Renal cell carcinoma (RCC) is a complex cancer with multiple histological subtypes, including clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC). The treatment landscape for metastatic ccRCC has been transformed by the introduction of immune checkpoint inhibitors (ICIs) and their combinations with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs).
The frontline treatment options for metastatic ccRCC currently revolve around ICI doublets such as ipilimumab/nivolumab, and combinations of VEGF-TKIs with ICIs like axitinib/pembrolizumab and lenvatinib/pembrolizumab. These combinations have demonstrated significant improvements in response rates and survival compared to older single-agent therapies.
Non-clear cell RCC, which makes up approximately 25% of new RCC diagnoses, represents a diverse group of molecularly distinct tumors that have historically been underrepresented in clinical trials. These subtypes include papillary, chromophobe, unclassified, and translocation RCC, each with different biological behavior and treatment responses.
This review summarizes the most impactful kidney cancer research presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, covering clinical trials, novel therapeutic approaches, and translational research across both ccRCC and nccRCC subtypes.
Two landmark Phase III trials received updated long-term follow-up reports at ASCO 2023. The KEYNOTE-426 trial compared axitinib plus pembrolizumab (axi/pem) versus sunitinib, while the CLEAR trial compared lenvatinib plus pembrolizumab (len/pem) versus sunitinib. Both were conducted in treatment-naive metastatic ccRCC patients.
With over four years of follow-up, both trials continued to show significant improvements in objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) compared to sunitinib alone. Among responders, the median duration of response was 43.7 months for len/pem and 23.6 months for axi/pem.
However, an important caveat emerged: fewer than 30% of responders in both studies maintained their response at 48 months, and the response curves had not yet reached a plateau. This raised questions about the long-term durability of these VEGF-TKI/ICI combinations compared to the ICI doublet ipilimumab/nivolumab, where over 50% of responses remain durable beyond 60 months.
The durability comparison sparked debate, with experts suggesting that ipilimumab/nivolumab may be preferable for most metastatic RCC patients without oligometastatic disease, reserving VEGF-TKI/ICI combinations for patients needing rapid response or those with impending organ failure.
The CONTACT-03 study addressed one of the most pressing clinical questions in metastatic ccRCC: whether adding immunotherapy to a new regimen after progression on an initial immunotherapy-containing regimen could improve outcomes. The trial compared atezolizumab plus cabozantinib versus cabozantinib alone in this post-immunotherapy setting.
Results were striking and practice-informing: there were no significant differences in ORR, PFS, or OS between the combination and monotherapy arms. Patients who received atezolizumab plus cabozantinib did not gain any additional benefit from the re-introduction of immunotherapy compared to cabozantinib alone.
Moreover, the atezolizumab plus cabozantinib combination led to a notable increase in grade III/IV adverse events, meaning patients experienced more toxicity without any corresponding clinical benefit. These findings provide strong prospective evidence against immediate immunotherapy rechallenge after progression.
While this study discourages sequential immunotherapy immediately after failure, questions remain about whether immunotherapy might have a role in later treatment lines, or whether CTLA-4 targeted therapies could offer benefit in this salvage setting where PD-1/PD-L1 agents did not.
Several early-phase studies explored innovative therapeutic strategies in ccRCC. Etinostat, an HDAC inhibitor capable of modulating immunosuppressive tumor microenvironments, was tested in combination with atezolizumab and bevacizumab. In immunotherapy-naive patients, this triplet achieved an impressive ORR of 60%, with manageable side effects including hypophosphatemia and diarrhea.
Batiraxcept, an antibody targeting the AXL receptor involved in RCC metastasis, showed limited activity as monotherapy. However, when combined with cabozantinib in previously treated patients, it produced an ORR of approximately 44%, supporting further investigation in Phase III trials.
The KEYMAKER trial explored belzutifan (an HIF-2 alpha inhibitor) combined with lenvatinib in patients who had progressed on both immunotherapy and VEGF-TKI therapies. Despite heavy prior treatment exposure, this combination achieved a 50% ORR, demonstrating potential for a difficult-to-treat patient population.
In preclinical research, engineered T-cells targeting the human endogenous retrovirus HERV-E showed remarkable activity against ccRCC tumor grafts in mice, with median survival increasing from 20 to 50 days. A Phase I clinical trial of this approach in treatment-refractory ccRCC patients demonstrated safety, with one partial response and four patients achieving stable disease among 14 enrolled.
Multiple clinical trials evaluated immunotherapy and TKI combinations specifically in non-clear cell RCC subtypes. The KEYNOTE-B561 study tested lenvatinib/pembrolizumab as first-line treatment across 158 patients with various nccRCC histologies and achieved a combined ORR of 49% with a disease control rate of 82%.
