Navigating Systemic Therapy for RCC: Balancing Risk Status and Response

Vincent (Wenxin) Xu, MD

Despite a perhaps overwhelming number of combination regimens available for use in the frontline setting for patients with renal cell carcinoma (RCC), treatment decisions can still largely boil down to a patient’s risk status, according to Vincent (Wenxin) Xu, MD. For second-line therapy, investigators are looking to contemporary trials for guidance, he added.

Xu is a physician at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School, both in Boston, Massachusetts. He discussed systemic therapy for patients with clear cell and non–clear cell RCC in a presentation delivered at the 16th Annual Interdisciplinary Prostate Cancer Congress and Other Genitourinary Malignancies.¹ 

Choosing Between Frontline Systemic Therapy for Clear Cell RCC

Approvals for clear cell RCC over the past 17 years can broadly be defined in 3 waves, Xu said: VEGF TKIs, immunotherapy, and combination regimens thereof, each demonstrating more durable responses than the last. As a result, median overall survival (OS) in frontline, phase 3 trials have improved from 6.0 months in 1999 to 55.7 months in 2021. “There’s been a clear progression in improvement in the past several years, and almost a linear increase in OS over time,” Xu said.

“Now in 2023, it’s really a question of how to apply these agents and which combinations to use in the first line,” Xu said.

The first criteria that should be applied when looking at frontline treatment is International Metastatic RCC Database Consortium (IMDC) risk score. “Despite many years of working on biomarkers for kidney cancer, right now the standard of care is still to choose systemic therapy based largely on a clinical biomarker as opposed to a molecular or biologic biomarker,” Xu said. The model considers 6 variables, including time from diagnosis to systemic therapy (less than 1 year), Karnofsky performance status (under 80%), anemia, hypercalcemia, neutrophil count, and thrombocytosis. Patients with 0 risk factors have favorable risk, patients with at least 3 have poor risk, and the rest have intermediate risk. “In general, the fewer risk factors one has, the more favorable risk the biology is, the more likely the cancer is to be angiogenicly driven vs immune inflamed,” Xu said.

Although multiple potential regimens are approved for use in the frontline setting, Xu argued that providers should largely be deciding between just 4: ipilimumab (Yervoy) and nivolumab (Opdivo); nivolumab and cabozantinib (Cabometyx); pembrolizumab (Keytruda) and lenvatinib (Lenvima), and pembrolizumab and axitinib (Inlyta). Each regimen has demonstrated improved progression-free survival (PFS) and OS vs sunitinib (Sutent).² However, Xu noted that the approval for ipilimumab and nivolumab is limited to intermediate- and poor-risk patients because only a benefit was demonstrated in that population in the pivotal phase 3 CheckMate 214 trial (NCT02231749).³

At the 2023 Genitourinary (GU) Cancers Symposium, updated findings from the phase 3 CheckMate 9ER (NCT03141177) and COSMIC-313 (NCT03937219) trials were presented.^4,5 In 3-year follow-up data from CheckMate 9ER, outcomes were stratified by risk status, showing improved OS, PFS, as well as objective response and complete response rates, with cabozantinib and nivolumab vs sunitinib across all subsets. Additionally, the median time to subsequent therapy with the combination was 20.6 months (95% CI, 7.9–not evaluable) in patients who completed the entire 2-year course of nivolumab.

Outcomes according to risk status were also presented in updated findings from the COSMIC-313 trial. “We still don’t have the most important new data, which is OS, but we did get some more granularity about the PFS data,” Xu said. In the intention-to-treat (ITT) analysis, cabozantinib plus nivolumab and ipilimumab showed sustained PFS benefit vs ipilimumab and nivolumab (HR, 0.74; 95% CI, 0.61-0.90). However, in this case, the triplet showed improved PFS only in the intermediate-risk subset (HR, 0.68; 95% CI, 0.54-0.86) compared with the poor-risk subset (HR, 0.93; 95% CI, 0.64-1.35). Similarly, objective responses were higher only in the ITT and intermediate-risk groups.

One potential explanation for the disparate outcomes between risk groups was treatment exposure. However, upon closer examination, investigators showed that adverse effects (AEs) leading to treatment discontinuation occurred more frequently in the intermediate-risk group compared with the poor-risk group. “One hypothesis that some folks raised after the initial data came out was that maybe people getting the triplet had more toxicity, therefore got less treatment. Maybe they had less ipilimumab, or maybe they had less cabozantinib, and that toxicity and dose reduction contributed to lack of benefit for the triplet. But, with this new data, it's not so clear that’s the case,” Xu said.

With this new data, Xu recommended that ipilimumab and nivolumab should be considered in patients with sarcomatoid or rhabdoid RCC because of enrichment for immune response, and intermediate- and poor-risk patients who are not too symptomatic from their disease and can afford the risk of progressive disease in exchange for a proportion of long-term responses. In data from the phase 3 CheckMate 214 trial in the sarcomatoid population, the median OS was not reached with ipilimumab plus nivolumab vs 14.2 months with sunitinib. Median PFS was 26.5 months vs 5.1 months, respectively.⁶ “If they can’t get ipilimumab/nivolumab, we should at least offer some regimen that has an immunotherapy component,” Xu said.

