First-Line Treatment for Advanced Renal Cell Carcinoma: Highlights From ASCO Genitourinary Cancers Symposium 2023

During the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium held from February 16 to 18, 2023, oncologists gathered to discuss treatment advances, new clinical trial results, and basic and genomic research. This year’s conference included several major presentations on the treatment of advanced RCC, including updated results from several large-scale clinical trials.
 
Kathryn E. Beckermann, MD, PhD, is an assistant professor of medicine and chief academic fellow in the Division of Hematology and Oncology at the Vanderbilt University School of Medicine in Nashville, Tennessee. Dr Beckermann provided insight into research on the first-line treatment of advanced RCC presented at the meeting.

The 3-year follow-up results from the CheckMate 9ER trial (ClinicalTrials.gov identifier: NCT03141177) were presented by Burotto et al, showing favorable results on survival for nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced RCC.¹ However, serious adverse events were higher with the combination than sunitinib alone. What are your thoughts on these findings? Particularly, how do these findings reinforce the significance of this immunotherapy-tyrosine kinase inhibitor (TKI) regimen and its potential to change survival expectations for patients with metastatic RCC, especially for those classified as higher risk?

It was fantastic to see the updated 3-year overall survival (OS) data; the community is very excited to see this continuing improved OS trend, compared with the prior standard of care. PFS in the combination arm was 16.6 months vs 8.4 months with sunitinib, and the objective response rate (ORR) was 56% in the combination arm, double that of sunitinib. Patients with favorable, intermediate, and poor risk disease were allowed in this trial, and the OS was 49.5 months in the combination arm vs 35.5 months in the sunitinib arm.¹ Importantly, compared to the results reported at the 2022 ASCO symposium,² ASCO 2023 shows that the hazard ratio stayed the same at 0.7, or a 30% risk reduction in death. Everyone is hoping that the tail of the survival curve will now remain stable.
 
In the subgroup analysis, expectedly PFS was worse in the poor-risk population but still better in the combination arm at 9.9 months vs 4.2 months for sunitinib. The trial was not statistically powered to specifically study this, but in that population, there was an OS of 34.8 months with the combination, compared with 10.5 months with monotherapy.¹ If you only have a single chance to treat poor-risk patients, you hope that you make the right choice as a clinician.
 
Furthermore, 28% of patients discontinued treatment in the combination arm vs 11% in the sunitinib arm. But, breaking it down, you see that it was actually 10% who had to discontinue either the nivolumab or the cabozantinib.¹ This updated analysis showed an expected safety effect profile, and I did not see any new safety signals. Of course, we want to cure the disease, but we also want prolongation of life and minimal symptoms, so this is a very nice finding.

The CaboPoint trial (ClinicalTrials.gov identifier: NCT03945773) evaluated the activity of second-line cabozantinib after the first-line, standard-of-care immunotherapy combinations.³ Can you speak to the findings of investigation, and were there any significant differences in OS or time to treatment failure based on type of preceding first-line therapy?

This trial aimed to address gaps in our understanding regarding what to do when patients have refractory disease after initial immunotherapy treatment. The METEOR trial (ClinicalTrials.gov identifier: NCT01865747) looked at second-line treatment of RCC with cabozantinib vs everolimus.⁴ Only a very small percentage of those patients had received prior immune checkpoint inhibitor therapy, so we really do not have a lot of data. Albiges et al presented data on 2 cohorts: patients treated with front-line programmed death 1 (PD-1) inhibitor plus cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor, and patients treated with PD-1 inhibitor plus TKI (not cabozantinib). In the first cohort, which contained patients who were TKI-naive, the ORR was 31.7%, compared with 25% for the second cohort, which consisted of patients who had previous TKI exposure.³ The study suggests that in using cabozantinib following frontline treatment, which has a broad set of targets, not just vascular endothelial growth factor receptor (VEGFR), was beneficial in either TKI-naive or TKI refractory patients. This study was a great effort from a group of institutions to understand how to treat patients in the contemporary setting of frontline immunotherapy combinations.

In the HCRN GU16-260 trial (ClinicalTrials.gov identifier: NCT03117309), Atkins et al looked at ways to reduce toxicity and reduce immunotherapy duration in patients with metastatic RCC, reporting a reduction in toxicity and significant treatment-free survival.⁵ What are your thoughts on this immunotherapy-only approach and the types of patients this might be suitable for?

