Navigating Adjuvant and Neoadjuvant Therapy in RCC

In an interview with Targeted Oncology, Naomi Haas, MD, discusses the evolving landscape of adjuvant and neoadjuvant immune checkpoint inhibitor therapy in renal cell carcinoma (RCC), patient selection, shared decision-making, and emerging clinical trials shaping the field.

Dr Haas is a professor of medicine at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, where she specializes in genitourinary malignancies with a particular focus on renal cell carcinoma (RCC). She also serves on the American Society of Clinical Oncology (ASCO) guideline panel for RCC.

Targeted Oncology: How would you characterize the optimal patient who should be offered adjuvant therapy in RCC, and how do we avoid overtreating them?

Naomi Haas, MD: When I speak with patients, I try to inform them about all of the trials in the adjuvant setting using immune checkpoint inhibitors that have been conducted so far. We know there are currently three adjuvant trials that have shown efficacy, at least for relapse-free survival. Two of them used pembrolizumab (Keytruda) as a backbone, and the third used the combination of durvalumab (Imfinzi) with tremelimumab (Imjudo), which was presented at the Fall 2025 European Society of Medical Oncology Congress.^1-3

When thinking about the highest-risk population, I focus on the patient populations included in those clinical trials where there was demonstrated benefit. The only setting with an overall survival benefit so far is the KEYNOTE-564 (NCT03142334) trial. That population included patients with pathologic tumor stage pT2 with high nuclear grade (grade 3 to 4) and tumors greater than 7 centimeters in the American Joint Committee on Cancer staging system, extending up to the M1 NED population — patients who had undergone metastatectomy within a year of primary tumor resection.

I do caution against assuming the M1 NED patient population might be undertreated simply because they technically have metastatic disease. The number of M1NED patients included in these studies was small; nevertheless, they did fit within the trial guidelines, and some colleagues include them in the population offered adjuvant therapy.

What about the distinction between clear cell and non-clear cell histology — how does that factor into adjuvant therapy decisions?

The non-clear cell population that we know would benefit from immune checkpoint inhibitor therapy includes patients with sarcomatoid histology. In KEYNOTE-564 and many other adjuvant trials, patients with predominantly sarcomatoid features were listed as “unclassified.” The FDA approval label is broad — it does not specify clear cell or non-clear cell. However, I caution people that there is really no data in the adjuvant setting for non-clear cell histology beyond the sarcomatoid subgroup.

There is an Eastern Cooperative Oncology Group trial, ECOG 8292, set to launch in about two months, which will examine adjuvant pembrolizumab for 1 year versus close surveillance in the non-clear cell population to help answer that question. In general, I do not recommend adjuvant therapy off study for non-clear cell RCC outside of sarcomatoid features.

Pembrolizumab is FDA-approved in the adjuvant setting. How do you decide between observation and treatment, given that not all patients relapse?

That is one of the most difficult questions. Looking at the recurrence-free survival curves and overall survival data, a large proportion of patients would never relapse — and some will relapse even with adjuvant therapy. This is where there is great interest in developing new biomarkers.

One very interesting biomarker being investigated is kidney injury molecule-1 (KIM-1), which is a simple and relatively inexpensive blood test. It has been studied in the ASSURE trial (NCT00326898)⁴ — a trial that did not show a benefit for adjuvant targeted therapy — and in IMmotion010 (NCT03024996), which evaluated adjuvant atezolizumab (Tecentriq).

In both cases, KIM-1 levels measured before treatment appeared to separate patients at higher risk of relapse from those who might benefit. That said, these are aspirational; there is not yet a CLIA-certified lab making this clinically usable.

In practice, the decision comes down to shared decision-making. I walk patients through all of the adjuvant trials, including those that showed no benefit, and I go through potential side effects carefully. Patient preference plays a significant role. Some patients are very concerned about toxicity, while others are primarily worried about relapse — and they tend to self-select accordingly. I also consider comorbidities that would make immune checkpoint inhibition risky, such as rheumatoid arthritis or inflammatory bowel disease, and I assess overall health and life expectancy before recommending a year of adjuvant therapy.

How do you frame the risk-benefit discussion of adjuvant therapy for a patient who has just completed nephrectomy and feels cured?

I talk to them about the overall benefit: roughly a 7% improvement in overall survival and a somewhat greater improvement in disease-free survival. I also make sure they understand that while single-agent adjuvant immune checkpoint inhibitor therapy has generally been well-tolerated, there are some potentially permanent side effects.

