Considerations When Treating Patients With Metastatic Renal Cell Carcinoma

The incidence of kidney cancer has been increasing over the past decade with an anticipated 79,000 diagnoses in 2022 and approximately 13,920 deaths.¹ Clear cell renal cell carcinoma (ccRCC) remains the most common histology, accounting for nearly 75% of all RCC diagnoses. Other less common histologies include papillary, chromophobe, and translocation RCC, each of which represents distinct tumors associated with unique molecular features and pathogenesis.²

Treatment for patients with localized or locally advanced disease includes surgical resection and, for those at high-risk for recurrence, adjuvant therapy with either sunitinib (Sutent) or pembrolizumab (Keytruda), the only FDA-approved agents for adjuvant treatment in RCC.^3,4 However, treatment for patients with synchronous metastatic disease includes systemic therapy with the decision to offer cytoreductive nephrectomy in select patients based on the CARMENA (NCT00930033) and SURTIME (NCT01099423) trials evaluating the role of cytoreductive nephrectomy in the targeted therapy era.^5,6

The backbone of systemic therapy for patients with advanced disease includes immunotherapy with immune checkpoint inhibitors and targeted therapy with VEGF tyrosine kinase inhibitors (TKIs). More recently, combination immune-oncology (IO)-IO or IO-VEGF agents have become the standard of care for first-line treatment for patients with locally advanced or metastatic disease, given demonstrated efficacy and improvement in overall survival.

At present, subsequent-line treatment remains VEGF monotherapy or VEGF targeted therapy with mTOR inhibition. Several clinical trials are investigating triplet and doublet combinations in the first- and subsequent-line settings and novel treatment options for patients with refractory disease.

First-line Therapy for Metastatic RCC

Treatment for first-line metastatic RCC (mRCC) has evolved in the past few years to include either first-line IO-IO drug combinations with a PD-1 inhibitor and CTLA-4 inhibitor or a combination of IO plus VEGF TKI, with these combinations showing benefit in progression-free survival (PFS) or overall survival (OS) in landmark phase 3 trials (Table 1).^7-13 Although direct comparative data are lacking, the choice of therapy highly depends on varying factors, including International Metastatic RCC Database Consortium (IMDC) risk group, patient comorbidities, disease factors, and burden of disease. The IMDC Risk Model was developed as a prognostic tool in patients with mRCC initiating treatment with first-line therapy in the era of VEGF TKI.¹⁴

The choice for first-line therapy involves the use of dual IO therapy or combined IO plus VEGF-TKI, and, rarely, VEGF-TKI monotherapy in a select group of patients. Collectively, these treatments yield a robust overall response rate (ORR) ranging from 40% to 70%. In addition, complete responses are achieved in up to 11% of patients. Furthermore, with 5 years of follow-up data from the phase 3 CheckMate 214 trial (NCT02231749) of nivolumab (Opdivo) plus ipilimumab (Yervoy), this regimen is associated with long-term disease control and potential cure.¹⁵

Second-line Therapy for mRCC

Although investigators see good responses in most frontline combination regimens, not all patients achieve durable responses, and the majority of patients develop resistance. In addition, historic clinical trials that led to approvals of later-line agents in RCC were mostly conducted following VEGF-TKI failure and had a very limited number of patients who had received prior IO. Therefore, guidance regarding current treatment beyond contemporary first-line therapy options highly relies on retrospective trials. Limited prospective trials are available that inform the efficacy of subsequent treatment following IO combination therapy.

The current standard following progression on frontline IO treatment is VEGF TKI monotherapy. The efficacy for post-IO VEGF inhibition is derived from several retrospective trials and a limited number of prospective trials that demonstrated an ORR ranging from 23% to 45%.^16-20

The control arm of the contemporary phase 2 CANTATA trial (NCT03428217), which explored the benefits of the novel glutaminase inhibitor telaglenastat plus cabozantinib (Cabometyx) vs cabozantinib alone, provides further evidence of the efficacy of VEGF inhibition post IO.²¹ Although the trial was negative given the failure of the combination to show improvement in the primary end point of PFS over cabozantinib alone, the cabozantinib arm had a PFS of 9.2 months. Among the participants, 62% had received prior IO.

Similarly, the TIVO-3 trial (NCT02627963) comparing tivozanib (Fotivda) vs sorafenib (Nexavar) in the third- and fourth-line settings also demonstrated activity of VEGF inhibition post IO. In this study, 26% of patients were pretreated with IO and achieved a median PFS of 7.3 months.22 In aggregate, these results support further use of VEGF TKIs as second-line therapy after prior IO failure.

Ipilimumab Following Prior IO Exposure

Given the success of IO drugs in first-line therapy, several studies have investigated the question of salvage IO. In a retrospective series, salvage nivolumab plus ipilimumab after IO therapy showed a response rate of 20%.²³ A series of adaptive trials, including OMNIVORE (NCT03203473), HCRN GU16-260 (NCT03117309), and TITAN-RCC (NCT02917772), investigated salvage ipilimumab after lack of response to nivolumab.^24-26 Collectively, these trials resulted in lower ORRs and minimal complete responses, suggesting that salvage ipilimumab yields limited activity.

Similarly, investigators assessed the activity of nivolumab plus ipilimumab post IO in the FRACTION-RCC trial (NCT02996110), which demonstrated an ORR of 17.4% and no complete responses.²⁷ Although these studies are overall limited by small number of patients and varying trial design, they collectively suggest limited benefit of ipilimumab in the salvage setting and that dual IO therapy may be best utilized up front rather than in sequential fashion.

