Cabozantinib With Nivolumab for Metastatic Renal Cell Carcinoma: A New Front-Line Standard

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The pace of clinical research in metastatic renal cell carcinoma is faster than ever. Over the past 5 years, we have seen data from six phase III clinical trials evaluating combination strategies with checkpoint inhibitors.

The era began with data from CheckMate 214, evaluating nivolumab with ipilimumab, showing a significant benefit in overall survival in patients with intermediate- and poor-risk disease.1 Since then, multiple data sets have evaluated combination strategies with targeted therapy and checkpoint inhibitors. Not all have been clear wins—studies evaluating bevacizumab with atezolizumab and axitinib with avelumab have not demonstrated a gain in overall survival over sunitinib, a common comparator across all these studies.2,3 Nonetheless, three trials have hit three classic milestones, showing improvements in progression-free survival, response rate, and overall survival relative to sunitinib: the CheckMate 9ER trial4 of cabozantinib with nivolumab—reviewed in this issue of The ASCO Post—the KEYNOTE-426 trial5 of axitinib with pembrolizumab, and the CLEAR trial6 of lenvatinib with pembrolizumab.

Neal S. Chawla, MD

Neal S. Chawla, MD

Sumanta K. Pal, MD, FASCO

Sumanta K. Pal, MD, FASCO

Choosing Among First-Line Options

How does the practicing clinician choose among these first-line therapeutic options for metastatic renal cell carcinoma? Some investigators suggest there is equipoise between regimens. Although it is impossible to conduct cross-trial comparisons, we do feel that elements of the data sets allow us to be more precise in guiding therapy. One such element is quality-of-life data. As of now, these data are available from the KEYNOTE-426 and CheckMate 9ER studies.

In the KEYNOTE-426 clinical trial, evaluations using the European Organisation for Research and Treatment of Cancer QLQ-C30, EQ-5D-3L visual analog scale, and Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI) Disease-Related Symptoms measures failed to demonstrate any significant improvement in quality of life with axitinib plus pembrolizumab vs sunitinib. These findings stand in sharp contrast with data from CheckMate 9ER, in which there was a significant improvement in quality of life with cabozantinib plus nivolumab using the FKSI-19 index. Although different measures were used across studies, these tools are nonetheless well validated to address quality of life. In our opinion, these data are compelling to suggest use of cabozantinib with nivolumab over axitinib with pembrolizumab.

The choice between lenvatinib with pembrolizumab and cabozantinib with nivolumab is more challenging. The CLEAR trial established a high-water mark for progression-free survival, which approached 2 years with lenvatinib plus pembrolizumab. However, relating to the challenge of cross-trial comparisons, it is important to note that the study had a much higher proportion of good-risk patients and fewer patients with poor-risk metastatic disease as compared with CheckMate 9ER—both of these elements could undoubtedly have an impact on estimates of progression-free survival.

In deciding between these regimens, one must lean on clinical acumen. Lenvatinib with everolimus is a regimen that has been approved for use in refractory disease, although clinical implementation of this regimen has been limited. Although this may be because of the level of evidence (lenvatinib with everolimus was approved on the basis of phase II data), it could also be an issue with toxicity.7 Efforts have been made to address this; a recent randomized phase II study compared lenvatinib at 18 mg and 14 mg with everolimus following prior targeted therapy.8 Unfortunately, the trial showed no advantage with dose reduction, with treatment-related adverse events being similar in both arms.

Imagine the challenge now in implementing an even higher dose of lenvatinib (20 mg) in combination with pembrolizumab as first-line therapy, as in the CLEAR trial. As one might expect, the rate of treatment discontinuation was high—a total of 37.2% of patients discontinued lenvatinib, pembrolizumab, or both drugs. In contrast, in the CheckMate 9ER study, a lower dose of cabozantinib was implemented (40 mg) as compared with the previously approved dose for refractory disease (60 mg). Perhaps as a result, the rate of treatment discontinuation of cabozantinib or nivolumab was 19.7%, approximately half the rate observed in CLEAR.

Three trials have hit three classic milestones, showing improvements in progression-free survival, response rate, and overall survival [with checkpoint inhibitors] relative to sunitinib.
— Neal S. Chawla, MD, and Sumanta K. Pal, MD, FASCO

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A Nuanced First Choice

With these arguments in mind, cabozantinib with nivolumab now represents our first choice for systemic therapy in patients with metastatic renal cell carcinoma. Of course, there are nuances. For example, for patients who have relevant comorbidities (eg, uncontrolled hypertension), avoiding VEGF-directed therapy with regimens such as nivolumab with ipilimumab might be preferred. Nivolumab with ipilimumab is also an option to consider for those patients with de novo metastatic disease who warrant immediate cytoreductive nephrectomy. In that scenario, systemic therapy can be initiated without concern for wound-healing issues.

Non–clear cell disease represents another area in which more nuanced management can be applied. Recent randomized data support the use of cabozantinib monotherapy for patients with a papillary histology.9 Although there are compelling data for the single-agent checkpoint inhibitor (eg, pembrolizumab) and combination therapy (eg, cabozantinib with atezolizumab) for non–clear cell histologies, we await randomized data to determine how to align these strategies.10,11 Thus, although we will likely use cabozantinib with nivolumab in the majority of patients we encounter in the first-line setting, it is always critical to bear in mind individual patient characteristics in deciding upon therapy. 

Dr. Chawla and Dr. Pal work in the Department of Medical Oncology & Experimental Therapeutics at City of Hope Comprehensive Cancer Center, Duarte, California.

DISCLOSURE: Dr. Chawla reported no conflicts of interest. Dr. Pal has served as a consultant or advisor to Astellas Pharma, Aveo, Bristol Myers Squibb, Eisai, Exelixis, Genentech, Ipsen, Myriad Pharmaceuticals, Novartis, and Pfizer.


1. Motzer RJ, Tannir NM, McDermott DF, et al: Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277-1290, 2018.

2. Rini BI, Powles T, Atkins MB, et al: Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): A multicentre, open-label, phase 3, randomised controlled trial. Lancet 393:2404-2415, 2019.

3. Motzer RJ, Penkov K, Haanen J, et al: Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1103-1115, 2019.

4. Choueiri TK, Powles T, Burotto M, et al: Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 384:829-841, 2021.

5. 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 21:1563-1573, 2020.

6. Motzer R, Alekseev B, Rha SY, et al: Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 384:1289-1300, 2021.

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 16:1473-1482, 2015.

8. Pal SK, Puente J, Heng DYC, et al: Phase II trial of lenvatinib at two starting doses + everolimus in patients with renal cell carcinoma: Results by independent imaging review and prior immune checkpoint inhibition. 2021 Genitourinary Cancers Symposium. Abstract 307.

9. Pal SK, Tangen C, Thompson Jr 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 397:695-703, 2021.

10. McDermott DF, Lee JL, Ziobro M, et al: Open-label, single-arm, phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma. J Clin Oncol 39:1029-1039, 2021.

11. McGregor BA, Agarwal N, Suarez C, et al: Cabozantinib in combination with atezolizumab in non-clear cell renal cell carcinoma: Results from cohort 10 of the COSMIC-021 study. Ann Oncol 31(suppl 4)S558, 2020.