For example, patients can develop hypophysitis, where the pituitary gland is affected — that would require them to be on steroids permanently. Hyper- or hypothyroidism can also be irreversible, requiring lifelong thyroid medication. Insulin-dependent diabetes is another serious possibility that does not go away. And while rare, severe events like myocarditis can occur.

I stress that most patients will not experience these complications, but that when they do occur, they can be serious. What I have found interesting is how patients self-select: some are far more concerned about side effects, while others are most worried about relapse. I suspect it depends on their current health situation and what they are willing to accept.

What is the current evidence for neoadjuvant therapy in RCC, and is it ready for routine community practice?

The trials conducted in the neoadjuvant setting have been relatively small. What we have demonstrated is that neoadjuvant therapy is feasible and reasonably safe. The only trial with a neoadjuvant component that was phase 3 is the PROSPER trial (NCT03055013),⁵ and unfortunately it did not show a benefit. That trial had a somewhat hybrid design — patients received 1 or 2 doses of nivolumab (Opdivo) prior to nephrectomy and then nine months of adjuvant nivolumab, while the comparator arm went straight to surgery with observation. It did not truly isolate the neoadjuvant contribution.

In my practice, the patients I consider for neoadjuvant therapy are those with unresectable disease who will need systemic therapy regardless. I discuss with them that if they have a really strong response, we may be able to bring them to surgery. That is a different paradigm from what most people think of as neoadjuvant treatment.

What would be your key takeaway message for the community oncologist when a patient with high-risk RCC presents after nephrectomy?

The key takeaway is to be transparent about the full landscape of adjuvant clinical trials — including those that did not show benefit — and to clearly explain both the potential side effects and the magnitude of benefit. Most importantly, truly listen to the patient. Give them time to formulate their questions and make sure those questions get answered. That is hard in a busy community practice where time is limited, but it is essential.

I also want to highlight the LITESPARK-022 (NCT05239728) trial,⁶ which I did not mention earlier. This trial evaluated adjuvant pembrolizumab in combination with belzutifan (Welireg), and it was presented at 2026 ASCO GU Cancers Symposium.

It did show a disease-free survival benefit, though overall survival data are not yet mature. There was a meaningful amount of toxicity in the belzutifan arm, and interestingly, the patients who derived the most benefit tended to have intermediate-high-risk disease rather than the highest-risk disease. That raises fascinating biological questions — similar to what we see in the metastatic favorable-risk population — about whether lower-grade tumors have more of an angiogenic signature that makes them particularly responsive.

There is also the question of whether additional clinical trials will be needed for FDA consideration of LITESPARK data, given that the study was conducted predominantly outside the United States, though it is the largest adjuvant RCC trial ever conducted.

Is there an important unanswered clinical question you think deserves more attention in the field?

Yes — and it is one that has not been well-addressed in the literature yet. The question is: do patients who experience significant toxicity and discontinue adjuvant therapy early still derive the same benefit as patients who complete the full year of treatment? It would be very valuable to go back to KEYNOTE-564 and examine whether patients who stopped treatment due to toxicity had similar outcomes — in terms of overall survival or recurrence-free survival — compared with those who completed therapy. That is a clinically meaningful question that I hope the field will address.

REFERENCES

1. Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390(15):1359–1371. doi:10.1056/NEJMoa2312695

2. Choueiri TK, Motzer RJ, Karam JA, et al. Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): the randomized phase 3 LITESPARK-022 study. J Clin Oncol. 2026;44(suppl 7):LBA418. doi:10.1200/JCO.2026.44.7_suppl.LBA418

3. Larkin J, Powles TB, Frangou E, et al. First results from RAMPART: an international phase III randomised-controlled trial of adjuvant durvalumab monotherapy or combined with tremelimumab for resected primary renal cell carcinoma (RCC) led by MRC CTU at UCL. Presented at ESMO Congress 2025; October 17–21, 2025; Berlin, Germany. Abstract LBA93

4. Haas NB, Manola J, Dutcher JP, et al. Adjuvant Treatment for High-Risk Clear Cell Renal Cancer: Updated Results of a High-Risk Subset of the ASSURE Randomized Trial. JAMA Oncol. 2017;3(9):1249-1252. doi:10.1001/jamaoncol.2017.0076

5. Allaf M, Kim SE, Harshman LC, et al. Phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients (Pts) with renal cell carcinoma (RCC) undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial. Ann Oncol. 2022;33(suppl_7):S808-S869. doi:10.1016/annonc/annonc1089

6. Choueiri TK, Motzer RJ, Karam JA, et al. Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): the randomized phase 3 LITESPARK-022 study. J Clin Oncol. 2026;44(suppl 7):LBA418. doi:10.1200/JCO.2026.44.7_suppl.LBA418