Recent updates to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for kidney cancer management reflect expanding evidence in support of tailored approaches based on histologic subtype and mark a shift toward broader accessibility of immunotherapy regimens in renal cell carcinoma (RCC), according to Moshe Ornstein, MD, MA.

On September 6, 2024, the NCCN released version 2.2025 of the guidelines, which further adjusts the recommendations made in version 1.2025, previously 

 In version 1.2025 pembrolizumab (Keytruda) was upgraded to a category 1 recommendation for adjuvant treatment in patients with clear cell histology in the stage II and III pathways. Additionally, ipilimumab (Yervoy) plus nivolumab (Opdivo) was highlighted as a preferred first-line regimen for favorable-risk patients with relapsed or stage IV disease.

Among the changes made for non–clear cell histology, lenvatinib (Lenvima) combined with pembrolizumab was introduced as a preferred regimen with a category 2A recommendation, and cabozantinib (Cabometyx) plus nivolumab was moved to the preferred regimens section.

“IO [immuno-oncology]/TKI combinations are a standard of care [SOC] in the [non–clear cell] setting, and these are both good options for patients,” said Ornstein, who is a medical oncologist in the Department of Hematology and Medical Oncology at Cleveland Clinic in Ohio. “The choice of treatment comes down to personal preference and interpretation of the data, but I’m glad to see these options available for patients and included in the NCCN guidelines, which makes them more accessible to patients.”

®, Ornstein highlighted ongoing research aimed at better understanding non–clear cell RCC subtypes to enable tailored treatment approaches, recent trials that led to the inclusion of select IO/TKI doublets in the NCCN guidelines, and the need for clinical trial prioritization for patients with these histologies.

: What has research shown about the makeup of makeup of RCC subtypes, and how could this allow for more tailor treatment approaches?

Historically, RCC has been broken down into clear cell vs non–clear cell [histologies]. One of the primary challenges with that [categorization] is that non–clear cell [RCC] is not 1 type of disease. There are different [types of] non–clear cell RCCs. There’s papillary, there’s chromophobe, there’s unclassified, there’s translocation, etc. Therefore, the primary unmet need in this space has been the identification of treatment options that are not just for all non–clear cell RCC [variants]. [We are] trying to better understand the biology of the individual non–clear cell subtypes and specific treatment recommendations that would be appropriate for each one.

It has been difficult, and lot of work has been done [to address this]. [For one], papillary RCC has been reclassified as this larger group that is potentially a MET-driven tumor. In chromophobe RCC, there are some

 mutations that may be more responsive to, for example, mTOR inhibition. There’s a lot of genomic work ongoing right now. The treatment paradigm seems to be a one-size-fits-all [approach] across the non–clear cell variants. Hopefully, as we develop more trials and a better understanding of the underlying biology of each variant, those treatments will be more tailored for specific subtypes.

What was the rationale for designating clinical trials and cabozantinib monotherapy as preferred options for non–clear cell RCC prior to recent developments?

Up until recently, the preferred regimens for non–clear cell histology in the NCCN guidelines were either a clinical trial or cabozantinib as monotherapy. The rationale for clinical trial enrollment was that this area has not been studied extensively in terms of large, randomized trials, and these patients tend to do poorly relative to patients with clear cell RCC. Therefore, enrolling onto a clinical trial with a novel therapy, novel mechanisms, or even approved agents [in RCC] that are being studied prospectively in the non–clear cell setting makes sense. The rationale for cabozantinib monotherapy really came from the phase 2 PAPMET study [NCT02761057],which investigated cabozantinib vs 3 other TKIs and demonstrated that cabozantinib was the TKI of choice as a monotherapy in papillary RCC. That became a standard and preferred regimen for non–clear cell histology.

What findings led to the inclusion of lenvatinib plus pembrolizumab and cabozantinib plus nivolumab in the NCCN guidelines for first-line non–clear cell RCC?

