Treatment Strategies for Advanced Renal Cell Carcinoma: Insights From 2022 IKCS: North America

Clinicians and scientists gathered for the 2022 International Kidney Cancer Symposium (IKCS): North America, which took place virtually and in-person in Austin, Texas, from November 4 to November 5, 2022. Groundbreaking science was discussed, including basic and clinical research, immunotherapy, innovative treatment options, and emerging diagnostic tools and techniques.
 
Moshe C. Ornstein, MD, MA, who is a genitourinary medical oncologist at Cleveland Clinic in Cleveland, Ohio, shared his insights into research presented at this year’s meeting, including lenvatinib plus pembrolizumab for RCC, the role of CD200R in RCC immune evasion, and CA-125 as a potential therapeutic target in renal medullary carcinoma (RMC).

There were several interesting presentations at this year’s meeting. In your opinion, which of the presented studies were the most interesting or clinically impactful?

I did not feel as though there were any studies that had the potential to change current practices. Rather, I found 2 clinically impactful studies that could inform our understanding of RCC and, therefore, inform clinical practice.

The first study was an update to CheckMate 9ER (ClinicalTrials.gov identifier: NCT03141177), a phase 3, randomized, open-label trial. This updated analysis offered insights into the association between depth of response and clinical outcomes. This was an exploratory analysis in patients with previously untreated aRCC. In this study by Suárez and colleagues,¹ eligible patients received either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily), or sunitinib (50 mg once daily) alone. The study shows that greater decreases in tumor burden in cabozantinib plus nivolumab were generally associated with improved outcomes. However, this study also tells us that patients do not necessarily need to achieve a complete response to have a good, durable outcome. This depth of response can provide prognostic implications regarding survival.
 
The second study of interest was by Voss and colleagues,² which looked at the impact of subsequent therapies in patients with aRCC receiving lenvatinib plus pembrolizumab vs sunitinib in the open-label, randomized, phase 3 CLEAR study (ClinicalTrials.gov identifier: NCT02811861). Currently, the combination of lenvatinib and pembrolizumab is one of the standard options in treatment-naive mRCC. In this study, patients received lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously every 3 weeks), or sunitinib (50 mg orally once daily with 4 weeks on followed by 2 weeks off). The results showed that lenvatinib plus pembrolizumab had a statistically significant and clinically meaningful benefit over sunitinib. These findings remained consistent after accounting for subsequent therapies and confirm lenvatinib plus pembrolizumab as a suitable first-line treatment for aRCC.

Davies and colleagues³ presented data in which they aimed to characterize the novel immune checkpoint CD200R and its role in RCC immune evasion. Their work suggests that the inhibition of the CD200R immune checkpoint may present a novel therapeutic strategy in clear cell RCC (ccRCC). Could CD200R also play a role as a biomarker for ccRCC, and what implications would this have on treatment approaches?

For years, checkpoint inhibition in RCC focused on the inhibition of programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Davies and colleagues presented a novel checkpoint, CD200R, that appears to have a role in allowing RCC to evade the immune system. The development of novel checkpoint inhibitors is critical in a field that is saturated with traditional anti-PD-L1 and CTLA-4 inhibitors. However, it remains to be seen whether the inhibition of other cellular checkpoints will improve the clinical outcomes of patients in an era where we see extremely positive results with the current checkpoint inhibitor-based therapies. The potential for the use of CD200R as a biomarker in this setting is intriguing; however, the question is whether the clinical utility of CD200R will be similar to the current PD-L1 biomarker together with the checkpoint inhibitors, which is clinically limited. Taken together, it is exciting to see novel checkpoint inhibitors being developed, but only time will tell whether they will add any clinical benefit and whether any biomarker can successfully be developed alongside it.

Long-term follow-up data for an early phase trial of nivolumab plus ipilimumab with the novel bifidogenic live bacterial product CBM588 in patients with mRCC was presented by Dizman.⁴ Results demonstrated that nivolumab plus ipilimumab with CBM588 has superior clinical activity over just nivolumab plus ipilimumab. The use of a live bacterial product to complement chemotherapeutic regimes is relatively novel. What are your thoughts on this approach, and do you think it shows promise for the future of RCC treatment?

The role of the microbiome in patients treated with checkpoint inhibitors in RCC is fascinating, but it is important to keep in mind that this was a small phase 1b trial with a total of 29 patients eligible for analysis. There is likely to be some role for microbiome manipulation to enhance the response to immunotherapy, but more work is needed to define it. This is particularly important given the complexity of the microbiome and the fact that it can be affected by diet, medications, and genetics. Although the data are impressive, further work is needed to demonstrate the true contribution of CBM588 to the efficacy of checkpoint inhibitors. Fortunately, larger trials to address this are either currently ongoing or planned. In short, this data shows promise and is exciting, but it is still too early to draw definitive, clinically impactful conclusions.

Research presented by Blum⁵ discussed biomarkers of disease burden and treatment response in RMC. He established a large RMC cohort where he assessed known serum tumor markers with RMC disease severity (eg, metastatic burden). CA-125 was consistently elevated above upper-limit normal ranges. Do you have any comment regarding the specificity of serum biomarkers such as these for RCC? Could CA-125 have potential as a therapeutic target?

