Reflections on IKCS 2020: The Nuance of Treatment Selection in RCC

Reflections on IKCS 2020: The Nuance of Treatment Selection in RCC

Question

In your view, what were the most important abstracts presented this year at the 19th Annual Meeting of the International Kidney Cancer Symposium (IKCS 2020)?

Answer

There were quite a few posters that were worthwhile. One was presented by Dr Voss evaluating depth of response and correlation with clinical outcomes from the phase 3 JAVELIN Renal 101 study investigating avelumab plus axitinib compared to sunitinib.¹ The analysis demonstrated deeper responses in the avelumab plus axitinib–treated patients, and greater tumor shrinkage at early imaging time points was associated with longer progression-free survival.

Additionally, Dr Toni Choueiri presented data that were presented at the ESMO virtual meeting from the CheckMate 9ER trial of nivolumab plus cabozantinib compared to sunitinib in patients with advanced renal cell carcinoma (RCC).² The study met all efficacy endpoints, demonstrating superiority [in] progression-free survival, overall survival, and overall response rate of the combination compared to sunitinib alone. Additionally, patients had improved quality of life over sunitinib with the combination.

Another [study] was a correlative serum biomarker analysis from a phase 1b/2 trial reported by Dr Lee looking at lenvatinib plus pembrolizumab.³ It evaluated blood-based biomarkers — both angiogenesis and immune activation [biomarkers] — and looked at whether there were signals that were predictive of response to therapy in that context. There did seem to be candidate biomarkers that emerged as potentially important.

Another interesting poster was presented by a team from Rutgers looking at factors associated with clinical trial participation for kidney cancer patients and various socioeconomic and social barriers that exist.⁴ It is always important for us to think about how we can ensure that our trial populations are reflective of the populations that are receiving therapy in the clinic, and how to bridge that disparity gap.

Another abstract by Dr Campbell discussed tremelimumab with or without cryoablation in metastatic renal cell carcinoma.⁵ There was a post-hoc analysis of patients with clear cell vs non–clear cell histologies. It demonstrated that baseline tumor microenvironment in clear cell is more favorable to anti-[cytotoxic T-lymphocyte antigen 4; CTLA] therapy compared with non–clear cell and that anti-CTLA therapy generated an inflammatory tumor microenvironment in clear cell histology. There are limited data about the role of novel therapies in advanced disease in non–clear cell. It is important to get insight into the underlying biology of those diseases and to try to understand the role of therapies typically used in clear cell when used in non–clear cell disease.

There was also a remarkable keynote address by William G. Kaelin, Jr, MD, one of the 2019 Nobel Laureates, for his work on [hypoxia-inducible factors; HIFs] in cancers and particularly, in RCC. His work has led to the development and clinical testing of MK-6482, a HIF-2α inhibitor. He gave an excellent discussion about the role of [cyclin-dependent kinase 4/6; CDK4/6] in RCC pathogenesis and how this can be a potential therapeutic target.

There was also a wonderful international panel highlighting 5 speakers including Drs Laurence Albiges, Guillermo de Velasco, Masatoshi Eto, Andre Fay, and Viktor Grunwald. The panel gave perspective — as is always the case for IKCS — about the international use of the novel immunotherapy combinations, the role of cytoreductive nephrectomy, and biomarkers in RCC. It was an excellent meeting.

Question

Researchers examined records from the National Cancer Database and found that patients with clinically localized T1b-T2bN0Mo renal cell carcinoma who delayed surgery for 3 months did not have an increased risk of tumor progression.⁶ Was this a surprising finding? Why or why not?

Answer

I am not surprised by a 3-month delay in surgery not impacting long-term outcomes. Many renal tumors are found incidentally on imaging done for some other reason and not necessarily because the patient was having pain or bleeding. By definition, a T1b tumor is 4 to 7 cm in size. These tumors may not necessarily be symptomatic to prompt diagnosis. T2 tumors are larger. Different tumors have different growth rates, but certainly for small renal masses there is a slower growth rate. In general, it is unlikely that within a 3-month interval someone will develop overt metastatic disease or micrometastatic disease.