A Phase II trial of nivolumab/cabozantinib in nccRCC demonstrated an ORR of 54% in first-line and 36% in second-line treatment. Median PFS and OS across all patients were 13 months and 28 months, respectively, providing further evidence that ICI/TKI combinations have meaningful activity in these rarer subtypes.
The CaNI study explored a more aggressive triplet approach using cabozantinib, ipilimumab, and nivolumab in metastatic nccRCC. However, 84% of patients required cabozantinib dose reduction and only 45% completed all planned ipilimumab doses, leading to a lower-than-expected ORR of 18% and raising questions about the feasibility of triplet therapy.
A consistent finding across all three nccRCC studies was that chromophobe RCC exhibited worse outcomes compared to other histological subtypes. Single-cell RNA sequencing analysis revealed that chromophobe tumors have lower infiltrating lymphocyte density and that their T-cells lack exhaustion markers, suggesting they may be immunologically inert "bystander" cells rather than tumor-reactive immune cells.
The search for reliable biomarkers to predict immunotherapy response in RCC remains a critical research priority. Analysis of the CHECKMATE 914 adjuvant trial revealed that patients with grade 4 ccRCC and those with sarcomatoid features derived greater benefit from ipilimumab/nivolumab, suggesting sarcomatoid de-differentiation may serve as a predictive biomarker in both metastatic and adjuvant settings.
Multiparametric immunofluorescence studies confirmed that higher levels of CD8+ PD-1+ T-cells that are negative for TIM-3 and LAG-3 exhaustion markers were associated with better immunotherapy response. Additionally, whole exome and single-cell RNA sequencing identified amplification of chromosome 11q13 and enrichment of SLAMF7+ cytotoxic T-cells as potential markers of primary immunotherapy resistance.
Cytokine profiling in nccRCC patients revealed that elevated baseline levels of inflammatory cytokines including MIP-1b, IL-1, MCP-1, IL-6, and IL-13 correlated with worse IMDC prognostic scores and decreased PFS, potentially serving as circulating biomarkers for treatment stratification.
A novel approach using CD8 cell PET imaging with a specialized radiotracer showed that CD8 T-cell density measured by PET strongly correlated with tissue immunohistochemistry results and could distinguish immunotherapy responders from non-responders, potentially enabling non-invasive immune monitoring during treatment.
RCC is increasingly recognized as having significant molecular heterogeneity, and molecular-based classifiers are being developed to better subdivide the disease. Research presented at ASCO showed that genetic ancestry influences IMmotion151 molecular subgroup classification, with African ancestry associated with a higher frequency of the "proliferative" cluster characterized by VHL wild-type disease.
Machine learning models were developed that can predict IMmotion151 cluster types from RNA sequencing data on individual patient samples, overcoming a key limitation of the original classifier which required batch processing. This approach is now being applied in the OPTIC trial, which aims to allocate patients to either TKI/IO or IO/IO treatment arms based on their molecular cluster type.
The relationship between the gut microbiome and immunotherapy response in RCC was explored through several studies. Low serum levels of ssMAdCAM-1 were linked to antibiotic use and reduced immunotherapy benefit, while microbial metabolites of tryptophan were associated with immune checkpoint blockade resistance in treatment-naive patients.
Intratumoral microbiome analysis in 96 metastatic RCC patients revealed that increased bacterial diversity within tumors was linked to improved immunotherapy response, while a live bacterial product producing butyric acid showed associations between short-chain fatty acid levels and treatment response, suggesting potential for microbiome-directed therapeutic strategies.
The 2023 ASCO conference delivered several practice-changing findings for kidney cancer. The CONTACT-03 results provide strong evidence against immunotherapy rechallenge immediately after IO progression, while long-term updates from KEYNOTE-426 and CLEAR confirm sustained benefits of VEGF-TKI/ICI combinations though with questions about response durability compared to ICI doublets.
In non-clear cell RCC, lenvatinib/pembrolizumab and nivolumab/cabozantinib combinations demonstrated clinically meaningful activity across multiple subtypes, though chromophobe RCC remains a therapeutic challenge. The biological basis for chromophobe resistance, including low immune infiltration and bystander T-cell phenotypes, suggests that novel approaches beyond checkpoint inhibition may be needed.
Early-phase studies of novel agents such as HDAC inhibitors, AXL-targeting antibodies, HIF-2a inhibitors, and engineered T-cells targeting HERV-E offer promising new treatment avenues for patients with limited options. These approaches target distinct biological pathways and may complement existing immunotherapy and TKI combinations.
Translational research is advancing the field toward precision medicine through biomarker-driven treatment selection, molecular classification, and microbiome-based strategies. The integration of these approaches into prospective clinical trials, such as the OPTIC trial, represents an important step toward individualizing kidney cancer treatment based on tumor biology rather than histology alone.