Editor's Note: For patients with kidney cancer who undergo radical surgery, reducing the risk of postoperative recurrence, prolonging disease-free survival, and ultimately improving overall survival have long remained key clinical priorities. In recent years, postoperative adjuvant therapy for kidney cancer has evolved from investigations of targeted therapies to breakthroughs with immunotherapy and, more recently, combinations of immunotherapy with novel targeted agents. However, because adjuvant therapy is administered to patients with no radiographically evident disease, accurately identifying microscopic residual disease, selecting patients most likely to benefit, and balancing efficacy against toxicity remain major challenges in clinical practice. Oncology Frontier · UroStream invited Professor Liangyou Gu of the Chinese PLA General Hospital for an in-depth interview to discuss major advances in postoperative adjuvant therapy for kidney cancer, strategies for identifying patients most likely to benefit, and future directions in the field.From Long-Term Exploration to Survival Benefit: Adjuvant Therapy for Kidney Cancer Reaches an Important Breakthrough
Oncology Frontier · UroStream: In recent years, the field of postoperative adjuvant therapy for kidney cancer has continued to advance, with treatment evolving from conventional targeted therapies toward immunotherapy. Could you introduce some of the most important developments in this field?
Professor Liangyou Gu: Among patients with kidney cancer, a proportion remain at high risk of recurrence and metastasis even after radical surgery. In clear cell renal cell carcinoma (ccRCC), clinical risk is generally assessed according to tumor stage, nuclear grade, lymph node status, sarcomatoid differentiation, and whether the patient has achieved an M1 no evidence of disease (M1 NED) status following complete resection of metastatic lesions.
For example, patients with pT2 disease accompanied by grade 4 nuclear features or sarcomatoid differentiation, pT3–pT4 disease, regional lymph node-positive disease, and M1 NED are all considered populations requiring particular attention after surgery. Without postoperative treatment, the five-year risk of recurrence in these patients may be approximately 30%–60%. Historically, there were no clearly effective interventions for these patients, and postoperative management mainly consisted of surveillance and follow-up. Therefore, reducing recurrence through adjuvant therapy has long been an important research question in kidney cancer.
Early research into postoperative adjuvant therapy for kidney cancer primarily focused on antiangiogenic targeted therapies. Some studies suggested that sunitinib could improve disease-free survival, but results were not entirely consistent across studies, and a clear overall survival benefit was not established. In addition, treatment-related adverse events were considerable. Consequently, adjuvant targeted therapy did not become a broadly accepted and uniform standard of care worldwide.
The truly landmark breakthrough came from the KEYNOTE-564 study. This phase III trial enrolled patients with ccRCC at increased risk of recurrence after surgery and compared adjuvant pembrolizumab with placebo. The study first demonstrated a significant disease-free survival benefit with pembrolizumab and subsequently confirmed an overall survival benefit. At a median follow-up of 57.2 months, the 48-month overall survival rates were 91.2% with pembrolizumab and 86.0% with placebo, corresponding to a 38% reduction in the risk of death. This was the first phase III study in the adjuvant kidney cancer setting to demonstrate a statistically significant overall survival improvement with immunotherapy, establishing pembrolizumab as an important adjuvant treatment for patients with high-risk ccRCC.
At the same time, it is important to recognize that different immune checkpoint inhibitors and treatment strategies have not produced consistent results. In CheckMate 914, neither nivolumab plus ipilimumab nor nivolumab monotherapy significantly improved disease-free survival. Similarly, the IMmotion010 and PROSPER studies failed to meet their primary endpoints. Therefore, the success of KEYNOTE-564 cannot simply be extrapolated to all immunotherapies or all perioperative treatment strategies.
More recently, adjuvant treatment has evolved further from immunotherapy monotherapy toward combination approaches. The phase III LITESPARK-022 study, reported in 2026, compared pembrolizumab plus the HIF-2α inhibitor belzutifan with pembrolizumab alone. The combination significantly improved disease-free survival, with 24-month disease-free survival rates of 80.7% and 73.7%, respectively, corresponding to a 28% reduction in the risk of recurrence or death.
