Limited Treatment Options in nccRCC Expanding With IO/TKI Combinations

Peers & Perspectives in OncologyDecember I, 2023
Volume 1
Issue 10
Pages: 58

Clinical trials are shedding light into best treatment approaches for non–clear cell renal cell carcinoma, including immunotherapy plus tyrosine kinase inhibitor combinations, as discussed in Case-Based Roundtable events.

Image credit: © [Catalin] -

Image credit: © [Catalin] -

THE AVAILABILITY OF data for treatments of patients with clear cell renal cell carcinoma (ccRCC) dominates the field of therapeutics for these patients, as most patients with RCC will have ccRCC. However, according to the American Cancer Society, about 20% of patients with RCC will have non–ccRCC (nccRCC) with histology that presents a greater challenge to their care because the available treatments are not as plentiful and proven as in the ccRCC space.1 Yet, this has begun to change for these patients with an unmet need as new approaches to treatment grow.

According to Bradley McGregor, MD, who led a Targeted Oncology Case-Based Roundtable event discussing current data for the treatment of patients with nccRCC, the field of treatment for this patient population is showing more promise as clinical trials move forward. Much of what he had to discuss involved promising survival outcomes among these recent clinical trials. This is especially important because according to the Surveillance, Epidemiology, and End Results database the 5-year relative survival rate for all patients with kidney cancer is 77.6%, but in patients with metastatic disease that rate falls to 17.4%,2 with nccRCC having historically worse prognosis compared with ccRCC.

Emerging from these new data to address this unmet need is the potential for the combination of immune checkpoint inhibitors with tyrosine kinase inhibitors (TKIs) as a first-line treatment for patients with metastatic nccRCC. The data are already there for this approach in the ccRCC setting, and now they are starting to show potential for this approach in the nccRCC setting, to the surprise of some physicians. Importantly, more study is needed to identify the best treatment for these patients as the sequencing of treatment in the nccRCC setting has proven a challenge.


One of the biggest challenges in the nccRCC space is that there is no standard-of-care therapy, and according to the National Comprehensive Cancer Network (NCCN) guidelines, the preferred treatment for patients with nccRCC is to put them into a clinical trial.3 In the NCCN guidelines, once a patient either shows disease relapse or has stage IV metastatic disease and non–clear cell histology is confirmed, then aside from enrolling the patient in a clinical trial, the preferred systemic therapy is cabozantinib (Cabometyx).3 Cabozantinib is a TKI that targets receptors including MET, RET, AXL, VEGFR2, FLT3, and c-KIT, and because of its approval for patients with metastatic ccRCC it was approved for use in patients with nccRCC as well.4

Cabozantinib showed its benefit in a multicenter, international, retrospective cohort study of 112 patients with nccRCC treated with cabozantinib in any line across 22 cancer centers.5 The investigators found that, among patients in all these centers, there was a 27% (95% CI, 19%- 36%) objective response rate across all subgroups of nccRCC histology. After a median follow-up of 11 months the median progression-free survival (PFS) was 7.0 months (range, 5.7- 9.0) and the median overall survival (OS) was 12.0 months (range, 9.2-17.0). No new safety signals were observed, and investigators concluded in this 2019 study, published in The Lancet, that although the field awaits the final data from these trials with cabozantinib, the real-world evidence supports the use of cabozantinib in patients with nccRCC.5

Although cabozantinib has demonstrated promising efficacy in this space, it has opened the door for more consideration of TKIs, particularly combinations of TKIs with immunotherapy (IO). According to the NCCN guidelines, other recommended regimens now include nivolumab (Opdivo) plus cabozantinib; pembrolizumab (Keytruda); and lenvatinib (Lenvima) plus everolimus.3

At the Case-Based Roundtable event for physicians in the New England region, led by McGregor, director of clinical research at the Lank Center of Genitourinary Oncology and medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts, he asked attending physicians how they would treat a patient with metastatic nccRCC after surgery. Polling their answers, most physicians chose to put the hypothetical patient into a clinical trial. Comparatively, when looking at answers from another Case-Based Roundtable event examining the same case, moderator Robert J. Motzer, MD, asked physicians from across Georgia, North Carolina, and South Carolina the same question but had different results. In the polled answers there was a tie between cabozantinib and pembrolizumab, with some physicians considering clinical trials or looking ahead to the combination of pembrolizumab and lenvatinib [Polls].