We know from CheckMate 214 (ClinicalTrials.gov identifier: NCT02231749) that 10.7% of intent-to-treat patients achieve complete remission with PD-1 and CTLA-4 inhibitors, and other patients discontinue treatment due to toxicities and do not require further systemic therapy.⁶ Atkins and colleagues designed this prospective trial to try and decrease toxicity by starting with single agent PD-1, asking whether they would see the same benefit, and later adding second agent CTLA-4, depending on efficacy assessment. They showed that they could achieve decreased toxicity and good treatment-free survival using this type of framework.⁵ I commend the authors on the design and conduct of this trial emphasizing novel clinical trial endpoints and biologic correlates. Now we need to challenge ourselves on how to apply this in clinical practice.

There were 2 presentations focused on biomarker identification in RCC, 1 being the CheckMate 9ER trial (ClinicalTrials.gov identifier: NCT03141177) presented by Choueiri et al.⁷ From this trial or others, are there any predictive biomarkers for response to first-line novel therapies in advanced RCC that are more established or, in your view, are of particular interest for further investigation?

Many of our trials collect tissues for these types of analyses, so it was wonderful to see this data presented by Choueiri et al. From this presentation, there was not a clear “winner” found, but we can still learn from it. Programmed death-ligand 1 (PD-L1) expression was not predictive, which has been shown before. They also identified some trends regarding cluster of differentiation 8 (CD8) T-cells and looked at where they were spatially located in the tumor microenvironment, not just the total numbers, and looked at gene expression from RNA-Seq, identifying some biologically relevant gene expression pathways, which were related to outcome. They also looked at previously published gene expression profiles and cross-referenced them to their results, finding no overlap.⁷ While we remain without a singular checkpoint inhibitor biomarker, I believe work such as this is advancing the understanding behind pathophysiology and response to treatment for patients with kidney cancer.

Last year, initial results from the COSMIC 313 trial (ClinicalTrials.gov identifier: NCT03937219) comparing the triplet combination of cabozantinib/nivolumab/ipilimumab with doublet immunotherapy alone showed an improved PFS but greater toxicity.⁸ This year, the investigators presented outcomes by International mRCC Database Consortium (IMDC) risk groups.⁹ Does this analysis further inform which patients might be most likely to benefit from the triplet therapy?

Personally, it did not for me, but it does contribute some good information. Inhibition of PD-1 and CTLA-4 was the first approved immuno-oncology combination in the frontline setting but left a 17.6% best response of primary progression^6,10; thus, it was reasonable to ask whether we can use all mechanisms of action, including a TKI, all upfront to see whether there is benefit. The investigators did meet their primary endpoint and increased PFS by adding on a TKI. However, PFS is not always the best endpoint for immunotherapies. As a community, we hope that combining all of our treatments would help patients who are at highest risk, but this study actually showed that the poor-risk IMDC patients did worse on the triplet combination: 9.5 months compared with 11.2 months for ipilimumab/nivolumab only.⁹ However, the researchers did highlight that fewer patients in the triplet group had prior nephrectomy, which could affect the results.
 
Perhaps the findings in this trial suggest there is some different biology in patients with poor-risk disease that is not targeted by immunotherapies or TKIs. This presentation made me think: what are we missing in the poor-risk population that we could better treat? Hopefully, we will see some biomarker studies from this trial as well.

Several presentations covered trials of immune checkpoint inhibitors, either in combination with other drugs or with each other.^1,3,9 How much are immune checkpoint inhibitors influencing clinical practice in advanced RCC currently, and what would you like to see in the next 5 years in terms of results from existing trials, new combination trials, or analysis such as biomarkers?