These data are important in the context of surgical planning during the COVID pandemic, and in places where resources are being restricted because of the pandemic, I think these data can at least provide some reassurance around the timing of surgery in patients who have stage T1b-T2b disease. That being said, surgery is of curative intent and the The European Association of Urology guidelines for RCC management during the pandemic recommend surgery within 3 months for T1b-T2 tumors.⁷

Question

Although patients with high-risk locoregional RCC may be eligible to receive adjuvant systemic therapy after undergoing nephrectomy, investigators discovered that few patients in this subgroup received therapies in the adjuvant setting.⁸ Can you propose an explanation for why this may be?

Answer

There are a lot of nuances around adjuvant therapy for RCC. Essentially every trial, except for the S-TRAC trial, has reported to be negative.⁹ Sunitinib is currently the only [US Food and Drug Administration]-approved adjuvant treatment. This approval was based on the S-TRAC trial, which enrolled patients with T3 tumors that were at high risk of recurrence (and only patients with clear cell histology). The trial demonstrated an improvement in disease-free survival without an overall survival benefit. Most patients probably do not receive adjuvant therapy. The question of which patients benefit from adjuvant therapy for is still evolving given that there is toxicity associated with treatment and there is no overall survival benefit.

The other data that could be applicable in this context were from a large ECOG-ACRIN trial that was conducted in patients who had undergone metastasectomy and had no evidence of disease.¹⁰ You would think that these patients would be the most at risk for recurrence. These patients were given adjuvant pazopanib vs placebo and the trial was negative. The use of a [tyrosine kinase inhibitor; TKI] did not improve outcomes for these patients. I think the question of whether TKI therapy is resolving microscopic disease is unclear. Clinically, I am not surprised by this abstract’s results because there are lots of reasons not to use adjuvant therapy.

Question

Authors of an abstract NAS102 presented at IKCS concluded that the presence of certain plasma cytokines can predict benefit from systemic immunotherapies/targeted therapies in metastatic renal cell carcinoma.¹¹ But, is it also possible that the immunologic profiles present in a given patient are not there as a result of exposure to drug treatment, but for some other reason? What could be some potential alternative reasons for the appearance of these cytokines?

Answer

When we look at predictive biomarkers, we are looking for them to help predict that someone is going to respond to a given therapy. These are patients that have not yet received that therapy. They have a certain biomarker, and based on that, we then think they could do better on a given therapy.

The validation of clinically applicable predictive biomarkers has been very elusive in renal cancer. There is not yet a biomarker used for selection of therapy for people with advanced disease. The closest we have gotten is with [programmed cell death ligand 1; PD-L1] status, but we know that is not a pure biomarker. It is prognostic but not purely predictive. We know there are responses in PD-L1–negative patients.

There are other biomarkers being looked at from tumor mutational burden — with mixed data — to neoantigen load, mutation status, and PBRM1. Some of the most exciting work has come from gene signatures that were looked at in the context of the IMmotion150 and applied across other trials. We are not there yet with predictive biomarkers, but there are a lot being explored in RCC.

The unique aspect of the biomarkers explored in this study were that they were derived from assessment of plasma cytokines as opposed to tissue, which potentially are more feasible in implementation in the clinic given barriers to procurement of tumor tissue.

Question

What are some therapies in the RCC pipeline that were mentioned at IKCS that seem most promising to you? Are there any new biomarkers in RCC that you think deserve more attention?

Answer

There are a lot of agents in the pipeline. One of the agents that is furthest along with MK-6482, a HIF-2α inhibitor that is in phase 3 testing in the treatment of refractory RCC. There is also a glutaminase inhibitor that has demonstrated promising data from a study combining a first-in-class glutaminase inhibitor (CB-839, telaglenastat) plus everolimus in the ENTRATA trial were already presented and the CANTATA trial looking at the glutaminase inhibitor plus cabozantinib has completed accrual and we are eagerly awaiting the results of this study.

Another agent of interest is pegylated IL-10. This is in development in early studies and has demonstrated a signal of efficacy. I think we need more drugs with novel mechanisms of action now that we PD-L1, CTLA-4, and [vascular endothelial growth factor; VEGF] inhibitors have become standard options for patients with advanced RCC.

With regard to biomarkers, the data are still evolving. The most promising is gene-signature scores to help define subsets of patients who will benefit from a pure VEGF strategy or pure immunotherapy or a combination VEGF/immunotherapy strategy. Another novel area is looking at circulating tumor cells and developing integrative blood-based assays that can — in real time — monitor disease. It will be really interesting and exciting to see this develop in the future.