Data on combination IO-TKI therapies in the secondline setting come from limited prospective studies. The phase 1b/2 KEYNOTE-146 trial (NCT02501096) investigated the activity of pembrolizumab plus lenvatinib (Lenvima) in mRCC in 104 patients who received prior IO therapy.²⁸ The ORR was 62.5%, however the nature of the single-arm design precludes definitive interpretation of the value of combination IO-TKI in the later-line setting. Several other trials, including CONTACT-03 (NCT04338269) and TiNivo-2 (NCT04987203), are underway to address this important clinical question (Table 2).

Considerations When Making Treatment Decisions

The management of mRCC has rapidly evolved, and a paradigm shift has occurred over the past several years. Although there are multiple clinical factors worthy of consideration when choosing treatment in either first-line or second-line treatment settings, biomarker data are currently lacking in mRCC to guide specific therapeutic selection. Decisions are often based on several disease and patient characteristics, physician preferences and familiarity, formulary preference, cost, and patient choice.

The first-line treatment option hinges upon the IMDC risk classification such that CheckMate 214 use with nivolumab and ipilimumab is limited to patients in intermediate- and poor-risk categories, whereas combination IO/TKI typically encompasses all groups.

In the second-line setting, IMDC risk categorization is less relevant. However, similar to first-line therapy choices, particular treatment factors, including type and duration of response to prior therapy, pace of disease progression, and toxicities associated with first-line treatment, are all practical considerations that help guide therapy selection especially in the absence of prospective trials to guide therapy. It is important to emphasize that shared decision-making and alignment of therapeutic goals with each individual patient remain key in any informed decision-making.

References

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi:10.3322/caac.21708
2. Moch H, Amin MB, Berney DM, et al. The 2022 World Health Organization classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours. Eur Urol. 2022;82(5):458-468. doi:10.1016/j.eururo.2022.06.016
3. Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246-2254. doi:10.1056/NEJMoa1611406
4. Choueiri TK, Tomczak P, Park SH, et al; KEYNOTE-564 Investigators. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391
5. Mejean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675
6. Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 2019;5(2):164-170. doi:10.1001/jamaoncol.2018.5543
7. Motzer RJ, Escudier B, McDermott DF, et al. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer. 2020;8(2):e000891. doi:10.1136/jitc-2020-000891
8. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982
9. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716
10. Rini BI, Plimack ER, Stus V, et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714
11. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115. doi:10.1056/NEJMoa1816047
12. Choueiri TK, Powles TB, Albiges L, et al. 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):S808-S869. 10.1016/annonc/annonc1089
13. Aragon-Ching JB. Balancing efficacy and quality of life measurements among metastatic renal cell carcinoma (RCC) studies. Oncoscience. 2021;8:40-45. doi:10.18632/oncoscience.528
14. Heng DYC, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141-148. doi:10.1016/S1470-2045(12)70559-4
15. Motzer RJ, Tannir NM, McDermott DF, et al.661P Conditional survival and 5-year follow-up in CheckMate 214: first-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Ann Oncol. 2021;32(suppl 5):S685-S687. doi:10.1016/j.annonc.2021.08.057
16. Ornstein MC, Pal SK, Wood LS, et al. Individualised axitinib regimen for patients with metastatic renal cell carcinoma after treatment with checkpoint inhibitors: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2019;20(10):1386-1394. doi:10.1016/S1470-2045(19)30513-3
17. Wiele AJ, Bathala TK, Hahn AW, et al. Lenvatinib with or without everolimus in patients with metastatic renal cell carcinoma after immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies. Oncologist. 2021;26(6):476-482. doi:10.1002/onco.13770
18. Auvray M, Auclin E, Barthelemy P, et al. Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma. Eur J Cancer. 2019;108:33-40. doi:10.1016/j.ejca.2018.11.031
19. McGregor BA, Lalani AA, Xie W, et al: Activity of cabozantinib after immune checkpoint blockade in metastatic clear-cell renal cell carcinoma. Eur J Cancer. 2020;135:203-210. doi:10.1016/j.ejca.2020.05.009
20. Shah AY, Kotecha RR, Lemke EA, et al. Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors. Eur J Cancer. 2019;114:67-75. doi:10.1016/j.ejca.2019.04.003
21. Tannir NM, Agarwal N, Porta C, et al. Efficacy and safety of telaglenastat plus cabozantinib vs placebo plus cabozantinib in patients with advanced renal cell carcinoma: the CANTATA randomized clinical trial. JAMA Oncol. 2022;8(10):1411-1418. doi:10.1001/jamaoncol.2022.3511
22. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21(1):95-104. doi:10.1016/S1470-2045(19)30735-1
23. Gul A, Stewart TF, Mantia CM, et al. Salvage ipilimumab and nivolumab in patients with metastatic renal cell carcinoma after prior immune checkpoint inhibitors. J Clin Oncol. 2020;38(27):3088-3094. doi:10.1200/JCO.19.03315
24. McKay RR, McGregor BA, Xie W, et al. Optimized management of nivolumab and ipilimumab in advanced renal cell carcinoma: a response-based phase ii study (OMNIVORE). J Clin Oncol. 202;38(36):4240-4248. doi:10.1200/JCO.20.02295
25. Atkins MB, Jegede OA, Haas NB, et al. Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naive patients with advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A). J Clin Oncol. 2022;40(25):2913-2923. doi:10.1200/JCO.21.02938
26. Grimm MO, Schmitz-Dräger BJ, Zimmermann U, et al. Tailored immunotherapy approach with nivolumab in advanced transitional cell carcinoma. J Clin Oncol. 2022;40(19):2128-2137. doi:10.1200/JCO.21.02631
27. Choueiri TK, Kluger H, George S, et al. FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy. J Immunother Cancer. 2022;10(11):e005780. doi:10.1136/jitc-2022-005780
28. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946-958. doi:10.1016/S1470-2045(21)00241-2