondary focuses, plus exploratory looks at DMFS and recurrence time. Early on, an interim analysis showed pembrolizumab's DFS benefit (HR 0.68), leading to FDA approval in November 2021 for adjuvant use in high-risk RCC patients post-surgery. As a quick example, this approval changed clinical practice by offering a new option where options were limited, potentially preventing recurrences that could shorten lives.
These 5-year results build on prior data presented at the 2025 ASCO Annual Meeting, emphasizing how the survival benefits endure. In an interview, oncologist Naomi B. Haas, MD, from the University of Pennsylvania's Abramson Cancer Center, highlighted the milestone: "This marks the longest follow-up for adjuvant immune checkpoint inhibitors (ICIs) like pembrolizumab, showing DFS and OS advantages across subgroups." She noted the early curve separation and robustness of the data, reinforcing pembrolizumab's role as a standard of care.
But here's where it gets controversial: Did the long-term follow-up uncover any hidden dangers? The study affirms pembrolizumab's safety profile, with treatment lasting a median of 11.1 months and side effects in 79% of patients—18.6% severe (grade 3 or 4). Serious events hit 11.9%, leading to 18.2% discontinuing. Immune-related issues, like those from the body's overactive response, affected 36.7%, with 9.6% being severe, but no new problems emerged after 3 years. This stability is reassuring for beginners worried about immunotherapy's potential for autoimmune-like side effects, such as thyroid issues or skin rashes, which were managed without long-term surprises.
References:
1. Haas NB, Powles T, Tomczak P, et al. Five-year follow-up results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab for the treatment of clear cell renal cell carcinoma. Presented at: Society of Urologic Oncology Annual Meeting; December 2-5, 2025; Phoenix, Arizona. Poster #158.
2. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. News release. FDA; November 17, 2021. Accessed December 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma
3. Haas NB, Powles T, Tomczak P, et al. Five-year follow-up results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab (pembro) for the treatment of clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2025;43 (suppl 17):4514. doi:10.1200/JCO.2025.43.16_suppl.4514
4. Chan A. 5-year analysis of KEYNOTE-564 reinforces role of adjuvant pembrolizumab as SOC in ccRCC: Q&A with Naomi B. Haas, MD. OncLive.com. June 24, 2025. Accessed December 4, 2025. https://www.onclive.com/view/5-year-analysis-of-keynote-564-reinforces-role-of-adjuvant-pembrolizumab-as-soc-in-ccrcc
5. Haas NB. Dr Haas on the rationale for evaluating adjuvant pembrolizumab in clear cell RCC. OncLive.com. September 2, 2025. Accessed December 4, 2025. https://www.onclive.com/view/dr-haas-on-the-rationale-for-evaluating-adjuvant-pembrolizumab-in-clear-cell-rcc
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What do you think—should pembrolizumab be the go-to adjuvant therapy for all high-risk ccRCC patients, or do cost, accessibility, and potential side effects make it too controversial? And is the lack of new safety signals enough to quell worries about long-term risks in immunotherapy? We'd love to hear your opinions—agree, disagree, or share your own experiences in the comments below!
