The standard of care for metastatic renal cell carcinoma (mRCC) in patients with clear cell subtype has evolved over recent years, following the completion of a number of phase 3 clinical trials that utilized combination therapy based on immune checkpoint inhibitor (ICI) therapy targeting the programmed death 1 (PD-1) or its ligand (PD-L1).1,2 In each combination, the ICI was complemented by either another ICI targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) or a tyrosine kinase inhibitor (TKI) targeting the vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor (PDGF) receptor, and/or other receptors. Several of these trials demonstrated clear clinical benefits associated with immunotherapy, but few direct comparisons have been made between the different regimens used in the most recent trials.
In the Journal of Urology (January 2022), a multinational team of investigators reports the results of a comprehensive network meta-analysis of the clinical outcomes, specifically objective response rates (ORRs), and treatment–related adverse events associated with the immunotherapy regimens used as first line in recent trials in patients with mRCC.3 The aim of the meta-analysis was to “provide a rank order” that might assist clinicians in identifying the most favorable option among existing approaches.
Luigi Nocera, MD (IRCCS Ospedale San Raffaele, Milan, Italy) and colleagues in Europe, North America, and Australia performed an electronic database search to locate original papers and medical society meeting abstracts that reported clinical trials comparing combination therapy to sunitinib, a previous standard of care, as first-line treatment of locally advanced and/or metastatic RCC. Only studies published in English between January 1, 2016 and March 6, 2021 were considered. Eventually, four eligible phase 3 clinical trials were identified: CheckMate 214,4-6 KEYNOTE-426,7,8 CLEAR (KEYNOTE-581),9 and CheckMate 9ER.10,11
CheckMate 214 utilized a CTLA-4 inhibitor (ipilimumab) plus a PD-I inhibitor (nivolumab) combination. The other three trials each utilized a TKI plus PD-1/PD-L1 doublet: KEYNOTE-426, axitinib plus pembrolizumab; CLEAR, lenvatinib plus pembrolizumab; and CheckMate 9ER, cabozantinib plus nivolumab. All trials compared the investigational combination with sunitinib, the oral multitargeted TKI first approved in the United States in 2006 for use in advanced RCC and now available worldwide.
In total, 3320 patients with mRCC with a clear cell component were enrolled in the four trials, all within the past 7 years. Their average age was 62-63 years and most patients enrolled (71-77%) were male. Differences in recruitment criteria and patient characteristics made comparisons difficult, the investigators observed. In terms of (International RCC Database Consortium) risk groupings, the highest proportion of poor-risk patients (20.7%) occurred in CheckMate 9ER compared with the lowest (10.4%) in CLEAR, but CheckMate 9ER also included the lowest proportion of nephrectomy patients (71.0%) compared with the highest (83.7%) in KEYNOTE-426. Differences were reported in outcomes within the control arms, including complete response (CR), partial response (PR), stable disease (SD), and progression-free survival (PFS). Median follow-up times also varied widely between the trials, from 18 months for CheckMate 9ER to 55 months for CheckMate 214.
In terms of the primary outcome, all the investigational combination therapies showed a statistically significant benefit in OS. Network meta-analysis ranked the combination of cabozantinib plus nivolumab (CheckMate 9ER) as having the highest likelihood of providing maximal OS benefit, followed by, in ranked order lenvatinib plus pembrolizumab (CLEAR), axitinib plus pembrolizumab (KEYNOTE-426), and ipilimumab plus nivolumab (CheckMate 214).
Among the secondary endpoints, all the combination therapies except ipilimumab plus nivolumab (CheckMate 214) were associated with a statistically significant improvement in PFS. Network meta-analysis ranked lenvatinib plus pembrolizumab (CLEAR) as having the highest likelihood of providing PFS benefit. No combination was individually associated with a significantly lower likelihood of CR, with lenvatinib plus pembrolizumab (CLEAR) ranked as most likely to provide maximal CR rate. For the other secondary endpoints, all the combinations, with the exception of ipilimumab plus nivolumab (CheckMate 214), were associated with a significantly lower likelihood of a CR and/or PR. as well as a lower likelihood of CR and/or PR and/or SD.
The investigators explain that “CR represents a highly desirable endpoint of systemic agents,” but caution that “it cannot be interpreted without accounting for duration of follow-up that distinguishes the studies from one another.” They explain that the data for CheckMate 214 trial (CR 10.7%) were more mature, with a median follow up of 55 months, than the data from the other three trials. Therefore, “CheckMate 214 data weigh more heavily and are more robust,” they state, advising “clinical discretion” when interpreting the results of network analyses. They observe that the same considerations should apply to the interpretation of OS, PFS, PR, and SD outcomes and that longer-term data are needed to confirm the apparent superiority of cabozantinib plus nivolumab in most of these outcomes.
Only ipilimumab plus nivolumab (CheckMate 214) was associated with a significantly lower likelihood of adverse events (AEs). The network analysis ranked this combination as having the highest and lenvatinib plus pembrolizumab the lowest likelihood of providing lowest Grade ≥3 adverse events. This suggests that the combination of ICI and TKI therapy results in more high-grade adverse events, although many of them are short lived and fully reversible after discontinuation of the TKI, the investigators note. They add that despite the lower rates of adverse events seen with ipilimumab plus nivolumab. the combination is also associated with higher rates of protracted or permanent toxicities, as well as more frequent use of high-dose steroids, which may also be toxic.
Although the study seemed to point to greatest benefit with cabozantinib plus nivolumab when the endpoints of OS and CR + PR + SD were considered, lenvatinib plus pembrolizumab appeared most advantageous with respect to PFS, CR, and CR + PR, and ipilimumab plus nivolumab appeared safest with respect to Grade ≥3 adverse events. These findings may have been undermined by a number of biases, related to follow-up duration, study composition, definition and reversibility of adverse events, and the need for secondary therapies, the investigators acknowledge. The network meta-analysis approach provides a crude and indirect comparison, and its robustness of the approach is too limited to directly implement rank order into medical decision making, Dr Nocera and his colleagues conclude. Network meta-analyses cannot substitute for randomized non-inferiority trials, they stress.
Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.
- National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Oncology Guidelines). Kidney Cancer. Version 4.2022. December 21, 2021. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1440 Accessed December 29, 2021.
- Tran J, Ornstein MC. Clinical review on the management of metastatic renal cell carcinoma. JCO Clin Pract. Published online September 16, 2021. DOI: 1200/op.21.00419
- Nocera L, Karakiewicz PI, Wenzel M, et al. Clinical outcomes and adverse events after first-line treatment in metastatic renal cell carcinoma: a systematic review and network meta-analysis. J Urol. 2022;207 16-24. DOI: 1097/ju.0000000000002252
- Motzer RJ, Tannir NM, McDermott DF, et al. CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. DOI: 1056/nejmoa1712126
- Motzer RJ, Rini BJ, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019;20(10):1370-1385. DOI: 1016/S1470-2045(19)30413-9
- 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:e001079. DOI: 10.1136/esmoopen-2020-001079
- 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: 1056/NEJMoa1816714
- Powles T, Plimack ER, Soulières D, et al: Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. DOI: 1016/S1470-2045(20)30436-8
- 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: 1056/nejmoa2035716
- 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: 1056/NEJMoa2026982
- Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. J Clin Oncol. 2021;39(suppl 6):Abstract 308. DOI: 1200/JCO.2021.39.6_suppl.308