Renal Carcinoma Therapeutics: ccRCC Vs nccRCC, An Unclear And Uneven Struggle to Include Everyone
Folinas Konstantinos *1, Apostolopoulou Valentina 2, Bartzi Dimitra 1
*Correspondence to: Folinas Konstantinos, Oncology Department,251 General Airforce Hospital, 3 Panagiotis Kanellopoulos Avenue, Athens, Greece.
Copyright
© 2026 Folinas Konstantinos is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 27 July 2026
Published: 01 August 2026
DOI: https://doi.org/10.5281/zenodo.21767699
Abstract
Renal carcinoma (RCC) accounts for roughly 2% of global cancer diagnoses, with over 430,000 new cases and 150,000+ deaths annually as of 2022. Major contributors include obesity, smoking, hypertension, and occupational exposure, with up to 34% of cases considered preventable. RCC is a malignant neoplasm of the renal tubular epithelium, primarily classified into three main histological subtypes: clear cell (65–75%), papillary (10–15%), and chromophobe (5%) and other histologies, most commonly categorized as clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC), respectively. nccRCC is a heterogeneous group comprising about 20–30% of all kidney cancers, with over 10 recognized, distinct histological subtypes rather than a single type. The therapeutic algorithm for ccRCC is straightforward according to guidelines of every oncologic society even if the use of certain biomarkers in order for certain therapy module to be matched with certain subpopulations. In contrast, the therapeutic algorithm of nccRCC is not such a solid pathway that includes also the possibility of a clinical trial. There have been many advancements in the last year into renal cell carcinoma management that may alter the current status and improve the survival of these patients.
Introduction
Renal cancer is the 6th most common cancer among men and the 9th most common cancer among women. Five-year survival diminishes throughout the stages, specifically 93.3% in the local setting, 75.1% in the regional setting and, only, 18.2% in the metastatic setting (1).
The risk factors that are implicated for the development of renal cancer are:
Staging of kidney cancer is related to tumor size (stage Ι-ΙΙ), the infiltration of Gerota’s fascia (stage ΙΙΙ) and the infiltration of superior vena cava (stage ΙV).
Renal cancer, though, is a heterogeneous carcinoma with various subtypes that increase in numbers as the time passes by. Specifically, 70% of renal tumors consists of renal cell carcinomas (RCC) and 70% of renal cell carcinomas consists of clear-cell renal cell carcinomas (ccRCCs). This is reflected in the following pie-chart (2)(5) (Figure 1).
Specifically:
It should be noted that molecularly defined renal carcinomas are new entities that reflect recent discoveries in renal tumour genomics (TFE3 rearranged RCC, TFEB altered RCC etc.).
Moreover, the diversity across renal cell carcinoma histologies originate from the differences across the sites of the kidney but the whole molecular signature of this heterogeneity is yet to be revealed in its fullest.
This heterogeneity is reflected in the therapeutic algorithm presented across the oncologic guidelines, as highlighted below (Figure 4):
In the oncologic guidelines, all these different histologies are divided into 2 major categories: Α) Clear-cell RCC and B) Non-Clear-cell carcinoma RCC, with the former having more options throughout the therapeutic algorithm(Figure 5):
Also, patients with clear-cell RCC are subclassified to certain risk groups (low, intermediate, high) according to certain criteria {MSKCC (Memorial Sloan Kettering Cancer Center) Prognostic Model and IMDC (International Renal Cell Carcinoma Database Consortium) Criteria} (Figure 6):
The fact that patients with ccRCC receive a more personalized treatment than non ccRCC, is reflected on the available treatment regimes on first line therapy (Figure 7) :
As far as, non ccRCC is concerned, though, the preferred first line treatment is clinical trial and three other options, far less than ccRCC (Figure 9).
Clinical trails for Approved Systemic Therapies in Non ccRCC
From all those mentioned above, it is evident that non ccRCC therapy is less personalized and there are less molecules and less combinations at our disposal than ccRCC. Also, clinical trials that studied therapeutics options in ccRCC did not have strength statistically as those in ccRCC (5). Specifically:
The clinical trial that evaluated the use of cabozantinib in combination with nivolumab was a phase 2 trial that included advanced or metastatic non ccRCC patients that could have received one prior line of therapy at most. Patients were assigned to receive Cabozantinib 40mg po daily with nivolumab 240mg iv q2 weeks (or 480mg iv q4 weeks). The primary endpoint was ORR (Objective Response Rate) and the secondary endpoints were PFS (Progression Free Survival), OS (Overall Survival) and Safety (Figure 10).The trial included mostly patients with papillary non ccRCC patients, at various risk group and the patients either received prior nephrectomy or a VEGF inhibitor, chemotherapy or an mTOR inhibitor (Figure 11).
As far as ORR was concerned, there was a slight decrease in 2nd line (36%) as opposed to 1st line therapy (54%), but was stable throughout the different histologies (approximately 50%). As far as PFS was concerned, it was around 13 months and 13 months in the second and the first line therapy respectively (Figure 12). I must be noted that there no statistically significant difference between patients across different risk groups (Figure 12).
As far as safety was concerned, out of 35 patients (88%) experienced at least an adverse event, 22 patients (55%) experienced an adverse event grade 3/4. Of those grade 3/4 adverse events, most of them were attributed to AST/ALT elevation (18%) and the rest were attributed to hypertension and pain. Nine patients (28%) discontinued study therapy (Figure 13).