Fortunately, over the past couple of years, there have been prospective investigations in the non–clear cell setting of IO/TKI combinations that we’re familiar with from the clear cell setting. The largest of these studies was the phase 2 KEYNOTE-B61 trial [NCT04704219] that evaluated lenvatinib plus pembrolizumab, which is a regimen that we’re comfortable with in the clear cell setting, in all-comers in the non–clear cell space. The study included [patients with] papillary, chromophobe, unclassified, and translocation [histologies]. This was a large international study that enrolled 158 patients at the standard dosing of lenvatinib plus pembrolizumab. 

[The study] showed remarkable response rates of approximately 50% across [histologies], [although] the chromophobe subpopulation had a lower response rate closer to 35%. Even more impressive than that was the median progression-free survival [(PFS) data]. We’re used to seeing [a median PFS of] 10 or 11 months in this setting, but with lenvatinib and pembrolizumab, we saw a median PFS of 17.9 months. Overall survival [OS] had not yet been reached. This [combination of lenvatinib plus pembrolizumab] is a wonderful choice for patients with non–clear cell RCC regardless of [subtype]. KEYNOTE-B61 ultimately led to its inclusion as a preferred regimen in the NCCN guidelines.

Cabozantinib plus nivolumab is also included in the NCCN guidelines as a preferred regimen for non–clear cell RCC, which is based on data from a single-arm phase 2 study [NCT03635892]. [There are] a couple of differences between the cabozantinib/nivolumab study and [KEYNOTE-B61]. [In the phase 2 study of cabozantinib plus nivolumab], there was a chromophobe cohort that was closed early, so we don’t have a deep analysis of patients in [this subpopulation.] The study enrolled [47] patients, which is much smaller than the [KEYNOTE-B61 trial], and it evaluated the standard dosing of cabozantinib plus nivolumab in papillary, unclassified, [chromophobe], and translocation RCC. Here, the easiest number to keep in mind is also the [approximately] 50% [response rate achieved] by patients who received cabozantinib plus nivolumab in the first line. When we narrow it down to the papillary cohort, because that was the most common [histology] of the non–clear cell patients [n = 32], the response rate was 47%. The median PFS for the cohort at large was 12.5 months, and the median OS was 28 months. This is another terrific option for non–clear cell RCC. 

Given these recommendations, how do you decide between these potential options and clinical trial enrollment for patients with non–clear cell histologies?

We always view clinical trials as a priority. Even though we have better options now for non– clear cell RCC than we used to have, we still know that a lot of patients will not respond to treatment. These trials don’t tell us much about the specific biology behind these tumors. We might be talking about response rates of approximately 50% with approved agents, but we see response rates of 70% in the clear cell setting. We’re certainly hoping that clinical trials can improve on that.

The rationale to continue to pursue clinical trials in non–clear cell RCC, even with these options available, is to have randomized phase 3 data available to us, to conduct studies that are more biologically-driven towards specific subtypes, and to improve outcomes [with current SOC agents]. We’re very excited about these outcomes because they’re so much better than what we had historically, but there’s still a long way to go to get that response rate higher, the PFS longer, and ultimately, to improve upon the gold standard of survival.

What are the potential clinical implications of the NCCN recommendation for ipilimumab plus nivolumab as a preferred treatment option in favorable-risk clear cell RCC?

There was a very important update to the NCCN guidelines [regarding] the preferred regimen in favorable-risk clear cell RCC. Up until a couple of months ago, the way the NCCN guidelines were broken down was that the IO/TKI regimens of axitinib [Inlyta] plus pembrolizumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab were approved and preferred regimens across International Metastatic RCC Database Consortium [IMDC] risk groups. However, ipilimumab and nivolumab was only a preferred regimen in intermediate- and poor-risk RCC by IMDC criteria. This was because the primary end point in the phase 3 CheckMate 214 trial [NCT02231749], which ultimately led to the FDA approval of ipilimumab and nivolumab in clear cell RCC, was [evaluated] in intermediate- and poor-risk patients. That was one of the preferred options in the NCCN guidelines. With this recent update, ipilimumab plus nivolumab is an approved and preferred regimen for the IMDC favorable-risk population as well.