The importance of finding the right care for a patient with nccRCC also relies on these ongoing clinical trials, looking at these recommended regimens, and feeling comfortable with the current data, but for certain patients the stage of disease provides an extra challenge if they have nccRCC histology, so that physicians will have to tailor treatment further in the adjuvant setting. “The trials right now are looking to balance risk of therapy with maximum benefit, and I think when we start looking at [stage IV] disease, this balance becomes less clear,” McGregor explained. “For a lot of these patients I’m offering surveillance, and in the adjuvant setting there’s…no OS benefit to date, and treatment with very real toxicities.”


Considering the patient’s stage and histology of nccRCC makes a difference in treatment considerations for physicians, but the options remain limited outside of a clinical trial as treatment options are first based on their impact in the ccRCC setting. According to a review of characteristics and treatment challenges in patients with nccRCC in Cancers, the most common subtypes of nccRCC are papillary RCC, chromophobe RCC, collecting duct RCC, renal medullary RCC, and translocation RCC tumors.6 Most common of these are papillary RCC tumors, which make up 10% to 15% of all RCC cases, whereas the rarest are translocation and renal medullary RCC tumors. Translocation RCC is characterized by chromosome translocations that involve Xp11.2 and result in gene fusions of the TFE3 transcription factor gene, according to the review of nccRCC histology in Cancers.6

This subtype is particularly aggressive with widespread systemic metastases in the patient but is rare in the medical oncology space. This is because this subtype of nccRCC makes up one-third of pediatric RCC cases and accounts for 15% of RCC in patients younger than 45 years. Adult patients with translocation RCC are rare, making treatment dependent on knowing the nccRCC histology.6 However, with limited options, these patients depend on treatments tested across all of nccRCC and not solely within their population, as there are no specifically approved treatments for these subtypes.

“My experience with it is that it’s slow progressing but relentless,” said Motzer, section head, kidney cancer, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, in the other Case-Based Roundtable virtual event discussing nccRCC. “It’s different than clear cell, where clear cell patients may have stable disease or rapid disease, but [with] translocation disease it kind of keeps going and growing slowly. I haven’t found any particular program…that’s effective that I’ve seen responses with.”

Again, with ccRCC making up most cases, treatments are derived from these studies first and then applied to a wide group of patients with nccRCC with subgroup analyses performed for the different histology types. Patients with papillary nccRCC make up most nccRCC patients on clinical trials, and increasing understanding of the molecular makeup of papillary RCC has been helpful to identifying it in patients, allowing physicians to determine a distinction between type 1 papillary RCC and type 2 papillary RCC. Patients with type 1 papillary RCC have better clinical outcomes compared with patients with type 2 disease; further, some recent research has indicated that type 2 papillary RCC could potentially be divided into even more subtypes of nccRCC and that although type is associated with MET alterations, several mutations may be underappreciated in their role in developing type 2 papillary RCC.6 Still, this has not changed the approach to treatment in nccRCC and led to specified targeted treatment for these subtypes; however, new data from combinations associated with ccRCC are starting to build a new path for these patients.


Results from the phase 2 KEYNOTE-B61 trial (NCT04704219) showed that the use of lenvatinib and pembrolizumab continued positive efficacy for patients with ccRCC in those with nccRCC.7 Initially, a cohort of 82 patients with nccRCC showed antitumor activity with the combination at 24 weeks or more of follow-up. In the complete cohort of 158 patients, the trial met its primary end point of an overall response rate of 49% (95% CI, 41%-57%) with 6% of these being complete responses, and 44% had a partial response (PR) to the combination therapy.7

A median PFS of 18 months (95% CI, 14-not reached) was seen in this cohort along with an estimated 12-month PFS rate of 63% (95% CI, 54%-70%). Median OS was not reached but the estimated 12-month OS rate was 82% (95% CI, 75%-88%).8 According to McGregor, these results were nowhere close to the ccRCC results with the same combination in the phase 3 CLEAR trial (NCT02811861), where a significant PFS was seen compared with sunitinib at a median of 23.9 months vs 9.2 months, respectively (HR, 0.39; 95% CI, 0.32-0.49, P < .001).9 This study also resulted in approval for this combination to treat patients with advanced disease as, again, ccRCC approvals allow for use in nccRCC.10 However, he noted that the results of KEYNOTE-B61 are very encouraging because the nccRCC patient population has such a poor prognosis, especially in the metastatic setting. Further, Motzer echoed these sentiments in the event he moderated by highlighting that most trials with patients with nccRCC showed PFS of 7 months, so to reach 18 months was highly encouraging.

