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

Bradley McGregor, MD

The changes in the 2024 update to 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.¹ 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 22.8 months (range, 16.6-27.6), patients with previously untreated stage IV non–clear cell RCC (n = 148) achieved an objective response rate (ORR) of 50.6% (95% CI, 42.6%-58.7%), including a complete response rate of 8.2% and a partial response rate of 42.4%.²

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).³

In an interview with OncLive^®, 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.

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

McGregor: 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 [50.6% 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.⁴ 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.

References

1. 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
2. Voss MH, Gurney H, Atduev V, et al. First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): Extended follow-up of the phase 2 KEYNOTE-B61 study. J Clin Oncol. 2024;42(suppl 4):2. doi:10.1200/JCO.2024.42.4_suppl.2
3. 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. J Clin Oncol. 2023;41(suppl 16):4537. doi:10.1200/JCO.2023.41.16_suppl.4537
4. 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). J Clin Oncol. 2024,42(suppl 4):LBA359. doi:10.1200/JCO.2024.42.4_suppl.LBA359
5. 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