A lot of this [decision] has to do with prolonged follow-up from the CheckMate 214 study. When we look at the favorable-risk population in CheckMate-214, the outcomes for those patients with favorable risk who were treated with sunitinib [Sutent] were superior to those patients treated with ipilimumab plus nivolumab up until approximately 48 months. However, with approximately 100 months of median follow up, there was a crossing of the curves, and the survival curve now favors ipilimumab plus nivolumab in the favorable-risk population with a HR of 0.82. 

Looking at landmark OS after 72 months of median follow-up, 52% of patients treated with ipilimumab plus nivolumab are still alive vs 46% with sunitinib. When we look at these data after 90 months, that number is approximately 43% with ipilimumab plus nivolumab in the favorable-risk population compared with only 34% with sunitinib. As we see these additional follow-up data for favorable-risk patients treated with ipilimumab plus nivolumab, we’re seeing a shift within the guidelines to include it as a preferred regimen. It’s not the right treatment for all patients, obviously; patients who need [to achieve] a response and who might be symptomatic [could likely achieve] a better response rate with an IO/TKI regimen. [However], having this discussion and considering [the use of] IO/TKI and IO/IO regimens even in the favorable-risk group is important, and I’m certainly glad to see it included as a preferred regimen for favorable-risk clear cell RCC.

NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 2.2025. Accessed September 16, 2024. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

Articles

Moshe Ornstein, MD, MA, discusses the implications of updates to NCCN guidelines for the management of non–clear cell and clear cell renal cell carcinoma

NCCN Guideline Updates Expand IO/TKI Options and Precision Medicine Approaches in RCC 

the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology

 for the treatment of patients with kidney cancer include new recommendations for the treatment of those with advanced non–clear cell renal cell carcinoma (RCC), and future research and data could help inform more specific recommendations based on the subtype of disease within this histology, according to Bradley McGregor, MD.

In the updated guidelines, the combinations of lenvatinib (Lenvima) and pembrolizumab (Keytruda), as well as cabozantinib (Cabometyx) plus nivolumab (Opdivo), were moved to preferred regimens for those with metastatic stage IV or relapsed non–clear cell RCC.

 Other preferred recommendations for this subtype include cabozantinib monotherapy and clinical trials.

“In the future, we would like to break down [these recommendations] a little bit further. Hopefully, we will be able to think about not just histology but also genomics to try to pin down what therapy works best for each disease type. We have a lot of work to get there, but we're taking steps forward with each year that goes by,” said McGregor, who is a senior physician, the director of Clinical Research at the Lank Center for Genitourinary Oncology, and the Marra Lochiatto Investigator at Dana-Farber Cancer Institute, in Boston, Massachusetts.

The recommendation for lenvatinib plus pembrolizumab was based on data from the phase 2 KEYNOTE-B61 trial (NCT04704219), which showed that at a median follow-up of 14.9 months (interquartile range, 11.1-17.4), patients with previously untreated stage IV RCC (n = 148) achieved an objective response rate (ORR) of 49% (95% CI, 41%-57%), including a complete response rate of 6% and a partial response rate of 44%.

In a phase 2 trial (NCT03635892), the combination of cabozantinib and nivolumab elicited an ORR of 48% (95% CI, 31.5%-63.9%) in patients with advanced non–clear cell RCC (n = 40).

, McGregor, who also serves as an assistant professor of medicine at Harvard Medical School, discussed the latest updates to the NCCN Guidelines in kidney cancer, breaking down changes in the non–clear cell space and beyond.

: What is the importance of the NCCN Guidelines in treatment decision-making for patients with RCC?