Looking deeper into the responses of the IO and TKI combination showed that stable disease was seen in 33% of patients and there was a confirmed clinical benefit in 72% (95% CI, 64%-78%) of patients. Breaking the results out by subtype, the majority of patients had a papillary histology (n = 93) but within that subgroup they had an objective response rate of 54% (95% CI, 43%-64%).8 Only 4 patients in the trial had a translocation histology, but all of 4 of them had confirmed PRs with 1 patient exhibiting stable disease and just 1 more with progressive disease at the time of follow-up [Table8]. Overall, these responses showed positive benefit for this patient population and especially in patients with a chromophobe histology, who had an objective response rate of 52% (95% CI, 30%-74%) and good signs of survival in these subgroups.8

table: Responses by RCC Histology to Pembrolizumab and Lenvatinib in KEYNOTE-B61

“I think what’s actually remarkable, of the 29 patients with chromophobe histology, 28% had a response, which is the highest we’ve seen with any IO-based regimen in the chromophobe histology,” McGregor said. Other physicians in his Case-Based Roundtable discussion also noted that historically, physicians thought of patients with chromophobe histology disease as not being responsive to IO therapy, so to see these results was rewarding.

No new safety signals were observed with either drug, with adverse events (AEs) leading to a dose reduction of lenvatinib in 54 patients with the most common including diarrhea (6%) and palmar-plantar erythrodysesthesia syndrome (6%).8 AEs that led to a dose interruption occurred in 72% of patients whereas 15% of patients discontinued lenvatinib compared with 7% who discontinued pembrolizumab. The most common AEs of clinical interest were hypertension (61%), hypothyroidism (66%), proteinuria (31%), and palmar-plantar erythrodysesthesia syndrome (30%).

Immune-related AEs were seen in 53% of patients with the most common of these including hypothyroidism (42%), hyperthyroidism (12%), adrenal insufficiency (4%), and pneumonitis (3%).8 According to physicians in both Case-Based Roundtable groups, these were AEs that were mainly expected and can be difficult to accept for patients with later stages of disease, but not unmanageable for the patients who will benefit from treatment the most.

“For years, if we were to have a non–clear cell RCC talk [with other physicians] we’d say, ‘There [are] no new data,’ and now we have so much more to discuss,” McGregor concluded.


1. What’s new in kidney cancer research? American Cancer Society. Updated February 1, 2020. Accessed November 7, 2023.

2. Cancer stat facts: kidney and renal pelvis cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed November 7, 2023.

3. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2024. Accessed November 8, 2023.

4. Cabozantinib (Cabometyx). FDA. Updated April 25, 2016. Accessed November 8, 2023.

5. Martínez Chanzá N, Xie W, Asim Bilen M, et al. Cabozantinib in advanced non–clear cell renal cell carcinoma: a multicentre, retrospective, cohort study. Lancet Oncol. 2019;20(4):581-590. doi:10.1016/S1470-2045(18)30907-0

6. Sepe P, Ottini A, Pircher CC, et al. Characteristics and treatment challenges of non-clear cell renal cell carcinoma. Cancers (Basel). 2021;13(15):3807. doi:10.3390/cancers13153807

7. Lee CH, Gurney H, Atduev V, et al. First-line lenvatinib + pembrolizumab treatment across non–clear cell renal cell carcinomas: results of the phase 2 KEYNOTE-B61 study. J Clin Oncol. 2023;41(suppl 16):4518. doi:10.1200/JCO.2023.41.16_suppl.4518

8. Albiges L, Gurney H, Atduev A, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non–clear cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2023:24(8):881-891. doi:10.1016/S1470-2045(23)00276-0

9. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

10. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Updated August 11, 2021. Accessed November 9, 2023.

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