“For highly selected patients who either don’t want a TKI or who really prioritize the chance of treatment-free survival and are willing to tolerate a lower response rate, ipilimumab and nivolumab might still be reasonable with a shared decision-making model, and for all other patients, I would generally offer immunotherapy/TKI or TKI monotherapy,” Xu said.

Specifically, for patients with bone metastases in need of fast response and improved quality of life, nivolumab and cabozantinib should be considered. Due to tolerability challenges, Xu stated that pembrolizumab and lenvatinib may be best reserved for more robust patients with symptomatic disease. “This is a great regimen for people who are symptomatic, who want rapid tumor shrinkage, and are robust and can tolerate 20 mg of lenvatinib, which is not easy,” Xu said.

Lastly, because axitinib has a short half-life of just 6 hours, Xu said that pembrolizumab plus axitinib may be most appropriate for patients who may need to stop TKI therapy quickly because of surgery, bleeding complications, or tolerability issues.

Although the latter 3 combinations are preferred regimens for first-line therapy for favorable-risk patients in the National Comprehensive Cancer Network guidelines,⁷ Xu added that single-agent TKIs are a reasonable option to consider, particularly for patients with indolent disease or those with a contraindication to immunotherapy. Ipilimumab and nivolumab, though not approved for favorable-risk patients, may have a role to play for those without any IMDC risk factors, Xu said, citing data showing a 39% objective response rate and 8.0% complete response rate in this population.⁸ 

“While I do not use ipilimumab and nivolumab as my default option in favorable risk, this data [are] worth discussing with patients, especially patients who have some sort of contraindication to TKI therapy,” Xu said.

Altogether, Xu explained that treatment for favorable-risk patients starts with the question: Does this patient need immediate treatment?

Selecting Second-line Therapy and Beyond

The current state of data is evident in the NCCN guidelines, Xu said, with no preferred regimens, only other recommended regimens and therapies that are useful in certain circumstances.⁷

“Several major trials in refractory clear cell RCC have shown an OS benefit. The problem is all the randomized trials were done using old comparator arms. Everolimus [Afinitor] or sorafenib [Nexavar] are no longer really a relevant second-line comparator arms, and therefore the trials are outdated,” Xu said.

However, interim findings from the phase 2 CaboPoint trial (NCT03945773) presented at the 2023 GU Cancers Symposium demonstrated that cabozantinib is active following progression on an immunotherapy-based combination, with overall response rates (ORRs) ranging from 29.5% (95% CI, 20.3%-40.2%) to 31.7% (95% CI, 20.3%-45.0%).⁹ Final analysis from the trial is expected in September 2023.

“For most patients in the second-line setting, single-agent TKI should still be the preferred option. Among single-agent TKIs, I would favor the TKIs that have shown activity in the second-line setting after prior immunotherapy or after prior other TKIs. Specifically, cabozantinib, axitinib, the combination of lenvatinib and everolimus, as well as tivozanib [Fotivda] in the third-line setting and beyond,” Xu said.

The role of checkpoint inhibition and VEGF TKI is less clear following an announcement that the phase 3 CONTACT-03 trial (NCT04338269) evaluating atezolizumab (Tecentriq) and cabozantinib vs cabozantinib alone following progression on immunotherapy did not meet its primary PFS end point.¹⁰ 

“What do we do in the second line? My approach is that we would prioritize treatments with different mechanisms of action compared with what the patients already received,” Xu stated.

Emerging Data on Targeting HIF-2alpha in RCC

Although clear cell RCC is driven by von Hippel-Lindau (VHL) pathway alterations, with over 90% of clear cell kidney cancers having biallelic inactivation of VHL,1 only recently have investigators been able to target alterations further upstream from the pathway compared with VEGF, such as HIF-2alpha, explained Xu. This was first demonstrated with the HIF-2alpha inhibitor belzutifan (Welireg) in patients with germline VHL-associated RCC. In the study, treatment-naïve patients who received 120 mg of oral belzutifan once daily experienced an ORR of 64% and a 92% decrease in target lesions.¹¹ Data from the trial served as the basis for the approval of belzutifan in this indication.¹²

The efficacy of the agent was also shown in patients with metastatic clear cell RCC pretreated with immunotherapy and/or VEGF in the phase 1 LITESPARK-001 trial (NCT02974738). At a median follow-up of 41.0 months, the ORR was 25% (n = 14), with a disease control rate (DCR) of 60% (n = 44).¹³

Belzutifan was also shown to be effective in combination with cabozantinib in the phase 2 LITESPARK-003 trial (NCT03634540) in a refractory setting, with an ORR of 31% and a DCR of 92%.¹⁴ In the treatment-naïve setting, the ORR and DCR were 57% and 94%, respectively, with a median duration of response of 28.6 months.

Regarding toxicity, Xu highlighted, “Belzutifan’s AEs are highly specific to the VHL pathway, related to oxygen sensing, so the most common AEs are anemia and fatigue. A significant, not particularly common, but important AE is hypoxia.”