Our big development in the last 5 years has been frontline treatment with immunotherapy. In the next 5 years, I think we will be able to improve frontline treatment further but also really address immunotherapy use in second-line treatment and beyond. There are a couple of ongoing trials, including Contact-03 (ClinicalTrials.gov identifier: NCT04338269), looking at second-line use of cabozantinib monotherapy or combination with atezolizumab. Another trial, which I am an investigator on, is TiNivo-2 (ClinicalTrials.gov identifier: NCT04987203) that is prospectively studying the continuation of checkpoint inhibition after frontline failure of the same with tivozanib with or without nivolumab. These large, randomized phase 3 trials will give us a lot more information about whether there is any benefit to continuing immunotherapy treatment after first-line. Some clinicians are already doing this, but we do not have the data currently to inform whether this is the right thing to do. In the next 5 to 10 years, I would love to see continued biomarker discovery, which has really come back into focus with the use of immunotherapy. I think we all hope to identify a biomarker that can predict response to checkpoint inhibition in advanced RCC, reducing financial toxicity and side effect profiles.

Is there anything else of note you would like to mention about first-line treatment of advanced RCC presented at the meeting?

The ASCO 2023 symposium showcased updated results from ongoing studies. A highlight for me was the Atkins study showing that treatment-free survival really could and should be a primary endpoint going forward. We will continue to learn from COSMIC 313 and CheckMate 9ER. It is wonderful to see all of the biomarker data, and I would like to encourage the community, including our industry partners and our academic colleagues, to strive to continue pushing these analyses forward.

This Q&A was edited for clarity and length.

Disclosures

Kathryn E. Beckermann, MD, PhD, reported affiliations with Alpine Biosciences, Inc; Aravive, Inc; AVEO Pharmaceuticals, Inc; AstraZeneca Pharmaceuticals, LP; Bristol-Myers Squibb Company; Exelixis, Inc; Merck & Co, Inc; Seagen, Inc; and Sanofi-Aventis U.S. LLC.

References

1. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl 6):603. doi:10.1200/JCO.2023.41.6_suppl.603
 
2. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl 6):350. doi:10.1200/JCO.2022.40.6_suppl.350
 
3. Albiges L, Powles T, Sharma A, et al. CaboPoint: interim results from a phase 2 study of cabozantinib after checkpoint inhibitor (CPI) therapy in patients with advanced renal cell carcinoma (RCC). J Clin Oncol. 2023;41(suppl 6):606. doi:10.1200/JCO.2023.41.6_suppl.606
 
4. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823. doi:10.1056/NEJMoa1510016
 
5. Atkins MB, Jegede O, McDermott DF, et al. Treatment-free survival (TFS) outcomes from the phase II study of nivolumab and salvage nivolumab + ipilimumab in advanced clear cell renal cell carcinoma (aRCC) (HCRN GU16-260-Cohort A). J Clin Oncol. 2023;41(suppl 6):604. doi:10.1200/JCO.2023.41.6_suppl.604
 
6. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):E001079. doi:10.1136/esmoopen-2020-001079
 
7. Choueiri TK, Motzer RJ, Powles TB, et al. Biomarker analysis from the phase 3 CheckMate 9ER trial of nivolumab + cabozantinib v sunitinib for advanced renal cell carcinoma (aRCC). J Clin Oncol. 2023;41(suppl 6):608. doi:10.1200/JCO.2023.41.6_suppl.608
 
8. Choueiri TK, Powles TB, Albiges L, et al. LBA8 Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Ann Oncol. 2022;33(suppl 7):S1430-S1431. doi:10.1016/j.annonc.2022.08.070
 
9. Powles T, Motzer RJ, Albiges L, et al. Outcomes by IMDC risk in the COSMIC-313 phase 3 trial evaluating cabozantinib (C) plus nivolumab (N) and ipilimumab (I) in first-line advanced RCC (aRCC) of IMDC intermediate or poor risk. J Clin Oncol. 2023;41(suppl 6):605. doi:10.1200/JCO.2023.41.6_suppl.605
 
10. U.S. Food and Drug Administration approves Opdivo® (nivolumab) + Yervoy® (ipilimumab) as first-line treatment of patients with metastatic non-small cell lung cancer whose tumors express PD-L1≥1%. News release. Bristol Meyers Squibb. May 15, 2020. Accessed March 9, 2023. https://news.bms.com/news/corporate-financial/2020/US-Food-and-Drug-Administration-Approves-Opdivo-nivolumab–Yervoy-ipilimumab-as-First-Line-Treatment-of-Patients-with-Metastatic-Non-Small-Cell-Lung-Cancer-Whose-Tumors-Express-PD-L11/default.aspx

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