However, overall survival data from the study remain immature, and the incidence of grade 3 or higher adverse events was higher with the combination than with pembrolizumab monotherapy. Therefore, while this study provides new evidence supporting intensified adjuvant treatment, further follow-up and clinical validation are needed to determine its long-term survival benefit and establish the optimal balance between recurrence risk, treatment intensity, and toxicity.
Overall, postoperative adjuvant therapy for kidney cancer has moved from an era of surveillance, in which there were essentially no effective systemic options, into a new stage centered on immunotherapy, with combination strategies continuing to expand. Yet as treatment options increase, an even more important question emerges: Which patients truly require adjuvant therapy? Who can benefit from monotherapy? Who may require intensified combination treatment? And which patients can safely undergo active surveillance? These are the fundamental questions that precision adjuvant therapy must address.
Beyond Conventional Staging: Using Biomarkers to Identify Microscopic Residual Disease
Oncology Frontier · UroStream: In clinical practice, how should we identify patients most likely to benefit from adjuvant immunotherapy after kidney cancer surgery and make treatment decisions more individualized?
Professor Liangyou Gu: This is one of the most important and challenging questions in current clinical practice. Existing studies have demonstrated that some patients at high risk of recurrence benefit from adjuvant therapy. However, not every patient meeting clinical trial eligibility criteria will necessarily relapse, and not every patient requires treatment of the same intensity.
Currently, clinical risk assessment primarily relies on T stage, N stage, nuclear grade, sarcomatoid differentiation, tumor necrosis, and a history of metastatic disease. This approach is practical and remains an important basis for selecting adjuvant treatment. Fundamentally, however, pathological risk stratification is an indirect way of estimating whether microscopic residual disease remains in the patient’s body that cannot yet be detected by conventional imaging.
The patients who truly require adjuvant therapy should be those with residual micrometastatic or molecular disease after surgery. If a patient has actually been cured by surgery, adjuvant therapy may only expose them to toxicity, financial burden, and immune-related adverse events without providing additional benefit. Therefore, clinical staging alone is insufficient for truly precise treatment, and we need more sensitive and direct biological tools.
One promising biomarker is kidney injury molecule-1 (KIM-1). KIM-1 is a transmembrane protein whose extracellular domain can enter the circulation, making it detectable in plasma. Previous studies have suggested that circulating KIM-1 levels may be associated with tumor burden, postoperative recurrence risk, and clinical outcomes in kidney cancer.
An exploratory analysis of the IMmotion010 study found that higher circulating KIM-1 levels were associated with poorer disease-free survival. Among patients with high KIM-1 expression, atezolizumab showed a trend toward improved disease-free survival compared with placebo, whereas a similar signal was not observed in patients with low KIM-1 expression. These findings suggest that KIM-1 may have both prognostic and predictive potential. However, these remain exploratory findings, and KIM-1 cannot currently be used alone to determine whether a patient should receive adjuvant immunotherapy.
Another important area is circulating tumor DNA (ctDNA). At the 2026 ASCO Annual Meeting, ctDNA analyses from KEYNOTE-564 were reported. Depending on the detection method, approximately 5.4%–8.2% of patients were ctDNA-positive at baseline after surgery. Although the positivity rate was relatively low, ctDNA-positive patients had significantly poorer disease-free survival, suggesting that ctDNA has considerable potential for recurrence-risk stratification.
The study also found that ctDNA clearance occurred more frequently among patients receiving pembrolizumab than among those receiving placebo, and dynamic changes in ctDNA were associated with disease-free survival. However, the major limitation of current detection methods is their relatively low sensitivity despite high specificity. In other words, ctDNA positivity often indicates a high risk of recurrence, but a negative ctDNA result cannot reliably exclude microscopic residual disease. Therefore, at present, we cannot simply conclude that a patient does not need adjuvant therapy because their ctDNA test is negative.
This also reflects the unique biology of kidney cancer. Compared with some other solid tumors, kidney cancer generally releases relatively small amounts of tumor DNA into the peripheral circulation. This is particularly problematic after surgery, when tumor burden is low and ctDNA detection may frequently yield negative results. Future approaches may therefore need to improve detection depth, expand mutation coverage, or integrate tumor tissue information to increase sensitivity.