“What’s next for clear cell kidney cancer? We have several trials that are ongoing, hopefully soon to read out that might change our practice. First, is there a role for triplets? We already know that COSMIC-313 met is PFS end point, but it’s highly toxic. We need to see whether cabozantinib, ipilimumab, and nivolumab improves overall survival,” Xu stated.

Options for Non–Clear Cell RCC

The ongoing phase 2 PAPMET/SWOG 1500 trial (NCT02761057) is a good option for patients with this histology. Following histological confirmation of papillary RCC, patients who have received no more than 1 prior line of therapy and have a Zubrod score of 0 or 1 will be randomly assigned to sunitinib, cabozantinib, crizotinib (Xalkori), or savolitinib. PFS is the primary end point. Preliminary data have shown improved PFS with cabozantinib of 9.0 months (95% CI, 5.6-12.4) and an ORR of 23% compared with sunitinib.¹⁵ “For patients who are going to receive single-agent TKI for papillary RCC, cabozantinib should be considered the preferred TKI,” Xu said.

In nonrandomized data, several immunotherapy-based combinations have shown activity in unclassified, papillary, and translocation RCC. Chromophobe RCC, on the other hand, shows poor responses to immunotherapy, Xu said. In a small dataset of just 9 patients, those with chromophobe disease experienced a 44% ORR with lenvatinib and everolimus.¹⁶ “Until we get more data, lenvatinib and everolimus may be the preferred regimen for chromophobe RCC,” Xu said.

Until more data are compiled, Xu stated that clinical trials remain the recommended option for patients with non–clear cell RCC. Ongoing trials open for enrollment include CAN-I (NCT04413123), PAPMET-2 (NCT05411081), PAXIPEM (NCT05096390), and SAMETA (NCT05043090).

Disclosures: Xu is on the scientific advisory board for Jazz and Exelixis and has received research funding from the Department of Defense CDMRP KCRP, ASCO/Conquer Cancer Foundation, and DF/HCC Kidney Cancer Spore.

References

1. Xu V, Systemic therapy for renal cell carcinoma. Presented at: 16th Annual Interdisciplinary Prostate Cancer Congress and Other Genitourinary Malignancies. March 10-11, 2023. New York, NY.
2. Lalani AKA, et al. Evolving landscape of first-line combination therapy in advanced renal cancer: a systematic review. Ther Adv Med Oncol. 2022;14:17588359221108685. doi:10.1177/17588359221108685
3. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. News release. FDA. April 16, 2018. Accessed March 13, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-combination-intermediate-or-poor-risk-advanced-renal-cell
4. 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
5. 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
6. Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Cancer Res. 2021;27(1):78-86. doi:10.1158/1078-0432.CCR-20-2063
7. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 4.2023. Accessed March 13, 2023. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf
8. Escudier B, Motzer RJ, Tannir NM, et al. Efficacy of nivolumab plus ipilimumab according to number of IMDC risk factors in CheckMate 214. Eur Urol. 2020;77(4):449-453. doi:10.1016/j.eururo.2019.10.025
9. Albiges L, Powles T, Sharma A, et al. CaboPoint: interim results from a phase 2 study of cabozantinib after checkpoint inhibitor therapy in patients with advanced renal cell carcinoma. J Clin Oncol. 2023;41(suppl 6):606. doi:10.1200/JCO.2023.41.6_suppl.606
10. Exelixis provides update on phase 3 CONTACT-03 trial evaluating cabozantinib in combination with atezolizumab in patients with previously treated advanced kidney cancer. News release. Exelixis, Inc. March 2, 2023. Accessed March 13, 2023. https://ir.exelixis.com/news-releases/news-release-details
11. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. News release. FDA. August 13, 2021. Accessed March 13, 2023. https://bit.ly/3g0bv8G
12. Srinivasan R, Donskov F, Iliopoulos O, et al. Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2021;39(suppl 15):4555. doi:10.1200/JCO.2021.39.15_suppl.4555
13. Jonasch E, Bauer TM, Papadopoulos KP, et al. Phase 1 LITESPARK-001 (MK-6482-001) study of belzutifan in advanced solid tumors: update of the clear cell renal cell carcinoma (ccRCC) cohort with more than 3 years of total follow-up. J Clin Oncol. 2022;40(suppl 16):4509. doi:10.1200/JCO.2022.40.16_suppl.4509
14. Choueiri TK, Bauer T, Merchan J, et al. Phase II study of belzutifan plus cabozantinib as first-line treatment of advanced renal cell carcinoma (RCC): cohort 1 of LITESPARK-003. Ann Oncol. 2022;33(suppl 7):S660-S680. doi:10.1016/annonc/annonc1072
15. Pal SK, Tangen C, Thompson IM, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet. 2021;397(10275):695-703. doi: 10.1016/S0140-6736(21)00152-5
16. Hutson TE, Michaelson MD, Kuzel TM, et al. A single-arm, multicenter, phase 2 study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. Eur Urol. 2021;80(2):162-170. doi:10.1016/j.eururo.2021.03.015