: The NCCN Guidelines remain a critical part of thinking about the management of any cancer. When we look at the NCCN Guidelines, they give an idea of how a large group of experts who meet feel is the best way to approach things; that has implications for how oncologists across the United States think about cancer care.

It also has implications for payers, as well. If [a treatment] is [listed] on the NCCN Guidelines, it certainly will allow for easier coverage when thinking about payer support.

What were some of the most significant changes in the 2024 NCCN Guidelines update in the treatment of kidney cancer?

The largest update with the [updated] NCCN Guidelines was the changes to the approach of the frontline treatment of metastatic [clear cell] RCC. For years now, we’ve had a separation of favorable-, intermediate-, and poor-risk [disease]. When we look at intermediate and poor risk, we had ipilimumab [Yervoy] plus nivolumab as an option, as well as different TKI/immuno-oncology [IO] combinations, [such as] lenvatinib plus pembrolizumab, pembrolizumab plus axitinib [Inlyta], or nivolumab plus cabozantinib, with cabozantinib [monotherapy] as an option as well.

We then look at favorable risk, the 3 IO/TKI [combination] were the standard: nivolumab plus cabozantinib, lenvatinib plus pembrolizumab, or pembrolizumab plus axitinib.

A lot of that was based on the way that the phase 3 CheckMate 214 trial [(NCT02231749) of nivolumab plus ipilimumab] was designed; the primary end point was looking at outcomes in those with poor-risk disease. However, on the initial readouts, the objective response rate and the progression-free survival certainly favored sunitinib [Sutent] monotherapy over nivolumab plus ipilimumab in those with favorable-risk disease with extended follow-up.

Now, we’re seeing a numerically higher overall survival [OS] benefit with a tail to the curve in those patients with favorable-risk disease. With a now 8-year follow-up, the NCCN Guidelines recognized that nivolumab plus ipilimumab plays a role independent of the International mRCC Database Consortium risk category. [Nivolumab plus ipilimumab] is now an option for the frontline treatment of favorable-risk disease.

What was updated in the guidelines for patients with non–clear cell RCC?

Another big change in the NCCN Guidelines is how to approach those patients with divergent histologies, or non–clear cell RCC. The guidelines haven't taken the approach of looking at histology by histology, but we did have some impressive data in the past couple of years [in the advanced non–clear cell space]. We looked at both lenvatinib plus pembrolizumab and nivolumab plus cabozantinib, where we saw activity with IO/TKI doublets in these divergent histologies.

The KEYNOTE-B61 trial showed an ORR of 49% [with lenvatinib plus pembrolizumab], and that included patients with chromophobe, papillary, and translocation [histologies].

In [another] phase 2 trial, nivolumab plus cabozantinib showed an ORR of 48% in those with papillary, translocation, or unclassified [histologies].

Now, the NCCN Guidelines reflect [these data], with lenvatinib plus pembrolizumab and nivolumab plus cabozantinib both listed as potential first-line options, along with cabozantinib [monotherapy].

What is the significance of pembrolizumab being updated to a category 1 recommendation as adjuvant therapy for patients with clear cell histology in the stage II and III pathways?

For years, we've been trying to improve outcomes after surgery for patients with localized RCC. We had several trials with TKIs; [the phase 3 S-TRAC trial (NCT00375674)] showed a disease-free survival [DFS] benefit [with sunitinib vs placebo] but no OS benefit.

Subsequently, we had an explosion of interest in the role of immunotherapy. The phase 3 KEYNOTE-564 trial [NCT03142334] showed a positive improvement in DFS with [adjuvant] pembrolizumab vs placebo in patients with RCC [at intermediate to high risk of disease recurrence]. Pembrolizumab improved DFS with an HR of 0.72 [95% CI, 0.59-0.87]. Updated data presented [at the 2024 Genitourinary Cancers Symposium] showed that [pembrolizumab] not only prevented relapse, but also improved OS.

