Advanced Kidney Cancer Research: Insights From IKCS 2021

From November 5th to 6th, oncologists from around the world gathered for the 2021 International Kidney Cancer Symposium (IKCS) to discuss the latest research and innovations in kidney cancer care. The conference was held both in person in Austin, Texas, and virtually.

Ulka Vaishampayan, MBBS, shared key takeaways from the research focused on advanced renal cell carcinoma (aRCC) presented at the meeting. Dr Vaishampayan is a professor of internal medicine/oncology and director of the Multitumor Experimental Therapeutics Team/Phase I program at the University of Michigan Rogel Cancer Center.

Did you notice any trends in aRCC research presented at IKCS 2021?

Yes, I noticed several specific trends, one of which is related to the timing and optimization of targeted therapy, because a lot of these treatments have emerged in parallel and we have not quite figured out how to optimize their sequence. Then there is the question of a local therapy’s impact on the management of kidney cancer and the use of molecular biomarkers as predictors of response to treatment. Some related issues covered by the presented abstracts include how to incorporate local therapy with systemic therapy, whether or not to perform surgery, and whether ablation is better than radiation for the management of kidney masses.

One of the trends you mentioned relates to combining localized treatment, such as surgery or radiation, with systemic therapy in advanced kidney cancer. Can you highlight any relevant ongoing studies in this area?

Our phase 3 study, S1931/PROBE (ClinicalTrials.gov Identifier: NCT04510597), aims to enroll patients who present with primary tumor and metastases at the same time to determine whether there is benefit from combining cytoreductive nephrectomy with an immune checkpoint inhibitor.¹ One of the previous studies, CARMENA (ClinicalTrials.gov Identifier: NCT00930033), showed that the addition of nephrectomy, or removing the primary tumor, is of no benefit when you use sunitinib as the treatment, which was available at the time.² Our argument is that with immune therapy in the mix, there is the potential that cytoreductive nephrectomy will add benefit to the management of metastatic kidney cancer. So, after patients are started on any of the approved immune-based regimens — whether ipilimumab plus nivolumab, axitinib plus pembrolizumab, or axitinib plus avelumab — they get randomly assigned to either remove the primary tumor or continue with systemic therapy. The primary endpoint of this trial is overall survival, and the study is in the recruiting phase.

Can you comment on the significance of 5-year follow-up data from CheckMate 214, which reported on long-term survival of 5 years or more in patients with clear cell aRCC treated with first-line nivolumab plus ipilimumab vs sunitinib?

These data showed that immune checkpoint inhibitor therapy [with nivolumab plus ipilimumab] can result in long-term durable remission, even after the treatment is stopped.³ CheckMate 214 (ClinicalTrials.gov Identifier: NCT02231749) has the longest follow-up to date of immune-based combination therapy as frontline therapy for aRCC. The investigators reported that 163 of 425 patients with intermediate/poor-risk aRCC and 73 of 125 patients with favorable-risk aRCC randomly assigned to nivolumab plus ipilimumab were long-term survivors compared with 112 of 422 patients with intermediate/poor-risk aRCC and 59 of 124 patients with favorable-risk aRCC randomly assigned to sunitib.

In long-term survivors, the responses with nivolumab plus ipilimumab were more durable and complete, regardless of risk group. In addition, compared with sunitinib, fewer patients treated with nivolumab plus ipilimumab required subsequent systemic therapy and more patients experienced a treatment-free interval. This is a valuable takeaway because for a lot of these treatments, the 18-month follow-up results are reported and incorporated into practice. It is good to see that we are on the right track in terms of long-term treatment.

Were there any relevant findings from the studies of predictive biomarkers in kidney cancer presented at IKCS 2021?

Yes, this conference highlighted another promising area of research in aRCC — one that is not fully established yet but which I think will be incorporated into prospective trials — and that is studies of predictive biomarkers.

Dr Pedro Barata from Tulane University reported on gene expression profiling and predictive values of proliferative vs angiogenic gene panels in non-clear cell RCC (nccRCC).⁴ His team found that the proliferative genomic cluster was more likely to indicate sensitivity to immune therapy in nccRCC. The presence of an angiogenic cluster would be, of course, more amenable to the vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (TKI) therapy combination. Prospective validation of these exciting results is warranted.

There is also an ongoing phase 2 study by Dr Yu-Wei Chen from the Vanderbilt-Ingram Cancer Center that is examining whether patients with clusters enriched in immunogenic/proliferative pathways will have improved outcomes with ipilimumab/nivolumab compared with the control group, and whether patients with angiogenic clusters will have improved outcomes with an immunotherapy/TKI combination compared with the control group.⁵ This study is building on the findings from the phase 3 IMmotion151 trial (ClinicalTrials.gov Identifier: NCT02420821), which identified 7 gene expression clusters in ccRCC based on RNA sequencing data.⁶

Another study by researchers from the University of Michigan and other centers analyzed the prognostic significance of cell cycle proliferation and an epithelial-mesenchymal transition gene expression signature consisting of 22 genes to investigate the impact on progression-free survival and disease-specific survival in patients with localized ccRCC who underwent radical nephrectomy and resection for localized disease.⁷ The study demonstrated that use of the gene signature improved the accuracy of predicting recurrence risk in addition to the clinical parameters of tumor size, grade, and stage. This needs validation in a larger population; it has the potential for clinical application, particularly in identifying high-risk patients who are much more likely to experience relapse and then target them with adjuvant therapy.

Are there any concluding remarks that you would like to make regarding IKCS 2021?

IKCS was a remarkable platform for a stimulating interaction with researchers within the kidney cancer field and provided an opportunity to review current advances and brainstorm future ideas to make an impact on this disease.