Nivolumab plus Cabozantinib Continues to Show Benefit in Advanced RCC

CASE

• The patient is a 61-year-old man, married, father of 2 grown children and 5 grandchildren who live nearby, active lifestyle (daily walks, golfs regularly)​.
• History of low-volume, indolent metastatic clear cell renal cell carcinoma (RCC), status post‒left nephrectomy and adrenalectomy.​
• He was observed based on low-volume, indolence of disease, and patient preference​.
• Three years after nephrectomy: continued indolent growth on scans, increased total tumor burden, new paratracheal lymph node (2.0 x 1.5 cm) and greater than 10 pulmonary nodules seen on CT scan. ​
• Lung biopsy confirmed metastatic clear cell RCC​.
• Laboratory results: within normal limits
• ECOG performance status: 0

Targeted Oncology^TM: Did results with nivolumab (Opdivo) plus cabozantinib (Cabometyx) vs sunitinib (sutent) in the CheckMate 9ER (NCT03141177) study change depending on the patient’s site of metastasis?

RANA MCKAY, MD: A post hoc analysis, presented at the 2021 American Society of Clinical Oncology Annual Meeting, looked at overall survival [OS] by the patient’s site of metastasis, and also looked [at progression-free survival (PFS) in these subgroups].¹ Investigators looked at patients with advanced RCC who had liver metastases, bone metastases, or lung metastases. What was striking about [the group of patients with] bone metastases, in particular, was just how poorly patients with bone metastases do with single-agent tyrosine kinase inhibitors [TKIs] like sunitinib, but with nivolumab plus cabozantinib, their PFS is approaching that of the PFS of the patients with lung metastases [at a median of 18.2 months and 16.8 months, respectively].

Rana McKay, MD​

Medical Oncologist

Associate Professor of Medicine

University of California San Diego​

San Diego, CA​

The HR for those patients with advanced RCC and bone metastases [on the combination therapy compared with the single TKI] was 0.38 [95% CI, 0.25-0.59]. Patients with liver metastases certainly continue to do better with nivolumab plus cabozantinib, but their median PFS was 11 months, [compared with 18.2 months in the bone metastases subgroup]…. They still do better with [the combination] than sunitinib, but they seem to do worse from a PFS standpoint [compared with the other groups].

What was the time to subsequent therapy for patients who completed at least 2 years of treatment?

The analysis [of patients who completed to 2 years of therapy]—not to say it was skewed, but you are taking in the best [responders] by looking at those individuals who had completed 2 years of therapy. [The total of patients who completed therapy in that time] was 115, but the number of at risk [patients] there was 115 people…. The time to subsequent therapy was a median of 20.6 months [95% CI, 7.9­–not estimable], compared with that 2-year mark. So, if people hit that 2-year mark, they could do well, and among patients who discontinued nivolumab after 2 years, 101 [88%] continued to receive the cabozantinib as well.²

What does the most recent safety data show for this regimen?

At a median follow-up of 32.9 months, any-grade diarrhea [59.4%], palmar-plantar erythrodysesthesia [38.4%], and hypertension [32.8%] are the key [treatment-related adverse events (TRAE) to deal with]. The aspartate transaminase or alanine aminotransferase level increases were [lower overall but notable compared with sunitinib], and the decreased appetite as well. The TRAEs leading to discontinuation of either drug on the combination arm was 27.2%, but 10.6% [discontinued only] nivolumab and 9% for cabozantinib, and both drugs were stopped in 7.5% of patients.³

How is the patient’s quality of life impacted by this therapy?

In regard to their health-related quality of life [HRQOL], I think it’s a little bit challenging to interpret it. These were largely exploratory endpoints in the context [of the studies looking at this patient group] as when people completed the surveys was different across the KEYNOTE-426 [NCT02853331], CheckMate 9ER, and CLEAR studies [NCT02811861].

HRQOL surveys were completed differently across each of the trials. Nonetheless, these were large phase 3 trials with an active control arm, and you can at least compare how people did in relation to sunitinib. In general, in KEYNOTE-426 the AE profile wasn’t better than sunitinib,⁴ but in CheckMate 9ER, with nivolumab plus cabozantinib, patients did have improvement of their HRQOL over sunitinib [in all risk groups] with an improved Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 and European Quality of Life 5 Dimensions 3 Level Version score.⁵

^References

^{1. Apolo A, Powles T, Burotto M, et al. Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): Outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;39(15):4553-4533. doi:10.1200/JCO.2021.39.15_suppl.4553}

^{2. 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(6):603. doi:10.1200/JCO.2023.41.6_suppl.603}

^{3. Powles T, Choueiri T, Burrotto 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(6):350-350. doi:10.1200/JCO.2022.40.6_suppl.350}

^{4. Bedke J, Rini BI, Plimack ER, et al. Health-related quality of life analysis from KEYNOTE-426: Pembrolizumab plus axitinib versus sunitinib for advanced renal cell carcinoma. Eur Urol. 2022;82(4):427-439. doi:10.1016/j.eururo.2022.06.009}

^{5. Cella D, Motzer RJ, Suarez C, et al. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(2):292-303. doi:10.1016/S1470-2045(21)00693-8}