 Given that improvement in OS, pembrolizumab is now a category 1 recommendation for adjuvant therapy for those patients who meet the KEYNOTE-564 criteria.

In the adjuvant setting, I feel there's no role for TKI therapy.

What were some of the most significant adjustments made in the surgical and disease management space?

As we think about the role of surgical management in RCC, the NCCN Guidelines reflect that whenever treating localized disease, if a partial nephrectomy is feasible, that's always a preferred approach to optimize kidney function. If the patient has a second primary [tumor, we want to] ensure that the patient is able to undergo definitive local therapy.

When we start thinking about the role of surgical therapy in metastatic disease, the NCCN Guidelines reflect the phase 3 CARMENA trial [NCT00930033] that offers cytoreductive nephrectomy in select patients in combination with systemic therapy, specifically for those with poor-risk features.

Surgery continues to play a role in the treatment of metastatic RCC. There are ongoing trials looking at the role of consolidated nephrectomy, where if a patient starts systemic therapy and has a good response, we then remove the primary [tumor]. Therefore, ongoing studies will certainly help frame how we think about the role of surgery in the treatment of metastatic RCC.

Another other aspect I would make clear is that now we have a nice emphasis on the role for germline testing in the NCCN Guidelines. Who should get those done? Should any patient who has a family history of RCC [be tested].

It is great that we see that right away in the Guidelines now, reflecting what we knew; we know we need to be thinking about this, not just for a patient but for their family members as well.

NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2025. Accessed September 12, 2024. 

https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

Lee C-H, Fitzgerald KN, Voss MH, et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: updated results from a phase 2 trial. 

. 2023;41(suppl 16):4537. doi:10.1200/JCO.2023.41.16_suppl.4537

Choueiri TK, Tomczak P, Park SH, et al. Overall survival results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab versus placebo for the treatment of clear cell renal cell carcinoma (ccRCC). 

. 2024,42(suppl 4):LBA359. doi:10.1200/JCO.2024.42.4_suppl.LBA359

Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. 

. 2024;390(15):1359-1371. doi:10.1056/NEJMoa2312695

Bradley McGregor, MD, shared his insights on the updated NCCN Clinical Practice Guidelines in kidney cancer.

Updated NCCN Kidney Cancer Guidelines Bring New Recommendations for Advanced Non–Clear Cell RCC

Dr McGregor on the Updated NCCN Guidelines for Non–Clear Cell RCC

Bradley McGregor, MD, director, clinical research, Lank Center for Genitourinary Oncology, Marra Lochiatto Investigator, Dana-Farber Cancer Institute; assistant professor, medicine, Harvard Medical School, discusses 2024 updates to the National Comprehensive Cancer Network (NCCN) Guideline recommendations for the treatment of patients with renal cell carcinoma (RCC) with divergent histologies.

Although NCCN Guidelines do not offer histology-specific treatment recommendations for patients with non–clear cell RCC (non-ccRCC) histologies, they still offer research-supported guidance regarding the management of these disease subtypes, McGregor begins. Immuno-oncology/TKI doublets, including lenvatinib (Lenvima) plus pembrolizumab (Keytruda) and cabozantinib (Cabometyx) plus nivolumab (Opdivo), have shown activity in patients with divergent RCC histologies, he says.

In the phase 2 KEYNOTE-B61 trial (NCT04704219), the combination of pembrolizumab and lenvatinib in the frontline setting yielded a confirmed objective response rate (ORR) of 51% (95% CI, 43%-59%) in patients with advanced non-ccRCC. This included an 8% confirmed complete response (CR) rate and a 42% confirmed partial response rate. This patient population included those with chromophobe, papillary, and translocation histologies, McGregor notes.