The combination of pembrolizumab and Lenvatinib was evaluated during Keynote B61 trial (presented during ASCO 2023) that included non ccRCC patients with no prior systemic therapy history. It was an one arm trial ,with patient that would receive pembrolizumab 400mg q6 weeks for no more than 18 cycles (approximately 2 years) with lenvatinib 20mg po once a day. The primary endpoint was ORR (Objective Response Rate) and the secondary endpoints were PFS (Progression Free Survival), DOR (Duration of Response), OS (Overall Survival) and Safety and Tolerability (Figure 14)The patients included in this trial had papillary, unclassified, translocation and chromophobe histology, may have had sarcomatoid featured and most of them had a CPS score >1.
ORR was 50% for the overall population (with 10 CRs and 10 PRs) and ,as far as different histologies are concerned, translocated and papillary were observed to b the histologies with the greatest response by percentage.
In the SWOG 1500 study was ,initially, a four arm study with patients with papillary RCC that could have received in the past no more than one line of systemic therapy (but no prior therapy with sunitinib). The patients were randomized to receive either sunitinib or cabozantinib or crizotinib or savolitinib.
Due to a futility analysis that demonstrated a hazard ratio for PFS higher than 1, the accrual for the savolitinib and the crizotinib arms was halted early while accrual continued for sunitinib and cabozantinib arms. The results of the trial was: mPFS was significantly prolonged with the use of cabozantinib (9 months) versus sunitinib (5.6 months) with a HR of 0.60.
ORR was, also, higher in the cabozantinib arm than that of sunitinib, savolitinib and crizotinib arm ,with 2 CRs and 8 PRs in the cabozantinib arm among 44 patients. Median OS was 20 months in the cabozantinib arms versus 16.4 months in the sunitinib arms.
Grade ¾ AEs occurred in 68% of patients in the sunitinib arm, 74% of patients in the cabozantinib arm, 37% of patients in the crizotinib arm and 39% of patients in the savolitinib arm. It must be noted that grade 5 AE was seen in the cabozantinib arm.
Discussion
Renal cell carcinoma (RCC) is a heterogeneous carcinoma with many categories of histologies that are divided, roughly, into 2 subcategories, A) the clear-cell Renal Cell Carcinoma (ccRCC) and B) the non-clear-cell Renal Cell Carcinoma (non ccRCC).
In contrast to ccRCC where the treatment is personalized and with more options, there is a problematic in the treatment of non ccRCC (at least in the metastatic setting. The first treatment option is a clinical trial and a few more molecules and combinations follow (that were approved in trials with less statistical significance than in ccRCC patients) in the therapeutic algorithm (as there were cited above).
Also, the SUNNIFORECAST trial should be mentioned that compared the efficacy nivolumab with ipilimumab followed by nivolumab maintenance versus standard of care. The results showed an increase in median OS in the investigational arm 32.8% versus 19.4%. No numerical difference was found in the median PFS when comparing both arms.
In Calypso trial, the combination of savolitinib with durvalumab (one arm trial) showed an increase in the OS in MET-driven population versus ITT population (27.4 versus 18.3 months) and in the PFS in MET-driven population versus ITT population (13.9 versus 6,5 months). The highlight of the trial is that ctDNA baseline positivity was correlated with shorter OS in contrast to baseline ctDNA negativity.
The therapeutic pathway for non ccRCC seems brighter with ongoing trials that test the efficacy of novel molecules or novel combinations in a broader or a narrower, histologically speaking, population, including the molecularly defined renal carcinomas. This subcategory foster subsets of renal carcinomas like TFE3- rearranged, FH-deficient, SDH-deficient and ALK-rearranged tumors and increasingly testing targeted agents and immunotherapy in rare subtypes. Key strategies involve TKIs and immune checkpoint inhibitors specifically for these genetically driven non ccRCC. Indicatively, NCT05043090 trial, includes patients with papillary RCC, is a 3 arm trial comparing the efficacy of the combination savolitinib with durvalumab versus sunitinib monotherapy versus durvalumab monotherapy and Papmet 2 trial, includes patients with papillary RCC, a 2 arm trial comparing the efficacy of the combination of cabozantinib with atezolizumab versus cabozantinib monotherapy.
But there is a question that lies in front of us when we review the therapeutic landscape of clear-cell RCC vs non-clear-cell RCC. What is the reason that there are more therapeutic choices in ccRCC vs non ccRCC in the metastatic setting?
Clear cell renal cell carcinoma (ccRCC) has more metastatic treatment choices than non-ccRCC (nccRCC) because of clear driver mutations, extensive clinical trial representation, and distinct metabolic reprogramming. The defining factors are specific genetic vulnerabilities and high research focus. Specifically, as far as biological and metabolic drivers are concerned, most ccRCC cases involve loss of the VHL gene, which triggers hypoxia-inducible factors (HIF) and heavy angiogenesis. Also, ccRCC relies heavily on the Warburg effect (aerobic glycolysis), lipid accumulation, and altered glutamine pathways. In that context, these specific metabolic and blood-vessel pathways create clear targets for anti-angiogenic drugs and targeted pills. As far as clinical trials and research bias is concerned, ccRCC makes up about 75–80% of all kidney cancers, attracting the vast majority of research funding and clinical trials. Also, nccRCC groups together rare, distinct subtypes (such as papillary and chromophobe) with different biology, making large randomized trials difficult. In that context, many nccRCC treatments are simply guessed or borrowed from ccRCC trials because dedicated data for non-clear cell types remain scarce.
Conclusion
This article highlights the inequality in the therapeutics of those two big subcategories of RCC that tend to plarge, randomizedd and direct research to the origin of the non ccRCCs, with use of -omics and possibly the metabolic essence of RCC on its all.
References