RMC is a serious form of kidney cancer with a median survival of a little over 1 year. Although it is kidney cancer, it is primarily treated with cytotoxic chemotherapy compared with the immunotherapy-based regimens in ccRCC. In this retrospective study by Blum, CA-125 was found to be extremely high in patients with metastatic disease, which was proportional to metastatic disease burden. The CA-125 levels decreased with response to therapy. The most likely benefit of using CA-125 for RCC will be to determine its correlation with disease burden and its use as a biomarker of response to therapy. I think that the role of CA-125 as a new therapeutic target will prove to be more challenging. CA-125 is almost synonymous with ovarian cancer and research has shown that it has been difficult to use CA-125 as a therapeutic target in this setting. Considering these findings, I feel we would encounter the same challenges in RMC.

Hahn and colleagues⁶ examined the role of lenvatinib plus everolimus as compared with cabozantinib in patients with mRCC who have progressed following prior treatment with an immune checkpoint inhibitor. Cabozantinib and lenvatinib have been noted to be comparable in terms of mechanisms of action, yet distinct. How do you predict lenvatinib plus everolimus will compare head to head with cabozantinib in terms of progression-free survival?  

This is an important clinical question. In most patients, the disease will eventually progress while they are receiving an immune checkpoint inhibitor. In this case, they will then be treated with targeted therapy. Cabozantinib is an inhibitor of vascular endothelial growth factor (VEGF), tyrosine-protein kinase MET (c-MET), and AXL with demonstrated efficacy in refractory RCC. Similarly, lenvatinib (a VEGF inhibitor and fibroblast growth factor receptor [FGFR] inhibitor) in combination with everolimus (a mechanistic target of rapamycin [mTOR] inhibitor) has also demonstrated efficacy in a randomized, phase 2, open-label trial (ClinicalTrials.gov identifier: NCT01136733) in patients previously treated for mRCC.⁷ For patients receiving ipilimumab plus nivolumab as front-line therapy, I suspect they will both show good efficacy. However, I am not certain that there would be a significant difference in the efficacy between the 2 treatments.

What are your thoughts on the future of RCC treatment given the research discussed?

There are 3 primary areas of investigation in RCC treatment. The first is the use of triplet therapy in the front-line mRCC setting. Although the standard of care is currently a doublet treatment with a checkpoint inhibitor backbone, it remains to be seen whether a front-line triplet (such as a double immunotherapy plus tyrosine kinase inhibitor [IO/IO/TKI] approach) will improve clinical outcomes. The second area of investigation is the role of biomarkers to select treatments for individual patients. Currently, patients are treated regardless of their cancer’s underlying biology, and efforts are ongoing to develop genomically driven treatment choices for patients. Lastly, the development of novel agents, such as hypoxia-inducible factor 2a (HIF-2a) inhibitors and patient-specific vaccines, are ongoing.

This Q&A was edited for clarity and length.

Disclosures

Moshe C. Ornstein, MD, MA, reported affiliations with Aravive, Inc; Astellas Pharma, Inc; AstraZeneca; AVEO Pharmaceuticals, Inc; Bristol Myers Squibb; Eisai Co, Ltd; Exelixis, Inc; Merck & Co, Inc; Pfizer, Inc; and Surface Oncology, Inc.

References

1. Suárez C, Choueiri TK, Burotto M, et al. Association between depth of response (DepOR) and clinical outcomes: exploratory analysis in patients with previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 9ER. J Clin Oncol. 2022; 40(suppl 16):4501. doi:10.1200/JCO.2022.40.16_suppl.4501
 
2. Voss MH, Powles T, McGregor BA, et al. Impact of subsequent therapies in patients (pts) with advanced renal cell carcinoma (aRCC) receiving lenvatinib plus pembrolizumab (LEN + PEMBRO) or sunitinib (SUN) in the CLEAR study. J Clin Oncol.  2022;40(suppl 16):4514. doi:10.1200/JCO.2022.40.16_suppl.4514
 
3. Davies G, Girish P, Smalley M. CD200-mediated immune evasion in clear cell renal cell carcinoma. Paper presented at: 2022 International Kidney Cancer Symposium (IKCS): North America; November 4-5, 2022; Austin, TX. Abstract 5.
 
4. Dizman N. Clinical outcomes with nivolumab/ipilimumab with or without CBM588 in metastatic renal cell carcinoma: long-term follow-up of a randomized phase Ib clinical trial. Paper presented at: 2022 International Kidney Cancer Symposium (IKCS): North America; November 4-5, 2022; Austin, TX. Abstract 6.
 
5. Blum KA. Biomarkers of disease burden and treatment response in renal medullary carcinoma. Paper presented at: 2022 International Kidney Cancer Symposium (IKCS): North America; November 4-5, 2022; Austin, TX. Abstract 2.
 
6. Hahn AW, Chahoud J, Skelton WP IV, et al. A phase II study of lenvatinib plus everolimus versus cabozantinib in patients with metastatic renal cell carcinoma (mRCC) that progressed on a PD-1/PD-L1 checkpoint inhibitor (LenCabo). Poster presented at: 2022 International Kidney Cancer Symposium (IKCS): North America; November 4-5, 2022; Austin, TX. Abstract 51.
 
7. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-1482. doi:10.1016/S1470-2045(15)00290-9

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