Furthermore, the combination of cabozantinib and nivolumab was evaluated in patients with advanced non-ccRCC in a phase 2 trial (NCT03635892). The overall population (n = 40) included patients with papillary, translocation, and unclassified RCC. Findings showed that the ORR was 48% (95% CI, 31.5%-63.9%). In patients with papillary disease, the ORR was 47% (95% CI, 30%-64%). The median PFS was 13 months (95% CI, 7-16) in the overall population, and the median overall survival was 28 months (95% CI, 23-43).

Based on the data from KEYNOTE-B61 and the phase 2 study, the NCCN Guidelines list both doublets as preferred frontline treatment options for patients with non-ccRCC. The guidelines also recommend the use of upfront cabozantinib monotherapy for these patient populations based on data from the phase 2 PAPMET trial (NCT02761057), McGregor adds. Enrollment in a clinical trial is also a preferred recommendation. As future research aims to determine the optimal therapies for each disease subtype, NCCN Guideline recommendations may be further divided by histology and genomics, McGregor concludes.

Videos

Bradley McGregor, MD, discusses the current NCCN guideline recommendations for the treatment of patients with divergent RCC histologies.

Dr Ornstein on the Use of IO/TKI Doublets in Non-ccRCC

Moshe Ornstein, MD, MA, medical oncologist, Department of Hematology and Medical Oncology, Cleveland Clinic, discusses the use of first-line immune-oncology (IO)/TKI doublet regimens in patients with non–clear cell renal cell carcinoma (non-ccRCC).

Recent prospective clinical trials in non-ccRCC have investigated IO/TKI combinations, and data have demonstrated the efficacy of these types of regimens for patients with ccRCC, Ornstein begins. For instance, the phase 2 KEYNOTE-B61 trial (NCT04704219) evaluated lenvatinib (Lenvima) plus pembrolizumab (Keytruda) in an all-comer population of patients with non-ccRCC, including those with papillary, chromophobe, translocation, and unclassified disease histologies, he says. In this international trial, among 158 patients in the overall population who received the doublet at the standard dose, the objective response rate (ORR) was 51% (95% CI, 43%-59%). Patients with chromophobe histology (n = 29) had an ORR of 35% (95% CI, 18%-54%). Furthermore, in the overall population, the median progression-free survival (PFS) was 17.9 months (95% CI, 15.1-22.1) with the doublet, and the median overall survival (OS) was not reached (NR; 95% CI, NR-NR). These findings support the National Comprehensive Cancer Network (NCCN) Guideline recommendation for lenvatinib plus pembrolizumab as a frontline treatment option for patients with non-ccRCC.

The NCCN also recommends cabozantinib (Cabometyx) plus nivolumab (Opdivo) for use in patients with previously untreated non-ccRCC based on findings from a smaller phase 2 trial (NCT03635892), Ornstein explains. In the overall population (n = 40), which included patients with papillary, translocation, and unclassified RCC, the ORR was 48% (95% CI, 31.5%-63.9%). In the subgroup of patients with papillary disease, the ORR was 47% (95% CI, 30%-64%). In the overall population, the median PFS with the doublet was 13 months (95% CI, 7-16), and the median OS was 28 months (95% CI, 23-43).

Both doublets are effective treatment options for patients with non-ccRCC, and IO/TKI combination regimens should be the standard of care for this patient population, Ornstein emphasizes. Treatment decision-making in the upfront setting relies on patient preference and individual data interpretation, he concludes.

Moshe Ornstein, MD, MA, discusses the use of first-line IO/TKI doublet regimens in patients with non–clear cell renal cell carcinoma.

On July 1, 2024, the National Comprehensive Cancer Network (NCCN) released their updated Clinical Practice Guidelines in Oncology for the treatment of patients with kidney cancer. Version 1.2025 updates the recommendations offered in version 4.2024 of the kidney cancer Clinical Practice Guidelines in Oncology, which were released in May 2024; all recommendations were category 2A unless otherwise indicated.