I believe that future precision stratification is unlikely to depend on a single biomarker. Instead, we will probably develop multidimensional models integrating clinicopathological characteristics, KIM-1, ctDNA, genomic features, the tumor immune microenvironment, and imaging findings. Only by combining these complementary sources of information can we more accurately identify patients with genuine microscopic residual disease and determine who is suitable for active surveillance, immunotherapy monotherapy, or intensified combination treatment.
Three Key Directions: Moving Adjuvant Therapy from “Broad Intervention” to “Precision Matching”
Oncology Frontier · UroStream: Looking ahead, what research directions and potential breakthroughs in postoperative adjuvant therapy for kidney cancer deserve particular attention?
Professor Liangyou Gu: I believe there are three major areas that deserve particular attention.
First, we need to further refine patient selection and biomarker-guided treatment strategies. As evidence continues to accumulate for pembrolizumab monotherapy and pembrolizumab plus belzutifan, clinical decision-making will move beyond the simple question of whether to treat. We will increasingly need to determine what intensity of treatment is appropriate for each individual patient.
Future studies should explore risk-adapted clinical trials based on ctDNA, KIM-1, and other molecular biomarkers. For example, should patients with clearly detectable molecular residual disease and an extremely high risk of recurrence receive intensified combination therapy? Could treatment intensity be reduced or surveillance strengthened in patients who are clinically high risk but remain persistently negative for molecular biomarkers? For patients whose biomarkers fail to clear after treatment, should therapy be modified or prolonged? These are key questions that precision adjuvant therapy must answer.
Second, we need to expand the evidence base for adjuvant therapy in non-clear cell renal cell carcinoma. The major positive adjuvant therapy studies to date have primarily focused on ccRCC. Papillary RCC, chromophobe RCC, collecting duct carcinoma, and other non-clear cell subtypes have distinct molecular characteristics, natural histories, and treatment sensitivities, and the findings from ccRCC cannot simply be extrapolated to them.
Some non-clear cell subtypes are highly aggressive and carry substantial postoperative recurrence risks, yet dedicated prospective evidence for adjuvant therapy remains limited. Future research should involve multicenter collaborative studies based on histological and molecular subtyping, while basket trials and platform trials could improve research efficiency and help establish more reliable evidence for these relatively uncommon kidney cancer subtypes.
Third, molecular imaging should be further developed for postoperative recurrence-risk assessment and the detection of microscopic residual disease. Conventional CT and MRI primarily rely on lesion morphology and size and therefore have limited ability to detect cellular or molecular-level micrometastatic disease.
Promising progress has been made with molecular imaging probes targeting carbonic anhydrase IX (CAIX) and CD70, both of which are associated with ccRCC. For example, CAIX-targeted PET/CT has demonstrated encouraging lesion-detection capabilities in ccRCC diagnostic studies, while CD70-targeted immuno-PET/CT has shown potential for identifying metastatic kidney cancer lesions in early clinical research.
If these technologies can further improve their ability to detect low-volume and microscopic lesions, they may eventually enable clinicians to identify patients with residual tumor before conventional imaging demonstrates clear evidence of recurrence. This concept has some similarities to the development of PSMA PET/CT in prostate cancer.
In the future, molecular imaging may not only be used to localize recurrent disease but could also be integrated with liquid biopsy, pathology, and molecular profiling to establish a more comprehensive system for assessing microscopic residual disease. It may ultimately help guide adjuvant treatment decisions, monitor therapeutic response, and even inform targeted radioligand therapy.
Overall, postoperative adjuvant therapy for kidney cancer has moved beyond the initial question of “Does treatment provide a benefit?” and is entering a more precise phase focused on “Who needs treatment, which regimen should be selected, how long should treatment continue, and how should therapy be dynamically adjusted?”
The next major breakthroughs will come not only from new drugs and combinations, but also from more accurate patient selection, more sensitive detection of residual disease, and more scientifically informed management of treatment intensity. Ultimately, the goal is to ensure that patients at high risk of recurrence receive timely and effective intervention, while avoiding unnecessary treatment in patients who have already been cured by surgery—maximizing oncological benefit while minimizing toxicity and impairment of quality of life.
Professor Liangyou Gu