In terms of primary treatment and follow-up for stage II and III disease (KID-2), the NCCN Kidney Cancer Panel changed adjuvant treatment with pembrolizumab (Keytruda) to a category 1 recommendation from a category 2A recommendation for patients with clear cell histology in the stage II and III pathways. Additionally, adjuvant sunitinib (Sutent) was removed from the guidelines for patients with stage II clear cell disease. The stage II and III pathways were both moved from KID-1 to KID-2.

In the KID-A section, which encompasses the general principles of management for renal cell carcinoma (RCC) the panel added bullets to the general principles of management of RCC noting that thermal ablation is suitable for renal masses of 3 cm or less, ablative techniques may require retreatment to achieve the same result as surgery, stereotactic body radiation therapy (SBRT) is an ablative therapy and can be used in patients with stage I, II, or III kidney cancer who are non-optimal surgical candidates. The panel also added a new subsection to KID-B, titled 

The KID-C section, which describes the guidelines for follow-up, received multiple updates. During active surveillance, the panel now recommends abdominal CT or MRI both with and without IV contrast within 6 months of surveillance initiation, followed by CT, MRI, or ultrasound at least once per year. Following ablative techniques, the panel recommends abdominal CT or MRI, both with and without IV contrast, or a contrast-enhanced ultrasound at 1 to 3 months, 6 months, and 12 months following ablation, then annually thereafter.

Following a partial or radical nephrectomy, patients with stage I disease should receive a baseline abdominal CT or MRI, both with and without IV contrast within 3 to 12 months of surgery, then annually for up to 5 years or longer as clinically indicated. The panel made the same imaging recommendation for patients with stage II disease, except indicating that it should occur every 6 months for 2 years, then annually for up to 5 years or longer if needed.

Patients with stage III disease should receive a baseline abdominal CT or MRI, both with and without IV contrast, within 3 to 6 months, followed by CT or MRI, with MRI being preferred, or ultrasound as a category 2B recommendation, every 3 to 6 months for a minimum of 3 years, then annually up to 5 years. Patients with relapsed and surgically unresectable stage IV disease are advised to undergo CT or MRI, both with and without IV contrast to assess baseline pretreatment or before observation.

The principles of systemic therapy for relapsed or stage IV disease (KID-D) was updated to remove high-dose IL-2d and temsirolimus (Torisel) as being useful in certain circumstances for the frontline treatment of patients with clear cell histology with favorable and poor/intermediate risk and poor/intermediate risk disease, respectively. Additionally, ipilimumab (Yervoy) plus nivolumab (Opdivo) was identified as a preferred regimen for favorable risk patients in the first line. For subsequent therapy in clear cell histology, high-dose IL-2d and temsirolimus were removed from the useful in certain circumstances classification for patients who were both naive to immuno-oncology agents and those who had previously received this treatment class.

For patients with non-clear cell histology, lenvatinib (Lenvima) in combination with pembrolizumab was added to the preferred regimens as a category 2A recommendation and cabozantinib (Cabometyx) plus nivolumab was moved to this section from other recommended regimens. Bevacizumab (Avastin), erlotinib (Tarceva), pazopanib (Votrient), and temsirolimus were all removed from the useful in certain circumstances section, and erlotinib with bevacizumab for select patients with advanced papillary RCC was moved to other recommended regimens.

Finally, in the kidney-specific systemic therapy for patients with confirmed hereditary RCC (HERED-RCC-D) section, erlotinib plus bevacizumab was shifted from useful in certain circumstances to another recommended regimen for patients with hereditary leiomyomatosis and RCC. Cabozantinib in combination with nivolumab was added to useful in certain circumstances as a category 2A recommendation for this patient population. For patients with tuberous sclerosis complex, everolimus was moved from useful in certain circumstances to a preferred regimen and sirolimus was added to the other recommended regimens as a category 2A recommendation.

NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2025. Accessed July 16, 2024. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf

The National Comprehensive Cancer Network has published their updated Clinical Practice Guidelines in Oncology for kidney cancer.

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